ASSESSMENT OF HEPATIC SENSITIVITY TO GLUCAGON IN NIDDM - USE AS A TOOL TO ESTIMATE THE CONTRIBUTION OF THE INDIRECT PATHWAY TO NOCTURNAL GLYCOGEN-SYNTHESIS

NIDDM is associated with excessive rates of endogenous glucose product ion in both the postabsorptive and postprandial states. To determine w hether this is due to an intrinsic increase in hepatic sensitivity to glucagon, 9 NIDDM and 10 nondiabetic subjects were studied on three oc casions. On each occasion, glycogen was labeled the evening before the study with subjects ingesting meals containing [6-H-3]galactose. Begi nning at 6:00 A.M. on the following morning, somatostatin was infused to inhibit endogenous hormone secretion. Insulin concentrations were m aintained constant at basal levels (defined as that necessary to keep glucose at similar to 5 mmol/l) in each individual. On one occasion gl ucagon was infused at a rate of 0.65 ng.kg(-1).min(-1) throughout the experiment, resulting in glucagon concentrations of similar to 130 pg/ ml and a slow but comparable fall in endogenous glucose production wit h time in both groups. On the other two occasions, the glucagon infusi on was increased at 10:00 A.M. to either 1.5 or 3.0 ng.kg(-1).min(-1), resulting in an increase in glucagon concentrations to similar to 180 and 310 pg/ml, respectively. The increment in endogenous glucose prod uction (i.e., area above basal) did not differ in diabetic and nondiab etic subjects during either the 1.5 ng.kg(-1).min(-1) (0.75 +/- 0.055 vs. 0.78 +/- 0.048 mmol/kg) or 3.0 ng.kg(-1).min(-1) (1.06 +/- 0.066 v s. 1.10 +/- 0.073 mmol/kg) glucagon infusions. In contrast, the amount of [6-H-3]glucose released from glycogen was lower (P < 0.05) in the diabetic than nondiabetic subjects during both glucagon infusions. The specific activity of glycogen, calculated as the integrated release o f [6-H-3]glucose divided by the integrated release of unlabeled glucos e, was lower (P < 0.05) in diabetic subjects than in nondiabetic subje cts during both the 1.5 ng.kg(-1).min(-1) (19.0 +/- 3.9 vs. 41.4 +/- 5 .7 dpm/pmol) and 3.0 ng.kg(-1).min(-1) (19.1 +/- 3.1 vs. 36.5 +/- 7.2 dpm/mu mol) glucagon infusions, implying that a greater portion of the glucose released from glycogen was derived from the indirect pathway. We concluded that although NIDDM is not associated with an intrinsic alteration in hepatic sensitivity to glucagon, it does alter the relat ive contributions of the direct and indirect pathways to nocturnal gly cogen synthesis.