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Abstract
Resistance to insulin-stimulated glucose uptake is present in the majority of patients
with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM)
and in approximately 25% of nonobese individuals with normal oral glucose tolerance.
In these conditions, deterioration of glucose tolerance can only be prevented if the
beta-cell is able to increase its insulin secretory response and maintain a state
of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation
of glucose homeostasis occurs. The relationship between insulin resistance, plasma
insulin level, and glucose intolerance is mediated to a significant degree by changes
in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also
resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations
can be reduced by relatively small increments in insulin concentration. Consequently,
elevations of circulating plasma FFA concentration can be prevented if large amounts
of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration
will not be suppressed normally, and the resulting increase in plasma FFA concentration
will lead to increased hepatic glucose production. Because these events take place
in individuals who are quite resistant to insulin-stimulated glucose uptake, it is
apparent that even small increases in hepatic glucose production are likely to lead
to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia
may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals,
this compensatory response of the endocrine pancreas is not without its price. Patients
with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and
hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration
and blood pressure has been noted. Hypertension can also be produced in normal rats
when they are fed a fructose-enriched diet, an intervention that also leads to the
development of insulin resistance and hyperinsulinemia. The development of hypertension
in normal rats by an experimental manipulation known to induce insulin resistance
and hyperinsulinemia provides further support for the view that the relationship between
the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)