REVIEW ARTICLE

Intermittent fasting vs daily calorie restriction

for type 2 diabetes prevention: a review of
human findings

ADRIENNE R. BARNOSKY, KRISTIN K. HODDY, TERRY G. UNTERMAN, and KRISTA A. VARADY

CHICAGO, ILL

Intermittent fasting (IF) regimens have gained considerable popularity in recent

years, as some people find these diets easier to follow than traditional calorie restric-
tion (CR) approaches. IF involves restricting energy intake on 13 d/wk, and eating
freely on the nonrestriction days. Alternate day fasting (ADF) is a subclass of IF, which
consists of a fast day (75% energy restriction) alternating with a feed day (ad
libitum food consumption). Recent findings suggest that IF and ADF are equally as
effective as CR for weight loss and cardioprotection. What remains unclear, however,
is whether IF/ADF elicits comparable improvements in diabetes risk indicators, when
compared with CR. Accordingly, the goal of this review was to compare the effects of
IF and ADF with daily CR on body weight, fasting glucose, fasting insulin, and insulin
sensitivity in overweight and obese adults. Results reveal superior decreases in body
weight by CR vs IF/ADF regimens, yet comparable reductions in visceral fat mass,
fasting insulin, and insulin resistance. None of the interventions produced clinically
meaningful reductions in glucose concentrations. Taken together, these preliminary
findings show promise for the use of IF and ADF as alternatives to CR for weight loss
and type 2 diabetes risk reduction in overweight and obese populations, but more
research is required before solid conclusions can be reached. (Translational
Research 2014;-:110)

Abbreviations: ADF Alternate day fasting; BMI Body mass index; CR Calorie restriction;
HOMA-IR Homeostatic model assessment-insulin resistance; IF Intermittent fasting

INTRODUCTION

From the Division of Endocrinology, Department of Medicine,
University of Illinois at Chicago, Chicago, Ill; Department of
Kinesiology and Nutrition, University of Illinois at Chicago,
Chicago, Ill.
Submitted for publication January 15, 2014; revision submitted May
5, 2014; accepted for publication May 8, 2014.
Reprint requests: Krista A. Varady, Department of Kinesiology and
Nutrition, University of Illinois at Chicago, 1919 West Taylor Street,
Room 506F, Chicago, IL 60612; e-mail: varady@uic.edu.
1931-5244/$ - see front matter
2014 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.trsl.2014.05.013
A
t present, 35% of adults older than 20 years in
the United States have prediabetes.1 If no life-
style changes are made to improve health,
15%30% of these individuals will develop type 2 dia-
betes within 5 years.1 A key strategy to prevent the
progression of prediabetes to type 2 diabetes is weight
loss.2 Accumulating evidence suggests that even modest
weight loss (5%7% of initial weight) helps to improve
several diabetes risk parameters, including fasting
glucose, insulin, and insulin sensitivity.3,4
Daily calorie restriction (CR) regimens are still the
most common diet strategies implemented for weight
loss.5 CR regimens involve reducing energy intake

1

2 Barnosky et al
every day by 20%50% of needs.5 Although CR is
effective for weight loss in some individuals, many peo-
ple find this type of dieting difficult, as it requires vigi-
lant calorie counting on a daily basis.6 People also grow
frustrated with this diet, as they are never able to eat
freely throughout the day. In light of these issues with
CR, another approach termed intermittent fasting (IF)
has shown promise in achieving weight loss goals.7 IF
differs from CR, in that it only requires an individual
to restrict energy 13 d/wk, and allows for ad libitum
food consumption on the nonrestriction days.7 Alternate
day fasting (ADF) is a subclass of IF, which consists of a
fast day (75% energy restriction) alternating with
a feed day (ad libitum food consumption). Recent
reviews suggest that IF and ADF are equally as effective
as CR for weight loss cardioprotection.7,8 What has yet
to be elucidated, however, is whether IF and ADF elicit
comparable improvements in diabetes risk indicators,
when compared with CR. Accordingly, the goal of this
review was to compare the effects of IF and ADF with
daily CR on body weight, fasting glucose, fasting
insulin, and insulin sensitivity in overweight and
obese adults.
METHODS
We performed a systematic search in MEDLINE
PubMed using the following search strings: (1) inter-
mittent fasting and weight loss, (2) alternate day fast-
ing and weight or alternate day calorie restriction, physiological and metabolic effects was first introduced
(3) calorie restriction and weight loss and insulin,
(4) caloric restriction and weight loss and obesity,
and (5) calorie restriction and metabolic syndrome.
Two reviewers (A.B. and K.H.) separately screened
the abstracts for inclusion and exclusion. Full text arti-
cles were retrieved from all abstracts that were poten-
tially relevant and were reviewed independently by
the 2 researchers. The comprehensive literature search
revealed 108 articles under the umbrella category of
IF and 4945 articles in the category of CR. Articles
that were excluded if they did not meet the inclusion
criteria, were review articles, editorials, letters, com-
ments, or conferences proceedings. References of the
retrieved articles were also screened for additional
studies. Inclusion criteria were as follows: (1) random-
ized control trials and nonrandomized trials, (2) total
sample size $8 subjects, (3) primary endpoints of
body weight and one or more relevant diabetes risk
parameter, (4) average daily energy restriction ,50%
(to exclude very low calorie diets that result in muscle
wasting9), (5) trial duration between 3 and 24 weeks,
(6) male and female subjects, (7) age between 25 and
75 years, (8) body mass index (BMI) between 25 and
40 kg/m2, (9) nonsmokers (because of the effects of
Translational Research
- 2014
smoking on lipid metabolism),10 (10) sedentary or
moderately active individuals, and (11) articles pub-
lished after 2003. We chose 2003 as a cutoff date
because all the IF studies found were published within
this time frame, and we wanted to use the same time
frame for CR studies. Exclusion criteria were as fol-
lows: (1) cohort and observational studies; (2) trials
that combined CR/IF with supplements, pharmacologic
substances, or exercise; (3) diabetic; and (4) very active
individuals or athletes. Ten CR trials and 9 IF trials were
found that matched these criteria. None of the papers
retrieved implemented intention to treat analyses.
BODY WEIGHT AND VISCERAL FAT MASS
Obesity is a well-established risk factor for the devel-
opment of type 2 diabetes. Findings from the Nurses
Health Study demonstrate a 100-fold increase in diabetes
risk over 14 years in those with a BMI .35 kg/m2
compared with normal weight individuals.11 At least
one contributing factor to insulin resistance that occurs
in obesity is the decrease in insulin-mediated peripheral
glucose uptake.12 Weight loss results in substantial
reductions in insulin resistance, with every 1 kg lost asso-
ciated with a 16% reduction in estimated risk of devel-
oping diabetes.2
The distribution of excess fat mass also contributes
to the risk for metabolic derangements.13 In 1947, the
concept of regional fat distribution having different
by Vague.14 Over the subsequent decades, it has been
shown that visceral obesity has a stronger correlation
with a risk for the development of diabetes, hyperten-
sion, hyperlipidemia, hepatic steatosis, and coronary
artery disease compared with that of a gluteoemoral
fat distribution.13 The presence of visceral obesity has
also been shown to have a strong inverse relationship
with insulin sensitivity.13 Evaluation of glucose disposal
rates by euglycemic insulin clamps and visceral adipose
tissue by the computed tomography technique, illus-
trated an inverse association.15 Thus a higher visceral
fat content is correlated with lower insulin sensitivity.15
Weight loss has been shown to decrease both visceral fat
and improve markers of insulin sensitivity.16
IF: effects on body weight and visceral fat mass. Body
weight changes were assessed in 2 IF studies17,18 and 7
ADF studies19-25 (Table I). Findings from these trials
demonstrate 3%8% reductions in body weight after
324 weeks of treatment. Providing food to subjects on
the fast day appears to be a key factor in determining
greatest weight loss. For instance, the most pronounced
weight loss was seen in a study performed by Johnson
et al,21 where ADF subjects were provided with a
320380 kcal meal replacement shake on each fast day.
Table I. Intermittent fasting: effect on body weight and type 2 diabetes risk parameters

Volume -, Number -
Translational Research
Insulin
Average Fasting Fasting resistance/
Trial prescribed Body weight Body Visceral fat Lean mass Lean glucose insulin sensitivity
Reference Subjects length Intervention restriction/d (% change) weight (kg) (% change) (% change) mass (kg) (% change) (% change) (% change)

Intermittent fasting studies

Klempel et al17 n 5 54, F 8 wk 1.1 d/wk 100% CR, 1.40% 1.Y4%* 1.Y4* WC DXA 1.Y3%* 1.Y21%* HOMA-IR
48 6 2 y 6 d/wk 30% 2.40% 2.Y3%* 2.Y3* 1.Y7%* 1.Y1 2.Y2% 2.Y13% 1.Y23%*
Obese CR-liquid diet 2.Y5%* 2.0 2.Y12%
Prediabetic 2.1 d/wk 100% CR,
6 d/wk 30%
CR-food diet
Food provided
Harvie et al18 n 5 53, F 24 wk 1.2 d/wk 75% CR, 1.20% 1.Y7%* 1.Y6* WC BIA BIA 1.Y2% 1.Y29%* HOMA-IR
3045 y 5 d/wk ad libitum 1.Y6%* 1.Y3%* 1.Y1* 1.Y27%*
Overweight Food not provided
Obese
Alternate day fasting studies
Heilbronn et al19 n 5 16, MF 3 wk 1. Fast day: 100% 1.50% 1.Y3%* DXA DXA 1.Y1% 1.Y57%*
2353 y CR, feed day: 1.Y1%* 1.Y1*
Overweight ad libitum
Food not provided
Eshghinia and n 5 15, F 6 wk 1. Fast day: 70% CR, 1.35% 1.Y7%* 1.Y3 WC DXA DXA 1.Y6%
Mohammadzadeh20 34 6 6 y feed day: ad libitum 1.Y6%* 1.Y1% 1.Y2
Obese Food not provided
Johnson et al21 n 5 10, MF 8 wk 1. Fast day: 80% CR, 1.40% 1.Y8%* 1.Y9* 1.[6% 1.Y37%* HOMA-IR
Age NR feed day: ad libitum 1.Y33%*
Obese Food provided on the
fast day
Varady et al22 n 5 16, MF 8 wk 1. Fast day: 75% CR, 1.35% 1.Y6%* 1.Y6* WC BIA BIA 1.Y4%* 1.Y20%* HOMA-IR
46 6 2 y feed day: ad libitum 1.Y4%* 1.0% 1.0 1.Y19%*
Obese Food provided on the
Prediabetic fast day
Klempel et al23 n 5 32, F 8 wk 1. Fast day: 75% CR, 1.35% 1.Y5%* 1.Y4* WC DXA DXA 1.Y2%
42 6 2 y feed day: ad 2.35% 2.Y4%* 2.Y4* 1.Y7%* 1.[1% 1.[1
Obese libitum-HF 2.[1% 2.[1
2. Fast day: 75% CR,
feed day: ad
libitum-LF
Food provided on the
fast day

