DIABETES MELLITUS TYPE 2
Type 2 diabetes mellitus is a group of disorders characterized by hyperglycemia and associated with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular), and neuropathic (ie, autonomic, peripheral) complications. Unlike type 1 diabetes mellitus, patients are not absolutely dependent upon insulin forlife, even though many of these patients are ultimately treated with insulin.
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 and an inadequateresponse by the pancreatic beta cell. 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]). Evidencesupports 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. However, insulin resistance per se is not the sine qua non for type 2 diabetes mellitus because many people with insulin resistance (particularlypatients who are obese) do not develop glucose intolerance. Therefore, insulin deficiency 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 younger than 25 years,correction of fasting hyperglycemia without insulin for at least 2 years, and absence of ketosis. At least 6 genetically different types of MODY have been described. Some patients ultimately 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 moreproximal than defects specifically related to glycemia, then therapies aimed at correcting this phenomenon would be highly beneficial.
Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The extent of excess weight may vary with different groups. Forexample, overweight patients from Asia may not be overweight by Western standards, but excess weight is often much more pronounced in these ethnic groups. Recent work suggests that in utero environment resulting in low birth weight may predispose some individuals to develop type 2 diabetes mellitus.
Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However,glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels, elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventionalatherosclerotic risk factors (eg, family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C), determine cardiovascular risk.
Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably because of the effects of insulin resistance. Stern in 1996 and Haffner and D'Agostino in 1999 developed the "ticking...
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