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

Endocrine Pancreas and
Pharmacotherapy of Diabetes
Mellitus and Hypoglycemia
Alvin C. Powers
and David D’Alessio
Diabetes mellitus is a spectrum of common metabolic
disorders, arising from a variety of pathogenic mechanisms,
all resulting in hyperglycemia. The number of
individuals with diabetes is rising rapidly throughout
the world. Both genetic and environmental factors contribute
to its pathogenesis, which involves insufficient
insulin secretion, reduced responsiveness to endogenous
or exogenous insulin, increased glucose production,
and/or abnormalities in fat and protein metabolism.
The resulting hyperglycemia may lead to both acute
symptoms and metabolic abnormalities. However, the
major sources of the morbidity of diabetes are the
chronic complications that arise from prolonged hyperglycemia,
including retinopathy, neuropathy, nephropathy,
and cardiovascular disease. Fortunately, these
chronic complications can be mitigated in many
patients by sustained control of the blood glucose.
There are now a wide variety of treatment options for
hyperglycemia that target different processes involved
in glucose regulation or dysregulation.
Following a brief review of glucose homeostasis
and the pathogenesis of diabetes, this chapter discusses
the general approaches and specific agents used in the
therapy of diabetes. The last section describes agents
used for hypoglycemia.
PHYSIOLOGY OF GLUCOSE
HOMEOSTASIS
Regulation of Blood Glucose. In healthy humans, blood
glucose is tightly maintained despite wide fluctuations
in glucose consumption, utilization, and production.
The maintenance of glucose homeostasis, generally
termed glucose tolerance, is a highly developed systemic
process involving the integration of several
major organs through multilayered communication
(Figure 43–1). Although endocrine control of blood
glucose, primarily through the actions of insulin, is of
central importance, myriad levels of inter-organ communication,
via other hormones, nerves, local factors
and substrates, also play a vital role. The pancreatic β
cell is central in this homeostatic process, adjusting the
amount of insulin secreted very precisely to promote
glucose uptake after meals and to regulate glucose output
from the liver during fasting.
In the fasting state (Figure 43–1A), most of the
fuel demands of the body are met by the oxidation of
fatty acids. Importantly, the brain does not effectively
utilize fatty acids to meet energy needs and in the fasting
state requires glucose for normal function; glucose
requirements are ~2 mg/kg per minute in adult humans,
largely to supply the central nervous system (CNS) with
an energy source. Fasting glucose requirements are primarily
provided by the liver, with a minor contribution
from the kidney. Liver glycogen stores provide some of
this glucose; conversion of gluconeogenic precursors,
primarily lactate, alanine and glycerol, into glucose
accounts for the remainder. The dominant regulation of
hepatic glycogenolysis and gluconeogenesis are the
pancreatic islet hormones insulin and glucagon. Insulin
inhibits hepatic glucose production at several levels,
and the decline of circulating insulin concentrations in
the postabsorptive state (fasting) is permissive for
higher rates of glucose output. Glucagon maintains
blood glucose concentrations at physiological levels in
the absence of exogenous carbohydrate (overnight and
in between meals) by stimulating gluconeogenesis and
glycogenolysis by the liver.
Ingestion of a meal provides a substantial challenge
to glucose homeostasis (Figure 43–1B). Adults