by glucagon-induced PKA activation, through activation of fructose-1,6-
bisphosphatase (F1,6BisPase; indirect effect through phosphorylation of a
bifunctional enzyme, resulting in decreased intracellular levels of fructose 2,6-
bisphosphate, an allosteric inhibitor of F1,6BisPase) and pyruvate kinase
(reverse of PP1 effects). Glycogenolysis- and gluconeogenesis-derived glu-
cose is exported out of the liver to help maintain blood glucose levels.
Abnormalities in the above described glucose homeostatic mechanisms
arise during diabetes mellitus. Two major forms of diabetes mellitus exist,
insulin-dependent (type I) and non-insulin-dependent (type II) diabetes. Type
I diabetes is caused by a severe lack or complete absence of insulin. Also
known as early onset diabetes, this disease is often caused by an autoimmune
destruction of pancreatic P-cells. In contrast, type II diabetes is caused by
insulin resistance in the face of insulin insufficiency. Insulin resistance is
defined as an inability to respond to a physiologic concentration of insulin.
The pancreas initially compensates by producing more insulin. At this stage,
the patient is described as glucose intolerant. As the disease progresses, the
degree of insulin resistance often worsens. Type II diabetes occurs when
insulin secretion is not sufficient to maintain normoglycemia. The disease is
thus characterized by both hyperinsulinemia and hyperglycemia (Figure 22-3).
Figure 22-3. Schematic diagram showing the effects of insulin resistance leading
to diabetes mellitus.
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