Barnosky et al
Bhutani et al24 n 5 32, MF 12 wk 1. Fast day: 75% CR, 1.35% 1.Y4% 1.Y3 WC BIA BIA 1.Y3% 1.Y11% HOMA-IR
43 6 3 y feed day: ad libitum 2.0% 2.0% 2.0 1.Y4% 1.Y1 1.Y2% 2.[3% 2.[1% 1.Y9%
Obese 2. Control: ad libitum 2.Y1% 2.0% 2.0% 2.[2%
fed every day
Food provided on the
fast day (week

3
14 only)
(Continued )
 Translational Research
4 Barnosky et al - 2014

After 8 weeks of treatment, subjects lost 8% of

Abbreviations: BIA, bioelectrical impedance analysis; CR, calorie restriction; DXA, dual-energy X-ray absorptiometry; F, female; HF, high-fat diet; HOMA-IR, homeostatic model of assessment for
restriction/d (% change) weight (kg) (% change) (% change) mass (kg) (% change) (% change) (% change)
resistance/

HOMA-IR
sensitivity

1.Y28%
2.[2%
Insulin body weight.21 Comparable decreases in body weight
(6%7%) were also noted in the other 8-week ADF
studies that provided food on the fast day.22,23,25
An exception to this rule is the ADF study by Bhutani
1.Y31%
2.[2%
Fasting
insulin

et al.24 In this 12-week trial, fast day food was

provided, but only a 4% weight loss was observed.24
This limited weight loss may be explained by the fact

Significantly different from the control group (P , 0.05). Prescribed daily restriction estimated assuming 0% restriction (ie, 100% intake) on the ad libitum feed days.
1.Y6%
glucose

that food was only provided for the first 4 weeks of the
Fasting

2.[1%

study,24 and not for the entire duration of trial. Another

factor that appears to impact degree of weight loss is
the number of fast days per week. Not surprisingly, a
2.0%
1.Y2
Lean

DXA

faster rate of weight loss was observed in the ADF

studies,19-25 which required subjects to fast 34 d/wk,
compared with the IF studies,17,18 which required
Visceral fat Lean mass

1.Y3%
2.Y1%

subjects to only fast 12 d/wk. On average, ADF

DXA

appears to produce a 0.75 kg weekly reduction in body

weight, whereas IF produces a 0.25 kg weekly weight
loss. As such, clinicians may want to recommend ADF
1.Y6%
2.Y1%

to their patients who are eager to lose weight more

WC

rapidly, and IF to patients who would prefer to lose

weight at a slower pace.
Visceral fat changes were assessed in 2 IF studies17,18
1. Y5
Body

2.Y1

and 5 ADF studies.20,22-25 Results reveal 4%7% re-

ductions in visceral fat after 624 weeks of treatment.
In most studies, the percentage of visceral fat loss
prescribed Body weight

1.Y7%
2.Y1%

closely paralleled the percentage of weight loss. For

example, in the ADF study by Varady et al,22 a 6%
decrease in visceral fat was observed corresponding to
7% weight loss. Bhutani et al24 had a similar study
insulin resistance; LF, low-fat diet; M, male; NR, not reported; WC, waist circumference.
Average

1.35%

design, however, only a 4% decrease in visceral fat was

2.0%

observed corresponding to a 4% weight loss. Similar

reductions in visceral fat were also demonstrated in
IF studies (3%7%),17,18 suggesting that IF and ADF
feed day: ad libitum
n 5 32, MF 12 wk 1. Fast day: 75% CR,

Food provided on the

2. Control: ad libitum

produce comparable decreases in this body composition

Intervention

*Post-treatment value significantly different from baseline (P , 0.05).

fed every day

parameter. It should be noted, however, that visceral fat

All data reported are for subjects who completed the entire trial.

was assessed indirectly in each of these trials by

fast day

measuring waist circumference. Thus, these studies are

limited, in that actual kilogram decreases in visceral fat
were not determined. Future studies of IF and ADF
length
Trial

should therefore strive to use more robust techniques,

such as magnetic resonance imaging, to measure actual
Overweight
Prediabetic

kilogram changes in visceral fat mass.

Normal wt
Subjects

47 6 4 y

CR: effects on body weight and visceral fat mass. Body

weight changes were assessed in 10 CR trials16,18,26-33
(Table II). Findings from these studies demonstrate
a 4%14% reduction in weight after 624 weeks of
Table I. (Continued )

treatment. The greatest weight loss was observed in

the trials with the largest average weekly caloric
Reference

restriction.16,27,33 In a study by Larsen-Meyer et al,33

Varady et al25

overweight participants were randomized into 1 of 3

groups: (1) 50% CR every day, (2) 25% CR every day,
or (3) a control group with ad libitum feeding every
day. After 24 weeks of treatment, participants in the

Table II. Daily CR: effect on body weight and type 2 diabetes risk parameters

Volume -, Number -
Translational Research
Insulin
Average Fasting Fasting resistance/
Trial prescribed Body weight Body Visceral fat Lean mass Lean glucose insulin sensitivity
Reference Subjects length Intervention restriction/d (% change) weight (kg) (% change) (% change) mass (kg) (% change) (% change) (% change)

