It is generally believed that glucose production (GP) cannot be adequately suppressed in insulin-treated diabetes because the portal-peripheral insulin gradient is absent. To determine whether suppression of GP in diabetes depends on portal insulin levels, we performed 3-h glucose and specific activity clamps in moderately hyperglycemic (10 mM) depancreatized dogs, using three protocols: (a) 54 pmols kg-' bolus + 5.4 pmol* kg-' -min' portal insulin infusion (a = 7; peripheral insulin = 170±51 pM); (b) an equimolar peripheral infusion (a = 7; peripheral insulin = 294±28 pM, P < 0.001); and (c) a half-dose peripheral infusion (a = 7), which gave comparable (157±13 pM) insulinemia to that seen in protocol 1. Glucose production, use (GU) and cycling (GC) were measured using HPLC-purified 6-13Hj-and 2-13Hjglucose. Consistent with the higher peripheral insulinemia, peripheral infusion was more effective than equimolar portal infusion in increasing GU. Unexpectedly, it was also more potent in suppressing GP (73±7 vs. 55±7% suppression between 120 and 180 min, P < 0.001). At matched peripheral insulinemia (protocols 2 and 3), not only stimulation of GU, but also suppression of GP was the same (55±7 vs. 63±4%). In the diabetic dogs at 10 mM glucose, GC was threefold higher than normal but failed to decrease with insulin infusion by either route. Glycerol, alanine, FFA, and glucagon levels decreased proportionally to peripheral insulinemia. However, the decrease in glucagon was not significantly greater in protocol 2 than in 1 or 3. When we combined all protocols, we found a correlation between the decrements in glycerol and FFAs and the decrease in GP (r = 0.6, P < 0.01). In conclusion, when suprabasal insulin levels in the physiological postprandial range are provided to moderately hyperglycemic depancreatized dogs, suppression of GP appears to be more dependent on peripheral than portal insulin concentrations and may be mainly mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and by the suppressive effect of insulin on glucagon secretion. These results suggest that a portal-peripheral insulin gradient might not be necessary to effectively suppress postprandial GP in insulin-treated diabetics. (J. Clin. Invest. 1992. 90:1769-1777

A bstract. Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 120) during exercise alone, exercise plus ST infusion (0.5 gg/kg-min), or exercise plus ST plus glucose replacement (3.5 mg/kgmin) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306±147 pg/ml, 360±80 pg/ml, 443±140 pg/ml, 541±173 geq/liter, and 6.3±0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2±4 ttU/ml and cortisol (C) increased only slightly (2.1±0.3 ug/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6±2.2 mg/ kg-min and 6.2±1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130±20 pg/ml, Ra rose by only 3.6±0.5 mg/kg-min, and plasma glucose decreased by 29±6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2±2.0 ,U/ ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4±1.3 ig/dl, 1,166±182 geq/liter and 15.5±7.0 mg/dl. The peak increment in E (765±287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7±0.8 mg/kg-min. During glucose replacement, IRG decreased by 109±30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5±0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled -70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not to the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E; (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagon during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.

During exercise, increased energy demands are met by increased glucose production that occurs simultaneously with the increased glucose uptake. We had previously observed that, during exercise, metabolic clearance rate of glucose (MCR) increases markedly in normal, but only marginally in poorly controlled diabetic dogs. We wished to determine (i) whether in a more general model of stress matched increases in rate of appearance of glucose and MCR also occur, or if MCR is suppressed, as during catecholamine infusion; and (ii) whether diabetes affects stress-induced changes in rate ofglucose appearance and MCR. Therefore, we injected carbachol (27 nmol/50 pl), an analog of acetylcholine, intracerebroventricularly in seven conscious dogs before and after induction of alloxan diabetes. In normal dogs, plasma epinephrine and cortisol increased 4-to 5-fold, whereas norepinephrine and glucagon doubled. Plasma insulin, however, remained unchanged. Tracer-determined hepatic glucose production increased rapidly, but transiently, by 2.5-fold. This increment can be fully explained by the observed increments in the counterregulatory hormones. Surprisingly, however, MCR also promptly increased, and therefore, plasma glucose changed only marginally. After induction of diabetes, the animals were given intracerebroventricular carbachol while plasma glucose was maintained at moderate hyperglycemia (9.0 ± 0.4 mM). Increments in counterregulatory hormones were similar to those seen in normal dogs, except for exaggerated norepinephrine release. Peripheral insulin levels were higher in diabetic than in normal dogs; however, MCR was markedly reduced and the lipolytic response to stress increased, indicating insulin resistance. Interestingly, the hyperglycemic response to stress was 6-fold greater in diabetic than normal animals, relating mainly to the failure of MCR to rise. Plasma lactate increased equivalently in diabetic and normal animals despite suppression ofMCR in the diabetics, indicating either greater muscle glycogenolysis and/or impairment in glucose oxidation. We conclude that in this stress model MCR increases as in exercise in normal but not in diabetic dogs. We speculate that glucose uptake in stress could be mediated through an insulin-dependent neural mechanism.The obligatory requirement of the brain for glucose necessitates a precise mechanism for glucose homeostasis. The hormonal and metabolic responses to stress have been examined under a variety of stress conditions such as severe injury (1, 2), major surgery (3, 4), myocardial infarction (4, 5), and emotional stress (6); however, the glucoregulatory mechanisms are not fully understood. In exercise, another form of stress, the peripheral energy requirements necessitate changes in glucose metabolism, whereby the augmented rate ofglucose utilization (glucose disappearance; Rd) is precisely matched with an elevated rate of hepatic glucose production (glucose appearance; Ra), thus averting the threat of hypoglycemia (7). There is also a safeguard against hyperg...

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