Nutrient Effect On Glucose Homeostasis

Nutrients other than carbohydrates: their effects on
glucose homeostasis in humans
Martina Heer1, Sarah Egert2
1
Profil, Neuss, Germany,
2
Department of Nutrition and Food Science, Nutritional Physiology, University of Bonn,
Germany;
Short title: Glucose homeostasis affected by non-carbohydrates
Correspondence to:
Martina Heer, PhD
Profil, Neuss, Germany,
Hellersbergstr. 9,
41460 Neuss, Germany,
Phone +49 (0) 2131 4018 253,
Fax +49 (0) 2131 4018 553,
Mail Martina.Heer@profil.com
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article
as doi: 10.1002/dmrr.2533
This article is protected by copyright. All rights reserved.

Abstract
Besides carbohydrates, other nutrients, such as dietary protein and amino acids; the supply of
fat, vitamin D, and vitamin K; and sodium intake seem to affect glucose homeostasis.
Although their impact is less pronounced than that of the amount and composition of
carbohydrates, it seems reasonable to consider how nutrient intake habits may be modified to
support an improved glucose homeostasis. For instance, taking into account the effect of
some nutrients to lower blood glucose concentration on a day-by-day basis might support
improvement of glucose homeostasis in the long run. On the other hand, lowering sodium
intake too much, as recommended to avoid the development of hypertension, particularly in
sodium-sensitive people, might lead to insulin resistance and thereby might risk increasing
fasting as well as postprandial blood glucose concentrations. This review summarizes the
state of our knowledge of how several nutrients other than carbohydrates, such as protein,
fatty acids, vitamin D, vitamin K, magnesium, zinc, chromium, and sodium affect blood
glucose concentrations. Sufficient evidence exists to show that, in prospective studies based
on randomized controlled trials, these selected nutrients affect blood glucose regulation. The
review describes potential mechanisms leading to the observed effect. As much as is possible
from the available data, the extent of the effect, as well as differences in population
subgroups, are considered.
Keywords: (up to 6)
glucose metabolism, dietary protein, dietary fatty acids, vitamin D, dietary sodium

Introduction
An elevated blood glucose concentration indicates the beginning or the existence of glucose
intolerance and/or insulin resistance, which may result in the manifestation of type 2 diabetes
mellitus (T2DM). In recent years, T2DM has reached epidemic numbers and studies predict
that in 2030 the prevalence of T2DM will be 4.4% worldwide [1]. Not only is this true in
older people but also it is expected to continue to increase in children and adolescents [2,3].
Aside from a sedentary lifestyle, an aggravating factor for the development of T2DM is
visceral obesityin most cases caused by a chronic positive energy balance, which is
considered to account for 60% to 90% of new cases of T2DM [4]. However, in day-to-day
blood glucose homeostasis, inadequate nutrient composition of the daily dietaside from the
amount and kind of carbohydratesmay also play an important role and may interact with
good glycemic control. There is no doubt that consumption of certain kinds of carbohydrates,
that is, single or complex carbohydrates, available or unavailable carbohydrates, or foods
having different glycemic indices, produces different effects on blood glucose concentrations
in all metabolically healthy people as well as people with impaired glucose tolerance (IGT) or
patients with T2DM [5-13]. But it is not only different kinds of carbohydrates which affect
blood glucose levels or insulin secretion differently. Fat or protein content and their
respective fatty acid or amino acid composition, and certain vitamin or mineral content in the
diet may also affect insulin secretion, sensitivity, or resistance and thereby postprandial blood
glucose concentration. These effects might be evoked by encouraging insulin secretion in the
pancreas or affecting insulin resistance in the periphery.
As the effects of nutrients other than carbohydrates may have significant effects on blood
glucose concentrations and might also be used to support a dietary therapy, we will focus in
this review on macro- and micronutrients other than carbohydrates and their potential effects
on blood glucose control. In particular, we will summarize data which allow us to interpret

effects of single nutrients rather than food containing certain amounts of the respective
nutrients. Although it is very important to show how food and food products, for instance
dairy products, may affect blood glucose concentration, these effects are far beyond the scope
of this review and should be summarized separately. As a first step we therefore will focus on
the effects of single nutrients on blood glucose regulation. The focus on the selected nutrients
is based on evidence showing an effect of these nutrients on blood glucose regulation in
prospective studies and randomized controlled trials. This is true for the orally applied
macronutrients such as protein and amino acids fat and fatty acids as well as the
micronutrients vitamin D and vitamin K, calcium, magnesium, zinc, chromium and sodium.
Phytochemicals such as polyphenols, phytosterols and caffeine were excluded because of
limited evidence from randomized intervention studies applying nutritional doses rather than
pharmacological doses. Additionally, for those substances the bioavailability is not
sufficiently characterized and a cause-and-effect relationship has rarely been shown in
humans.
We will summarize the respective effects of these nutrients and potential mechanisms. To
present the direct effect of each nutrient on blood glucose concentrations, we considered
mainly results published since January 2000 in relevant articles reporting original research,
carried out in humans, which applied randomized clinical trial designs and well standardized
conditions. In some cases, however, we also refer to meta-analyses or systematic reviews
since they are of utmost importance to convey key results from several recent studies..

2 Nutrients and their effects on glucose metabolism
2.1 Protein
In light of many intervention studies it is almost accepted that in acute studies high, but still a
nutritional dose of protein intake, such as up to 40 g in one meal, has an insulinotropic effect
[14,15]. As many review articles have already been published in this field, we summarize in
Table 1 only the details of the more recent studies showing the acute and long-term effects of
increased protein intake on blood glucose regulation. The effect of protein on blood glucose
concentration depends very much on the kind of protein and its amino acid composition. To
compare the effects of different protein sources, several studies have been carried out using
food products with high protein content, for instance egg, turkey, casein, soy, whey, and tuna
[14,16-19]. These acute studies seem to show that the most pronounced effect on lowering
blood glucose levels is caused by whey protein, in both metabolically healthy subjects and
diabetic patients [16,17,20,21]. The mechanism of the blood glucose lowering-effect of whey
protein seems to be mainly mediated by an increase in glucagon-like peptide 1 (GLP-1),
which may on one hand lead to increased insulin secretion [20,22] and on the other hand
decrease gastric emptying, thereby preventing a more pronounced increase in blood glucose
concentration [22,23]. Other proteins, for instance casein and soy protein, do not cause such a
pronounced effect on GLP-1 and insulin secretion but seem to have a positive effect on
insulin sensitivity [17] (Table 1). Although the mechanism is not well understood, some in
vitro studies show how the insulinotropic effect might be induced [24-26]. In cell
experiments with the application of L-alanine, the increase in insulin secretion might be
caused by an increased intracellular oxidation of amino acids, which raises the ATP content
of the cell. Increase in intracellular ATP content leads to closure of the ATP-sensitive
potassium channels, and this channel closure leads to depolarization of the cell membrane
and activation of the calcium channels. Activation of the calcium channels then causes an
exocytosis of insulin from the cells [24,25].
Another possibility could be that amino acids are co-transported into the cell together with
sodium, as shown in further cell experiments [26]. This could also lead to a depolarization of
the plasma membrane and finally to an exocytosis of insulin.

As shown in another randomized crossover design study, applying a nutritional dose of 30 g
of whey protein to the regular daily diet might also decrease uptake of insulin by the liver and
thereby keep serum insulin levels increased [20]. On the other hand, whey protein in
particular has an effect on the small intestine by decreasing gastric emptying. This seems to
be caused by changes in cholecystokinin, GLP-1, and gastric inhibitory peptide (GIP)
concentrations [14,15].
In most of these studies an acute effect of the protein has been tested. Data from medium- or
long-term studies on the effects of controlled nutrient intake are scarce and have led to
contrary results. Weickert et al. found in an 18-week outpatient study in obese subjects with
features of the metabolic syndrome that an isoenergetic increase in protein consumption from
15% to 25-30% of the daily energy intake decreased insulin sensitivity somewhat after 6
weeks, but it came back to baseline values after 18 weeks [27]. Similar results were obtained
in a one-year study where protein intake was increased at an expense of carbohydrate intake
in patients with T2DM [28]. Therefore, the positive effect which would have been expected
from the acute studies could not be supported by the study by Weickert et al. [27]. However,
when using bed rest as a model to induce insulin resistance in healthy young female subjects
for 60 days in an extremely standardized study design, we came to the opposite conclusion.
We supplemented a protein intake of 1.0 g per kg body mass per day, about 13% of daily
energy intake, with 0.6 g protein per kg body mass per day, of which 0.15 g were branched-
chain amino acids. Including the supplementation, the daily protein intake amounted to 22%
of the daily energy intake. All the other macro- and micronutrients were controlled and met
the dietary recommended intake each day. In our study, high protein intake was able to
almost fully compensate for the bed rest-induced 35% reduction in insulin sensitivity in these
healthy women [29].
2.2 Dietary fat and fatty acids

The acute glycemic response is affected by the fat content of the diet. A recent meta-analysis
of the existing literature on low-carbohydrate and high-fat diets suggests that these diets,
unlike high-carbohydrate and high glycemic index diets, may be effective in improving
glycemic control, weight, and lipid profiles [30]. On the one hand this seems to be caused by
an exchange of carbohydrate against fat and on the other hand by a prolonged gastric
emptying induced by high fat intake independent of fatty acid composition. In addition to the
fat content, the composition of dietary fat could play a role in improving insulin sensitivity

and reducing risk of diabetes mellitus and its complications. Through our daily dietary intake,
we ingest a variety of fatty acids with different chain length and number of double bonds.
The most abundant dietary fatty acids are oleic acid, linoleic acid, palmitic acid, and stearic
acid. These are reflected in plasma and tissue lipids. Thus, dietary fatty acid composition, to a
large extent, determines the relative availability and storage of fatty acids in tissues and cell
membranes and, consequently, cell membrane function [31,32]. The fatty acid composition of
cell membranes is thought to alter several cellular functions, including membrane fluidity, ion
permeability, and insulin receptor binding or affinityfunctions affected by translocation of
glucose transporters interacting with second messengers [31,33]. Such alterations could, in
turn, affect tissue and whole-body insulin sensitivity [31]. More recent experimental data also
point toward other mechanisms which involve direct regulatory effects on gene expression
and enzyme activity [34]. For example, in vitro studies and studies in animal models suggest
that fatty acids could act directly on insulin-sensitive tissues [35]. In several experiments,
polyunsaturated fatty acids (e.g., linoleic acid) suppressed expression of lipogenic genes and
enhanced oxidative metabolism. By contrast, saturated fatty acids (palmitic acid, in
particular) had an opposite effect [31,34].
2.2.1 Importance of fatty acid composition

Saturated fatty acids
Most international dietary recommendations aim to reduce the intake of saturated fatty acids
(SFA) to 10% of total energy intake [36]. Typically these recommendations do not specify
the isoenergetic replacement macronutrient (e.g., carbohydrates, monounsaturated or
polyunsaturated fatty acids). In addition, we do not yet have enough evidence to give dietary
recommendations for individual SFA consumption. However, available data from controlled
intervention studies suggest that beneficial effects on insulin sensitivity occur when SFA are
replaced with monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA)
[31]. Data from controlled feeding studies in metabolically healthy subjects and in patients
with T2DM are very limited. In addition, no long-term dietary intervention studies have been
conducted to determine the relationship between the quality of dietary fat and risk of T2DM.
Lovejoy et al. compared the effects of three 4-week isoenergetic diets enriched in SFA
(palmitic; 9% of total energy), MUFA (oleic; 9% of energy), or trans fatty acids (elaidic; 9%
of energy) on insulin sensitivity and substrate oxidation in metabolically healthy adults [37].
There were no significant differences in insulin sensitivity between the three groups of

subjects. In another study metabolically healthy subjects received for 3 months a controlled,
isoenergetic diet containing a high proportion of either SFA (SFA diet; 17% of energy from
SFA, 14% of energy from MUFA) or MUFA (MUFA diet; 23% of energy from MUFA, 8%
of energy from SFA). Insulin sensitivity was significantly impaired on the SFA diet (-10%, P
= 0.03) but did not change on the MUFA diet (+2%, NS) (P = 0.05 for difference between
diets). Insulin secretion was not affected. [38]. In addition, no long-term dietary intervention
studies have been conducted to determine the relationship between the quality of dietary fat
and risk of T2DM.
Isomeric fatty acids

Isomeric fatty acids have the same number of carbon and hydrogen atoms, but may have
distinct metabolic and health effects. Two well-known examples of isomeric fatty acids are
cis and trans monounsaturated fatty acids, and conjugated isomers of linoleic acid (CLA)
[39]. More so than other macronutrients, trans fatty acids (TFA) have been associated with
cardiovascular mortality and morbidity [40]. The increased cardiometabolic risk associated
with TFA consumption could be attributed to a TFA-induced unfavorable lipid profile (e.g.,
increase in total and LDL cholesterol, decrease in HDL cholesterol), accentuation of systemic
inflammation, endothelial dysfunction, or disruption of glucose homeostatsis [40]. In
addition, evidence from observational studies has suggested that TFA consumption may be
associated with insulin resistance and T2DM [41,42]. However, several human trials which
focused on glucose homeostasis have revealed conflicting results. A recent meta-analysis of
seven randomized, placebo-controlled clinical trials showed that an increase in TFA intake
from 2.59% to 7.80% of total energy intake did not lead to any significant change in
circulating glucose or insulin concentrations [43]. The meta-regression analysis also revealed
the absence of any dose-response relationship between the dose of TFA intake and any effect
on glucose and insulin concentrations. Thus, the authors concluded that there is no evidence
that a reduction of TFA intake below the average 2% of total energy intake in the habitual
American diet could lead to any improvement in terms of insulin resistance and glycemia
[43].
In recent years, CLA isomers (especially trans10cis12 and cis9trans11 in different

concentrations) found in dairy fat and partially hydrogenated vegetable oils have received a
lot of attention, as many animal studies have suggested that CLA isomers have a wide variety
of health effects. In particular, positive effects on body fat mass and lean body mass have

been demonstrated in several animal models [44,45]. This has resulted in wide availability of
CLA supplements and products enriched with CLA to control body weight [39]. Clinical
studies are, however, less conclusive. Recent comprehensive reviews even concluded that
CLA supplements are not very effective as weight-loss agents for humans [46-48]. In
addition, in some human studies it was observed that the administration of various CLA
isomers may have diabetogenic and other adverse effects in humans (e.g., on lipid profiles
and systemic inflammation) [31,46-48]. Data have demonstrated that the trans10cis12-CLA
isomer, in doses of 1% of energy intake, impaired insulin sensitivity in abdominally obese
men with the metabolic syndrome traits [49]. The amount of CLA in the habitual diet is
generally very low and probably has negligible metabolic effects.
2.2.2 Marine and plant n-3 polyunsaturated fatty acids

A large body of epidemiological data and evidence from randomized controlled human trials
has demonstrated the cardioprotective effects of the marine n-3 fatty acids eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA) [50-52]. For example, EPA and DHA have
been shown to reduce serum triglyceride concentrations, to lower arterial blood pressure, to
reduce inflammation, and to improve vascular function [52-55]. In addition, EPA and DHA
prevented excessive adiposity and insulin resistance in rodents. Mechanistically, the latter
effects are related to the ability of these fatty acids to increase fatty acid oxidation in liver,
skeletal muscle, and adipose tissue, and their ability to reduce lipogenesis [56]. An alternative
(n-3) PUFA is plant-derived alpha-linolenic acid (ALA), which may also protect against
coronary heart disease. However, the data concerning the protective role of ALA are less
definitive than data for the long-chain (LC) n-3 PUFA EPA and DHA [57].
Despite the known benefits of n-3 fatty acids, our understanding of their role in glucose
metabolism and insulin resistance in humans is still marred by controversy. Although some
human studies have reported an unfavorable effect of marine n-3 PUFA on blood glucose
[58-61], other studies have reported no effects of n-3 LCPUFA on glucose metabolism [62-
65]. Different findings about the effects of marine n-3 PUFA on glycemic control in patients
with T2DM may be related to the high, rather pharmacological doses used (10-20 g fish oil
per day, equivalent to 3-8 g/day EPA or DHA, or more) [58,66], or to the duration of the
study. Moreover, oral diabetic medication, obesity or insulin resistance, and other conditions
such as hypertension may also have affected insulin sensitivity [58,67]. Recent
comprehensive systematic reviews and meta-analyses on the effects of fish oil

supplementation on parameters of glucose and insulin metabolism in diabetic and/or
dyslipidemic patients conclude that fish oil supplementation in moderate dosages (equivalent
to 1-2 g/day n-3 LCPUFA) has no significant adverse effects on fasting glucose, HbA1c,
fasting insulin, or insulin sensitivity [58,64,66,68-73].
The few human intervention studies that have addressed ALA intake in relation to glucose
metabolism have yielded inconsistent results [62,74,75]. However, some observational
evidence exists that a high ALA status may be related to a lower risk of T2DM [76] and
metabolic syndrome [77].
2.3 Vitamins
2.3.1 Vitamin D
Emerging evidence suggests that vitamin D may play a role in the etiology of T2DM [78,79].
When 25-hydroxyvitamin D concentrations were correlated with blood glucose levels, a
significant inverse relationship existed in those with T2DM or impaired glucose tolerance but
not in those with normal glucose tolerance [80-82]. These observations are underlined by
prospective studies showing that higher serum 25-hydroxyvitamin D levels are associated
with a significantly reduced risk of diabetes in adult men and women [83-86].
However, as is nicely summarized in a review by Alvarez and Ashraf [87], the results from
cross-sectional or prospective studies on the correlation of 25-hydroxyvitamin D levels and
fasting glucose or insulin concentration or insulin sensitivity are inconsistent. One argument
for vitamin D supplementation, for instance, is that this supplement may increase insulin
secretion. However, if the pancreatic -cells are exhausted, vitamin D supplementation is not
able to increase insulin secretion and therefore does not show any effect. In glucose-tolerant
subjects there seems to be a direct correlation between 25-hydroxyvitamin D concentration
and insulin sensitivity index derived from the average glucose infusion rate divided by the
average insulin concentration during the last hour of a 180-min hyperglycemic clamp [88].
Nazarian et al. [89] could also demonstrate in a prospective study a positive interaction of 25-
hydroxyvitamin D with insulin sensitivity after supplementation of a pharmacological dose of
10000 IU vitamin D 3 per day for 4 weeks in patients with vitamin D deficiency and
prediabetes. Insulin sensitivity analyzed by a frequently sampled intravenous glucose
tolerance test before and after vitamin D 3 supplementation was about 37% higher after

vitamin D 3 supplementation. Additionally, a subsample of the 1972 Framingham Offspring
Study, followed for 7 years with respect to their 25-hydroxyvitamin D concentration, showed
that those in the highest tertile had a 40% lower incidence of T2DM [90].
The data from long-term intervention studies with vitamin D are also inconsistent, as
summarized by Alvarez and Ashraf [87]. These authors listed 19 intervention studies
published through March 2009. These studies were carried out in different groups, i.e.,
metabolically healthy subjects, patients with impaired glucose tolerance, and T2DM patients.
The subjects had different ages, fat mass or body mass index, and ethnicity, and started with
different levels of 25-hydroxyvitamin D concentrations. Often the study design had flaws, for
instance lack of a randomized, placebo-controlled design; use of indirect measures of insulin
secretion and sensitivity; small sample size; and inadequate vitamin D supplementation to
increase 25-hydroxyvitamin D concentration.
Since 2009 three additional randomized, placebo-controlled trials (Table 2) in subjects with
pre- or early diabetes have been carried out and shown positive effects. Supplementation of
cholecalciferol for 16 weeks led to a less pronounced increase in glycated hemoglobin
(vitamin D 3 group, 0.08 0.03%; no vitamin D 3 , 0.15 0.05%; P=0.024) and improved the
disposition index (vitamin D 3 group, 300 130; no vitamin D 3 , -126 127; P=0.011) and
insulin secretion (vitamin D 3 group, 62 39 mU/L; no vitamin D 3 , -36 37 mU/L;
P=0.046), but had no effect on insulin sensitivity [91]. In South Asian women, vitamin D
supplementation did not change insulin secretion but improved insulin resistance and
sensitivity [92]. In the third intervention trial, 4000 IU/day vitamin D was supplemented to
African Americans. The 12-week supplementation period increased insulin secretion but did
not show increased insulin sensitivity [93]. However, these findings are consistent with those
by van Hurst et al. [92], who could not see any significant effect on glucose homeostasis after
3 months of supplementation. In the latter study, an effect could be obtained only after 6
months.
Although it is not fully understood how vitamin D affects glucose and insulin metabolism
aside from suppression of chronic inflammation, further indications derived from in vitro
studies highlight potential mechanisms. In rat pancreatic cells, the application of vitamin D
leads to increased biosynthesis of 1,25-dihydroxyvitamin D, which increases insulin secretion
[94]. In cultured myocytes, vitamin D application inhibits free fatty acid-induced insulin

resistance [95]. Furthermore, on one hand vitamin D deficiency increases intracellular
calcium levels and thereby decreases dephosphorylation of glycogen synthase and the insulin
regulatable glucose transporter (GLUT-4) [87]; on the other hand it increases parathyroid
hormone concentration, which in turn increases intracellular calcium. A sustained high
intracellular calcium level inhibits the ability of insulin target cells to sense acute increases in
intracellular calcium flux. Increased intracellular calcium flux induces insulin secretion [96]
and insulin action, namely glucose uptake [97]. As a result, insulin concentration increases
and glucose concentration should be reduced.
According to these findings, an insufficient 25-hydroxyvitamin D concentration might affect

insulin secretion and insulin sensitivity, in particular in pre- and early type 2 diabetes.
However, it seems reasonable that these effects might be obtained only when a concentration
of 80 nmol/L is reached, as shown by von Hurst et al. [92]. Overall it seems that adequate
vitamin D supply may play a role in glucose and insulin metabolism and might postpone the
onset of T2DM. However, the confounding factors as well as the state of the subjects, with
respect to the risk of developing T2DM, make it difficult to clearly determine from the
existing literature when supplementation can be beneficial. Further randomized, placebo-
controlled studies are mandatory to get a clear picture. But, when examining the efficacy of
compounds affecting insulin secretion, sensitivity, and resistance, with these as primary
outcome variables, it seems to be worthwhile to at least assess 25-hydroxyvitamin D
concentrations as a confounding variable or, even better, to include only test subjects with a
25-hydroxyvitamin D concentration above 80 nmol/L.
2.3.2 Vitamin K
In recent years it has become more and more evident that vitamin K might also play a role in
glucose homeostasis. Vitamin K (phylloquinone and menaquinone) is a cofactor in
carboxylating several GLA proteins. In this respect, vitamin K is known to play a role in
blood clotting. However, more and more studies show that the concentration of the bone-
GLA protein osteocalcin, as well as the percentage of undercarboxylated osteocalcin, which
reflects an insufficient vitamin K supply, seem to be associated with glucose and insulin
metabolism. Most of the studies showing an association between vitamin K or osteocalcin
and glucose homeostasis are cross-sectional [98-101]. Yoshida et al. [102], for instance,
examined the Framingham Offspring cohort and demonstrated a beneficial role for
phylloquinone in glucose homeostasis.

