DYSFUNCTION OF THE ENDOCRINE PANCREAS: DIABETES

MELLITUS
Diabetes mellitus is not a single disease but a group of clini- cally heterogeneous
disorders that have glucose intolerance in common. It encompasses many causally
unrelated diseases and includes many different etiologies of disturbed glucose
tolerance. The term diabetes mellitus is used to describe a syn- drome characterized
by chronic hyperglycemia and other dis- turbances of carbohydrate, fat, and protein
metabolism. The American Diabetes Association classifies four categories of diabetes
mellitus (Table 21-5):

1. Type 1 (absolute insulin deficiency) 


2. Type 2 (insulin resistance with an insulin secretory 
 deficit) 


3. Other specific types 


4. Gestational diabetes 


Types 1 and 2 diabetes are the most common and are dis-

cussed in greatest detail in this text.
 The criteria for the diagnosis of diabetes include
symp-

toms, elevated fasting plasma glucose (FPG) concentration, and/or abnormal oral
glucose tolerance test (OGTT)98 (Box 21-1). Two conditions associated with a high
risk for diabetes, impaired fasting glucose (IFG) and impaired glucose toler- ance
(IGT), are considered prediabetes.98

A normal fasting glucose is less than 100 mg/dl. IFG is de- fined as a fasting glucose
greater than or equal to 100 mg/dl

but less than 126 mg/dl. Glucose tolerance is normal if the 2-hour postload glucose
level is less than 140 mg/dl. IGT is de- fined as a 2-hour postload glucose level greater
than or equal to 140 but less than 200 mg/dl. IGT results from reduced sup- pression
of hepatic glucose output and reduced pancreatic islet cell function.

Any abnormality of glucose tolerance has potentially se- rious consequences.

Numerous epidemiologic studies have shown an increased risk of cardiovascular
disease and prema- ture death in individuals with glucose intolerance. In addi- tion,
individuals with abnormal glucose tolerance have a 3% to 7% yearly risk of
developing overt diabetes. In compari- son, a healthy individual’s lifetime risk of
acquiring diabetes is around 7% to 10%.

Types of Diabetes Mellitus

Type 1 Diabetes Mellitus

Diabetes mellitus is the most common pediatric chronic dis- ease and affects 0.17% of
U.S. children.99 The common form of type 1 diabetes mellitus is the result of an
autoimmune- mediated specific loss of beta cells in the pancreatic islets. The
incidence of the condition is increasing in some areas, with other areas showing no
change in incidence.99 Table 21-6 summarizes the epidemiology of diabetes mellitus.

Type 1 diabetes mellitus is thought to be the result of a genetic-environmental

interaction. Between 10% and 13% of individuals with newly diagnosed type 1
diabetes have a first-degree relative (parent or sibling) with type 1 diabetes. Diagnosis
has a seasonal distribution, with more cases report- ed during autumn and winter in
the northern hemisphere. Diagnosis is rare during the first 9 months of life and peaks
at 12 years of age.

PATHOPHYSIOLOGY Two distinct types of type 1 diabetes have been

identified: autoimmune and nonim- mune. In autoimmune-mediated diabetes mellitus,
environ- mental-genetic factors are thought to trigger cell-mediated destruction of
pancreatic beta cells. Autoimmune type 1 dia- betes is called type 1A. Nonimmune
type 1 diabetes is far less common than immune. It occurs secondary to other diseases,
such as pancreatitis, or to a more fulminant disorder termed idiopathic (type 1B)
diabetes. Type 1B diabetes occurs mostly in people of Asian or African descent and
affected individuals have varying degrees of insulin deficiency.100

Genetic Susceptibility

The exact nature of genetic susceptibility to type 1A diabe- tes is not clearly
understood. The strongest association is with MHC (histocompatibility leukocyte
antigen [HLA]) class II alleles HLA-DQ and HLA-DR).100-102 The HLA-DR marker is
associated with other autoimmune disorders, such as Graves, Hashimoto, and Addison
diseases.101 The risk of develop- ing type 1 diabetes increases 5 to 8 times when one
of those specific markers is present. When the individual is heteroge- neous for HLA-
DR3 and HLA-DR4, the risk is 20 to 40 times higher than that of the general
population. Specific human antigens also are thought to decrease the risk of
developing type 1 diabetes. For example, HLA-DR2 is associated with an

unusually low risk. Current theories of causation hold that islet cell destruction occurs
predominantly in genetically sus- ceptible people.