Xydakis et al16 n 5 80, MF 6 wk 1.50% CR-high- 1.50% 1.Y7%* 1.Y18* WC 1.Y15%* 1.Y65%* HOMA-IR
47 6 1 y protein diet 1.Y8%* 1.Y70%*
Obese Food provided
Trussardi Fayh n 5 35, MF 6 wk 1.25% CR 1.25% 1.Y5%* 1.Y4* WC 1.Y3% 1.Y11%* HOMA-IR
et al26 30 6 6 y Food not provided 1.Y4%* 1.Y20%*
Obese
Prediabetic
Svendsen et al27 n 5 17, F 8 wk 1.50% CR-high- 1.50% 1.Y11%* WC 1.Y8%* 1.Y35%* HOMA-IR
25 6 3 y protein diet 1.Y22%* 1.Y32%*
Overweight Food not provided
Mollard et al28 n 5 40, MF 8 wk 1.25% CR-high- 1.25% 1.Y1% 1.Y1 WC 1.0% 1.[2% HOMA-IR
46 6 1 y fiber diet 1.Y2%* 1.[1%
Obese Food provided
Clifton et al29 n 5 62, F 12 wk 1.25% CR-LF diet 1.25% 1.Y11%* 1.Y10* 1.Y1%* 1.Y26%*
47 6 10 y 2.25% CR-high 2.25% 2.Y8%* 2.Y9* 2.Y2%* 2.Y41%*
Obese MUFA low-
Prediabetic protein diet
Food provided
De Luis et al30 n 5 40, MF 12 wk 1.25% CR-liquid diet 1.25% 1.Y8%* 1.Y8* WC BIA BIA 1.0% 1.Y24%* HOMA-IR
65 6 8 y 2.25% CR-food diet 2.25% 2.Y5%* 2.Y5* 1.Y5%* 1.Y1%* 1.Y1* 2.[1% 2.Y25% 1.Y25%*
Obese Food provided in the 2.Y4%* 2.Y3%* 2.Y1* 2.Y12%
liquid diet group
Agueda et al31 n 5 78, F 12 wk 1.25% CR every day 1.25% 1.Y9%* Y 8* WC DXA DXA 1.Y2%* 1.Y27%* HOMA-IR
37 6 7 y Food not provided 1.Y7%* 1.Y5%* 1.Y3* 1.Y30%*
Obese
Melanson et al32 n 5 157, MF 12 wk 1.30% CR-low 1.30% 1.Y5%* 1.Y4* 1.[1 1.[1% 1.Y16%* HOMA-IR
38 6 7 y energy density diet 2.30% 2.Y4%* 2.Y3* 2.Y1 2.[1% 2.Y8%* 1.Y17%*
Obese 2.30% CR-low 3.30% 3.Y4%* 3.Y4* 3.0 3.Y1% 3.Y12%* 2.Y7%*
Prediabetic glycemic index 3.Y17%*
diet
3.30% CR-portion
control diet
Food not provided
Larson-Meyer n 5 48, MF 24 wk 1.25% CR every day 1.25% 1.Y10% 1.Y8 CT DXA DXA 1.Y1% 1.Y29% OGTT-IS
et al33 2550 y 2.50% CR every day 2.50% 2.Y14% 2.Y11 1.Y28% 1.Y5% 1.Y3 2.[1% 2.Y15% 1.[27%*

Barnosky et al
Overweight until 15% body 3. No CR 3.0% 3.0 2.Y38% 2.6% 2.Y3 3.[2% 3.[2% 2.[52%*
weight lost 3.Y3% 3.0% 3.0 3.[11%
3. Control: ad libitum
fed every day
All food provided for
weeks 112 and

5
2224
(Continued )
 Translational Research
6 Barnosky et al - 2014

50% CR group had greater weight loss (14%), when

Abbreviations: BIA, bioelectrical impedance analysis; CR, calorie restriction; DXA, dual-energy x-ray absorptiometry; F, female; HOMA-IR, homeostasis model of assessment for insulin resistance; LF,
(% change) mass (kg) (% change) (% change) (% change)
resistance/

HOMA-IR
sensitivity

1.Y19%*
Insulin
compared with the 25% CR group (10% weight
loss).33 A faster rate of weight loss was also noted in
the other studies which implemented 50% CR16,27
when compared with the 25% CR trials.18,26,28-32 The
1.Y15%*
Fasting
insulin

background macronutrient composition of the CR

diets, however, did not seem to have any impact on
rate of weight loss. This is evidenced in the trial by
Melanson et al,32 which compared the effects of a 30%
glucose

1.Y2%
Fasting

CR-low energy density diet with that of a 30% CR-

low glycemic index diet. After 12 weeks of treatment,
both groups lost similar amounts of weight (4%5%)
despite differences in the background macronutrient
1.Y1*
Lean

profiles.32 It was also noted that the rate of weight loss

low-fat diet; M, male; MUFA, monounsaturated fatty acid; OGTT-IS, oral glucose tolerance test for insulin sensitivity; WC, waist circumference.

by CR is similar in overweight and obese individuals,

and males and females, when the same degree of CR
Lean mass

1.Y2%*

is applied. Similar amounts of weight loss were also

noted in older30 vs younger adult subjects.29 For
instance in the study by De Luis et al,30 elderly men
circumference

and women experienced comparable weight loss after

(% change)
Visceral fat

1.Y4%*

12 weeks of 25% CR, when compared with middle-

Waist

aged adults undergoing a similar intervention.29 Thus,

CR appears to be effective for weight loss independent
of BMI class, sex, and age.
Visceral fat changes were assessed in 8 CR
restriction/d (% change) weight (kg)

1.Y6*

studies.16,18,26-31,33 After 624 weeks of diet, 2%38%

Body

reductions in visceral fat mass were observed. Similar

to what was seen in IF studies, percentage of visceral
prescribed Body weight

fat loss generally paralleled the percentage of weight

1.Y5%*

loss. For example, the greatest decrease in visceral fat

(38%) was observed in the study by Larson-Meyer
et al,33 which implemented a 50% CR protocol for
24 weeks. This degree of visceral fat loss corresponded
Average