Inverse associations between osteocalcin concentrations and fasting glucose [99,103-109],
HOMA-IR [99,106-109], and HbA1c [104-106,110] have been shown in metabolically
healthy people and patients with T2DM in cross-sectional or longitudinal studies [27,106-
108]. However, the authors of these studies did not distinguish between total osteocalcin and
percentage of undercarboxylated osteocalcin. Which of these two variables is the potential
key in this correlation is not fully understood. Some researchers claim that in particular the
percentage of undercarboxylated osteocalcin is associated with insulin resistance; however,
results here are still controversial [111-113]. Vitamin K supplementation studies, however,
revealed opposite results. In two intervention studies in nondiabetic volunteers, one during 4
weeks with a pharmacological dose of 30 mg/day vitamin K2 supplementation [114] (Table
3) and the other one for 36 months with 500 g/day vitamin K1 supplementation [115] (Table
3), vitamin K supplementation improved insulin sensitivity, at least in men. The authors
hypothesized that vitamin K or the increase in carboxylated osteocalcin concentration had a
direct effect on glucose disposal from skeletal muscle tissue. The mechanism for such an
effect is unknown. Kumar et al. administered a pharmacological dose of 1 mg of vitamin K1
to postmenopausal women, leading to a 200% decrease in undercarboxylated osteocalcin.
However, they could not find any effect on insulin sensitivity analysed by HOMA-IR [116].
2.4 Minerals and trace elements

2.4.1 Calcium
Most of the studies showing potential benefit of high calcium intake on glucose homeostasis
are cross-sectional studies in which calcium has been applied in combination with protein, for
instance when increasing dairy or in combination with vitamin D supplementation [117-119].
The studies do have considerable heterogeneities in study design, participant characteristics,
and potential for confounding. From these studies it is very difficult to derive whether the
effect on blood glucose homeostasis is caused by high calcium intake or high protein intake,
the quality of protein, the vitamin D supplementation, or various combinations of these.
Intervention studies with high calcium intake as a single intervention are scarce. There is only
one intervention study in which vitamin D, either alone or combined with calcium, was
supplemented in subjects with high risk of diabetes [91]. In this 2-by-2 factorial, double-
masked, placebo-controlled randomized trial, subjects received either a pharmacological dose
of 2000 IU vitamin D 3 or placebo daily, and within these groups either 800 mg calcium or
placebo daily for 16 weeks. This study showed that in these subjects with high risk of

diabetes, only vitamin D 3 supplementation improved pancreatic beta-cell function as
measured by disposition index. Adding calcium did not make a significant difference [91].
2.4.2 Magnesium
Magnesium is an essential mineral and has been established as a cofactor for more than 300
metabolic reactions in the human body [120]. Some research has indicated that lower dietary
intakes of magnesium and lower serum magnesium concentrations may lead to and are
associated with the metabolic syndrome, insulin resistance, and/or T2DM [120-122]. Results
from clinical trials to test the effects of magnesium supplements on the metabolic profile of
diabetic subjects are scarce and controversial. Benefits were found in some, but not all,
clinical studies. A recent meta-analysis of randomized, double-blind controlled trials showed
that oral magnesium supplementation (median dose 360 mg/d) for 4-16 weeks may be
effective in reducing plasma glucose concentrations in type 2 diabetics [123]. However, the
analysis showed little evidence for an effect of magnesium supplementation on long-term
glycemic control as indicated by HbA1c levels. The authors stress that all individual
published trials were underpowered and used different doses and formulations of magnesium
supplements [123]. In addition, differences in baseline magnesium status and metabolic
control may explain the differences among the studies. Current American Diabetes
Association (ADA) nutrition guidelines summarize that there is currently no clear evidence of
benet from magnesium supplementation in people with diabetes (compared with the general
population) who do not have underlying clinical deciencies [124].
2.4.3 Zinc
Zinc is an essential trace element crucial for the function of more than 300 enzymes. In
addition, it is important for cellular processes like cell division and apoptosis. Hence, the
concentration of zinc in the human body is tightly regulated and disturbances of zinc
homeostasis have been associated with several diseases including diabetes mellitus [125]. In
a large cohort of type 2 diabetic patients, low serum zinc concentration (14.1 mol/L) was
an independent risk factor for coronary heart disease events [126]. Pharmacological doses of
zinc supplementation of animals and humans has been shown to ameliorate glycemic control
in type 1 and 2 diabetes, but the underlying molecular mechanisms have only slowly been
elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of
insulin and by reducing the production of cytokines, which lead to beta-cell death during the
inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might

play a role in the development of diabetes, as genetic polymorphisms in the gene for zinc
transporter 8 and in metallothionein (MT)-encoding genes were demonstrated to be
associated with T2DM [125]. The effect of supplementation with zinc for the prevention of
T2DM has been reviewed recently by Beletate and coworkers [127]. Only one study met the
inclusion criteria of the systematic review. Its subjects were 56 normal glucose-tolerant obese
women (aged 25 to 45 years, BMI 36.2 2.3 kg/m2). Follow-up was four weeks. The
outcomes measured were decrease of insulin resistance, anthropometrics and diet, plasma
leptin and insulin concentration, zinc concentration in the plasma and urine, lipid metabolism,
and fasting plasma glucose. There were no statistically signicant differences favouring
participants receiving still a nutritional dose of zinc supplementation (30 mg/day) relative to
placebo, for any outcome measured by the study. The authors concluded that there is
currently no evidence to suggest the use of zinc supplementation in the prevention of T2DM
[127].
2.4.4 Chromium
Chromium is an essential nutrient required for normal carbohydrate and lipid metabolism
[128]. Conclusive evidence for the essentiality of chromium in human nutrition was
published in 1977 when a patient who had received total parenteral nutrition for more than 5
years developed severe diabetic symptoms which were refractory to exogenous insulin [129].
Chromium balance was negative. Thus, the patient was given 250 g/day of supplemental
chromium. In the following 2 weeks, signs and symptoms of diabetes mellitus were
ameliorated, with markedly improved glycemic status and reduced insulin requirements
(from 45 units/day to zero) [129]. This phenomenon has been confirmed by others during
total parenteral nutrition [130].
The molecular mechanisms by which chromium alleviates insulin resistance are unclear.
Chromium supplementation to animals which were rendered insulin-resistant by either
genetic or nutritional methods indicates that chromium potentiates the actions of insulin,
augments the insulin signaling pathway, blunts the negative regulators of insulin signaling,
enhances AMP-activated protein kinase activity, upregulates cellular glucose uptake, and
attenuates oxidative stress [131].
Clinical trials on chromium in diabetic patients have yielded mixed results and fueled the
controversy surrounding the purported therapeutic benefits of chromium, especially outside
of a chromium deficiency status. Supplementation of the diet with chromium has shown

beneficial effects in improving insulin resistance in some clinical trials, but not in others. In a
recent systematic review involving 41 randomized controlled clinical trials, the authors found
that supplemented chromium has no significant effect on glucose metabolism in subjects who
do not have diabetes mellitus [132]. On the other hand, chromium supplementation
significantly improved HbA1c by -0.6% (95% CI -0.9 to -0.2) and fasting blood glucose by -
1.0 mmol/L (-1.4 to -0.5) among participants with T2DM. In addition, there were some
indications of dose effect and differences between chromium formulations [132]. However,
the authors expressed caution regarding these conclusions, given that about half of the
clinical trials examined in their review were of poor quality (e.g., lack of blinding, inadequate
randomization, high dropout rates, nonstandard outcome measurements), and also stated that
well-designed clinical trials are necessary before definitive claims can be made about the
effect of chromium supplementation [132]. Another recent review of clinical trials involving
chromium supplementation concluded that across all subject phenotypes (e.g., lean and
obese, insulin sensitive and insulin resistant), a consistent significant and beneficial effect of
chromium may not be observed [133]. Specifically, recent data failed to demonstrate
significant improvement in carbohydrate metabolism in individuals with metabolic syndrome
traits or impaired glucose tolerance, or consistently in individuals with type 2 diabetes.
However, patient selection may be an important factor in determining clinical response, as it
was concluded that a clinical response to chromium (i.e., decreased glucose and improved
insulin sensitivity) may be more likely in insulin-resistant individuals with T2DM who have
more elevated fasting glucose and HbA1c levels [133].
2.4.5 Sodium
Sodium plays an important role in osmotic regulation and body fluid homeostasis. It also
contributes to the establishment of the membrane potential of most cells and plays a direct
role in the action potential required for the transmission of nerve impulses and muscle
contraction. Sodium is mainly consumed in sodium chloride (NaCl). The actual adequate
intake recommended for young people by the Food and Nutrition Board of the National
Institutes of Health of the National Academy of Sciences of the US is 1500 mg sodium per
day, which equals less than a teaspoon of salt [134]. However, in Germany the average daily
sodium intake of women and men ranges from about 2500 mg (108 mEq) in women to 3500
mg (152 mEq/d) in men [135], taking into account that table salt added to meals is not
included. Because of the increased risk of developing hypertension with increasing NaCl
intake, lowering NaCl and thereby sodium intake is in general recommended. However, more

and more studies show that the level of dietary sodium affects insulin sensitivity, as
demonstrated in well-controlled, euglycemic insulin-clamp studies in metabolically healthy
volunteers [136,137]. High (200 mEq/d) versus low (10 mEq/d) salt intake may affect insulin
sensitivity by as much as 15% to 20% [136,138]. However, the findings are contradictory. In
the study by Donovan et al. [136], insulin sensitivity decreased by 16% with high salt intake
most likely induced by increased free fatty acid levels, whereas in the experiment by
Townsend et al. [137], insulin sensitivity increased by 21%. Although the design of the two
studies was rather comparable, other dietary factors besides carbohydrate, calcium,
potassium, and sodium content might have affected insulin sensitivity in the study by
Donovan et al. [136]. The effects of such factors can be excluded in the study by Townsend
et al. [137], as they repeated the daily menu and thereby the nutrient composition, and added
tabletsplacebo in the low-salt diet (intake: 20 mEq/d) , salt tablets (1 g NaCl per tablet) in
the high-salt (200 mEq/d) diet. In line with the results of the study by Townsend et al. [139],
many more studies support a decrease in insulin sensitivity when dietary salt intake is being
decreased [139], rather than an improvement.
A significant association of high plasma aldosterone concentration with insulin resistance

may be explained by reasoning that the higher aldosterone concentration induced by a low-
salt diet impairs insulin responsiveness and decreases insulin sensitivity. Another explanation
of this association could be that a low-salt diet activates sympathetic nervous activity (as well
as inducing an increase in plasma aldosterone), which in turn may also increase insulin
resistance [140-142]. According to some studies it seems that the effect of dietary sodium
intake on insulin sensitivity also depends on whether the subject is salt sensitive or salt
resistant, meaning whether an increase in salt intake leads to a rise in blood pressure (= salt
sensitive) [143-145]. It is tempting to speculate that the effect of high salt intake on insulin
sensitivity may occur in the presence of a polymorphism of the insulin receptor substrate-1
(IRS-1) gene as proposed by Dziwura et al. [144] or a polymorphism of the G-protein beta3
subunit (GNB3) gene as shown by Daimon et al. [146]. In these studies, test subjects who had
either polymorphism had an increased risk for insulin resistance when consuming less salt.

