Metabolic Homeostasis
Diagrammatic representation of insulin secretion from pancreatic
cells. The sequence of events of insulin secretion
coupled to glucose entry into
cells consists of glucokinase action, ATP production, inhibition of the ATP-sensitive K+
channel, membrane depolarization, Ca2+ influx, and insulin release. Neurotransmitters acetylcholine and
norepinephrine stimulate and inhibit insulin secretion via trimeric G-proteins
G q
and G;. respectively. Glucagon-like
peptide (GLP) promotes insulin release via the G-protein Gs. Sulfonamides and diazoxide have direct effects on
sulfonylurea receptors (SURs); the former promotes insulin release and the latter inhibits insulin release. +,
Stimulation; —, inhibition. Other abbreviations are given in the text.
tetrapeptide sequence (B23-B26), and hence the abnor-
mal insulins have greatly diminished biological activity.
The third mutation yields an abnormal form of proinsulin
in which the C-peptide remains attached to the A chain
after processing. It is expressed as an autosomal dominant
(familial hyperproinsulinemia).
Affected individu-
als show no signs of insulin resistance and may or may not
exhibit mild hyperglycemia.
Multiple factors regulate insulin secretion from the
cells. Glucose, amino acids, glucagon,
acetylcholine and /3-adrenergic agents stimulate insulin
secretion, whereas somatostatin and a-adrenergic agents
exert inhibitory influences. Most notable of the insulin sec-
retagogue is glucose. The sequence of events that leads to
insulin secretion by the
cells as the threshold of blood
glucose increases is shown in Figure 22-7.
The normal fasting plasma glucose is maintained be-
tween 70 and 105 mg/dL (3.89-5.83 mmol/L). Glucose en-
ters the yd cells by means of
glucose transporters
and GLUT2 (Chapter 13). GLUT lisa constitutive glucose
transporter and GLUT2 is a low-affinity glucose trans-
porter capable of sensing the glucose concentration in
cells. Glucose transport is not a rate-limiting step in
the /3-cell glucose metabolism because the transporters
are present in greater abundance relative to physiological
rates of glucose entry. After glucose enters the
cells, it is
converted to glucose-
-phosphate by glucokinase, which
is an isoenzyme of hexokinase. Glucokinase has a low
affinity for glucose, is the rate-limiting step for glucose
metabolism and is not affected by feedback inhibition.
The glucose-sensing device that allows rapid and precise
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