Mechanism of glucoregulatory responses to stress and their deficiency in diabetes.

Abstract

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...

Site and mechanism of leptin action in a rodent form of congenital lipodystrophy

“…obese and develop hepatic steatosis, while mice with a liver-specific knockout are not obese and do not develop hepatic steatosis (15). Our conclusion above is also consistent with previous studies showing that the CNS plays an important role in regulating glucose homeostasis (32). Several recent reports suggest that leptin can exert direct effects on peripheral tissues.…”

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

“…Basal alanine, glycerol, and FFA levels were higher than in normal dogs (32), but basal alanine and FFAs were lower in the group of dogs who underwent the half peripheral infusion than in the other groups, despite the same treatment in the basal state. Alanine decreased gradually (Fig.…”

“…In spite ofgreater hepatic insulinization with portal than half peripheral infusion, at matched peripheral insulin levels GP was suppressed to the same extent from 20.4± 1.0 to 9.0±1.3 ,umol -kg-*mind and from 19.3_±1.5 to 7.1±0. Basal MCR (not shown) was moderately lower than in normal dogs (32,33) and equivalent in the three groups (portal: 2.00±0.13; peripheral: 1.99±0.11; half peripheral: 1.97±0.16 ml* kg-' min-'). During the clamp, MCR increased to 2.84±0.31 with portal, 3.67±0.37 with equimolar peripheral, and 3.13±0.45 ml *kg-' -min' with half peripheral insulin infusion, levels that are also lower than those observed in normal dogs with similar infusion rates (15).…”

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