THE IMPACT OF GENETIC-HYPERTENSION ON INSULIN-SECRETION AND GLUCOREGULATORY CONTROL IN-VIVO - STUDIES WITH THE TGR(MREN2)27 TRANSGENIC RAT

Objective To examine the associations among hypertension, insulin secr etion, glucose tolerance and insulin resistance in vivo. Design Glucos e tolerance and insulin secretion during an intravenous glucose tolera nce test and action of insulin on whole-body glucose kinetics in the p ost-absorptive state and during hyperinsulinaemia were examined in con scious, unrestrained TGR(mRen2) 27 rats and age-matched transgene-nega tive controls. Methods Glucose tolerance and insulin secretion were ex amined after intravenous administration of 500 mg glucose/kg body weig ht. Endogenous glucose production and whole-body glucose disposal were estimated using [3-H-3]-glucose during euglycaemic-hyperinsulinaemic clamping. Muscle glucose utilization was estimated using 2-deoxy-[1-H- 3]-glucose. Results Despite there being higher insulin levels, whole-b ody glucose turnover was significantly lower in postabsorptive TGR(mRe n2) 27 rats than it was in transgene-negative controls. This was assoc iated with significant suppression of glucose uptake/phosphorylation b y oxidative skeletal muscles. TGR(mRen2) 27 rats also exhibited signif icantly lower blood glucose levels, higher plasma insulin levels and h igher rates of disappearance of glucose after intravenous administrati on of glucose. During hyperinsulinaemia, steady-state glucose infusion rates required to maintain euglycaemia in TGR(mRen2) 27 rats were sig nificantly greater, indicating that an increase in whole-body action o f insulin had occurred. This was due to significantly greater suppress ion of endogenous production of glucose: insulin-stimulated glucose di sposal rates did not differ significantly between the two groups. Conc lusions The results indicate that TGR(mRen2) 27 rats have an enhanced and sensitized insulin-secretory response to glucose, together with a greater than normal hepatic action of insulin. Insulin-mediated glucos e disposal was not impaired. The results therefore do not support the hypothesis that hypertension plays a primary role in the development o f insulin resistance. (C) 1998 Rapid Science Ltd.