3 Discussion
According to the acute, very controlled studies reviewed in this paper, it is obvious that other
nutrients in addition to carbohydrates may affect glucose metabolism. The effects of each of
the described nutrients might not be as pronounced as the very obvious effect of
carbohydrates on blood glucose concentration, but all of the blood glucose-lowering effects
together may help to keep blood glucose concentrations in reasonable ranges.
Increasing protein intake, in particular by consuming larger amounts of whey protein, seems
to affect glucose metabolism. Of the possible mechanisms by which protein intake can affect
glucose metabolism, the following are discussed: increasing insulin secretion [16,17,19] by
activation of calcium channels and exocytosis of insulin [19], increasing insulin sensitivity
[18,21] by increased GLUT4 translocation [21], delayed gastric emptying [20], reduced liver
insulin clearance [20], and inhibition of dipeptidyl peptidase IV activity [20]. On the basis of
these results, increasing protein intake in the daily diet may be recommended for lowering
blood glucose concentrations if a person is not at risk of kidney disease. However, caution
has to be taken regarding the upper limit of protein intake, as high intake of protein may also
have side effects such as increasing bone degradation by inducing a low-grade metabolic
acidosis [147-149].
There are limitations to both short- and long-term administration of protein, with respect to
the impact of protein on blood glucose concentrations. Quite often, the amount applied in an
acute study might be relatively high and therefore not applicable to a daily diet. In acute
studies having a well-controlled study design, in a small group of test subjects, applying
rather high amounts of a single nutrient is very reasonable to show potential effects, including
potential mechanisms, of this single nutrient. However, in cross-sectional or long-term
studies of, for instance, high protein intake, the results are very contradictory with respect to
their effect on blood glucose levels. In the study by Weickert et al. the percentage of protein
intake was increased from 15 energy percent to 25-30 percent over 18 weeks. This caused a
decrease in insulin sensitivity after 6 weeks, which was compensated for after 18 weeks [27].
In the cross-sectional, prospective EPIC-NL study it was found that high intake of animal
protein is associated with an increased diabetes risk whereas vegetable protein was not
related [150], the conclusion being that high protein intake increases diabetes risk. As,
habitually, a high intake of animal protein is usually associated with a low intake of fiber, the

results of these studies show that it is very difficult to obtain a cause-and-effect relationship
in a long-term study [28]. Here, the impact of other nutrients which affect blood glucose
concentrations or the risk of developing diabetes cannot be neglected as it can in randomized,
acute intervention studies.
With respect to 25-hydroxyvitamin D levels there is increasing evidence, in particular from

cross-sectional studies, that blood 25-hydroxyvitamin D concentrations are inversely
associated with glucose homeostasis and insulin sensitivity [87,91,151-155]. Even a role for
vitamin D in decreasing the development and progression of type 2 diabetes has been
discussed [153,155]. Increasing blood 25-OH vitamin D concentrations seems to increase
insulin sensitivity by way of the insulin signaling cascade [91,92] and improved -cell
function [91]. However, to conclude that there is a cause-and-effect relationship between
blood 25-OH vitamin D levels and blood glucose concentrations, or even the progression of
T2DM, prospective intervention studies in different population groups are warranted.
When summarizing the effects of different nutrients on blood glucose homeostasis in acute
studies it seems that other nutrients besides carbohydrates are involved. However, as
expected, the effect size of other nutrients is lower than the effect of carbohydrates, although
for instance whey protein may increase insulin sensitivity by about 10% [18,21] and lowering
sodium intake may decrease insulin sensitivity by about 20% [137]. This effect may hardly
be detectable in studies without control of nutrient intake and the subjects environment.
Therefore it is very difficult to demonstrate these effects in outpatient, long-term treatment
studies. However, when the effects of different kinds of insulin formulations, biosimilars, or
oral antidiabetics are examined in study designs in which subjects arrive at the lab in a fasting
state and the nutrient composition of the previous days dietary intake is not known, these
conditions may increase the variability of the respective outcome variables.
Conclusion
Taken together, our data clearly show that nutrients other than carbohydrates may
significantly affect glucose and insulin metabolism. This finding is of particular interest for
patients diagnosed with T2DM and might lead to more specific dietary recommendations in

the future. However, additional controlled, long-term studies which are sufficiently powered,
in subjects who are metabolically healthy or are well-characterized T2DM individuals, are
mandatory to identify the optimal dosage to achieve preventive effects. To elucidate
potential mechanisms leading to the described effects on glucose metabolism, studies which
are more integrative are also needed.
On the other hand, according to our results it seems to be extremely important, when studying
the effect of any compound on blood glucose metabolism, to consider the impact of non-
carbohydrates on glucose homeostasis by standardizing the dietary nutrient intake.
Although we are convinced of the impact of several non-carbohydrates on glucose

homeostasis, the clinical relevance of such an effect is still unclear. Even when a chosen
nutrient composition may optimize blood glucose concentration, safety concerns still need to
be addressed.
Acknowledgements
We are grateful to J. Krauhs for editorial review.

References
[1] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27(5):
1047-1053.
[2] Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2
diabetes in youth. Diabetes Care 1999; 22(2): 345-354.
[3] Bobo N, Evert A, Gallivan J, Imperatore G, Kelly J, Linder B et al. An update on type
2 diabetes in youth from the National Diabetes Education Program. Pediatrics 2004;
114(1): 259-263.
[4] Anderson JW, Kendall CW, Jenkins DJ. Importance of weight management in type 2
diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr 2003; 22(5):
331-339.
[5] Monro JA, Shaw M. Glycemic impact, glycemic glucose equivalents, glycemic index,
and glycemic load: definitions, distinctions, and implications. Am J Clin Nutr 2008;
87(1): 237S-243S.
[6] Nilsson A, Granfeldt Y, Ostman E, Preston T, Bjorck I. Effects of GI and content of
indigestible carbohydrates of cereal-based evening meals on glucose tolerance at a
subsequent standardised breakfast. Eur J Clin Nutr 2006; 60(9): 1092-1099.
[7] Wolever TM, Jenkins DJ, Ocana AM, Rao VA, Collier GR. Second-meal effect: low-
glycemic-index foods eaten at dinner improve subsequent breakfast glycemic
response. Am J Clin Nutr 1988; 48(4): 1041-1047.
[8] Aston LM, Gambell JM, Lee DM, Bryant SP, Jebb SA. Determination of the

glycaemic index of various staple carbohydrate-rich foods in the UK diet. Eur J Clin
Nutr 2008; 62(2): 279-285.
[9] Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM et al.
Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin
Nutr 1981; 34(3): 362-366.
[10] Jenkins DJ, Wolever TM, Collier GR, Ocana A, Rao AV, Buckley G et al. Metabolic
effects of a low-glycemic-index diet. Am J Clin Nutr 1987; 46(6): 968-975.
[11] Jenkins DJ, Wolever TM, Taylor RH, Griffiths C, Krzeminska K, Lawrie JA et al.
Slow release dietary carbohydrate improves second meal tolerance. Am J Clin Nutr
1982; 35(6): 1339-1346.
[12] Najjar AM, Parsons PM, Duncan AM, Robinson LE, Yada RY, Graham TE. The
acute impact of ingestion of breads of varying composition on blood glucose, insulin
and incretins following first and second meals. Br J Nutr 2009; 101(3): 391-398.
[13] Rijkelijkhuizen JM, Girman CJ, Mari A, Alssema M, Rhodes T, Nijpels G et al.
Classical and model-based estimates of beta-cell function during a mixed meal vs. an
OGTT in a population-based cohort. Diabetes Res Clin Pract 2009; 83(2): 280-288.
[14] Akhavan T, Luhovyy BL, Brown PH, Cho CE, Anderson GH. Effect of premeal
consumption of whey protein and its hydrolysate on food intake and postmeal
glycemia and insulin responses in young adults. Am J Clin Nutr 2010; 91(4): 966-
975.
[15] Anderson GH, Luhovyy B, Akhavan T, Panahi S. Milk proteins in the regulation of
body weight, satiety, food intake and glycemia. Nestle Nutr Workshop Ser Pediatr

Program 2011; 67: 147-159.
[16] Pal S, Ellis V. The acute effects of four protein meals on insulin, glucose, appetite and
energy intake in lean men. Br J Nutr 2010; 104(8): 1241-1248.
[17] Acheson KJ, Blondel-Lubrano A, Oguey-Araymon S, Beaumont M, Emady-Azar S,
Ammon-Zufferey C et al. Protein choices targeting thermogenesis and metabolism.
Am J Clin Nutr 2011; 93(3): 525-534.
[18] Pal S, Ellis V, Dhaliwal S. Effects of whey protein isolate on body composition,
lipids, insulin and glucose in overweight and obese individuals. Br J Nutr 2010;
104(5): 716-723.
[19] Jonker JT, Wijngaarden MA, Kloek J, Groeneveld Y, Gerhardt C, Brand R et al.
Effects of low doses of casein hydrolysate on post-challenge glucose and insulin
levels. Eur J Intern Med 2011; 22(3): 245-248.
[20] Lan-Pidhainy X, Wolever TM. The hypoglycemic effect of fat and protein is not
attenuated by insulin resistance. Am J Clin Nutr 2010; 91(1): 98-105.
[21] Breen L, Philp A, Shaw CS, Jeukendrup AE, Baar K, Tipton KD. Beneficial effects of
resistance exercise on glycemic control are not further improved by protein ingestion.
PLoS One 2011; 6(6): e20613.
[22] Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes
mellitus. Nat Rev Endocrinol 2012; 8(12): 728-742.
[23] Bendtsen LQ, Lorenzen JK, Bendsen NT, Rasmussen C, Astrup A. Effect of dairy
proteins on appetite, energy expenditure, body weight, and composition: a review of
the evidence from controlled clinical trials. Adv Nutr 2013; 4(4): 418-438.

[24] Brennan L, Shine A, Hewage C, Malthouse JP, Brindle KM, McClenaghan N et al. A
nuclear magnetic resonance-based demonstration of substantial oxidative L-alanine
metabolism and L-alanine-enhanced glucose metabolism in a clonal pancreatic beta-
cell line: metabolism of L-alanine is important to the regulation of insulin secretion.
Diabetes 2002; 51(6): 1714-1721.
[25] Cunningham GA, McClenaghan NH, Flatt PR, Newsholme P. L-Alanine induces
changes in metabolic and signal transduction gene expression in a clonal rat
pancreatic beta-cell line and protects from pro-inflammatory cytokine-induced
apoptosis. Clin Sci (Lond) 2005; 109(5): 447-455.
[26] Dunne MJ, Yule DI, Gallacher DV, Petersen OH. Effects of alanine on insulin-
secreting cells: patch-clamp and single cell intracellular Ca2+ measurements. Biochim
Biophys Acta 1990; 1055(2): 157-164.
[27] Weickert MO, Roden M, Isken F, Hoffmann D, Nowotny P, Osterhoff M et al.
Effects of supplemented isoenergetic diets differing in cereal fiber and protein content
on insulin sensitivity in overweight humans. Am J Clin Nutr 2011; 94(2): 459-471.
[28] Larsen RN, Mann NJ, Maclean E, Shaw JE. The effect of high-protein, low-
carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised
controlled trial. Diabetologia 2011; 54(4): 731-740.
[29] Heer M, Smith SM, Frings-Meuthen P, Zwart SR, Baecker N. High Protein Intake
Improves Insulin Sensitivity but Exacerbates Bone Resorption in Immobility (WISE
Study). FASEB J March 29[26], 633.9. 2012.
Ref Type: Abstract
[30] Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on

glycaemic control in patients with abnormal glucose metabolism: a systematic review
and meta-analysis. Ann Nutr Metab 2011; 58(4): 290-296.
[31] Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog
Lipid Res 2009; 48(1): 44-51.
[32] Hodson L, Skeaff CM, Fielding BA. Fatty acid composition of adipose tissue and
blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res 2008;
47(5): 348-380.
[33] Ginsberg BH, Brown TJ, Simon I, Spector AA. Effect of the membrane lipid
environment on the properties of insulin receptors. Diabetes 1981; 30(9): 773-780.
[34] Clarke SD. The multi-dimensional regulation of gene expression by fatty acids:
polyunsaturated fats as nutrient sensors. Curr Opin Lipidol 2004; 15(1): 13-18.
[35] Riserus U. Fatty acids and insulin sensitivity. Curr Opin Clin Nutr Metab Care 2008;
11(2): 100-105.
[36] Aranceta J, Perez-Rodrigo C. Recommended dietary reference intakes, nutritional
goals and dietary guidelines for fat and fatty acids: a systematic review. Br J Nutr
2012; 107 Suppl 2: S8-22.
[37] Lovejoy JC, Smith SR, Champagne CM, Most MM, Lefevre M, DeLany JP et al.
Effects of diets enriched in saturated (palmitic), monounsaturated (oleic), or trans
(elaidic) fatty acids on insulin sensitivity and substrate oxidation in healthy adults.
Diabetes Care 2002; 25(8): 1283-1288.
[38] Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC et al.
Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in

healthy men and women: The KANWU Study. Diabetologia 2001; 44(3): 312-319.
[39] Mensink RP. Metabolic and health effects of isomeric fatty acids. Curr Opin Lipidol
2005; 16(1): 27-30.
[40] Micha R, Mozaffarian D. Trans fatty acids: effects on metabolic syndrome, heart
disease and diabetes. Nat Rev Endocrinol 2009; 5(6): 335-344.
[41] Thompson AK, Minihane AM, Williams CM. Trans fatty acids, insulin resistance and
diabetes. Eur J Clin Nutr 2011; 65(5): 553-564.
[42] Mozaffarian D, Aro A, Willett WC. Health effects of trans-fatty acids: experimental
and observational evidence. Eur J Clin Nutr 2009; 63 Suppl 2: S5-21.
[43] Aronis KN, Khan SM, Mantzoros CS. Effects of trans fatty acids on glucose
homeostasis: a meta-analysis of randomized, placebo-controlled clinical trials. Am J
Clin Nutr 2012; 96(5): 1093-1099.
[44] Park Y, Albright KJ, Storkson JM, Liu W, Cook ME, Pariza MW. Changes in body
composition in mice during feeding and withdrawal of conjugated linoleic acid.
Lipids 1999; 34(3): 243-248.
[45] Belury MA. Dietary conjugated linoleic acid in health: physiological effects and
mechanisms of action. Annu Rev Nutr 2002; 22: 505-531.
[46] Salas-Salvado J, Marquez-Sandoval F, Bullo M. Conjugated linoleic acid intake in
humans: a systematic review focusing on its effect on body composition, glucose, and
lipid metabolism. Crit Rev Food Sci Nutr 2006; 46(6): 479-488.
[47] Dilzer A, Park Y. Implication of conjugated linoleic acid (CLA) in human health. Crit

