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The aim of the present study was to characterize the role of glucagon in countering the prolonged hypoglycemia resulting from insulin infusion and to determine whether its effect is manifest through glycogenolysis and/or gluconeogenesis. Two groups of 18-h fasted somatostatin-treated dogs were given intraportal insulin at 5 mU.kg-1.min-1. In one group (SimGGN; n = 6), glucagon was infused intraportally so as to mimic the normal response to hypoglycemia. In a second group (BasGGN; n = 6), glucagon was infused at a basal rate. Glucose turnover and gluconeogenesis were assessed by combining tracer and hepatic balance techniques. Exogenous glucose was infused as needed to maintain equivalent hypoglycemia at approximately 45 mg/dl in the two groups. Although glucagon concentrations were significantly different, the levels of other counterregulatory hormones were equivalent in both experimental protocols. Endogenous glucose production (EGP) in SimGGN doubled from 2.4 +/- 0.2 to 5.4 +/- 0.8 mg.kg-1.min-1 by 1 h before dropping to 4.5 +/- 0.2 mg.kg-1.min-1 in the 3rd h of insulin infusion. EGP in BasGGN was initially 2.5 +/- 0.1 mg.kg-1.min-1, unchanged by 1 h, and increased to 3.9 +/- 0.2 mg.kg-1.min-1 by the 3rd h of insulin infusion. In the 1st h of insulin infusion, the rise in gluconeogenesis in both groups was equal and represented only a small part of total EGP. By the 3rd h, gluconeogenesis was the major contributor to total EGP, and gluconeogenic efficiency increased significantly more in SimGGN than BasGGN (261 vs. 140%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia. Insulin was infused intraportally into normal 18-h-fasted conscious dogs at 2 (low, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during the high dose to maintain plasma glucose similar to low (50 +/- 1 mg/dl). Despite similar plasma glucose levels, epinephrine (2,589 +/- 260, 806 +/- 180 pg/ml), norepinephrine (535 +/- 60, 303 +/- 55 pg/ml), cortisol (12.1 +/- 1.5, 5.8 +/- 1.2 micrograms/dl), and pancreatic polypeptide (1,198 +/- 150, 598 +/- 250 pg/ml) were all increased in the presence of high-dose insulin (P < 0.05). Glucagon levels were similar during both insulin infusions. Hepatic glucose production, measured with [3-3H]-glucose, rose from 2.6 +/- 0.2 to 4.7 +/- 0.3 mg.kg-1.min-1 in response to high insulin (P < 0.01) but remained unchanged, 3.0 +/- 0.5 mg.kg-1.min-1, during low-dose infusions. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. By the final hour of the high-dose euglycemic clamps, cortisol (2.4 +/- 0.4 to 4.8 +/- 0.8 micrograms/dl) and norepinephrine (125 +/- 34 to 278 +/- 60 pg/ml) had increased (P < 0.05) compared with baseline. Plasma epinephrine levels remained unchanged during both series of euglycemic studies.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the relationship between decreases in glucose and metabolic regulation in the absence of counterregulatory hormones, we infused overnight-fasted, conscious, adrenalectomized dogs (lacking cortisol and EPI) with somatostatin (to eliminate glucagon and growth hormone) and intraportal insulin (30 pmol.kg-1.min-1), creating arterial insulin levels of approximately 2000 pM. Glucose was infused during one 120-min period, two 90-min periods, and one 45-min period to establish levels of 5.9 +/- 0.1, 3.4 +/- 0.1, 2.5 +/- 0.1, and 1.7 +/- 0.1 mM, respectively. NE levels were 1.24 +/- 0.23, 1.85 +/- 0.27, 2.04 +/- 0.26, and 2.50 +/- 0.20 nM, respectively. During the euglycemic control period, the liver took up glucose (7.5 +/- 1.9 mumol.kg-1.min-1), but hypoglycemia triggered successively greater rates of net hepatic glucose output (3.0 +/- 0.7, 4.6 +/- 0.9, and 6.9 +/- 1.4 mumol.kg-1.min-1). Total gluconeogenic precursor uptake by the liver increased with hypoglycemia. Intrahepatic gluconeogenic efficiency rose progressively (by 106 +/- 42, 199 +/- 56, and 268 +/- 55%). Both glycerol and NEFA levels rose, indicating lipolysis was enhanced. Net hepatic NEFA uptake and ketone production increased proportionally, but the ketone level rose only with severe hypoglycemia. In conclusion, despite marked hyperinsulinemia and the absence of glucagon, EPI, and cortisol, we observed that lipolysis and glucose and ketone production increase in response to decreases in glucose. This suggests that neural and/or autoregulatory mechanisms can play a role in combating hypoglycemia.