Flux of carbon through the pathways of hepatic glucose metabolism
described above is strongly influenced by the hormones insulin, glucagon, and
epinephrine. Insulin is secreted from the P-cells of pancreatic islets during
periods of increased glucose availability. This peptide hormone helps to lower
blood glucose back within the normal range by stimulating glycogenesis and
glycolysis, and simultaneously inhibiting glycogenolysis and gluconeogene-
sis. The effects of insulin on hepatic glucose metabolism are mediated in large
part by the enzyme protein phosphatase 1 (PP1). For a more detailed discus-
sion of the mechanism by which PP1 affects glucose metabolism, see Case 22.
When blood glucose levels begin to decline (e.g., during an overnight fast),
so too does insulin secretion. In contrast, secretion of glucagon from a-cells of
pancreatic islets is stimulated. The latter targets primarily hepatic glucose
glycogenolysis), and decreasing glucose utilization. Glucagon acts in larger part
by reversing the effects of insulin-mediated PP1 activation. On binding to its cell
surface receptor, glucagon increases the activity of protein kinase A (PKA),
which phosphorylates many of the proteins/enzymes that PP1 dephosphorylates.
For a detailed discussion, of the mechanism by which PKA acts, see Case 22.
Like glucagon, epinephrine secretion increases during periods of
decreased glucose availability. Binding of epinephrine to P-adrenergic recep-
tors on the surface of the hepatocyte results in activation of PKA, thereby
increasing further hepatic glucose production through glycogenolysis and glu-
coneogenesis (Figure 26-4). Epinephrine is also able to bind to a second recep-
tor on the surface of the hepatocyte, the P-adrenergic receptor, causing
elevation of intracellular Ca2+ levels. The latter allosterically activates a kinase
called phosphorylase
Abnormalities in the above described glucose homeostatic mechanisms
arise during diabetes mellitus. Two major forms of diabetes mellitus exist,
insulin-dependent (type I) and insulin-independent (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 destruc-
tion of pancreatic P-cells. Lack of insulin, in the face of elevated glucagon and
epinephrine, leads to high rates of hepatic glucose output, being driven by
P-oxidation of fatty acids. The latter results in an excessive production of ketone
bodies and subsequent ketoacidosis. Treatment of type I diabetes involves reg-
ular monitoring of blood glucose levels and insulin administration as required.
Insulin therapy associated with an evening meal will lower blood glucose lev-
els. The latter triggers release of the counter-regulatory hormones glucagon
and epinephrine, thereby stimulating hepatic glucose production. This inad-
vertently results in elevated glucose levels in the morning (the Somogyi
effect). In contrast to type I diabetes, type II diabetes is caused by insulin
resistance in the face of insulin insufficiency. The disease is thus characterized
by both hyperglycemia and hyperinsulinemia. Ketoacidosis is a much less
common complication of type II diabetes.
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