This weeks
Question:
What is the contribution of alpha cells to the hyperglycemic state in
type 2 diabetes?
Which is the incorrect answer?
1. They
are responsible for glucagon secretion
2. Is the major factor stimulating hepatic glucose output
3. Stimulates glycogenolysis and gluconeogenesis
4. Stimulates lipolysis and proteolysis
Discussion:
Glucagon was discovered in the early 1960s and is a potent insulin secretagogue.
It is a 29 amino acid polypeptide, and its secretion is regulated directly
by amino and free fatty acids and indirectly by meal-induced parasympathetic
activity and gut hormones. Hypoglycemia and sympathetic nervous stimulation
also result in glucagon release.
Glucagon is the major factor stimulating hepatic glucose output. It
does this by stimulating glycogenolysis and gluconeogenesis, especially
from alanine. In addition, in the absence of insulin, glucagon stimulates
ketogenesis in the liver by activating the carnitine shuttle at the
hepatocyte mitochondrial membrane. Glucagon probably has little effect
on lipolysis and proteolysis in humans.
There are not many new data on the role of endogenous glucagon in type
2 diabetes, although there is enormous interest in the potential therapeutic
options with glucagon-like peptide. Basal glucagon secretion in type
2 diabetes is increased and this almost certainly contributes to fasting
hyperglycemia by increasing fasting hepatic glucose output.[1-3] Glucagon
suppression by hyperglycemia or an amino acid infusion is blunted, and
this phenomenon is more marked in severe insulinopenia.[4] However,
lack of insulin is not the only factor, as glucagon levels remain high
even after starting insulin treatment,[1] and it is likely that the
alpha cells are also insulin-resistant in some way.
In type 1 diabetes there is almost complete destruction of beta cells.
The alpha cells are present in normal numbers but their function is
impaired.[5] There is no definite evidence for an immunologic cause
of this abnormality. In type 2 diabetes, the major islet pathology relates
to amyloid deposition. Beta-cell numbers are probably reduced by 25%
to 30% and this reduction is progressive. Alpha-cell numbers may actually
be increased.[6] Glucagon responses to hypoglycemia have been known
to be blunted in type 1 diabetes of long duration, and this may be a
result of a loss of alpha- and beta-cell communication secondary to
insulin deficiency.[7,8] Glucagon responses to hypoglycemia in type
2 diabetes are thought to remain intact.
References
1. Raskin P, Unger RH. Hyperglucagonemia and its suppression.
N Engl J Med. 1978;299:433-436. Abstract
2. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia
in maintenance of increased rates of hepatic glucose output in Type
II diabetes. Diabetes. 1987;36:274-283. Abstract
3. Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB. Documentation
of hyperglucagonemia throughout the day in non-obese and obese patients
with non-insulin-dependent diabetes. J Clin Endocrinol Metab. 1987;67:106-111.
4. Raskin P, Aydin I, Unger RH. Effect of insulin on the exaggerated
glucagon response to arginine stimulation in diabetes mellitus. Diabetes.
1976;25:227-299. Abstract
5. Kloppel Gm Lohr M, Habich K, Oberholzer M, Heitz PU. Islet pathology
and the pathogenesis of type 1 and type 2 diabetes revisited. Surv Synth
Path Res. 1985;4:110-125.
6. Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased alpha-cells,
reduced beta-cells, and exocrine fibrosis: quantitative changes in the
pancreas in type 2 diabetes. Diabetes Res. 1988;9:151-159. Abstract
7. Gerich J. Lack of glucagon response to hypoglycemia in diabetes:
evidence for an intrinsic pancreatic alpha cell defect. Science. 1973;182:171-173.
Abstract
8. Polonsky K, Bergenstal R, Pons G, Schneider M, Jaspan J, Rubenstein
A. Relation of counter regulatory responses to hypoglycemia in type
1 diabetes. N Engl J Med. 1982;307:1106-1112. Abstract
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