1.25%

to a 14% weight loss.33 Within the same study, a 28%

reduction in visceral fat was seen in the 25% CR group
*Post-treatment value significantly different from baseline (P , 0.05).

with a 10% weight loss.33 Moreover, Svendsen et al27

All data reported are for subjects who completed the entire trial.
24 wk 1.25% CR every day

showed a 22% decrease in visceral fat, corresponding

No food provided

to an 11% reduction in body weight. Taken together, it

Intervention

would appear as although greater degrees of energy

Significantly different from control group (P , 0.05).

restriction produce the most optimal changes in body

weight and visceral fat mass.
length
Trial

GLUCOSE AND INSULIN

Individuals are categorized as having prediabetes
when (1) fasting glucose falls between 100 and
Overweight
Subjects

n 5 54, F
3045 y

125 mg/dL, (2) plasma glucose falls between 140 and

Table II. (Continued )

Obese

199 mg/dL 2 after an oral glucose tolerance test, or

(3) hemoglobin A1c falls between 5.7% and 6.4%.34
Lifestyle modification, namely dietary changes and
Reference

Harvie et al18

exercise with the goal of weight loss, are commonly

used as the first line therapy. Randomized, controlled
trials have shown that with intensive dietary counseling
and increased physical activity, type 2 diabetes can be

Translational Research
Volume -, Number -
prevented in high-risk individuals with prediabetes.35,36
As expected, these studies have shown decreases in
fasting glucose levels and improvements in glucose
tolerance. The Finnish Diabetes Prevention Study
found a 58% reduction in the overall incidence of
diabetes in the intensive lifestyle group compared with
that of controls with similar benefit seen in other
studies.35-37
IF: effects on fasting glucose and insulin levels. Changes
in fasting glucose were assessed in 2 IF studies17,18 and
7 ADF studies19-25 (Table I). However, the present
discussion will be limited to studies that recruited
prediabetic individuals,17,22,25 as it may not be scien-
tifically valid to assess the effect of these diets on
glucose and insulin levels of normoglycemic subjects.
Results from these trials demonstrate consistent yet
minor decreases (3%6%) in fasting glucose after
812 weeks of treatment. The greatest decrease in
glucose was observed in the study by Varady et al.25 In
this trial,25 participants were randomized to an ADF
group (35% average daily CR) vs a control group (no
restriction). After 12 weeks of diet, a 6% reduction
in glucose concentrations was observed in the ADF
group relative to controls.25 Reductions in glucose
concentrations (3%4%) were also observed in the
8-week ADF study by Varady et al22 and the 8-week
IF study by Klempel et al.17 These less pronounced
decreases in glucose are most likely because of the
shorter intervention period imposed by these 2 studies,
that is 8 weeks17,22 vs the 12-week intervention imple-
mented by Varady et al.25
Fasting insulin levels were assessed in 2 IF studies17,18
and 5 ADF studies.19,21,22,24,25 However, as mentioned
previously, only studies that recruited prediabetic in-
dividuals will be discussed here.17,22,25 In these trials,
decreases in fasting insulin ranged from 20% to 31%
after 812 weeks of treatment.17,22,25 Similar reduc-
tions in fasting insulin were seen with ADF (20%)22
and IF (21%)17 after 8 weeks of diet. Remarkably, these
comparable decreases occurred despite the greater num-
ber of fasting days implemented by the ADF study (34
fast days)22 vs the IF study (1 fast day).17 However, it
should be noted that, overall, both interventions prescri-
bed the same level of energy restriction (35%40%).17,22
Thus, degree of restriction may be a stronger pre-
dictor of insulin lowering when compared with the
number of fasting days. The greatest decreases in
insulin concentrations (31%) were noted in the study
by Varady et al.25 These superior reductions are most
likely the result of the longer intervention period
(12 weeks) used by this trial.25
CR: effects on fasting glucose and insulin levels. Fasting
glucose levels were assessed in all the CR studies
reviewed here16,18,26-33 (Table II). Similar to IF and
Barnosky et al 7
ADF, we will limit our discussion for glucose to
those trials that recruited prediabetic subjects.26,29,32
Results from these studies indicate that 612 weeks
of 25%30% CR has virtually no effect on fasting
glucose concentrations.26,29,32 Moreover, modulating
the background nutrient composition of the diet (via a
high monounsaturated fat, low fat, or glycemic index
diet) also does not appear to impact fasting glucose
levels.29,32 It will be of interest in future trials to
examine whether improvements in glucose can be seen
with greater energy restriction or longer treatment
durations in this population group.
Fasting insulin levels were assessed in 10 CR
studies.16,18,26-33 However, our discussion will be
limited to those trials that recruited prediabetic subjects
only.26,29,32 Findings from these trials demonstrate
fairly consistent reductions in insulin levels, ranging
from 11% to 41% after 612 weeks of treatment.26,29,32
The most pronounced reductions in insulin (41%) were
noted in the study by Clifton et al,29 which implemented
a 25% CR-high monounsaturated fat-low-protein diet
intervention for 12 weeks. In a separate arm of this
study,29 less pronounced reductions in insulin (26%)
were observed in response to a 25% CR-low-fat diet.
Thus, a background diet that is high monounsaturated
fat may produce more optimal changes in insulin
compared with a diet that is low in fat. The degree to
which insulin is lowered may also be related to amount
of weight loss. For instance, the study by Clifton et al29
observed the greatest degree of weight loss (8%11%)
when compared with the studies by Trussardi Fayh
et al26 (5%) and Melanson et al32 (4%5%). Thus, there
may be a dose-response relationship between weight loss
and insulin lowering by CR in prediabetic individuals.
INSULIN SENSITIVITY
Insulin resistance is seen in virtually all patients
with type 2 diabetes and occurs early in the disease,
before overt diabetes is diagnosed. Both a decrease in
insulin sensitivity and insulin deficiency are thought to
contribute to type 2 diabetes. Interventions directed
at reducing body weight have shown promise for
improving insulin sensitivity, and have also been shown
to delay or prevent onset of type 2 diabetes.38
IF: effects on insulin sensitivity. Changes in insulin
sensitivity were assessed in 2 IF studies17,18 and 4
ADF studies21,22,24,25 (Table I). Results from these
trials demonstrate consistent improvements in insulin
sensitivity after 324 weeks of treatment in normo-
glycemic and prediabetic subjects. The primary
method of measuring insulin sensitivity was homeo-
static model assessment (HOMA-IR). In reviewing
these results, it would appear as although the greatest

