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[IP] Another one on Type 2 Diabetes and Obesity

Diabetes Mellitus, Type 2

Synonyms and related keywords: type 2 diabetes mellitus, type II diabetes
mellitus, DM, adult-onset diabetes mellitus, maturity-onset diabetes mellitus,
non-insulin-dependent diabetes mellitus, maturity-onset diabetes of the young,

Author: William Isley, MD, Medical Director of Saint Luke's Lipid and Diabetes
Research Center, Associate Professor, Department of Internal Medicine,
Division of Endocrinology, Diabetes, and Metabolism, University of
Missouri-Kansas City School of Medicine

Hyperglycemia is produced by lack of endogenous insulin, which is either
absolute, as in type 1 diabetes mellitus, or relative, as in type 2 diabetes
mellitus. Relative insulin deficiency usually occurs because of resistance to
the actions of insulin in muscle, fat, and the liver. This pathophysiologic
abnormality results in decreased glucose transport in muscle, elevated hepatic
glucose production, and increased breakdown of fat.
The genetics of type 2 diabetes are complex and not completely understood, but
presumably this disease is related to multiple genes (with the exception of
maturity-onset diabetes of the young [MODY]). Evidence supports inherited
components for both pancreatic beta-cell failure and insulin resistance.
Considerable debate exists regarding the primary defect in type 2 diabetes
mellitus. Most patients have both insulin resistance and some degree of
insulin deficiency. (Lean, older African American patients may have insulin
deficiency predominantly.) However, insulin resistance per se is not the sine
qua non for type 2 diabetes mellitus because many people with insulin
resistance (particularly patients who are obese) do not develop glucose
intolerance. Therefore, insulin deficiency apparently is necessary for the
development of hyperglycemia. Patients may have high insulin levels, but the
insulin concentrations are inappropriately low for the level of glycemia.
MODY is associated with autosomal dominant inheritance and is characterized by
onset in at least 1 family member at younger than 25 years of age, correction
of fasting hyperglycemia without insulin for at least 2 years, and absence of
ketosis. At least 4 genetically different types of MODY have been described.
Some patients ultimately will require insulin to control glycemia.
Recent work has suggested that elevated free fatty acids may be the driving
force behind insulin resistance and perhaps even beta-cell dysfunction. If
this defect is more proximal than defects specifically related to glycemia,
then therapies aimed at correcting this phenomenon would be highly
Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic
lifestyle (excessive calories, inadequate caloric expenditure, and obesity) is
superimposed upon a susceptible genotype. The extent of excess weight may vary
with different groups. For example, overweight patients from the Indian
subcontinent are mildly overweight by Western standards, but excess weight
often is much more pronounced in other ethnic groups. Recent work suggests
that in utero environment resulting in low birth weight may predispose some
individuals to develop type 2 diabetes mellitus.
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