Environmental Factors

Environmental factors are thought to have a significant contribution to the

development of type 1 diabetes mellitus. Some types of viral infections have been
implicated with au- toimmune damage to beta cells, including congenital rubella,
cytomegaloviruses, mumps, and Epstein-Barr virus.102,103 Bo- vine serum albumin, a
major constituent of cow’s milk, may be involved in triggering beta cell
autoantibodies.102 Stress may advance development of type 1 diabetes mellitus by
stimu- lating secretion of counterregulatory hormones and affecting immune
responses (see Chapter 10). Specific environmental

factors linked to type 1 diabetes mellitus are presented in Box 21-2.

Immunologically Mediated Destruction
of Beta Cells
Type 1 diabetes mellitus is a

slowly progressive autoim-

mune T cell–mediated disease that occurs in genetically susceptible individuals

(Figure 21-13 and see Chapter 8). Environmental mechanisms are thought to play a
role in trig- gering an autoimmune response to beta cells. The destruction of beta cells
progresses through the following stages:

1. Lymphocyte and macrophage infiltration of the islets re- sulting in inflammation

(insulinitis) and islet beta cell death. Autoantigens are expressed on the surface of
pancreatic islet cells and circulate in the bloodstream and lymphatics. Circulating
autoan- tigens are ingested by antigen-presenting cells that ac- tivate CD4+ T helper
lymphocytes.100,104 The activated T helper lymphocytes secrete interleukin 2 (IL-2)
that activates beta cell autoantigen-specific T cytotoxic lym- phocytes, causing them
to proliferate and attack many more islet cells through secretion of toxic perforins and
granzymes.104,105 The T helper lymphocytes also secrete interferon that activates
macrophages and stimulates the release of inflammatory cytokines (including IL-1
and tumor necrosis factor [TNF]), which cause further B-cell destruction and
apoptosis.100,104,106

2. Production of autoantibodies against islet cells, insulin, glutamic acid

decarboxylase (GAD), and other cyto- plasmic proteins. T helper lymphocytes also
produce IL-4, which stimulates B lymphocytes to proliferate and

produce antibodies (see Figure 21-13). Islet cell autoan- tibodies (ICAs) precede
evidence of beta cell deficiency and can be found in the serum years before symptoms
occur.100,102,106,107 Antiglutamic acid decarboxylase (an- tiGAD65) antibodies (an
enzyme in beta cells that is in- volved in glucagon synthesis) are more persistent
which makes them clinically useful in differentiating the etiol- ogy of diabetes in a
given individual.100 Autoantibodies against insulin (insulin autoantibodies [IAAs])
also have been noted. It is likely that IAAs may form during the process of active islet
cell and beta cell destruction.

Another mechanism being explored in the pathogenesis of type 1 diabetes is a relative

inactivity of T regulatory cells. These T lymphocytes normally serve to inhibit the
immune response. Mutations affecting T regulatory cells have been found in a rare
form of diabetes called neonatal diabetes, lead- ing investigators to hypothesize about
a role for T regulatory cell dysfunction in type 1A diabetes.101,108

Over time these immune mechanisms lead to a decrease in beta cell mass and insulin
production. C-peptide, a compo- nent of proinsulin cleaved during insulin synthesis,
declines. C-peptide may play a protective role in preventing beta cell destruction;
therefore, decreasing amounts of this important peptide may accelerate the decline in
beta cells.109 C-peptide deficiency also has been implicated in the glomerular and neu-
ronal complications of diabetes.110-113 There may be further effects on beta cell decline
as the individual ages. For exam- ple, the “accelerator hypothesis” suggests that
increased body weight and associated proinflammatory state are contributors to
worsening hyperglycemia in type 1 and type 2 diabetes.114

Hyperglycemia, Glucagon, and Hyperketonemia

Before hyperglycemia occurs, 80% to 90% of the function of the insulin-secreting

beta cells in the islet of Langerhans must be lost. Beta cell abnormalities are present
long before the acute clinical onset of type 1 diabetes.