Rev Food Sci Nutr 2012; 52(6): 488-513.
[48] Plourde M, Jew S, Cunnane SC, Jones PJ. Conjugated linoleic acids: why the
discrepancy between animal and human studies? Nutr Rev 2008; 66(7): 415-421.
[49] Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12
conjugated linoleic acid causes isomer-specific insulin resistance in obese men with
the metabolic syndrome. Diabetes Care 2002; 25(9): 1516-1521.
[50] He K. Fish, long-chain omega-3 polyunsaturated fatty acids and prevention of
cardiovascular disease--eat fish or take fish oil supplement? Prog Cardiovasc Dis
2009; 52(2): 95-114.
[51] Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B et al. n-3
Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit
cardiovascular disease outcomes in primary- and secondary-prevention studies: a
systematic review. Am J Clin Nutr 2006; 84(1): 5-17.
[52] Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine
omega-3 fatty acids. Lancet 2010; 376(9740): 540-550.
[53] de Roos B, Mavrommatis Y, Brouwer IA. Long-chain n-3 polyunsaturated fatty acids:
new insights into mechanisms relating to inflammation and coronary heart disease. Br
J Pharmacol 2009; 158(2): 413-428.
[54] Egert S, Stehle P. Impact of n-3 fatty acids on endothelial function: results from
human interventions studies. Curr Opin Clin Nutr Metab Care 2011; 14(2): 121-131.
[55] Jacobs B, Angelis-Schierbaum G, Egert S, Assmann G, Kratz M. Individual serum
triglyceride responses to high-fat and low-fat diets differ in men with modest and

severe hypertriglyceridemia. J Nutr 2004; 134(6): 1400-1405.
[56] Kalupahana NS, Claycombe KJ, Moustaid-Moussa N. (n-3) Fatty acids alleviate
adipose tissue inflammation and insulin resistance: mechanistic insights. Adv Nutr
2011; 2(4): 304-316.
[57] Geleijnse JM, de Goede J, Brouwer IA. Alpha-linolenic acid: is it essential to
cardiovascular health? Curr Atheroscler Rep 2010; 12(6): 359-367.
[58] Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE. Fish oil and glycemic control in
diabetes. A meta-analysis. Diabetes Care 1998; 21(4): 494-500.
[59] Friday KE, Childs MT, Tsunehara CH, Fujimoto WY, Bierman EL, Ensinck JW.
Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid
supplementation in type II diabetes. Diabetes Care 1989; 12(4): 276-281.
[60] Glauber H, Wallace P, Griver K, Brechtel G. Adverse metabolic effect of omega-3
fatty acids in non-insulin-dependent diabetes mellitus. Ann Intern Med 1988; 108(5):
663-668.
[61] Mostad IL, Bjerve KS, Bjorgaas MR, Lydersen S, Grill V. Effects of n-3 fatty acids in
subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent
alteration from carbohydrate to fat oxidation. Am J Clin Nutr 2006; 84(3): 540-550.
[62] Egert S, Fobker M, Andersen G, Somoza V, Erbersdobler HF, Wahrburg U. Effects of
dietary alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid on
parameters of glucose metabolism in healthy volunteers. Ann Nutr Metab 2008; 53(3-
4): 182-187.
[63] Annuzzi G, Rivellese A, Capaldo B, Di Marino L, Iovine C, Marotta G et al. A

controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in
non-insulin-dependent diabetic patients. Atherosclerosis 1991; 87(1): 65-73.
[64] Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in type 2
diabetes: a quantitative systematic review. Diabetes Care 2000; 23(9): 1407-1415.
[65] McManus RM, Jumpson J, Finegood DT, Clandinin MT, Ryan EA. A comparison of
the effects of n-3 fatty acids from linseed oil and fish oil in well-controlled type II
diabetes. Diabetes Care 1996; 19(5): 463-467.
[66] Nettleton JA, Katz R. N-3 long-chain polyunsaturated fatty acids in type 2 diabetes: a
review. J Am Diet Assoc 2005; 105(3): 428-440.
[67] Mori TA, Woodman RJ. The independent effects of eicosapentaenoic acid and
docosahexaenoic acid on cardiovascular risk factors in humans. Curr Opin Clin Nutr
Metab Care 2006; 9(2): 95-104.
[68] Robinson JG, Stone NJ. Antiatherosclerotic and antithrombotic effects of omega-3
fatty acids. Am J Cardiol 2006; 98(4A): 39i-49i.
[69] Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of
omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic
review. Atherosclerosis 2006; 189(1): 19-30.
[70] Lombardo YB, Chicco AG. Effects of dietary polyunsaturated n-3 fatty acids on
dyslipidemia and insulin resistance in rodents and humans. A review. J Nutr Biochem
2006; 17(1): 1-13.
[71] Akinkuolie AO, Ngwa JS, Meigs JB, Djousse L. Omega-3 polyunsaturated fatty acid
and insulin sensitivity: a meta-analysis of randomized controlled trials. Clin Nutr

2011; 30(6): 702-707.
[72] Hartweg J, Perera R, Montori V, Dinneen S, Neil HA, Farmer A. Omega-3
polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus. Cochrane Database
Syst Rev 2008;(1): CD003205.
[73] Hartweg J, Farmer AJ, Holman RR, Neil A. Potential impact of omega-3 treatment on
cardiovascular disease in type 2 diabetes. Curr Opin Lipidol 2009; 20(1): 30-38.
[74] Bloedon LT, Balikai S, Chittams J, Cunnane SC, Berlin JA, Rader DJ et al. Flaxseed
and cardiovascular risk factors: results from a double blind, randomized, controlled
clinical trial. J Am Coll Nutr 2008; 27(1): 65-74.
[75] Sioen I, Hacquebard M, Hick G, Maindiaux V, Larondelle Y, Carpentier YA et al.
Effect of ALA-enriched food supply on cardiovascular risk factors in males. Lipids
2009; 44(7): 603-611.
[76] Wu JH, Micha R, Imamura F, Pan A, Biggs ML, Ajaz O et al. Omega-3 fatty acids
and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr 2012;
107 Suppl 2: S214-S227.
[77] Truong H, DiBello JR, Ruiz-Narvaez E, Kraft P, Campos H, Baylin A. Does genetic
variation in the Delta6-desaturase promoter modify the association between alpha-
linolenic acid and the prevalence of metabolic syndrome? Am J Clin Nutr 2009;
89(3): 920-925.
[78] Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB et al. Levels
of vitamin D and cardiometabolic disorders: systematic review and meta-analysis.
Maturitas 2010; 65(3): 225-236.

[79] Pittas AG, Dawson-Hughes B. Vitamin D and diabetes. J Steroid Biochem Mol Biol
2010; 121(1-2): 425-429.
[80] Scragg R, Holdaway I, Singh V, Metcalf P, Baker J, Dryson E. Serum 25-
hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes
mellitus. Diabetes Res Clin Pract 1995; 27(3): 181-188.
[81] Isaia G, Giorgino R, Adami S. High prevalence of hypovitaminosis D in female type
2 diabetic population. Diabetes Care 2001; 24(8): 1496.
[82] Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M et al. Serum 25-
hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among
type 2 diabetic patients. Clin Endocrinol (Oxf) 2006; 65(5): 593-597.
[83] Gagnon C, Lu ZX, Magliano DJ, Dunstan DW, Shaw JE, Zimmet PZ et al. Serum 25-
hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results
from a national, population-based prospective study (the Australian Diabetes, Obesity
and Lifestyle study). Diabetes Care 2011; 34(5): 1133-1138.
[84] Knekt P, Laaksonen M, Mattila C, Harkanen T, Marniemi J, Heliovaara M et al.
Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology 2008;
19(5): 666-671.
[85] Liu E, Meigs JB, Pittas AG, Economos CD, McKeown NM, Booth SL et al. Predicted
25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring
Study. Am J Clin Nutr 2010; 91(6): 1627-1633.
[86] Pittas AG, Nelson J, Mitri J, Hillmann W, Garganta C, Nathan DM et al. Plasma 25-
hydroxyvitamin D and progression to diabetes in patients at risk for diabetes: an

ancillary analysis in the Diabetes Prevention Program. Diabetes Care 2012; 35(3):
565-573.
[87] Alvarez JA, Ashraf A. Role of vitamin d in insulin secretion and insulin sensitivity for
glucose homeostasis. Int J Endocrinol 2010; 2010: 351385.
[88] Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin
resistance and beta cell dysfunction. Am J Clin Nutr 2004; 79(5): 820-825.
[89] Nazarian S, St Peter JV, Boston RC, Jones SA, Mariash CN. Vitamin D3
supplementation improves insulin sensitivity in subjects with impaired fasting
glucose. Transl Res 2011; 158(5): 276-281.
[90] Liu E, Meigs JB, Pittas AG, Economos CD, McKeown NM, Booth SL et al. Predicted
25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring
Study. Am J Clin Nutr 2010; 91(6): 1627-1633.
[91] Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium
supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in
adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus
(CaDDM) randomized controlled trial. Am J Clin Nutr 2011; 94(2): 486-494.
[92] von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin
resistance in South Asian women living in New Zealand who are insulin resistant and
vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr 2010; 103(4):
549-555.
[93] Harris SS, Pittas AG, Palermo NJ. A randomized, placebo-controlled trial of vitamin
D supplementation to improve glycaemia in overweight and obese African

Americans. Diabetes Obes Metab 2012.
[94] Bourlon PM, Billaudel B, Faure-Dussert A. Influence of vitamin D3 deficiency and
1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat
endocrine pancreas. J Endocrinol 1999; 160(1): 87-95.
[95] Zhou QG, Hou FF, Guo ZJ, Liang M, Wang GB, Zhang X. 1,25-Dihydroxyvitamin D
improved the free fatty-acid-induced insulin resistance in cultured C2C12 cells.
Diabetes Metab Res Rev 2008; 24(6): 459-464.
[96] Wollheim CB, Sharp GW. Regulation of insulin release by calcium. Physiol Rev
1981; 61(4): 914-973.
[97] Worrall DS, Olefsky JM. The effects of intracellular calcium depletion on insulin
signaling in 3T3-L1 adipocytes. Molecular Endocrinology 2002; 16(2): 378-389.
[98] Bullo M, Moreno-Navarrete JM, Fernandez-Real JM, Salas-Salvado J. Total and
undercarboxylated osteocalcin predict changes in insulin sensitivity and beta cell
function in elderly men at high cardiovascular risk. Am J Clin Nutr 2012; 95(1): 249-
255.
[99] Lucey AJ, Paschos GK, Thorsdottir I, Martinez JA, Cashman KD, Kiely M. Young
overweight and obese women with lower circulating osteocalcin concentrations
exhibit higher insulin resistance and concentrations of C-reactive protein. Nutr Res
2013; 33(1): 67-75.
[100] Wang Q, Zhang B, Xu Y, Xu H, Zhang N. The Relationship between Serum
Osteocalcin Concentration and Glucose Metabolism in Patients with Type 2 Diabetes
Mellitus. Int J Endocrinol 2013; 2013: 842598.

