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

proportion to the nutrient load ingested and relay this information
to the islet as part of a feed-forward mechanism that allows an insulin
response appropriate to meal size. Insulin secretion rates in healthy
humans are highest in the early digestive phase of meals, preceding
and limiting the peak in blood glucose. This pattern of premonitory
insulin secretion is an essential feature of normal glucose tolerance.
How to mimic this pattern is one of the key challenges for successful
insulin therapy in diabetic patients.
Elevated circulating insulin concentrations lower glucose in
blood by inhibiting hepatic glucose production and stimulating the
uptake and metabolism of glucose by muscle and adipose tissue.
These two important effects occur at different concentrations of
insulin. Production of glucose is inhibited half-maximally by an
insulin concentration of ~120 pmol/L, whereas glucose utilization
is stimulated half-maximally at ~300 pmol/L. Some of the effects of
insulin on the liver occur rapidly, within the first 20 minutes of meal
ingestion, whereas stimulation of peripheral glucose uptake may
require up to an hour to reach significant rates. This is probably due
to the quick access of insulin to hepatocytes, via the hepatic-portal
circulation and the liver sinusoids, and the slower passage of insulin
to its receptors on muscle and adipose cells. Insulin has potent effects
to reduce lipolysis from adipocytes, primarily through the inhibition
of hormone-sensitive lipase, and increases lipid storage by promoting
lipoprotein lipase synthesis and adipocyte glucose uptake.
Finally, insulin stimulates amino acid uptake and protein synthesis
and inhibits protein degradation in muscle and other tissues; it thus
causes a decrease in the circulating concentrations of most amino
acids.
The demand for glucose as an energy source for skeletal muscle
increases dramatically during exercise. Glycogen stored in skeletal
muscle is mobilized for some of these needs, but there are limited
supplies that are used, mostly at the onset of activity. Most of the
glucose support of exercise comes from hepatic gluconeogenesis.
The dominant regulation of hepatic glucose production during exercise
comes from epinephrine and norepinephrine. The catecholamines
stimulate glycogenolysis and gluconeogenesis, inhibit
insulin secretion, and enhance release of glucagon, all contributing
to increased hepatic glucose output. In addition, catecholamines promote
lipolysis, freeing fatty acids for oxidation in exercising muscle
and glycerol for hepatic gluconeogenesis.
Pancreatic Islet Physiology and Insulin Secretion. The
pancreatic islets comprise 1-2% of the pancreatic volume
and are scattered throughout the exocrine pancreas. The
pancreatic islet is a highly vascularized, highly innervated
mini-organ containing five endocrine cell types:
α cells that secrete glucagon, β cells that secrete glucose,
δ cells that secrete somatostatin, cells that secrete
pancreatic polypeptide, and ε cells that secrete ghrelin.
The endocrine, exocrine, and ductal cells of the pancreas
share a common embryologic heritage but in the
adult are functionally distinct. Insulin and glucagon are
important pharmacological agents in the treatment of
diabetes, and an understanding of their synthesis, secretion,
and action are important in the therapeutic efforts
related to diabetes.
Preproinsulin
SP
24
–24 1 2 2 86
Insulin
S S
S S
B chain
30
Proinsulin
A
PC2
S S
B
1
C
S S
86
A
S S
S S
B
C peptide
31
SP cleavage
Folding
S–S bond formation
PC1
A chain
21
PC1: cleavage of Arg 31 /Arg 32
PC2: cleavage of Lys 64 /Arg 65
C peptide
C
Figure 43–2. Synthesis and processing of insulin. The initial peptide,
preproinsulin (110 amino acids) consists of a signal peptide
(SP), B chain, C peptide, and A chain. The SP is cleaved and S-
S bonds form as the proinsulin folds. Two prohormone convertases,
PC1 and PC2, cleave proinsulin into insulin, C peptide,
and two dipeptides. Insulin and C peptide are stored in granules
and co-secreted in equimolar quantities.
Insulin is initially synthesized as a single polypeptide chain,
preproinsulin (110 amino acid), which is processed first to proinsulin
and then to insulin and C-peptide (Figure 43–2). This complex
and highly regulated process involves the Golgi complex, the endoplasmic
reticulum, and importantly the distinctive secretory granules
of the β cell. Secretory granules are critical not only in bringing
insulin to the cell surface for exocytosis, but also in the cleavage and
processing of the prohormone to the final secretion products, insulin
and C-peptide. The structure of insulin is discussed in the section
describing its therapeutic use. Equimolar quantities of insulin and
C-peptide (31 amino acids) are co-secreted. Insulin has a t 1/2
of
5-6 minutes due to extensive hepatic clearance. C-peptide, in contrast,
with no known physiological function or receptor, has a t 1/2
of ~30 minutes. Because almost all of the C-peptide released into
the portal vein reaches the peripheral circulation where it can be
measured, this peptide is useful in assessment of β-cell secretion,
and to distinguish endogenous and exogenous hyperinsulinemia (for
example in the evaluation of insulin-induced hypoglycemia).
Importantly, the β cell also synthesizes and secretes islet amyloid
polypeptide (IAPP) or amylin, a 37–amino acid peptide. IAPP is not
essential for life but influences GI motility and the speed of glucose
absorption. Pramlintide is an agent used in the treatment of diabetes
that mimics the action of IAPP. As reflected by its name, IAPP forms
amyloid fibrils in the islets of individuals with type 2 diabetes;
whether this is a cause or a consequence of the islet dysfunction of
type 2 diabetes is not yet clear.
Insulin secretion is a tightly regulated process designed to
provide stable concentrations of glucose in blood during both
fasting and feeding. This regulation is achieved by the coordinated
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA