Regulation of Organic Metabolism and Energy Balance
T1DM is less common, affecting approximately 5 percent
of diabetic patients in the United States. T1DM is due
to the total or near-total autoimmune destruction of the
pancreatic beta cells by the body’s own white blood cells.
The triggering events for this autoimmune response are not
yet fully established. Treatment of T1DM always involves
the administration of insulin (by injection, because oral
administration of insulin would not be effective due to the
actions of gastrointestinal enzymes). Recent therapies for T1DM
make use of alternative routes of insulin administration, such as
a recently approved inhaled form of insulin. Transplantation of a
whole pancreas or normal islet cells into a person with T1DM is
also effective in reducing insulin requirements.
Because of insulin defi ciency,
patients with
T1DM always have elevated glucose concentrations in their
blood. The increase in plasma glucose occurs because (1) glucose
fails to enter insulin’s target cells normally, and (2) the liver
continuously makes glucose by glycogenolysis and gluco-
neogenesis, and secretes the glucose into the blood. Recall also
that insulin normally suppresses lipolysis and ketone formation.
Thus, another result of the insulin defi ciency is pronounced
lipolysis with subsequent elevation of plasma glycerol and fatty
acids. Many of the fatty acids are then converted by the liver
into ketones, which are released into the blood.
If extreme, these metabolic changes culminate in the
acute life-threatening emergency called
diabetic ketoacidosis
Figure 16–12
). Some of the problems are due to the effects
that extremely elevated plasma glucose concentration produces
on renal function. Chapter 14 pointed out that a typical
person does not excrete glucose because all glucose fi ltered at
the renal corpuscle is reabsorbed by the tubules. However, the
elevated plasma glucose of diabetes increases the fi ltered load
of glucose beyond the maximum tubular reabsorptive capacity,
and therefore large amounts of glucose are excreted. For the
same reasons, large amounts of ketones may also appear in the
urine. These urinary losses deplete the body of nutrients and
lead to weight loss. Far worse, however, is the fact that these
unreabsorbed solutes cause an osmotic diuresis—increased
urinary excretion of sodium and water, which can lead, by the
sequence of events shown in Figure 16–12, to hypotension,
brain damage, and death. It should be noted, however, that
apart from this extreme example, diabetics are more often
prone to hypertension, not hypotension (due to several causes,
including vascular and kidney damage, and the obesity often
associated with T2DM).
The other serious abnormality in diabetic ketoacidosis
is the increased plasma hydrogen ion concentration caused
by the accumulation of ketones. As described in Chapter 3,
ketones are four-carbon breakdown products of fatty acids.
Two ketones, known as hydroxybutyric acid and acetoacetic
acid, are acidic at the pH of blood. This increased hydrogen
ion concentration causes brain dysfunction that can contribute
to coma and death.
Diabetic ketoacidosis is seen primarily in patients with
T1DM—that is, those with almost total inability
to secrete insulin. However, at least 90 percent of diabetics
are in the T2DM category and rarely develop metabolic
derangements severe enough to develop diabetic ketoacidosis.
T2DM is a syndrome mainly of overweight adults, typically
starting in middle life. However, T2DM is
an age-
dependent syndrome. As the incidence of childhood obesity
has soared in the United States, so too has the incidence of
T2DM in children and adolescents. Given the earlier mention
of progressive weight loss in T1DM as a symptom of diabetes,
why is it that most people with T2DM are overweight? One
reason is that people with T2DM, in contrast to those with
T1DM, do not excrete enough glucose in the urine to cause
weight loss.
Several factors combine to cause T2DM. One major
problem is target cell hyporesponsiveness to insulin, termed
insulin resistance. Obesity accounts for much of the insulin
resistance in T2DM. Obesity in any person—diabetic or
not—induces some degree of insulin resistance, particularly
in muscle and adipose tissue cells. One hypothesis is that the
Brain blood flow
Arterial blood pressure
Sodium and water
Osmotic diuresis
Renal filtration of
glucose and ketones
Plasma [H
Plasma ketones
Ketone synthesis
Plasma glucose
Plasma volume
Plasma free fatty acids
Glucose uptake by cells
Insulin deficiency
Impaired brain function, coma, death
Figure 16–12
Diabetic ketoacidosis: Events caused by severe untreated insulin
defi ciency in type 1 diabetes mellitus.
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