Nielsen, Michael Festersen

Glucose production is inappropriately increased in people with type 2 diabetes both before and after food ingestion. Excessive postprandial glucose production occurs in the presence of decreased and delayed insulin secretion and lack of suppression of glucagon release. These abnormalities in hormone secretion, coupled with impaired insulin-induced suppression of glucose production and stimulation of splanchnic glucose uptake, likely account in large part for the excessive amounts of glucose that reach the systemic circulation for disposal by peripheral tissues following food ingestion. In contrast, when adequate basal insulin concentrations are present, neither glucagon-induced stimulation of glucose production nor glucose-induced suppression of glucose production differs in diabetic and nondiabetic subjects matched for gender, age, and degree of obesity. However, when insulin secretion is defective, lack of suppression of glucagon can cause substantial hyperglycemia by enhancing rates of glucose production. Therefore, normalization of hepatic glucose metabolism in people with type 2 diabetes mellitus likely will require normalization of insulin and glucagon secretion as well as hepatic insulin action.

NIDDM is associated with excessive rates of endogenous glucose production in both the postabsorptive and postprandial states. To determine whether this is due to an intrinsic increase in hepatic sensitivity to glucagon, 9 NIDDM and 10 nondiabetic subjects were studied on three occasions. On each occasion, glycogen was labeled the evening before the study with subjects ingesting meals containing [6-3H]galactose. Beginning at 6:00 A.M. on the following morning, somatostatin was infused to inhibit endogenous hormone secretion. Insulin concentrations were maintained constant at basal levels (defined as that necessary to keep glucose at ∼5 mmol/l) in each individual. On one occasion, glucagon was infused at a rate of 0.65 ng ∼ kg−1 · min−1 throughout the experiment, resulting in glucagon concentrations of ∼130 pg/ml and a slow but comparable fall in endogenous glucose production with time in both groups. On the other two occasions, the glucagon infusion 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 ∼180 and 310 pg/ml, respectively. The increment in endogenous glucose production (i.e., area above basal) did not differ in diabetic and nondiabetic 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 vs. 1.10 ± 0.073 mmol/kg) glucagon infusions. In contrast, the amount of [6-3H]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 of [6-3H]glucose divided by the integrated release of unlabeled glucose, was lower (P < 0.05) in diabetic subjects than in nondiabetic subjects during both the 1.5 ng · kg−1 · min−1 (19.0 ± 3.9 vs. 41.4 ± 5.7 dpmμmol) and 3.0 ng · kg−1 · min−1 (19.1 ± 3.1 vs. 36.5 ± 7.2 dpm/μmol) 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 relative contributions of the direct and indirect pathways to nocturnal glycogen synthesis.

Abstract —Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10 −12 to 10 −7 mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10 −4 mol/L N G -monomethyl- l -arginine (L-NMMA) or the potassium channel blocker 10 −2 mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5±1.0 versus 1.9±0.08 mmol/L; P <0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin ( P =0.80) or IGF-1 ( P =0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79±6% versus 42±8%; P =0.01) but not insulin (43±6% versus 53±7%; P =0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA ( P <0.001) and TEA ( P =0.01), whereas only L-NMMA attenuated insulin ( P <0.001). Staining for IGF-1 and IGF binding protein 2 was increased ( P <0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.