[101] Ibarrola-Jurado N, Salas-Salvado J, Martinez-Gonzalez MA, Bullo M. Dietary
phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of
cardiovascular disease. Am J Clin Nutr 2012.
[102] Yoshida M, Booth SL, Meigs JB, Saltzman E, Jacques PF. Phylloquinone intake,
insulin sensitivity, and glycemic status in men and women. Am J Clin Nutr 2008;
88(1): 210-215.
[103] Im JA, Yu BP, Jeon JY, Kim SH. Relationship between osteocalcin and glucose
metabolism in postmenopausal women. Clin Chim Acta 2008; 396(1-2): 66-69.
[104] Zhou M, Ma X, Li H, Pan X, Tang J, Gao Y et al. Serum osteocalcin concentrations
in relation to glucose and lipid metabolism in Chinese individuals. Eur J Endocrinol
2009; 161(5): 723-729.
[105] Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S et al.
Adiponectin is associated with changes in bone markers during glycemic control in
type 2 diabetes mellitus. J Clin Endocrinol Metab 2009; 94(8): 3031-3037.
[106] Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B. Association between
serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab
2009; 94(3): 827-832.
[107] Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U et al.
Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly
Swedish men. J Bone Miner Res 2009; 24(5): 785-791.
[108] Yeap BB, Chubb SA, Flicker L, McCaul KA, Ebeling PR, Beilby JP et al. Reduced
serum total osteocalcin is associated with metabolic syndrome in older men via waist

circumference, hyperglycemia, and triglyceride levels. Eur J Endocrinol 2010; 163(2):
265-272.
[109] Sarkar PD, Choudhury AB. Relationship of serum osteocalcin levels with blood
glucose, insulin resistance and lipid profile in central Indian men with type 2 diabetes.
Arch Physiol Biochem 2012; 118(5): 260-264.
[110] Dobnig H, Piswanger-Solkner JC, Roth M, Obermayer-Pietsch B, Tiran A, Strele A et
al. Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone
mass, and fracture risk. J Clin Endocrinol Metab 2006; 91(9): 3355-3363.
[111] Mori K, Emoto M, Motoyama K, Lee E, Yamada S, Morioka T et al.
Undercarboxylated osteocalcin does not correlate with insulin resistance as assessed
by euglycemic hyperinsulinemic clamp technique in patients with type 2 diabetes
mellitus. Diabetol Metab Syndr 2012; 4(1): 53.
[112] Iki M, Tamaki J, Fujita Y, Kouda K, Yura A, Kadowaki E et al. Serum
undercarboxylated osteocalcin levels are inversely associated with glycemic status
and insulin resistance in an elderly Japanese male population: Fujiwara-kyo
Osteoporosis Risk in Men (FORMEN) Study. Osteoporos Int 2012; 23(2): 761-770.
[113] Shea MK, Gundberg CM, Meigs JB, Dallal GE, Saltzman E, Yoshida M et al.
Gamma-carboxylation of osteocalcin and insulin resistance in older men and women.
Am J Clin Nutr 2009; 90(5): 1230-1235.
[114] Choi HJ, Yu J, Choi H, An JH, Kim SW, Park KS et al. Vitamin K2 supplementation
improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial.
Diabetes Care 2011; 34(9): e147.

[115] Yoshida M, Jacques PF, Meigs JB, Saltzman E, Shea MK, Gundberg C et al. Effect of
vitamin K supplementation on insulin resistance in older men and women. Diabetes
Care 2008; 31(11): 2092-2096.
[116] Kumar R, Binkley N, Vella A. Effect of phylloquinone supplementation on glucose
homeostasis in humans. Am J Clin Nutr 2010; 92(6): 1528-1532.
[117] Fumeron F, Lamri A, Abi KC, Jaziri R, Porchay-Balderelli I, Lantieri O et al. Dairy
consumption and the incidence of hyperglycemia and the metabolic syndrome: results
from a french prospective study, Data from the Epidemiological Study on the Insulin
Resistance Syndrome (DESIR). Diabetes Care 2011; 34(4): 813-817.
[118] da Silva FT, Torres MR, Sanjuliani AF. Dietary calcium intake is associated with
adiposity, metabolic profile, inflammatory state and blood pressure, but not with
erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal
women. Br J Nutr 2013; 110(6): 1079-1088.
[119] Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and
vitamin D supplementation on blood glucose and markers of inflammation in
nondiabetic adults. Diabetes Care 2007; 30(4): 980-986.
[120] Volpe SL. Magnesium, the metabolic syndrome, insulin resistance, and type 2
diabetes mellitus. Crit Rev Food Sci Nutr 2008; 48(3): 293-300.
[121] Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus,
metabolic syndrome and insulin resistance. Arch Biochem Biophys 2007; 458(1): 40-
47.
[122] Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes: meta-

analysis of prospective cohort studies. Diabetes Care 2011; 34(9): 2116-2122.
[123] Song Y, He K, Levitan EB, Manson JE, Liu S. Effects of oral magnesium
supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of
randomized double-blind controlled trials. Diabet Med 2006; 23(10): 1050-1056.
[124] Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ et al.
Nutrition recommendations and interventions for diabetes: a position statement of the
American Diabetes Association. Diabetes Care 2008; 31 Suppl 1: S61-S78.
[125] Jansen J, Karges W, Rink L. Zinc and diabetes--clinical links and molecular
mechanisms. J Nutr Biochem 2009; 20(6): 399-417.
[126] Soinio M, Marniemi J, Laakso M, Pyorala K, Lehto S, Ronnemaa T. Serum zinc level
and coronary heart disease events in patients with type 2 diabetes. Diabetes Care
2007; 30(3): 523-528.
[127] Beletate V, El Dib RP, Atallah AN. Zinc supplementation for the prevention of type 2
diabetes mellitus. Cochrane Database Syst Rev 2007;(1): CD005525.
[128] Hummel M, Standl E, Schnell O. Chromium in metabolic and cardiovascular disease.
Horm Metab Res 2007; 39(10): 743-751.
[129] Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium
deficiency, glucose intolerance, and neuropathy reversed by chromium
supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin
Nutr 1977; 30(4): 531-538.
[130] Freund H, Atamian S, Fischer JE. Chromium deficiency during total parenteral
nutrition. JAMA 1979; 241(5): 496-498.

[131] Hua Y, Clark S, Ren J, Sreejayan N. Molecular mechanisms of chromium in
alleviating insulin resistance. J Nutr Biochem 2012; 23(4): 313-319.
[132] Balk EM, Tatsioni A, Lichtenstein AH, Lau J, Pittas AG. Effect of chromium
supplementation on glucose metabolism and lipids: a systematic review of
randomized controlled trials. Diabetes Care 2007; 30(8): 2154-2163.
[133] Wang ZQ, Cefalu WT. Current concepts about chromium supplementation in type 2
diabetes and insulin resistance. Curr Diab Rep 2010; 10(2): 145-151.
[134] National Academy of Sciences. Sodium and chloride. Dietary reference intakes for
water, potassium, sodium, chloride, and sulfateSodium and chloride. Washington,
D.C.: The National Academic Press 2004: 269-423.
[135] Max-Rubner-Institut. National Verzehrsstudie II. Karlsruhe: Bundesforschungsinstitut
fr Ernhrung und Lebensmittel, 2008.
[136] Donovan DS, Solomon CG, Seely EW, Williams GH, Simonson DC. Effect of
sodium intake on insulin sensitivity. Am J Physiol 1993; 264(5 Pt 1): E730-E734.
[137] Townsend RR, Kapoor S, McFadden CB. Salt intake and insulin sensitivity in healthy
human volunteers. Clin Sci (Lond) 2007; 113(3): 141-148.
[138] Perry CG, Palmer T, Cleland SJ, Morton IJ, Salt IP, Petrie JR et al. Decreased insulin
sensitivity during dietary sodium restriction is not mediated by effects of angiotensin
II on insulin action. Clin Sci (Lond) 2003; 105(2): 187-194.
[139] Garg R, Williams GH, Hurwitz S, Brown NJ, Hopkins PN, Adler GK. Low-salt diet
increases insulin resistance in healthy subjects. Metabolism 2011; 60(7): 965-968.

[140] Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA. Insulin resistance
and hyperinsulinemia are related to plasma aldosterone levels in hypertensive
patients. Diabetes Care 2007; 30(9): 2349-2354.
[141] Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO. Reflex
sympathetic activation induces acute insulin resistance in the human forearm.
Hypertension 1993; 21(5): 618-623.
[142] Huan Y, Deloach S, Keith SW, Pequignot EC, Falkner B. High blood pressure and
obesity increase the risk of abnormal glucose tolerance in young adult african
americans. J Clin Hypertens (Greenwich ) 2011; 13(6): 397-403.
[143] Dengel DR, Hogikyan RV, Brown MD, Glickman SG, Supiano MA. Insulin
sensitivity is associated with blood pressure response to sodium in older
hypertensives. Am J Physiol 1998; 274(3 Pt 1): E403-E409.
[144] Dziwura J, Binczak-Kuleta A, Miazgowski T, Ziemak J, Widecka K. The associations
between G972R polymorphism of the IRS-1 gene, insulin resistance, salt sensitivity
and non-dipper hypertension. Hypertens Res 2011; 34(10): 1082-1086.
[145] Raji A, Williams GH, Jeunemaitre X, Hopkins PN, Hunt SC, Hollenberg NK et al.
Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium
intake. J Hypertens 2001; 19(1): 99-105.
[146] Daimon M, Sato H, Sasaki S, Toriyama S, Emi M, Muramatsu M et al. Salt
consumption-dependent association of the GNB3 gene polymorphism with type 2
DM. Biochem Biophys Res Commun 2008; 374(3): 576-580.
[147] Cardinale M, Leiper J, Farajian P, Heer M. Whole-body vibration can reduce calciuria

induced by high protein intakes and may counteract bone resorption: A preliminary
study. J Sports Sci 2007; 25(1): 111-119.
[148] Frassetto L, Morris RC, Jr., Sellmeyer DE, Todd K, Sebastian A. Diet, evolution and
aging--the pathophysiologic effects of the post-agricultural inversion of the
potassium-to-sodium and base-to-chloride ratios in the human diet. Eur J Nutr 2001;
40(5): 200-213.
[149] Frick KK, Bushinsky DA. Metabolic acidosis stimulates RANKL RNA expression in
bone through a cyclo-oxygenase-dependent mechanism. J Bone Miner Res 2003;
18(7): 1317-1325.
[150] Sluijs I, Beulens JW, van der AD, Spijkerman AM, Grobbee DE, van der Schouw YT.
Dietary intake of total, animal, and vegetable protein and risk of type 2 diabetes in the
European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study.
Diabetes Care 2010; 33(1): 43-48.
[151] Choi HS, Kim KA, Lim CY, Rhee SY, Hwang YC, Kim KM et al. Low serum
vitamin D is associated with high risk of diabetes in Korean adults. J Nutr 2011;
141(8): 1524-1528.
[152] Dalgard C, Petersen MS, Weihe P, Grandjean P. Vitamin D Status in Relation to
Glucose Metabolism and Type 2 Diabetes in Septuagenarians. Diabetes Care 2011.
[153] Gagnon C, Lu ZX, Magliano DJ, Dunstan DW, Shaw JE, Zimmet PZ et al. Serum 25-
hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results
from a national, population-based prospective study (the Australian Diabetes, Obesity
and Lifestyle study). Diabetes Care 2011; 34(5): 1133-1138.

[154] Kayaniyil S, Retnakaran R, Harris SB, Vieth R, Knight JA, Gerstein HC et al.
Prospective associations of vitamin D with beta-cell function and glycemia: the
PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study.
Diabetes 2011; 60(11): 2947-2953.
[155] Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review.
Eur J Clin Nutr 2011; 65(9): 1005-1015.