A disequilibrium of hormones produced by the islets of Langerhans occurs in diabetes

mellitus. Normally the para- crine action of insulin suppresses secretion of glucagon.
Al- pha and beta cell functions are abnormal, and a lack of insulin and a relative
excess of glucagon (produced by alpha cells) exist in type 1 diabetes. The ratio of
insulin to glucagon in the portal vein controls hepatic glucose and fat metabolism.
Con- siderable data have documented that high levels of glucagon relative to insulin
levels contribute to the generation of hyper- glycemia and hyperketonemia. Relative
hyperglucagonemia occurs in every form of diabetes mellitus. Thus the full meta-
bolic syndrome seen in diabetes is caused by both hormones,

a finding that ultimately may provide an entirely new thera- peutic approach to its
management.

Insulin normally stimulates lipogenesis and inhibits lipoly- sis, thus preventing fat
catabolism. With insulin deficiency, lypolysis is enhanced and there is an increase in
the amount of nonesterified fatty acids delivered to the liver. The con- sequence is
increased glyconeogenesis contributing to hy- perglycemia and production of ketone
bodies (acetoacetate, hydroxybutyrate, and acetone) by the mitochondria of the liver at
a rate that exceeds peripheral use. Accumulation of ketone bodies causes a drop in pH
and triggers the buffering system associated with metabolic acidosis. Diabetic ketoaci-
dosis (DKA), caused by increased levels of circulating ketones in the absence of the
antilipolytic effect of insulin, may occur (p. 755).

CLINICAL MANIFESTATIONS Historically, type 1 diabetes mellitus has

been thought to have an abrupt onset. More recently, however, prospective studies
show a distinc- tive natural history involving a long preclinical period with gradual
destruction of beta cells, eventually leading to insulin deficiency and hyperglycemia.
Generally, this latent period is longer in older individuals and often results in
misclassifica- tion of an older type 1 individual as having type 2 diabetes.

Type 1 diabetes mellitus affects the metabolism of fat, pro- tein, and carbohydrates.
Glucose accumulates in the blood and appears in the urine as the renal threshold for
glucose is exceeded, producing an osmotic diuresis and symptoms of polyuria and
thirst. Wide fluctuations in blood glucose levels occur. In addition, protein and fat
breakdown occur because of the lack of insulin, resulting in weight loss (Table 21-7).

EVALUATION AND TREATMENT The diagnosis of diabetes is not

difficult when the symptoms of polydip- sia, polyuria, polyphagia, weight loss, and
hyperglycemia are present in fasting and postprandial states. Nearly half of chil- dren
ages 4 years and younger and nearly one quarter of those between the ages of 5 and 15
with type 1 diabetes are first di- agnosed when they present with the signs and
symptoms of DKA.100 Acidosis causes a compensatory increase in the re- spiratory
rate and depth known as Kussmaul respirations. Ac- etone (a ketone body) is blown
off, giving the breath a sweet or fruity odor.

If the diagnosis is equivocal, based on FPG, then an OGTT may be needed. In

nonpregnant women, an OGTT con- sists of the administration of a 75-g oral glucose
load after a 10-hour fast followed by measurement of plasma glucose 2 hours later.
Another mechanism that can be used to identify the plasma glucose concentration
over time is the measurement of glycosylated hemoglobin or, more pre- cisely,
hemoglobin A1c (HgbA1c). In the normal 120-day life span of a red blood cell,
glucose molecules join hemoglobin, forming glycosylated hemoglobin. In individuals
with persis- tent hyperglycemia, increases in the quantities of three glyco- sylated
hemoglobins (A1a, A1b, and A1c) are noted. A buildup of glycosylated hemoglobin
within the red cell reflects the average level of glucose to which the cell has been
exposed during its life cycle (approximately 120 days). HgbA1c can

a finding that ultimately may provide an entirely new thera- peutic approach to its
management.

