C h a p t e r 3 3
Diabetes Mellitus and the Metabolic Syndrome
803
progressively decreased (by an average of approxi-
mately 4% per year), resulting in worsening hyperglyce-
mia even when the degree of insulin resistance remained
Stable.
17
Pathogenesis.
The pathogenesis of type 2 diabetes
involves genetic, epigenetic, behavioral, and environ-
mentally mediated factors. A positive family history
confers a twofold to fourfold increased risk for type 2
diabetes, and 15% to 25% of first-degree relatives of
persons with type 2 diabetes develop impaired glucose
tolerance or diabetes.
14
Despite the strong familial pre-
disposition, the genetics of type 2 diabetes is poorly
defined. This is probably because of the heterogeneous
nature of the disorder as well as the difficulty in sort-
ing out the contribution of acquired factors affecting
insulin action and glycemic control.
15
However, so
far more than 60 genetic loci associated with type 2
diabetes have been identified. Unfortunately, when all
these loci are added together they still only account
for approximately 10% of the apparent genetic causes
(i.e., heritability) of type 2 diabetes. Regardless, most
cases of type 2 diabetes develop in obese individuals
who have a genetic predisposition to beta–cell dysfunc-
tion and failure.
Among the acquired factors that predispose to type
2 diabetes, obesity and physical inactivity are para-
mount.
14,15,18
As the body mass index (BMI) increases,
the risk of developing diabetes increases, and approxi-
mately 90% of persons with type 2 diabetes are over-
weight. Obesity has profound effects on sensitivity of
tissues to insulin, and as a consequence, on glucose
homeostasis. Not only the absolute amount of body
fat, but also its distribution has an effect on insu-
lin resistance. People with upper body (or central)
obesity who have increased stores of visceral (intra-
abdominal) fat are at greater risk for developing type
2 diabetes and metabolic disturbances than persons
with lower body (or peripheral) obesity (see Chapter
10). Waist circumference and waist–hip ratio, which
are both surrogate measures of central obesity, have
been shown to correlate well with insulin resistance.
Thus, measures such as diet and exercise that reduce
visceral adiposity are important in the management
of type 2 diabetes. Other acquired factors include the
patient’s microbiome (i.e., the bacteria that live in or
on us) related metabolic factors and inflammatory
effects.
Role of AdiposeTissue inType 2 Diabetes.
Although
many details of the relationship between adipose tis-
sue, insulin resistance, and increased glucose produc-
tion in obese people with type 2 diabetes remain to
be elucidated, several pathways have been proposed.
Primary among these is the role of an increased con-
centration of free fatty acids (FFAs).
15,19
Visceral obe-
sity is accompanied by an increase in postprandial
FFA concentrations and subsequent triglyceride stor-
age, including in sites that do not normally store fat
such as the liver, skeletal muscle, heart, and pancreatic
beta cells.
20,21
This has several consequences. First,
excessive and chronic elevation of FFAs can directly
cause pancreatic beta cell dysfunction (lipotoxicity).
Second, at the level of the peripheral tissues, FFAs
inhibit glucose uptake and glycogen storage. Third, the
accumulation of FFAs and triglycerides reduces hepatic
insulin sensitivity, leading to increased hepatic glucose
production and hyperglycemia, especially in the fasting
state. In the liver, the uptake of FFAs from the por-
tal blood can lead to hepatic triglyceride accumulation
and nonalcoholic fatty liver disease (see Chapter 30).
In addition to the metabolic effects of visceral obe-
sity, adipocytes are the source of a number of impor-
tant factors (e.g., adiponectin, leptin, FFAs) involved in
a wide range of other processes, including glucose and
lipid metabolism, inflammation, and thrombosis.
15,20–23
In obesity and type 2 diabetes, there is a reduction
in the production of some factors that are normally
synthesized by adipocytes (i.e., adiponectin), whereas
there is an accelerated release of other factors such as
angiotensinogen, plasminogen activator inhibitor-1,
leptin, and proinflammatory cytokines (e.g., tumor
necrosis factor-
α
). Adiponectin, which is secreted by
adipocytes and circulates in the blood, is the only
known adipocyte-secreted factor that increases tissue
sensitivity to insulin.
23
It has been shown that decreased
levels of adiponectin coincide with insulin resistance in
persons with obesity and type 2 diabetes. In skeletal
muscle, adiponectin has been shown to decrease tissue
triglyceride content by increasing the use of fatty acids
as a fuel source. Adiponectin also appears to have
antidiabetes, anti-inflammatory, and antiatherogenic
effects.
Insulin Resistance and the Metabolic Syndrome.
There is increasing evidence to suggest that when people
with type 2 diabetes present predominantly with insulin
resistance, the diabetes may represent only one aspect of
a syndrome of metabolic disorders.
24
Hyperglycemia in
these people is frequently associated with intra-abdom-
inal obesity, high levels of plasma triglycerides and low
levels of high-density lipoproteins (HDLs), hyperten-
sion, systemic inflammation (as detected by C-reactive
protein [CRP] and other mediators), abnormal fibrino-
lysis, abnormal function of the vascular endothelium,
and macrovascular disease (coronary artery, cerebrovas-
cular, and peripheral arterial disease). This constellation
of abnormalities often is referred to as the
insulin resis-
tance syndrome, syndrome X,
or, the preferred term,
metabolic syndrome.
21
In clinical practice, the definition
of metabolic syndrome given in the Third Report of the
National Cholesterol Education Program (NCEP III) is
widely used
20
(Chart 33-1).
Other SpecificTypes of Diabetes
The category of other specific types of diabetes, for-
merly known as
secondary diabetes,
includes diabetes
that is associated with certain other conditions and syn-
dromes. Such diabetes can occur with pancreatic disease
