excess adipose tissue overproduces a messenger that causes
downregulation of insulin-responsive glucose transporters
or in some other way blocks insulin’s actions. Another
hypothesis is that excess fat deposition outside adipose
tissue (for example, in muscle) causes a decrease in insulin
Most people with T2DM not only have insulin
resistance but also have a defect in the ability of their beta
cells to secrete insulin in response to a rise in plasma glucose
concentration. In other words, although insulin resistance
is the primary factor inducing hyperglycemia in T2DM, an
as-yet-unidentiﬁ ed defect in beta cell function prevents these
cells from responding maximally to the hyperglycemia.
The most effective therapy for obese persons with
T2DM is weight reduction because obesity is a major cause of
insulin resistance. An exercise program is also very important
because insulin sensitivity is increased by frequent endurance-
type exercise, independent of changes in body weight. This
occurs, at least in part, because exercise training causes a
substantial increase in the total number of plasma membrane
glucose transporters in skeletal muscles.
If plasma glucose concentration is not adequately
controlled by a program of weight reduction, exercise, and
dietary modiﬁ cation (speciﬁ cally, low-fat diets), then the
person may be given orally active drugs that lower plasma
glucose concentration by a variety of mechanisms. The
lower plasma glucose by acting on the beta
cells to stimulate insulin secretion. Other drugs increase
insulin sensitivity or decrease hepatic gluconeogenesis.
Finally, in some cases the use of high doses of insulin itself is
Unfortunately, people with either form of diabetes
mellitus tend to develop a variety of chronic abnormalities,
including atherosclerosis, hypertension, kidney failure,
small-vessel and nerve disease, susceptibility to infection,
and blindness. Elevated plasma glucose contributes to most
of these abnormalities either by causing the intracellular
accumulation of certain glucose metabolites that exert
harmful effects on cells when present in high concentrations,
or by linking glucose to proteins, thereby altering their
This discussion of diabetes has focused on insulin, but
it is now clear that the hormones that elevate plasma glucose
concentration may contribute to the severity of the disease.
Glucagon is quite important in this regard. Most diabetics,
particularly those with T1DM, have inappropriately high
plasma glucagon concentrations, which contribute to the
metabolic abnormalities typical of diabetes. One reason these
individuals have high plasma levels of glucagon is that insulin
normally inhibits glucagon secretion, and the low insulin of
T1DM releases glucagon secretion from this inhibition.
Finally, as we have seen, all the systems that increase
plasma glucose concentration are activated during stress,
which explains why stress worsens diabetic symptoms.
Because diabetic ketoacidosis itself constitutes a severe
stress, a positive feedback cycle is triggered: a lack of insulin
induces ketoacidosis, which elicits activation of the glucose-
counterregulatory systems, which worsens the ketoacidosis.
Hypoglycemia is broadly deﬁ ned as an abnormally low plasma
glucose concentration. Plasma glucose concentration can
decrease to very low values, usually during the postabsorptive
state, in persons with several types of disorders.
and the relatively uncommon disorders
responsible for it can be understood in terms of the regulation
of blood glucose concentration. They include (1) an excess
of insulin due to an insulin-producing tumor, drugs that
stimulate insulin secretion, or taking too much insulin
(if the person is diabetic); and (2) a defect in one or more
glucose-counterregulatory controls, for example, inadequate
glycogenolysis and/or gluconeogenesis due to liver disease,
glucagon deﬁ ciency, or cortisol deﬁ ciency.
Fasting hypoglycemia causes many symptoms. Some—
increased heart rate, trembling, nervousness, sweating, and
anxiety—are accounted for by activation of the sympathetic
nervous system caused reﬂ exly by the hypoglycemia. Other
symptoms, such as headache, confusion, dizziness,
uncoordination, and slurred speech, are direct consequences
of too little glucose reaching the brain. More serious brain
effects, including convulsions and coma, can occur if the
plasma glucose concentration falls low enough.
In contrast, low plasma glucose concentration has not
been shown to routinely produce either acute or chronic
symptoms of fatigue, lethargy, loss of libido, depression, or
many other symptoms for which popular opinion frequently
holds it responsible. Most of the symptoms commonly
ascribed to hypoglycemia have other causes.
Increased Plasma Cholesterol
Earlier, we described the ﬂ ow of lipids to and from adipose
tissue in the form of fatty acids and triglycerides complexed
with proteins. One very important lipid—
not mentioned earlier because it, unlike the fatty acids and
triglycerides, does not serve as a metabolic fuel. Instead,
cholesterol is a precursor for plasma membranes, bile salts,
steroid hormones, and other specialized molecules. Thus,
cholesterol has many important functions in the body.
Unfortunately, it can also cause problems. Speciﬁ cally, high
plasma concentrations of cholesterol enhance the development
the arterial thickening that leads to heart
attacks, strokes, and other forms of cardiovascular damage
illustrates a schema for cholesterol
balance. The two sources of cholesterol are dietary cholesterol
and cholesterol synthesized within the body. Dietary
cholesterol comes from animal sources, egg yolk being by far
the richest in this lipid (a single egg contains about 250 mg of
cholesterol). Not all ingested cholesterol is absorbed into the
blood, however—much of it simply passes through the length
of the gastrointestinal tract and is excreted in the feces.
What about cholesterol synthesis within the body?
Almost all cells can synthesize some of the cholesterol
required for their own plasma membranes, but most cannot
do so in adequate amounts and depend upon receiving
cholesterol from the blood. This is also true of the endocrine