Abstract
Insulin resistance is a major component of non-insulin-dependent diabetes mellitus
(NIDDM). While a genetic contribution is likely, as yet none of several proposed candidate
genes have been incriminated in the typically obese patient with NIDDM to explain
their insulin resistance. Accordingly, this review focuses on some recent advances
in understanding three acquired factors contributing to insulin resistance: visceral
obesity, glucotoxicity and lipotoxicity. Newer computerized tomography scans allow
quantitation of fat accumulating in visceral organs including the mesentery and omentum.
This visceral fat relates much more to the insuin resistance syndrome than does subcutaneous
fat. Moreover, exercise, as performed by active Sumo wrestlers, is associated with
low visceral fat, absent hyperglycemia and absent dyslipidemia despite massive subcutaneous
obesity. It remains to be seen whether exercise programs more moderate than Sumo wrestling
will also mobilize visceral fat. A new metabolic pathway has recently been described
whereby hexosamines are formed by an increased flux of glucose into fat and muscle.
These hexosamine products appear to explain how glucotoxicity results in insulin resistance.
They act as a negative feedback system to limit further glucose transport by insulin
target tissue during hyperglycemia. Lipotoxicity has previously been implicated in
insulin resistance by its inhibitory effect on glucose uptake by muscle because of
the Randle-fatty acid cycle. Recently the role of elevated fatty acids in producing
“hepatic” resistance to insulin in NIDDM has also been documented, but the site of
insulin resistance may be the fat cell rather than the hepatocyte. Therapy consists
mainly of hygienic measures, including caloric restriction and exercise, which can
reverse all three of these acquired forms of insulin resistance. In addition, pharmacologic
measures to reduce hyperglycemia can reduce the glucotoxicity and lipotoxicity. The
use of insulin-sparing antihyperglycemia drugs may be particularly useful in the insulin-resistant
patient to avoid weight gain while correcting the hyperglycemia.
Key words
Reversible Insulin Resistance - Glucotoxicity - Hexosamine Pathway - Lipotoxicity