Insulin normally stimulates lipogenesis and inhibits lipoly- sis, thus preventing fat
catabolism. With insulin deficiency, lypolysis is enhanced and there is an increase in
the amount of nonesterified fatty acids delivered to the liver. The con- sequence is
increased glyconeogenesis contributing to hy- perglycemia and production of ketone
bodies (acetoacetate, hydroxybutyrate, and acetone) by the mitochondria of the liver at
a rate that exceeds peripheral use. Accumulation of ketone bodies causes a drop in pH
and triggers the buffering system associated with metabolic acidosis. Diabetic ketoaci-
dosis (DKA), caused by increased levels of circulating ketones in the absence of the
antilipolytic effect of insulin, may occur (p. 755).

CLINICAL MANIFESTATIONS Historically, type 1 diabetes mellitus has

been thought to have an abrupt onset. More recently, however, prospective studies
show a distinc- tive natural history involving a long preclinical period with gradual
destruction of beta cells, eventually leading to insulin deficiency and hyperglycemia.
Generally, this latent period is longer in older individuals and often results in
misclassifica- tion of an older type 1 individual as having type 2 diabetes.

Type 1 diabetes mellitus affects the metabolism of fat, pro- tein, and carbohydrates.
Glucose accumulates in the blood and appears in the urine as the renal threshold for
glucose is exceeded, producing an osmotic diuresis and symptoms of polyuria and
thirst. Wide fluctuations in blood glucose levels occur. In addition, protein and fat
breakdown occur because of the lack of insulin, resulting in weight loss (Table 21-7).

EVALUATION AND TREATMENT The diagnosis of diabetes is not

difficult when the symptoms of polydip- sia, polyuria, polyphagia, weight loss, and
hyperglycemia are present in fasting and postprandial states. Nearly half of chil- dren
ages 4 years and younger and nearly one quarter of those between the ages of 5 and 15
with type 1 diabetes are first di- agnosed when they present with the signs and
symptoms of DKA.100 Acidosis causes a compensatory increase in the re- spiratory
rate and depth known as Kussmaul respirations. Ac- etone (a ketone body) is blown
off, giving the breath a sweet or fruity odor.

If the diagnosis is equivocal, based on FPG, then an OGTT may be needed. In

nonpregnant women, an OGTT con- sists of the administration of a 75-g oral glucose
load after a 10-hour fast followed by measurement of plasma glucose 2 hours later.
Another mechanism that can be used to identify the plasma glucose concentration
over time is the measurement of glycosylated hemoglobin or, more pre- cisely,
hemoglobin A1c (HgbA1c). In the normal 120-day life span of a red blood cell,
glucose molecules join hemoglobin, forming glycosylated hemoglobin. In individuals
with persis- tent hyperglycemia, increases in the quantities of three glyco- sylated
hemoglobins (A1a, A1b, and A1c) are noted. A buildup of glycosylated hemoglobin
within the red cell reflects the average level of glucose to which the cell has been
exposed during its life cycle (approximately 120 days). HgbA1c can

those who received standard treatment. Intensively treated individuals who achieve
near-normal glucoses (HgbA1c less than 7%) can expect a 50% to 75% reduction in
the risk of developing or progression of retinopathy, neuropathy, and nephropathy
after 8 to 9 years.116 Although long-term com- plications were decreased in the tightly
controlled group, achieving near-normal glucose levels was accompanied by risks,
such as severe hypoglycemia and weight gain. How- ever, the benefits of tight glucose
control in the intensive- ly treated group continued to be evident for more than 20
years.100,117,118 Successful management requires individual planning according to type
of disease, age, and activity level. All individuals with type 1 diabetes require some
combina- tion of insulin, meal planning, exercise, and self-monitoring of blood
glucose.100,118,119 Several different types of insulin preparations are available, as well
as new technologies for more physiologic insulin delivery systems.120 Blood glucose
monitoring also is an essential part of management for which there are numerous
types of monitoring devices. Finally, islet cell and whole pancreas transplantation has
been successful in selected individuals (see What’s New? Islet Transplant and Type 1
Diabetes Mellitus). Individuals should be screened at least yearly for complications of
diabetes.