8 Barnosky et al
improvements in insulin sensitivity occurred with
the highest amount of weight loss. For instance, in the
ADF study by Johnson et al,21 subjects experienced
the greatest degree of weight loss (8%), which cor-
responded to the largest decline in HOMA-IR (33%).
In the ADF trial by Bhutani et al,24 body weight
decreased by 4% from baseline, which produced
moderate reductions in HOMA-IR (9%). Impressive
reductions in insulin resistance were also noted by IF.
For instance, 23% decreases in HOMA-IR were noted
after 8 weeks of fasting 1 d/wk with a liquid diet.17
Moreover, 27% decreases in HOMA-IR were obser-
ved after 24 weeks of fasting 2 d/wk.18 Weight loss in
these 2 IF trials was 4%17 and 7%,18 respectively.
Although reductions in body weight appear to be
an important factor in determining improvements in
insulin sensitivity, no relationship between visceral fat
mass and insulin sensitivity could be established from
the studies reviewed here. This is most likely because
of the small number of studies, and because visceral
fat mass was only measured indirectly via waist cir-
cumference. Implementing techniques that can quan-
tify actual kilogram decreases in visceral fat mass
(ie, magnetic resonance imaging), may help clarify the
relationship between abdominal fat reductions and
improvements in insulin sensitivity in future IF and
ADF trials.
CR: effects on insulin sensitivity. Modulations in insulin
sensitivity by CR were assessed in 9 studies16,18,26-28,30-33
(Table II). Substantial improvements in insulin sensitivity
after 624 weeks were noted in all but one CR study.28
The primary method for measuring insulin sensitivity
was HOMA-IR, with the exception of the study by
Larson-Meyer et al,33 which implemented an oral
glucose tolerance test. The most important factor in
determining improvement in insulin sensitivity appears
to be the degree of energy restriction imposed. For
instance, in the study by Xydakis et al,16 a 6-week 50%
CR-high-protein diet resulted in a 70% decrease in
HOMA-IR. Similarly, Svendsen et al27 demonstrated
a 32% decrease in insulin resistance after 8 weeks of a
high restriction regimen (50% CR combined with a
high-protein background diet). Findings from 25% CR
studies also demonstrated reductions in insulin resis-
tance,18,26,30,31 although these effects were less pro-
nounced than the 50% CR studies. For example, Harvie
et al18 implemented a 25% CR protocol in overweight
and obese subjects for 24 weeks, and a 15% decrease in
HOMA-IR was observed. Likewise, Trussardi Fayh
et al26 prescribed a 25% CR diet, and HOMA-IR
decreased by 20% from baseline. Although the higher
energy restriction diets (50% CR) seem to show a
greater decrease in HOMA-IR, sustainability of this
type of diet is likely to be challenging. This should be
Translational Research
- 2014
considered when prescribing CR protocols to patients in
a clinical setting. Unfortunately, none of these studies
included a follow-up period to investigate what happens
when the individual ceases the diet altogether. Whether
insulin resistance rebounds more quickly after stopping
a 50% CR protocol, vs a 25% protocol, warrants further
investigation, as this may help in determining which
level of energy restriction should be prescribed for
longer-term success.
SUMMARY OF FINDINGS: EFFECTIVENESS OF IF VS CR
FOR TYPE 2 DIABETES PREVENTION
Body weight and visceral fat mass. Findings from the
present review indicate that CR produces slightly supe-
rior weight loss when compared with IF/ADF after
similar durations of treatment. For instance, after
324 weeks of IF or ADF, 3%8% reductions in body
weight were observed. As for CR, 624 weeks of diet
produced reductions ranging from 4% to14%. Not sur-
prisingly, greater degrees of energy restriction and
longer treatment durations produced larger reductions
in body weight. IF, ADF, and CR appear to be effective
for reducing body weight in men and women, older and
younger adults, and prediabetic individuals. Similar
decreases in visceral fat mass were also noted by all 3
interventions, and the degree to which visceral fat
mass was reduced paralleled the degree of weight loss.
Glucose and insulin. The impact of IF, ADF, and
CR on fasting glucose concentrations in prediabetic
subjects was variable. Although IF and ADF studies
demonstrated minor decreases in glucose (3%6%
from baseline), CR studies general report no effect after
612 weeks of diet. Fasting insulin, on the other hand,
was highly responsive to all 3 interventions. In general,
insulin concentrations were reduced by 20%31% after
812 weeks of IF and ADF, and by 11%41% after
612 weeks of CR. Reductions in insulin concentrations
by IF, ADF, and CR appeared to be most strongly related
to the degree the of imposed restriction and amount of
weight loss.
Insulin sensitivity. Consistent improvements in insulin
sensitivity were noted by all 3 interventions after
324 weeks of treatment. These improvements occurred
in prediabetic subjects and subjects with normal fasting
glucose values. The degree to which insulin sensitivity
was improved appeared to be most strongly related
to the degree of energy restriction and amount of total
weight loss. This observation is supported by other
studies in this field.39,40 For instance, in a study by
Wing et al,39 subjects were randomized to either a
400 kcal/d group or a 1000 kcal/d group, with the goal
of losing 11% of baseline body weight in both groups.
Results reveal that those individuals in the 400 kcal/d
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group had lower fasting glucose and increased insulin
sensitivity when compared with the 1000 kcal/d group,
despite the same weight loss.39 Moreover, in an early
