CHRONIC MALNUTRITION IMPAIRS INSULIN SENSITIVITY THROUGH BOTH RECEPTOR AND POSTRECEPTOR DEFECTS IN RATS WITH MILD STREPTOZOCIN DIABETES

The effect of coexisting chronic malnutrition on insulin sensitivity in mild diabetes was studied in rats. Food intake was restricted over an 8-week period to 50% of ad libitum intake by pair-feeding 4-week-old littermate rats injected with streptozocin ([STZ] 40 mg/kg intraperitoneally) at 8 weeks. Significantly greater glucose intolerance and hypoinsulinemia were seen in response to a glucose load in the malnourished diabetic group (P < .00005), suggesting that chronic malnutrition significantly accentuated β-cell dysfunction from STZ. Significantly greater insulin resistance was also seen, with the percentage rate constant for glucose disappearance after a bolus of insulin being markedly impaired (P < .0001) in the malnourished diabetic group (1.5% ± 0.2% · min-1 [SE]) compared with ad libitum-fed diabetic and normal rats (3.6% ± 0.6% · min-1 and 4.7% ± 0.7% · min-1, respectively; P < .01). Insulin binding to receptor in liver plasma membranes was altered by malnutrition (P < .00005), with the affinity of binding being significantly reduced compared with that of ad libitum-fed diabetic controls (P < .0001) at both the high-affinity site (3.9 ± 0.2 v 13.7 ± 3.3 × 10-7 · mol/L-1) and low-affinity site (2.7 ± 0.4 v 20.1 ± 3.8 × 10-5 · mol/L-1). During a constant glucose and insulin infusion (1.67 mU/kg/min), glucose clearance was significantly lower in malnourished rats (5.3 ± 0.7 v 8.6 ± 1.7 mL/kg/min, P < .01). A fivefold increase in insulin infusion rate to 8.3 mU/kg/min resulted in a significant increase (P < .0005) in glucose clearance rate in the ad libitum-fed control group (to 11.5 ± 2.2), but not in malnourished rats (5.3 ± 1.1), indicating the additional presence of a postreceptor defect in insulin action. Serum fructosamine levels were not different, suggesting that the defects were not due to greater diurnal hyperglycemia. These observations indicate that the superimposition of chronic malnutrition in rats with mild diabetes not only impairs insulin secretion, but also reduces insulin sensitivity through both receptor and postreceptor defects. © 1993.