Table 1: Summary of recent prospective, randomized intervention studies showing the effect of different kinds of protein on blood glucose
homeostasis.
Source Study Overview Summary of Results Conclusions

Acheson et al. Aim: Metabolic responses to 4 isocaloric meals, of which 3 Parameters: Conclusions:
AJCN 2011 [17] provided 50% of the energy as whey, casein, or soy protein; - AUC energy expenditure Casein and soy protein revealed
the 4th was a high-carbohydrate meal over 330 min was 10 kcal their reduction of glycemia by
Subjects: 23 sedentary, lean, healthy men and women with whey protein vs an insulin- independent effect;
Age: men: 31 6.4 y; women: 35 5.2 y soy protein or casein, and whey protein increased insulin
Body mass: men: 73.5 5.9 kg; women: 62.2 2.9 kg 34, 24 and 24 kcal , secretion.
Study Design: respectively, vs
- Double-blind, placebo controlled, randomized trial carbohydrates.
- Identical meals the day before the acute test - Thermic effect was with
Intervention: all proteins but highest
Test meal consisting of a) 0.81g/kg body mass (BM) whey with whey protein vs.
protein, isocaloric carbohydrates.
b) 0.81g/kg BM casein, - Protein oxidation was not
c) 0.81g/kg BM soy protein or different between protein
d) respective calories as carbohydrates sources.
Length of each study: 330 min - Fat oxidation was after
Acute tests: NA ingestion of all protein
Parameters tested: sources
- Energy expenditure - Glycemia IAUC was
- Thermic effect with all protein sources
- Substrate utilization - Insulinemia IAUC was
- Fasting and postprandial glycemia and insulinemia after whey protein vs
casein. No difference with
soy protein or isocaloric
carbohydrates.
Potential Mechanisms: NA

Pal, S. et al. Aim: Compare the effect of whey and casein consumption Parameters: Conclusions:
Br J Nutr 2010 on lipids, insulin, glucose, and body composition in - Whey protein caused in Whey protein may have
[18] overweight/obese individuals TAG, TC, LDL potential as an added
Subjects: included: 89 male or female volunteers - No effect on plasma component in diets aiming at
Age: 18 65 y glucose reducing progression of the
BMI: 25 40 kg/m2 - 11% insulin metabolic syndrome
Study Design: concentration, insulin
- randomized, parallel design, 3 groups sensitivity
- weighed food intake records at baseline and every 2
weeks for 2 weekdays
Intervention: Potential Mechanisms:
group 1: 2 * 27 g/d whey protein isolate; - in insulinogenic amino
group 2: 2 * 27 g/d sodium caseinate; acids
group 3: 2 * 27 g/d glucose - Bioactive peptides in
Length of each study: 12 weeks whey or formed during
Acute tests: NA digestion
Parameters tested:
- Body composition
- Lipids (TAG, NEFA, TC, HDL, LDL, apo B)
- Plasma glucose, plasma insulin
Pal, S & Ellis, Aim: Effect of different protein sources, namely whey, tuna, Parameters: Conclusions:
V., Br J Nutr turkey and egg meals, on insulin release - plasma glucose at min Whey protein suppressed
2010 [16] Subjects: Selected: 30, completed: 22 subjects, healthy men 30 with whey protein appetite more than other kinds
Age (completers): 22.9 1.5 y - AUC glucose with whey of protein do, and resulted in
BMI: 22.6 0.8 kg/m2 protein vs. egg and turkey lower energy intake together
Study Design: - highest AUC for plasma with an insulinotropic effect.
- Randomized, single-blind, crossover design insulin concentration with
- Food diary 3 days before each intervention whey protein (102%
- Standard meal the night before intervention above egg protein, 57%
Intervention: above turkey protein, and
- Liquid test meal of tuna, turkey, whey, or egg 36% above tuna protein)
albumin - AUC VAS with whey
- Meals consisted of equal amounts of protein, fat, protein intake
SAFAs, MUFAs, PUFAs, and carbohydrates
Length of each study: 240 min
Acute tests: Liquid meal tests Potential Mechanisms:
Parameters tested: Increase in insulin secretion
- Plasma glucose
- Plasma insulin
- Satiety by visual analog scale (VAS)
Breen, L. et al. Aim: Investigate mechanisms modifying glucose Parameters: Conclusions:
PloS ONE, 2011 homeostasis and insulin sensitivity after resistive exercise - Glucose: Even a single bout of resistance
[21] plus whey protein Fasting: ns exercise activated the insulin-
Subjects: AUC OGTT : 173% in EX independent transfer of glucose
- 24 healthy, untrained males (< 2 training sessions per and EX+PRO vs. CON into cells. However, the
week of < 60 min of resistance or endurance - Insulin: increased insulin secretion
exercise) Fasting: ns caused by a concomitant acute
- 3 groups, n=8 each (CON: resting control; EX: AUC OGTT : 25% in application of whey protein did
exercise only; EX+PRO: exercise plus protein) EX+PRO vs. CON and not exacerbate the glucose-
- Age: CON: 223 y; EX: 203 y; EX+PRO: 226 y 8% in EX vs. CON lowering effect. The latter,
- Body mass: CON: 77.06.3 kg; EX: 79.814.5 kg; - Insulin sensitivity: however, might also be
EX+PRO: 75.613.1 kg HOMA-IR: ns attributed to the small sample
Study Design: Matsuda ISI: 10-11% in size per group.
- Randomized, parallel design EX and EX+PRO vs.
- Standardized, provided diet for 48-h test period, CON
before 3-day food diary - Phosphorylation:
Intervention: EX & EX+PRO Absolute
EX: 8 sets of 10 single-bout, bilateral repetitions on a leg- level of AS160/TBC1D4
extension machine at 75% of 1-repetition maximum (day 1 vs CON after OGTT
+ 2)
EX+PRO: 8 sets of 10 bilateral repetitions on a leg- Potential Mechanisms:
extension machine at 75% of 1-repetition maximum (day 1 Reduction of blood glucose levels
+ 2) + 25 g whey protein (day 2) by increase in GLUT4
Length of each study: 2 days translocation to cell surface via

Acute tests: OGTT the pathway involving the
Parameters tested: GTPase, Akt substrate
- Plasma glucose, plasma insulin (AS160/TBC1D4) following a
- Insulin sensitivity (HOMA-IR, Matsuda ISI) single bout resistance exercise.
- Endogenous glucose production
- Glucose disposal rate
- Muscle glycogen
- Protein phosphorylation
Lan-Pidhainy X. Aim: Investigate whether the fasting serum insulin Parameters: Conclusions:
et al. AJCN concentration has an impact on metabolic responses after Protein : Glucos- lowering effect of
2010 [20] protein and fat intake 30 g of whey protein protein (and fat) is not blunted
Subjects: 25 nondiabetic subjects, men and women - AUC glucose (100%) by insulin sensitivity.
- 3 groups: low fasting serum insulin (FSI): < 40 and AUC insulin, AUC The ability of fat and protein to
pmol/L; medium FSI: 40 pmol/L FSI 70 GLP-1 in all groups lower glucose responses is not
pmol/L); high FSI: >70 pmol/L - HIE in low and medium influenced by the degree of
- Age: low FSI: 27 3 y; medium FSI: 26 2 y; high FSI group insulin sensitivity
FSI: 38 2 y
- BMI: low FSI: 24 1.1 kg/m2; medium FSI: 27 1.5 Potential Mechanisms:
kg/m2; high FSI: 31 1.0 kg/m2 - Protein might be more
effective in delaying
Study Design: gastric emptying
- Randomized crossover design - Reduced liver insulin
- Intervention: clearance by whey protein
- 9 test drinks, not isocaloric: (low and medium FSI)
- 50 g anhydrous glucose - Whey protein inhibits
- 250 ml water small intestine dipeptidyl
- 0, 5, or 30 g of fat (canola oil) peptidase IV activity
- 0, 5, or 30 g of whey protein according to animal
studies.
Length of each study:
11 separate mornings, each 120 min
Acute tests: 3 OGTTs
Parameters tested:
- Serum glucose
- Insulin
- C-peptide
- GLP-1
- Insulin sensitivity rate (ISR)
- Hepatic insulin extraction (HIE)
Jonker J.T. et al. Aim: Examine the effect of 6 and 12 g of casein hydolysate Parameters: Conclusions: A minimum
Eur J Intern on postprandial hyperglycemia - Glucose: 12 g: glucose amount of casein is mandatory
Med 2011 [19] Subjects: 13 type 2 diabetes mellitus (T2DM) patients, 8 over time to activate glucose lowering
men and 5 women - Insulin: 12 g: 26% peak mechanisms.
- Treatment: stable medication with only biguanide for value; 12 g: over time
minimum of 3 months, refrained from biguanide 2 vs. control
days before intervention - C-peptide: 6 g: peak
- Age: 58 1 y value vs. control
- BMI: 27.9 0.9 kg/m2
- Fasting blood glucose: 8.9 0.4 mmol/L Potential Mechanisms:
Study Design: Randomized, placebo-controlled, double- Only an amount of at least 12 g of
blind casein hydrolysate added to
Standardized meal the evening before the study carbohydrates may affect insulin
Intervention: secretion finally by activation of
- Control: 50 carbohydrates Ca2+ channels and exocytosis of
- Examination 1: 50 carbohydrates + 6 g casein insulin
hydrolysate
- Examination 2: 50 carbohydrates + 12 g casein
hydrolysate
Length of each study: 1 study day for 1 intervention
Acute tests: Ingestion of the protein/carbohydrate drink
Parameters tested:
- Serum glucose
- Insulin

- C-peptide
- AUC glucose, AUC insulin, AUC peptide
- Matsuda insulin sensitivity index (ISI)
- Cederholm index

Weickert et al. Aim: High isoenergetic protein and cereal fiber intake may Parameters: Conclusions:
AJCN 2011 [27] improve glycemic control - Insulin sensitivity : A very high protein diet. i.e.
Subjects: after 6 weeks: 25-30% of energy intake
- 111 group-matched overweight subjects with HCF group: induces insulin resistance.
features of the metabolic syndrome (84 completers) HP group:
- no changes in body weight, physical activity level Mix group: -
- no intake of drugs affecting insulin sensitivity after 18 weeks:
- Age: 24 - 70 y no difference between HP
- BMI: >25 kg/m2 and HCF group
- Weight circumference: >80 cm in females; >94 cm - Endogenous glucose
in males production:
Study Design: randomized, controlled, parallel group after 6 and 18 weeks
Intervention: HP group:
- Continuation of respective diets HCF- and Mix group: -
- 4 study groups:
- isoenergetic high protein intake (HP)
- high cereal fiber intake (HCF)
- moderate increases in both protein and cereal fiber
- control group (Mix)
- During initial 6 weeks: isoenergetic period with
intense dietary advice
- During remaining 12 weeks: Continuation of
respective diet
- Provision with tailored dietary supplements
Length of each study: 18 weeks
Acute tests: n/a
Parameters tested: day 0, after 6 and 18 weeks
- Body composition
- Lipid content in liver
- Insulin sensitivity (euglycemic hyperinsulinemic
clamp
- Hepatic insulin sensitivity
- Blood glucose
- Insulin
- Adiponectin
- Leptin
- Plasminogen activator inhibitor-1
- Interleukin 10
- C-reactive protein
Larsen et al. Aim: Parameters: Conclusions: High protein diet
Diabetologia Subjects: 99 participants with T2DM - Body weight: in both is not superior to a high
2011 [28] - Treatment: stable medication with only biguanide for groups, no effect of diet carbohydrate diet for managing
minimum of 3 months, refrained from biguanide 2 composition T2DM.
days before intervention - Waist circumference: in
- Age: 30 - 75 y both groups, no effect of
2
- BMI: 27 - 40 kg/m diet composition
- HbA1c levels: 6.5 10% - HbA1c: in both groups,
Study Design: Randomized controlled trial no effect of diet
Intervention: 2 groups: composition
- High carbohydrate intake (HC): carbohydrates: 55% - Total- , LDL- , HDL-
of energy; protein: 15% of energy intake cholesterol,
- High protein intake (HP): 30% of energy intake; triacylglycerol: in both
carbohydrates: 40% of energy; protein: groups, no effect of diet
Length of each study: 12 month composition
Acute tests: n/a -
Parameters tested:
- Body weight
- Waist circumference
- HbA1c
- Lipids
- eGFR
- Urinary albumin
- Urinary calcium