study by Henry et al,40 improvements in glycemic
control were noted within 3 days of starting a hypo-
caloric diet, suggesting that dietary restriction can
affect glycemia even before actual weight loss occurs.
Limitations. This review has a number of limitations.
Firstly, the protocols, interventions, and populations
between studies are quite heterogeneous. This heteroge-
neity makes it difficult to draw clear conclusions from
the data as a whole, and needs to be taken into consid-
eration when interpreting the present findings. Sec-
ondly, the number of studies that have been conducted
in the IF and ADF field are very limited. Thus, it is
not possible to make clinical recommendations as to
the efficacy of these dietary restriction protocols for
use by the general public. Thirdly, we were not able to
report weight loss as change in mass per week, because
most of these studies only reported baseline and post-
treatment body weight values. Including these data
would have offered an indication of trends in weight
loss, that is whether weight loss was linear or greater
at the beginning of the trial, which would have been
of value.
CONCLUSIONS
In sum, IF, ADF, and CR regimens appear to be effec-
tive for reducing body weight, although CR may result
in slightly greater weight loss. As for visceral fat mass,
and fasting insulin and insulin sensitivity, the effect of
IF, ADF, and CR on these diabetic risk parameters
appears comparable. Whether these regimens are effec-
tive for glucose lowering remains uncertain, and war-
rants further investigation. Although these preliminary
findings show promise for the use of IF and ADF as
alternatives to CR for weight loss and type 2 diabetes
risk reduction, clear conclusions cannot be drawn
because of the limited number of studies published in
this field. Much work remains to be done to understand
these diet strategies fully.
ACKNOWLEDGMENTS
This work was funded by grants from the National
Institutes of Health (NIDDK T32DK080674, NHLBI
1R01HL106228-01).
Conflict of interests: None.
REFERENCES
[1]. Diabetes Facts. National Center for Chronic Disease Prevention
and Health Promotion Division of Diabetes Translation. 2013.
[2]. Hamman RF, Wing RR, Edelstein SL, et al. Effect of weight loss
with lifestyle intervention on risk of diabetes. Diabetes Care
2006;29:21027.
Barnosky et al 9
[3]. Andersen CJ, Fernandez ML. Dietary strategies to reduce
metabolic syndrome. Rev Endocr Metab Disord 2013;14:
24154.
[4]. Wycherley TP, Moran LJ, Clifton PM, Noakes M,
Brinkworth GD. Effects of energy-restricted high-protein,
low-fat compared with standard-protein, low-fat diets: a meta-
analysis of randomized controlled trials. Am J Clin Nutr 2012;
96:128198.
[5]. Omodei D, Fontana L. Calorie restriction and prevention of age-
associated chronic disease. FEBS Lett 2011;585:153742.
[6]. Das SK, Gilhooly CH, Golden JK, et al. Long-term effects of 2
energy-restricted diets differing in glycemic load on dietary
adherence, body composition, and metabolism in CALERIE: a
1-y randomized controlled trial. Am J Clin Nutr 2007;85:
102330.
[7]. Varady KA. Intermittent versus daily calorie restriction: which
diet regimen is more effective for weight loss? Obes Rev
2011;12:e593601.
[8]. Varady KA, Hellerstein MK. Alternate-day fasting and chronic
disease prevention: a review of human and animal trials. Am J
Clin Nutr 2007;86:713.
[9]. Bryner RW, Ullrich IH, Sauers J, et al. Effects of resistance vs.
aerobic training combined with an 800 calorie liquid diet on lean
body mass and resting metabolic rate. J Am Coll Nutr 1999;18:
11521.
[10]. Kabagambe EK, Ordovas JM, Tsai MY, et al. Smoking, inflam-
matory patterns and postprandial hypertriglyceridemia. Athero-
sclerosis 2009;203:6339.
[11]. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain
as a risk factor for clinical diabetes mellitus in women. Ann
Intern Med 1995;122:4816.
[12]. Ye J. Mechanisms of insulin resistance in obesity. Front Med
2013;7:1424.
[13]. Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implica-
tion of depot differences in adipose tissue for obesity complica-
tions. Mol Aspects Med 2013;34:111.
[14]. Vague J. La differenciation sexuelle, facteur determinant des
formes de lobesity. Presse Med 1947;30:33940.
[15]. Banerji MA, Lebowitz J, Chaiken RL, Gordon D, Kral JG,
Lebovitz HE. Relationship of visceral adipose tissue and
glucose disposal is independent of sex in black NIDDM sub-
jects. Am J Physiol 1997;273:E42532.
[16]. Xydakis AM, Case CC, Jones PH, et al. Adiponectin, inflamma-
tion, and the expression of the metabolic syndrome in obese in-
dividuals: the impact of rapid weight loss through caloric
restriction. J Clin Endocrinol Metab 2004;89:2697703.
[17]. Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF,
Varady KA. Intermittent fasting combined with calorie restric-
tion is effective for weight loss and cardio-protection in obese
women. Nutr J 2012;11:98.
[18]. Harvie MN, Pegington M, Mattson MP, et al. The effects of
intermittent or continuous energy restriction on weight loss
and metabolic disease risk markers: a randomized trial in young
overweight women. Int J Obes (Lond) 2011;35:71427.
[19]. Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E.
Alternate-day fasting in nonobese subjects: effects on body
weight, body composition, and energy metabolism. Am J Clin
Nutr 2005;81:6973.
[20]. Eshghinia S, Mohammadzadeh F. The effects of modified
alternate-day fasting diet on weight loss and CAD risk factors
in overweight and obese women. J Diabetes Metab Disord
2013;12:4.
[21]. Johnson JB, Summer W, Cutler RG, et al. Alternate day calorie
restriction improves clinical findings and reduces markers of

