DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

glucose production and promote hepatic glucose uptake and glycogen
synthesis after meals. Despite ineffective insulin effects on
hepatic glucose metabolism, the lipogenic effects of insulin in the
liver are maintained and even accentuated by fasting hyperinsulinemia.
This contributes to hepatic steatosis and further worsening of
insulin resistance.
Pathogenesis of Other Forms of Diabetes. Mutations in key genes
involved in glucose homeostasis cause monogenic diabetes, which is
inherited in an autosomal dominant fashion. These fall in two
broad categories: diabetes onset in the immediate neonatal period
(<6 months of age) and diabetes in children or adults (Murphy et al.,
2008; Vaxillaire and Froguel, 2008). Some forms of neonatal diabetes
are caused by mutations in the sulfonylurea receptor or its
accompanying inward rectifying K + channel and mutations in the
insulin gene. Monogenic diabetes beyond the first year of life may
appear clinically similar to type 1 or type 2 diabetes. In other
instances, young individuals (adolescence to young adulthood) may
have monogenic forms of diabetes known as maturity onset diabetes
of the young (MODY). Phenotypically, these individuals are not
obese and are not insulin resistant, or they may initially have modest
hyperglycemia. The most common causes are mutations in key
islet-enriched transcription factors or glucokinase (see discussion
about molecular mechanisms of insulin secretion; Table 43–2 and
Figure 43–3). Most individual with MODY are treated similarly to
those with type 2 diabetes. Importantly, sulfonylureas may be a particularly
effective treatment of individuals with MODY-3 or neonatal
diabetes caused by a mutation in the K ATP
channel complex.
Diabetes may also be the result of other pathological
processes such as acromegaly and Cushing’s disease (Table 43–2).
A number of medications promote hyperglycemia or lead to diabetes
by either impairing insulin secretion or insulin action (Table 43–3).
Most notable are asparaginase, glucocorticoids, pentamidine, nicotinic
acid, α-interferon, protease inhibitors, and in particular, atypical
antipsychotics (Chapter 16).
Epidemiology of Diabetes. The number of individuals with diabetes
is increasing worldwide. Although the annual rate of type 1
diabetes has increased modestly over the past decade, the increased
frequency of type 2 diabetes has been dramatic. In the U.S., 7-10%
of adults are affected, with up to three times that many at risk. There
is clear ethnic variability in the prevalence of type 2 diabetes. Among
adults living in the U.S., there is a spectrum of prevalence with
Native Americans (15%), Hispanics (12%), and African Americans
(12%) having greater rates than persons of European ancestry (8%).
While the upward trends in the industrialized world have been
similar in many countries, there are now alarming increases in rates
of type 2 diabetes worldwide. Most notable are China, India, and
other countries in the Far East where the disease was previously
uncommon (Chan et al., 2009). The largest increase in the number
of people with diabetes is predicted to take place in the regions or
countries with developing economies. Parallel increases in obesity
rates and changes in diet and activity appear to be the major factors
in this marked increase in diabetes.
Diabetes-Related Complications. Diabetes can cause metabolic
derangements or acute complications, such as the life-threatening
metabolic disorders of diabetic ketoacidosis and hyperglycemic
hyperosmolar state. These require hospitalization for insulin
Table 43–3
Some Drugs that may Promote Hyperglycemia
or Hypoglycemia
β Adrenergic antagonists
Ethanol
Salicylates
Non-steroidal anti-
inflammatory drugs
Pentamidine
ACE inhibitors
Lithium chloride
Theophylline
Bromocriptine
Mebendazole
HYPERGLYCEMIA
Glucocorticoids
Antipsychotics
(atypical, others)
Protease inhibitors
β Adrenergic agonists
Diuretics (thiazide, loop)
Hydantoins
(phenytoin, others)
Opioids (fentanyl,
morphine, others)
Diazoxide
Nicotinic Acid
Pentamidine
Epinephrine
Interferons
Amphotericin B
Asparaginase
Acamprosate
Basiliximab
Thyroid hormones
For additional details, see Murad et al., 2009.
HYPOGLYCEMIA
administration, rehydration with intravenous fluids, and careful monitoring
of electrolytes and metabolic parameters. Chronic complications
of diabetes have been described in all forms of the disease and
are commonly divided into microvascular and macrovascular complications.
Microvascular complications occur only in individuals
with diabetes, whereas macrovascular complications occur more frequently
in individuals with diabetes but are not diabetes specific. The
common microvascular complications include retinopathy, nephropathy
and neuropathy. Macrovascular complications refer to increased
atherosclerosis-related events such as myocardial infarction and
stroke. The pharmacological management of diabetes-related complications
is discussed elsewhere (e.g., Chapters 25, 28, 31, 64).
In the U.S., diabetes is the leading cause of blindness in
adults, the leading reason for renal failure requiring dialysis or renal
transplantation, and the leading cause of nontraumatic lower extremity
amputations. Fortunately, most of these diabetes-related complications
can be prevented, delayed, or reduced by near normalization
of the blood glucose on a consistent basis. How chronic hyperglycemia
causes these complications is unclear. For microvascular
complications, current hypothesis are that hyperglycemia leads to
advanced glycosylation end products (AGEs), increased glucose
metabolism via the sorbitol pathway, increased formation of diacylglycerol
leading to PKC activation, and increased flux through the
hexosamine pathway. Growth factors such as vascular endothelial
growth factor α may be involved in diabetic retinopathy and TGF-β
in diabetic nephropathy.
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA