The effects of the exercise-induced rise in glucagon were studied during 2.5 h of treadmill exercise in 18-h fasted dogs. Five dogs were studied during paired experiments in which pancreatic hormones were clamped at basal levels during a control period (using somatostatin and intraportal hormone replacement), then altered during exercise to stimulate the normal exercise-induced fall in insulin, while glucagon was 1) increased to mimic its normal exercise-induced rise (SG) and 2) maintained at a basal level (BG). Six additional dogs were studied as described with saline infusion alone (C). Gluconeogenesis (GNG) and glucose production (Ra) were measured using tracers [( 3-3H]glucose and [U-14C]alanine) and arteriovenous differences. Glucose fell slightly during exercise in C and was infused in SG and BG so as to mimic the response in C. Glucagon rose from 60 +/- 3 and 74 +/- 5 pg/ml to 118 +/- 14 and 122 +/- 17 pg/ml with exercise in C and SG and was unchanged from basal in BG (67 +/- 6 pg/ml). In C, SG, and BG, insulin fell during exercise by 5 +/- 1, 6 +/- 1, and 6 +/- 1 microU/ml. Ra rose from 3.3 +/- 0.2 and 3.0 +/- 0.2 mg.kg-1.min-1 to 8.6 +/- 0.8 and 9.5 +/- 1.5 mg.kg-1.min-1 with exercise in C and SG, but from only 3.0 +/- 0.2 to 5.5 +/- 0.8 mg.kg-1.min-1 in BG. GNG increased by 248 +/- 38 and 183 +/- 75% with exercise in C and SG but by only 56 +/- 21% in BG. Intrahepatic gluconeogenic efficiency was also enhanced by the rise in glucagon increasing by 338 +/- 55 and 198 +/- 52% in C and SG but by only 54 +/- 46% in BG. The rise in hepatic fractional alanine extraction was 0.38 +/- 0.04 and 0.33 +/- 0.04 during exercise in C and SG and only 0.08 +/- 0.06 in BG. Ra was increased beyond that which could be explained by effects on GNG alone, hence hepatic glycogenolysis must have also been enhanced by the rise in glucagon. In conclusion, in the dog, the exercise-induced rise in glucagon 1) controls approximately 65% of the increase in Ra, 2) increases hepatic glycogenolysis and GNG, and 3) enhances GNG by stimulating precursor extraction by the liver and precursor conversion to glucose within the liver.

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84±6 vs. 86±6 jU/ml) but differing insulin levels in the head (84±6 vs.195±5 jLU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56±2 mg/dl) at a value similar to that seen during head insulin infusion (58±2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792±198 vs. 2394±312 pg/ml), norepinephrine (404±33 vs. 778±93 pg/ml), cortisol (6.8±1.8 vs. 9.8±1.6 ,ug/dl) and pancreatic polypeptide (722±273 vs. 1061±255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6±0.2 to 4.3±0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6±0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes. (J. Clin. Invest. 1995. 95:593-602.)

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)

The aim of this study was to determine if differing periods of prior hyperinsulinemic nonhypoglycemia can modify the subsequent counterregulatory response to hypoglycemia. Experiments were carried out on 19 normal 18-h fasted conscious dogs. Insulin was infused intraportally at 8 mU.kg-1.min-1 for 3 h on two occasions and 3.5 h on a third separate occasion. This resulted in similar steady-state arterial insulin levels during each protocol (4,370 +/- 433 pmol/l). Each animal was maintained at a similar plasma glucose nadir (2.8 +/- 0.6 mmol/l) for 2 or 2.5h, depending on the protocol. In protocol I (n = 7) plasma glucose was allowed to fall to the desired hypoglycemic plateau by 30 min. In a second group of dogs (protocol II, n = 5) there was a 30-min period of euglycemic hyperinsulinemia followed by a 30-min fall (similar to protocol I) in plasma glucose. In a third group of dogs (protocol III, n = 7), there was an initial 15-min period of euglycemic hyperinsulinemia followed by a 45-min fall in plasma glucose. Differing periods of euglycemic hyperinsulinemia had distinct effects on subsequent counterregulation. During the final 2 h of hypoglycemia the incremental area under the curve (AUC) for glucagon was significantly greater in protocol I vs. II (3.0 +/- 1.0, -0.5 +/- 0.2 micrograms.l-1.min-1, P < 0.02, respectively). Conversely, catecholamine levels were increased in protocol II (30 min prior hyperinsulinemic euglycemia) compared with protocol I (epinephrine 1,448 +/- 268, 855 +/- 119 nmol.l-1.min-1; norepinephrine 244 +/- 30, 166 +/- 23 nmol.l-1.min-1, respectively, P < 0.05). During protocol III, glucagon and catecholamine levels were intermediate between protocols I (no euglycemic hyperinsulinemia) and II (30 min euglycemic hyperinsulinemia).(ABSTRACT TRUNCATED AT 250 WORDS)

To assess compensation for the absence of the exercise-induced fall in insulin, dogs underwent 150 min of treadmill exercise with insulin infused intraportally with (IC + Glc; n = 7) or without (IC; n = 6) glucose clamped. Glucose production (Ra), gluconeogenic conversion (Conv), and intrahepatic gluconeogenic efficiency (Eff) were assessed with tracers ([3H]glucose, [14C]alanine) and arteriovenous differences. Glucose fell by 6 +/- 4 and 11 +/- 2 mg/dl at 30 min of exercise and by 8 +/- 2 and 36 +/- 5 mg/dl at 150 min in IC + Glc and IC. Glucagon rose by 16 +/- 8 and 55 +/- 17 pg/ml by 30 min of exercise and by 18 +/- 6 and 93 +/- 22 pg/ml by 150 min in IC + Glc and IC. Norepinephrine was unaffected by the glycemic decrement in IC, whereas epinephrine was greater for the last 60 min of exercise. Ra rose by an average of 0.9 +/- 0.3 and 3.7 +/- 0.2 mg.kg-1.min-1 in IC + Glc and IC. Conv rose by 91 +/- 39 and 325 +/- 75% in IC + Glc and IC at 150 min of exercise, and Eff rose by 87 +/- 57 and 358 +/- 99%. The compensatory Ra exceeded the maximum possible gluconeogenic rate, indicating that glycogenolysis was also stimulated. In summary, in the absence of the exercise-induced fall in insulin 1) glycemia falls approximately fourfold faster; 2) minimal glycemic decrements elicit a large and rapid increase in Ra; 3) this compensation involves a glycogenolytic and gluconeogenic response; 4) the accelerated gluconeogenic rate is due, in large part, to stimulation of Eff; and 5) the compensatory Ra is likely mediated, in part, by glucagon. Hence, although the fall in insulin is essential for normal glucoregulation during exercise, a highly sensitive counterregulatory response prevents severe hypoglycemia. The remarkable sensitivity of the liver to small changes in glycemia implies that the normal coupling of the exercise-induced increase in Ra to glucose utilization may be signaled by small, nearly imperceptible changes in glucose.