10 Barnosky et al
oxidative stress and inflammation in overweight adults with
moderate asthma. Free Radic Biol Med 2007;42:66574.
[22]. Varady KA, Bhutani S, Church EC, Klempel MC. Short-term
modified alternate-day fasting: a novel dietary strategy for
weight loss and cardioprotection in obese adults. Am J Clin
Nutr 2009;90:113843.
[23]. Klempel MC, Kroeger CM, Varady KA. Alternate day fasting
(ADF) with a high-fat diet produces similar weight loss and
cardio-protection as ADF with a low-fat diet. Metabolism
2013;62:13743.
[24]. Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF,
Varady KA. Alternate day fasting and endurance exercise
combine to reduce body weight and favorably alter plasma lipids
in obese humans. Obesity (Silver Spring) 2013;21:13709.
[25]. Varady KA, Bhutani S, Klempel MC, et al. Alternate day fasting
for weight loss in normal weight and overweight subjects: a ran-
domized controlled trial. Nutr J 2013;12:146.
[26]. Trussardi Fayh AP, Lopes AL, Fernandes PR, Reischak-
Oliveira A, Friedman R. Impact of weight loss with or without
exercise on abdominal fat and insulin resistance in obese indi-
viduals: a randomised clinical trial. Br J Nutr 2013;110:48692.
[27]. Svendsen PF, Jensen FK, Holst JJ, Haugaard SB, Nilas L,
Madsbad S. The effect of a very low calorie diet on insulin sensi-
tivity, beta cell function, insulin clearance, incretin hormone
secretion, androgen levels and body composition in obese young
women. Scand J Clin Lab Invest 2012;72:4109.
[28]. Mollard RC, Luhovyy BL, Panahi S, Nunez M, Hanley A,
Anderson GH. Regular consumption of pulses for 8 weeks re-
duces metabolic syndrome risk factors in overweight and obese
adults. Br J Nutr 2012;108(Suppl 1):S11122.
[29]. Clifton PM, Noakes M, Keogh JB. Very low-fat (12%) and high
monounsaturated fat (35%) diets do not differentially affect
abdominal fat loss in overweight, nondiabetic women. J Nutr
2004;134:17415.
[30]. de Luis DA, Izaola O, Garcia Alonso M, Aller R, Cabezas G, de
la Fuente B. Effect of a commercial hypocaloric diet in weight
loss and post surgical morbidities in obese patients with chronic
arthropathy, a randomized clinical trial. Eur Rev Med Pharma-
col Sci 2012;16:181420.
Translational Research
- 2014
[31]. Agueda M, Lasa A, Simon E, Ares R, Larrarte E, Labayen I.
Association of circulating visfatin concentrations with insulin
resistance and low-grade inflammation after dietary energy
restriction in Spanish obese non-diabetic women: role of body
composition changes. Nutr Metab Cardiovasc Dis 2012;22:
20814.
[32]. Melanson KJ, Summers A, Nguyen V, et al. Body composition,
dietary composition, and components of metabolic syndrome in
overweight and obese adults after a 12-week trial on dietary
treatments focused on portion control, energy density, or glyce-
mic index. Nutr J 2012;11:57.
[33]. Larson-Meyer DE, Heilbronn LK, Redman LM, et al. Effect of
calorie restriction with or without exercise on insulin sensitivity,
beta-cell function, fat cell size, and ectopic lipid in overweight
subjects. Diabetes Care 2006;29:133744.
[34]. Association AD. Diagnosing diabetes and learning about pre-
diabetes. Diabetes basics. Centers for Disease Control Publi-
cation 2013.
[35]. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in pre-
venting NIDDM in people with impaired glucose tolerance. The
Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:
53744.
[36]. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type
2 diabetes mellitus by changes in lifestyle among subjects with
impaired glucose tolerance. N Engl J Med 2001;344:134350.
[37]. Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-
dependent) diabetes mellitus by diet and physical exercise. The
6-year Malmo feasibility study. Diabetologia 1991;34:8918.
[38]. Wilding JP. The importance of weight management in type 2
diabetes mellitus. Int J Clin Pract 2014;68:68291.
[39]. Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R,
Bergman RN. Caloric restriction per se is a significant factor
in improvements in glycemic control and insulin sensitivity dur-
ing weight loss in obese NIDDM patients. Diabetes Care 1994;
17:306.
[40]. Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of inten-
sive caloric restriction and isocaloric refeeding in noninsulin-
dependent diabetes mellitus. J Clin Endocrinol Metab 1985;
61:91725.