ADAPTATIONS IN GLUCOSE-HOMEOSTASIS DURING CHRONIC NUTRITIONAL DEPRIVATION IN RATS - HEPATIC RESISTANCE TO BOTH INSULIN AND GLUCAGON

The role of glucagon in glucose homeostasis during chronic malnutritio n was studied in weanling-littermate rats either fed ad libitum or res tricted to 60% of ad libitum intake for 8 weeks. Fasting glucose and i nsulin levels were lower in malnourished rats, and their response to g lucagon (0.02 mg/kg intravenous [IV]) after a 16-hour fast was signifi cantly less than in control littermates for both glucose (P = .039) an d insulin (P = .008). During euglycemic glucose clamp studies at ident ical plasma glucose (PG) levels, insulin suppression of hepatic glucos e production (HGP) was impaired in malnourished rats, indicating insul in resistance (mean +/- SE HGP: 48 +/- 5 v 32 +/- 10 mu mol . kg(-1). min(-1) for controls, P = .028). Glucose disposal was not significantl y different in the two groups. However, after IV glucagon, the increas e in HGP was markedly impaired in malnourished rats (P = .0004), with the total amount of glucose produced by the liver over 15 minutes bein g 1,397 +/- 114 mu mol/kg as compared with 2,031 +/- 118 in controls ( P = .0047). The impaired response was not due to defective glycogenoly sis, because the release of glucose from prelabeled glycogen in respon se to glucagon injection contributed only 6% to 8% of the overall incr ease in glucose output from the liver, and was not different in the tw o groups. Furthermore, liver glycogen stores were virtually exhausted after the 16-hour fast, without glucagon injection. Glucagon receptor affinity and number were not affected by malnutrition. It is concluded that (1) chronic malnutrition is associated with hepatic resistance t o both insulin and glucagon, (2) the glucagon resistance is not due to impaired glycogenolysis, and (3) it is mediated by a postreceptor def ect. It is proposed that resistance to glucagon stimulation of glucone ogenesis is an adaptive response that helps conserve protein at the ex pense of a lower PG level in chronic malnutrition. The risk of hypogly cemia is partially offset by the insulin deficiency and resistance, wh ich are other elements of this adaptive response. Copyright (C) 1995 b y W.B. Saunders Company