Pathways to Insulin Resistance And Type II Diabetes

Description
Our epidemiological research indicates that high prevalence rate diabetes populations have uniformly experienced widespread malnutrition within the last 2-4 generations and that their diabetes incidence rates have only begun to rise after they have begun to enjoy better nutrition and especially over nutrition. Existing interpretations of these data adduce variants of the hypothesis that the insulin resistance in these populations is strongly genetic and that their diabetes arises as their genetic insulin resistance is conjoined with better nutrition and over nutrition. Our epidemiological research, however, reveals genetically related populations with similar nutritional profiles that vary radically in diabetes prevalence rates. The difference between these populations appears to be in their nutritional histories and not their genetics: the high prevalence populations (e.g., San Carlos Apache -15%) have histories of widespread severe malnutrition while those with low prevalence rates (Dogrib .6%) do not.

These observations have led us to develop animal models in which we have subjected otherwise normal females to protein malnutrition during pregnancy and lactation. We have found their offspring to have normal to elevated sensitivity to insulin but to suffer impaired insulin secretory capacity. When such animals are then over nourished and develop insulin resistance (as do over nourished controls) they cannot compensate with increased insulin secretion and they develop glucose intolerance. When the insulin deficient females become pregnant we find that they cannot compensate for the increase in insulin resistance associated with pregnancy and they become hyperglycemic. Their offsprings? sizes at birth vary with the severity of their dams? hyperglycemia with insulin deficient dams on high fat diets producing microsomic neonates, those on nutritionally balanced but calorically restricted diets producing neonates that do not differ from controls and those on control diets producing macrosomic neonates. However, all the offspring of the insulin deficient dams were insulin resistant when adult. We further found that when female insulin resistant females were over nourished or maintained on the control diet during their pregnancies and lactation, their offspring replicated them. However, insulin resistant, non-overweight dams on a nutritionally balanced but calorically restricted diet produced offspring that did not differ from controls.

These findings, which indicate that insulin resistance may be induced in generation 3 when females in generation 1 are protein malnourished in pregnancy and that insulin resistant dams will produce insulin resistant offspring, suggest an acquired pathway leading from episodes of protein malnutrition to insulin resistance and glucose intolerance generations later. They also suggest that at least in insulin females that are not overweight or obese caloric restrictions in pregnancy may break the insulin resistance in pregnancy-increasing the risk of insulin resistance in offspring cycle.

Presently we are addressing the issue of whether caloric restriction in pregnancy among overweight and obese insulin resistant females will also suppress insulin resistance in offspring. We expect that it may not as such females are expected to mobilize their abundant fat stores for fuel, maintaining their hyperglycemia in the process. If these expectations are met in our current experiments we propose to examine the effects of treating overweight and obese pregnant females on calorically restricted diets with agents to reduce lipolysis in an effort to reduce their gestatational hyperglycemia and its effects on offspring.

We also propose to begin an examination of how hyperglycemia in pregnancy increases the probability of insulin resistance in offspring. This propensity is particularly puzzling because insulin resistance in offspring of hyperglycemic pregnancies develops slowly, often being undetectable in the very young except with the use of complex, expensive and intrusive procedures develops.