Type 2 Diabetes Mellitus

In the United States, type 2 diabetes mellitus affects 10.5% of those ages 45 to 64
years (up from 5.6% in 1985) and 18.4% of those ages 65 to 74 years (up from 10.2%
in 1985).99 The incidence of diabetes has doubled in all adult age groups in the past
two decades. Prevalence varies by ethnic group and gender. Although the increase in
overall prevalence of diabetes has increased the most in white men (116% increase
since 1980), the condition remains most common in black women with an overall
prevalence of 8.8% and a prevalence of 34% in those ages 65 to 74.99 There also is an
increased prevalence of type 2 diabetes in children, especially in Native Ameri- can
children ages 15 to 1999 and in obese children121-123 (see Table 21-6).

An environmental-genetic interaction appears to be re- sponsible for type 2 diabetes.

The most well-recognized risk factors are age, obesity, hypertension, physical
inactivity, and family history. The metabolic syndrome is a constellation of disorders
(central obesity, dyslipidemia, prehypertension, and a fasting blood glucose more than
or equal to 100 mg/dl) that together confer a high risk of developing type 2 diabetes
and associated cardiovascular complications (see What’s New? Metabolic Syndrome
and Diagnosis). Other novel risk factors being investigated include elevated C-
reactive protein, de- creased adiponectin, increased leptin, and increased IL-6.124 A
unique manifestation of insulin resistance in women of re- productive age is
polycystic ovary syndrome (PCOS), which is associated with a risk of diabetes seven
times the average risk for women without PCOS.

PATHOPHYSIOLOGY Many genes have been identi- fied that are associated
with type 2 diabetes, including those that code for beta cell mass, beta cell function
(ability to sense blood glucose levels, insulin synthesis, and insulin secretion),
proinsulin and insulin molecular structure, insulin receptors, hepatic synthesis of
glucose, glucagon synthesis, and cellular responsiveness to insulin stimulation.125-128
These genetic ab- normalities combined with environmental influences, such as
obesity, result in the basic pathophysiologic mechanisms of type 2 diabetes: insulin
resistance and decreased insulin secre- tion by beta cells (Figure 21-14). Both of these
mechanisms are essential to the development of type 2 diabetes. Although many
individuals with risk factors for type 2 diabetes (in- cluding obesity, metabolic
syndrome, and hypertension) are insulin resistant, only those individuals who are
genetically predisposed to beta cell dysfunction (and therefore a relative deficiency in
insulin) will develop type 2 diabetes.129-130

Insulin resistance is defined as a suboptimal response of insulin-sensitive tissues

(especially liver, muscle, and adi- pose tissue) to insulin. Several mechanisms are
involved in abnormalities of the insulin signaling pathway and contrib- ute to insulin
resistance. These include an abnormality of the insulin molecule, high amounts of
insulin antagonists, down-regulation of the insulin receptor, decreased or ab- normal
activation of postreceptor kinases, and alteration of glucose transporter (GLUT)
proteins.131 Obesity is present in 60% to 80% of those with type 2 diabetes and is a
major contributor to insulin resistance through several important mechanisms:

1. Adipokines are hormones produced in adipose tissue. A nuclear receptor, called

peroxisome proliferator- activated receptor gamma (PPARγ), is highly expressed in
adipose cells and is responsible for modulating the changes in adipokines, including
increased serum levels
of leptin (leptin resistance) and resistin and decreased levels of adiponectin.128,130-133
These changes are asso- ciated with decreased insulin sensitivity. Although the
specific mechanisms by which these adipokines alter insulin sensitivity are still being
explored, a group of insulin-sensitizing drugs, called the thiazolidinediones

that modulate PPARγ activity, have been used in the

treatment of type 2 diabetes for many years.
 2. Elevated serum free fatty acids
(FFAs) and intracellular deposits of triglycerides and cholesterol are also found in
obese individuals who have what has been termed “metabolic overload” (high caloric
and lipid intake). These changes interfere with intracellular insulin sig- naling and
thus decrease tissue responses to insulin. Increases in fatty acids also cause alterations
in insulin

secretion within the beta cell.131,133-135
 3. Inflammatorycytokines(TNF-α,IL-

6)arereleasedfrom

intra-abdominal adipocytes or adipocyte-associated mononuclear cells and induce

insulin resistance through a postreceptor mechanism.132,135-138

4. Obesity is correlated with hyperinsulinemia and de- creased insulin receptor

density.

Compensatory hyperinsulinemia prevents the clinical ap- pearance of diabetes for

many years. Eventually, however, beta cell dysfunction develops and leads to a
relative deficien- cy of insulin activity. The islet dysfunction may be caused by a
decrease in beta cell mass, abnormal function of the beta cells, or some combination.
A progressive decrease in the weight and number of beta cells occurs in type 2
diabetes, and several different mechanisms have been implicated. Beta cells are ex-
tremely sensitive to high levels of glucose and free fatty acids, and under these so-
called glucolipotoxic conditions, beta cells undergo apoptotic cell death.128,130,132,139
The adipokine leptin decreases insulin synthesis in the beta cell. A variety of inflam-
matory cytokines, including TNF-α and IL-1β, have also been shown to be toxic to
beta cells.128,130,132,140 Thus many of the obesity-related causes of insulin resistance
(elevated free fatty acids [FFA] hyperglycemia, adipokines, and inflammatory cy-
tokines) also promote programmed cell death in B cells. Beta cell “exhaustion” from
increased demand for insulin biosyn- thesis, associated with intracellular oxidative
stress and endo- plasmic reticulum dysfunction, also has been implicated in beta cell
apoptosis.132,141

Glucagon is a hormone produced by the alpha cells of the pancreas and acts primarily
in the liver to increase blood glucose by stimulating glycogenolysis and
gluconeogenesis. Glucagon acts as an antagonist to insulin. In healthy individu- als,
high glucose levels cause glucagon release to be inhibited. In type 2 diabetes,
pancreatic alpha cells are less responsive to glucose inhibition resulting in increased
glucagon secre- tion.142,143 These abnormally high levels of glucagon have long been
known to play a role in the increased hepatic pro- duction of glucose and resultant
hyperglycemia seen in type 2 diabetes.

Amylin is a hormone co-secreted with insulin by the beta cells. A deficiency of

amylin in type 1 and type 2 diabetes par- allels the reduction in insulin secretion.
Amylin inhibits glu- cagon secretion, and problems with glycemic control may be
related to altered glucagon control or assimilation of nutrients in relation to the deficit
of amylin. Drugs aimed at improv- ing amylin function are being studied.144 Amyloid
deposition in the pancreas resulting in islet cell destruction also may be related to
changes in amylin function.132,145,146 However, the role of amyloid accumulation in the
pathogenesis of type 2 diabetes is unclear.

The incretins are a class of peptides released from the gastrointestinal tract in
response to food intake that increase the sensitivity of beta cells to circulating glucose
levels, thus improving insulin responsiveness to meals. Glucagon-like peptide 1
(GLP-1) is cleaved from proglucagon in the in- testinal mucosa. Another incretin is
glucose-dependent insulinotropic polypeptide (GIP), which is synthesized in the
duodenum and jejunum. These incretins bind to receptors on beta cells and increase
the synthesis and secretion of insulin in response to glucose levels.147 They are then
inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV). Currently one GLP-1
agonist and one DPP-IV inhibitor are approved for use in the United States and others
are being evaluated for the treatment of type 2 diabetes147-150 (see What’s New?
Incretin Hormones for Diabetes Mellitus Therapy).