Table 2: Summary of recent prospective, randomized intervention studies showing the effect of vitamin D supplementation on blood glucose
homeostasis
Van Hurst et al. Br J Aim: Effect of improved vitamin D status Parameters: Conclusions: Vitamin D
Nutr 2010 [92] on markers of metabolic syndrome, Changes in vitamin D group supplementation increased
primarily insulin resistance (IR), in South baseline to end: insulin sensitivity in insulin-
Asian women who were insulin resistant Homa2%S: about 12 % resistant Asian women.
(HOMA-IR 1.93) and vitamin D deficient HOMA2-IR: about 12% However, a significant change
(serum 25-hydroxyvitamin D < 50 nmol/L). FSI: about 15% is detectable only if 25-
Subjects: 81 women completed the study; 2 hydroxyvitmin D concentrations
groups (vitamin D supplementation; Significant improvement because of of 80 nmol/L are reached.
placebo) vitamin D supplementation
Age: (between groups):
Vitamin D group: 41.8 10.1 y HOMA2%S
Placebo group: 41.5 9.1 y HOMA2-IR
Body mass index: FSI
Vitamin D group: 27.5 5.0 y hs-CRP
Placebo group: 27.4 3.7 y Potential Mechanisms:
Study Design: Placebo-controlled, A potential mechanism might lie in
randomized, double-blind, parallel design the regulation of the insulin
trial signaling cascade. In vitro treatment
Intervention: 4000 IU/D vitamin D with 1,25-dihydroxyvitamin D
Length of each study: 6 months resulted in increased transcription of
Acute tests: N/A the insulin receptor gene, together
Parameters tested: with improved insulin-dependent
Fasting serum glucose (FSG) glucose transport. Vitamin D
Fasting serum insulin (FSI) supplementation might thereby
High sensitivity C-reactive protein (hs- increase 1,25-dihydroxyvitamin D in
CRP) tissue and induce the mentioned
C-peptide effect.
Insulin sensitivity (HOMA2%S)

-cell function (HOMA2%B)
Mitri et al. AJCN 2011 Aim: Vitamin D and/or calcium Parameters: Conclusions: Vitamin D
[91] supplementation improves pancreatic -cell After adjustment (for age, BMI, supplementation was associated
function, insulin sensitivity, and glucose baseline disposition index, race, with improved pancreatic -cell
tolerance in adults at high risk of T2DM time of study entrance): function in subjects at high risk
Subjects: 92 subjects (male and female) - Insulin (mU/L) (6239) for T2DM
enrolled; 88 completed the 16-week with vitamin D and without
evaluation; 4 groups of 22 to 24 subjects (-3637)
Age: 57 2 y -Disposition index by 26%
Body mass: (+300130) for vitamin D and by
Group 1: Vitamin D + calcium: 93 2 kg 14% (-126127) for no vitamin D
Group 2: Vitamin D, no calcium: 94 3 kg - HbA1c: only a trend for
Group 3: No Vitamin D + calcium: 94 3 decrease with vitamin D
kg supplementation (p=0.081)
Group 4: No Vitamin D, no calcium: 92 3
kg
Study Design: 2-by-2 factorial, double-
masked, placebo-controlled, randomized
trial
Intervention:
Group 1: 2000 IU/d vitamin D + 800 mg/d
calcium
calcium
calcium
calcium
Length of each study: 16 weeks of
supplementation
Acute tests: OGTT
Parameters tested:
Fasting plasma glucose (FPG) and 2 h

after glucose load (2h PG)
HbA1c
Insulin
Insulin sensitivity index (Si)
Acute insulin response to glucose (AIRg)
Disposition index (AIRg x Si)
Harris et al. Diabetes, Aim: Effects of 4000 IU/d vitamin D 3 on Parameters: Vitamin D supplementation
Obesity and Metabolism glycemia and measures of insulin secretion Insulin secretion rate: more than 5 over 12 weeks led to increased
2012 [93] and sensitivity, in overweight and obese times greater in the vitamin D insulin secretion and decreased
African Americans with pre- or early group insulin sensitivity. The latter
diabetes C-peptide: about 15 times higher result may have occurred
Subjects: 89 African-American completers concentration in vitamin D group because of the more pronounced
(male and female); 2 groups MISI: decrease in vitamin D and increase in insulin sensitivity in
Age: increase in placebo group the placebo group (+12 %). The
Vitamin D group: 56.3 duration of 12 weeks might be
12.3 y too short to also affect insulin
Placebo group: 57.0 10.4 y sensitivity, as suggested by van
Body mass: Hurst et al [105].
Vitamin D group: 91.1 12.8 kg
Placebo group: 92.8 14.7 kg
Study Design: randomized, placebo-

controlled, parallel group trial
Intervention: 4000 IU/d vitamin D 3
Length of each study: 12 weeks of
supplementation
Acute tests: OGTT
Parameters tested:
Fasting plasma glucose (FPG) and
30,60,90,120 min after glucose load
Fasting insulin and 30,60,90,120 min after
glucose load

Fasting C-peptide and 30,60,90,120 min
after glucose load
HbA1c
Matsuda insulin sensitivity index (MISI)
Disposition index
HOMA-IR

Table 3: Summary of recent prospective, randomized intervention studies showing the effect of vitamin K supplementation on blood glucose
homeostasis
Choi H.J. et al, Diabetes Aim: Vitamin K2 supplementation and Parameters: Conclusions:
Care 2011 [114] consequent modulation of S i : 50% with vitamin K2 group Supplementation of high
undercarboxylated osteocalcin and its DI: 51% in vitamin K2 group amounts (30 mg/d) of vitamin
effects on -cell function and/or insulin (+2.7% in control group) K2 can increase insulin
sensitivity ucOC: 56% in vitamin K2 group sensitivity in healthy young
Subjects:42 healthy, young male volunteers; cOC: 67% in vitamin K2 group men.
33 completers
Age: 29 y Potential Mechanisms:
Vitamin K2 group: 24.0 31.0 y Modulation of adipokines or
Control group: 25.5 31.5 y inflammatory pathways by cOC or
Body mass index: vitamin K. As an alternative cOC
2
Vitamin K2 group: 22.9 26.8 kg/m might directly regulate glucose
Placebo group: 21.9 27.0 kg/m2 uptake by skeletal muscle or adipose
Study Design: placebo-controlled, parallel tissue.
group, intervention trial
Intervention: 30 mg vitamin K2/d
Length of each study: 4 weeks
Acute tests: Frequently sampled intravenous
glucose tolerance test (FSIGTT) before and
after treatment
Parameters tested:
- Insulin sensitivity index (S i )
- Acute insulin response to glucose (AIRg)
- Disposition index (DI)
- C-reactive protein (CRP)
- Undercarboxylated osteocalcin (ucOC)
- Carboxylated osteocalcin (cOC)
Yoshida M. et al., Aim: Assessment of 36 months of vitamin K Parameters: Conclusions:
Diabetes Care 2008 supplementation on insulin resistance - Plasma insulin: about 5%
[115] Subjects: 355 nondiabetic elderly men and only in older men
women enrolled; 289 volunteers evaluated supplemented with vit K
Study Design: randomized, double-blind, - HOMA-IR: about 6% only
controlled trial in older men supplemented
Age: with Vit K
Men: Vitamin K group: 68.9 5.5 y; Potential Mechanisms:
Placebo group: 69.7 6.2 y
Women: Vitamin K group: 67.3 5.5 y;
Body mass index:
Men: Vitamin K group: 28.2 4.7 kg/m2;
placebo group: 27.0 3.5 kg/m2
Women: Vitamin K group: 28.1 5.8
kg/m2; Placebo group: 26.8 4.9 kg/m2
Intervention: 500 g vitamin K1/d
Length of each study: 36 months
Acute tests: NA
Parameters tested:
- Fasting plasma glucose
- Fasting plasma insulin
- Plasma phylloquinone
- Serum total and undercarboxylated
osteocalcin
- HOMA-IR
Bullo M et al., AJCN Aim: Assessment of cross-sectional and Fasting plasma glucose
2012 [98] longitudinal associations between total and - Fasting plasma insulin
undercarboxylated osteocalcin - HOMA-IR
concentrations and measures of insulin - Serum total and undercarboxylated
resistance in elderly subjects at high osteocalcin
cardiovascular disease risk
Subjects: 79 elderly men (55 80 years)
with several cardiovascular disease risk

factors
Study Design: parallel-group, randomized,
controlled trial; subgroup of the
PREDIMED-trial randomly selected from 1
PREDIMED center. PREDIMED consists
of 3 interventions
Age:
Men: Vitamin K group: 68.9 5.5 y;
Body mass index: 25 kg/m 2

Women: Vitamin K group: 28.1 5.8
kg/m2; Placebo group: 26.8 4.9 kg/m2
Intervention: VOO diet, MeDiet with mixed
nuts, low-fat diet (control)
Length of each study: 24 months
Acute tests: NA
Parameters tested:
- Fasting plasma glucose
- Fasting plasma insulin
- HOMA-IR
- Serum total and undercarboxylated
osteocalcin

Nutrient Effect On Glucose Homeostasis

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Nutrient Effect On Glucose Homeostasis

Transféré par

Droits d'auteur :

Formats disponibles

Nutrients other than carbohydrates: their effects on

glucose homeostasis in humans

Martina Heer1, Sarah Egert2

Short title: Glucose homeostasis affected by non-carbohydrates

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

that is, single or complex carbohydrates, available or unavailable carbohydrates, or foods

pancreas or affecting insulin resistance in the periphery.

This article is protected by copyright. All rights reserved.

is based on evidence showing an effect of these nutrients on blood glucose regulation in

Phytochemicals such as polyphenols, phytosterols and caffeine were excluded because of

pharmacological doses. Additionally, for those substances the bioavailability is not

sufficiently characterized and a cause-and-effect relationship has rarely been shown in

conditions. In some cases, however, we also refer to meta-analyses or systematic reviews

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

2.2 Dietary fat and fatty acids

This article is protected by copyright. All rights reserved.

2.2.1 Importance of fatty acid composition

This article is protected by copyright. All rights reserved.

Isomeric fatty acids

In recent years, CLA isomers (especially trans10cis12 and cis9trans11 in different

This article is protected by copyright. All rights reserved.

2.2.2 Marine and plant n-3 polyunsaturated fatty acids

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

According to these findings, an insufficient 25-hydroxyvitamin D concentration might affect

This article is protected by copyright. All rights reserved.

2.4 Minerals and trace elements

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

A significant association of high plasma aldosterone concentration with insulin resistance

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

With respect to 25-hydroxyvitamin D levels there is increasing evidence, in particular from

This article is protected by copyright. All rights reserved.

Although we are convinced of the impact of several non-carbohydrates on glucose

We are grateful to J. Krauhs for editorial review.

This article is protected by copyright. All rights reserved.

[1] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes:

diabetes in youth. Diabetes Care 1999; 22(2): 345-354.

[6] Nilsson A, Granfeldt Y, Ostman E, Preston T, Bjorck I. Effects of GI and content of

indigestible carbohydrates of cereal-based evening meals on glucose tolerance at a

subsequent standardised breakfast. Eur J Clin Nutr 2006; 60(9): 1092-1099.

glycemic-index foods eaten at dinner improve subsequent breakfast glycemic

response. Am J Clin Nutr 1988; 48(4): 1041-1047.

This article is protected by copyright. All rights reserved.

Nutr 2008; 62(2): 279-285.

Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin

Nutr 1981; 34(3): 362-366.

effects of a low-glycemic-index diet. Am J Clin Nutr 1987; 46(6): 968-975.

1982; 35(6): 1339-1346.

acute impact of ingestion of breads of varying composition on blood glucose, insulin

This article is protected by copyright. All rights reserved.

energy intake in lean men. Br J Nutr 2010; 104(8): 1241-1248.

[17] Acheson KJ, Blondel-Lubrano A, Oguey-Araymon S, Beaumont M, Emady-Azar S,

Ammon-Zufferey C et al. Protein choices targeting thermogenesis and metabolism.

Am J Clin Nutr 2011; 93(3): 525-534.

Effects of low doses of casein hydrolysate on post-challenge glucose and insulin

levels. Eur J Intern Med 2011; 22(3): 245-248.