Ghrelin is a peptide produced in the stomach and pan- creatic islets that stimulates
GH receptors. Decreased levels of circulating ghrelin have been associated with
insulin resis- tance and increased fasting insulin levels; its use as a potential treatment
for type 2 diabetes is being investigated.151

CLINICAL MANIFESTATIONS Clinical manifes- tations of type 2 diabetes

are often nonspecific. Although younger people may develop the condition, it
generally affects those older than 30 years. The individual often is overweight,
dyslipidemic, hyperinsulinemic, and hypertensive. The indi- vidual with type 2
diabetes may show some classic symptoms of diabetes, such as polyuria and
polydipsia, but more often will have nonspecific symptoms such as fatigue, pruritus,
re- current infections, visual changes, or symptoms of neuropa- thy (paresthesias or
weakness) (Table 21-8).

EVALUATION AND TREATMENT The diagnostic criteria for type 2

diabetes are similar to that of type 1 (see Box 21-1, p. 747). As with type 1 diabetes,
the goal of treat- ment for individuals with type 2 diabetes is the restoration of

near-euglycemia (a normal blood glucose level) and correc- tion of related metabolic
disorders.

Dietary measures, including restriction of the total caloric intake, are of primary
importance in both the prevention and treatment of type 2 diabetes.119,121,152 As the
obese individual loses weight, the body’s resistance to insulin often diminish- es so
that weight loss results in improved glucose tolerance. Nonobese individuals with type
2 diabetes should consume calories consistent with their ideal weight and pattern of
ac- tivity. The emphasis of medical nutrition therapy (MNT) in type 2 diabetes
mellitus should be focused on achieving glu- cose, lipid, and blood pressure goals (see
Nutrition & Disease: Medical Nutrition Therapy [MNT] for Prevention and Treat-
ment of Diabetes).

Exercise is an important aspect of prevention and treat- ment of type 2 diabetes.119,121

Exercise reduces postpran- dial blood glucose levels, diminishes insulin requirements,
lowers triglyceride and cholesterol levels, and increases the level of high-density
lipoprotein (HDL) cholesterol. In ad- dition, exercise is a valuable adjunct to weight
loss for the overweight individual. Hypoglycemia may result, however, when the
exercising individual receives sulfonylurea or in- sulin therapy.

In those individuals with morbid obesity unresponsive to diet and exercise

interventions, bariatric surgery may be in- dicated. Recent studies suggest that gastric
bypass surgery is associated with a decrease in the incidence of type 2 diabetes and
marked improvements in glycemic control in those with established diabetes.152-155

Although the first approach to treatment of the indi- vidual with type 2 diabetes is
appropriate meal planning and exercise, medications are usually needed for optimal
management. Sulfonylurea, biguanide, thiazolidinedio- nes, DPP-IV inhibitors, and α-
glucosidase inhibitors are useful in treating some individuals with type 2 diabetes
(Table 21-9). Use of oral hypoglycemic agents requires a pancreas capable of
secreting insulin. Sulfonylureas acutely augment beta cell insulin secretion.
Biguanides (metformin) inhibit hepatic glucose production and in- crease the
sensitivity of peripheral tissue to insulin. α-Glu- cosidase inhibitors decrease
postprandial hyperglycemia through delaying carbohydrate digestion and absorp- tion.
The thiazolidinedione class of insulin-sensitizing compounds activate a nuclear
receptor termed the peroxi- some proliferator-activated receptor (PPARγ), which in
turn regulates cellular carbohydrate and lipid metabolism. As discussed previously,
DPP-IV inhibitors increase GLP-1 lev- els that in turn help augment endogenous
insulin secretion. Insulin therapy may be needed in the later stages of type 2 diabetes
because of loss of beta cell function.156 There is some evidence that exogenous insulin
may help prevent further beta cell apoptosis.157 Because the pathogenesis of type 2
diabetes involves a combination of insulin resistance and a relative insulin deficiency,
it is common to combine therapeutic agents from different classes of oral agents in
order to achieve acceptable glycemic control.