In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions
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Abstract:
Ventromedial hypothalamic (VMH)-lesioned rats were tested 1 and 6 wk after the lesions to determine, by euglycemic-hyperinsulinemic clamps, their tissue response to insulin. One week after the lesions, total glucose metabolism was more sensitive and responsive to insulin than in age-matched controls. In the two groups, hepatic glucose production was suppressed at almost identical insulin concentrations (approximately 550 microU/ml). Six weeks after the VMH lesions, the increased insulin responsiveness of total glucose metabolism disappeared and glucose metabolism became less insulin sensitive (right, shifted dose-response curve) than that of control animals. Furthermore, hepatic glucose production of VMH-lesioned rats was now inhibited by 45% at most and at the supraphysiological insulin concentration of 16,000 microU/ml, while it was totally suppressed by 550 microU/ml of the hormone in age-matched controls. This defect was accompanied by a lack of decrease in plasma glucagon levels during the clamps carried out at maximal insulin concentration. In summary, in a first phase after VMH lesion, rats are hypersensitive and hyperresponsive to insulin; and in a later phase, when obesity is well established, VMH-lesioned rats become insulin resistant and are characterized by a decreased in vivo sensitivity and responsiveness of liver and muscles to the hormone.Keywords:
Carbohydrate Metabolism
Using perfused liver of the rat, the hepatic uptake of glycosylated insulin (GI) and glucagon (GG) and its effects on hepatic glucose output were investigated. Insulin and glucagon were glycosylated in ambient high glucose concentration, and GI80 or GG80 (insulin or glucagon incubated with 0.08% glucose), GI350 or GG350 (incubated with 0.35% glucose), and GI1000 or GG1000 (incubated with 1% glucose) were prepared. The liver was perfused with the medium containing 1000 microU/ml insulin and 200 pg/ml glucagon or 200 microU/ml insulin and 1000 pg/ml glucagon. The fractional uptake of insulin or glucagon by perfused liver was not significantly altered by the glycosylation. In the liver perfused with 1000 microU/ml insulin and 200 pg/ml glucagon, glucose output was not changed by the glycosylation of the hormones, while in the liver perfused with 200 microU/ml insulin and 1000 pg/ml glucagon, GI1000 reduced its biological activity, as reflected by insulin-mediated decrease in glucose output. These results suggest that in the liver insulin incubated with markedly high concentration of glucose reduces its biological activity at a physiological concentration in the presence of high concentration of glucagon.
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The metabolic effects of glucagon leading to hyperglycaemia are well recognised. However, the spasmolytic properties of glucagon have only relatively recently been utilised in clinical medicine. The marked hyperglycaemia accompanying the smooth muscle relaxant action of glucagon has led to the development of smaller peptides derived from glucagon which may retain the spasmolytic effects without the metabolic consequences. This study compares the metabolic and hormonal response to one such peptide, glucagon‐(1‐21)‐peptide, with the parent peptide glucagon. The results demonstrate that glucagon‐(1‐21)‐peptide has no metabolic effects comparable to glucagon. In normal subjects and non‐ insulin dependent diabetics, glucagon‐(1‐21)‐peptide has no stimulatory effect on the pancreatic beta‐cell.
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Alpha cell
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We assessed hepatic glucagon sensitivity in overnight-fasted, conscious dogs. Six pancreatic replacement protocols were performed in each of five animals. Somatostatin was infused to inhibit endogenous insulin and glucagon, insulin was replaced intraportally at 200 microU.min-1.kg-1, and glucagon was infused intraportally at 0, 0.6, 1, 2, 5, or 20 ng.min-1.kg-1. One intravenous glucose tolerance test was also performed in each animal for measurement of insulin sensitivity (SI). During hormone replacement at a given glucagon dose, plasma glucose differed substantially among animals (P = 0.003). Therefore the dose required for restoration of euglycemia (“glucagon requirement”) varied nearly sevenfold among animals, suggesting appreciable differences in glucagon sensitivity (GS). The latter was quantitated in individual animals as the initial slope of integrated glucose output vs. glucagon concentration. GS varied from 0.22 to 3.9 mg.kg-1.pg-1.ml among various animals and was inversely and significantly related to glucagon requirement. SI varied less (approximately 4-fold) and was not associated with glucagon requirement. These observations suggested that interanimal differences in glucose during hormone replacement were the result of substantial differences in GS. In addition, we found the GS of a given animal to be highly associated (P = 0.01) with its fasting glucose level. We conclude that GS varies substantially, and as such may be an important determinant of the fasting glucose level in normal animals.
Hormone replacement
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Sepsis is associated with a decrease in the intrinsic gluconeogenic capacity of hepatocytes. The mechanism underlying this depression is unknown. This study sought to investigate whether decreased expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate limiting enzyme in hepatic gluconeogenesis, might contribute to the decreased gluconeogenesis in sepsis. Therefore, we determined the effects of sepsis on the steady-state level of PEPCK mRNA and on PEPCK activity. Further, levels of insulin and glucagon, which modulate PEPCK expression under normal conditions, were also measured. Rats were subjected to either cecal ligation and puncture, or sham operation. Twenty-four hr later, the steady-state level of PEPCK mRNA was determined by Northern Blot hybridization analysis, and PEPCK activity was measured by 14C incorporation into phosphoenolpyruvate. Insulin and glucagon levels were determined by radioimmunoassay, and the insulin/glucagon ratio calculated. The steady-state levels of PEPCK mRNA were significantly decreased in septic animals relative to sham-operated animals. The specific activity of PEPCK in sham-operated animals was 1.67 +/- 0.25 U/mg protein, compared to 0.93 +/- 0.18 U/mg protein in septic animals (P < 0.05). The insulin/glucagon ratio was lower in septic animals than in sham-operated controls. To investigate the specific effect of the insulin-glucagon ratios observed in septic and sham operated rats on hepatocytes under non-septic conditions, cultures of primary rat hepatocytes were used. These cells were incubated with levels of insulin and glucagon equivalent to those found following cecal ligation and puncture or sham operation. Hormonal conditions designed to mimic sepsis were associated with an increase in PEPCK expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Gluconeogenesis
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Insulin, glucagon and somatostatin concentration were determined in the developing pancreas between 16 days <i>post coitum</i> and 10 days postnatal. Plasma insulin and glucagon concentrations were also measured. Pancreatic insulin content increased rapidly during the perinatal period and peaked in concentration on day 6 postnatal. Glucagon content also increased rapidly with the largest percentage increase occurring around the time of birth. The largest increase in somatostatin also occurred postnatally. Plasma insulin and glucagon concentrations were very high during the late fetal period. The insulin concentration fell immediately after birth and rose slowly toward adult levels during the remainder of the period examined. Plasma glucagon was high during the entire neonatal period. The degree of differentiation of the islet cells, as estimated by their content of specific hormone products, is discussed in relation to the changes in cell volume reported in the preceding paper.
Perinatal period
Pancreatic polypeptide
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The possible existence of circulating pancreatic type glucagon (immunoreactive glucagon as measured with a highly specific antibody) of extrapancreatic origin was investigated in 20-25 kg pigs after pancreatectomy. In intact conscious animals intravenous arginine infusions stimulated glucagon as well as insulin secretion, while blood glucose remained unaffected. Two weeks after pancreatectomy, and 48 hours after insulin withdrawal, basal glucagon and glucose concentrations were elevated (from 22 +/- 3.7 to 55 +/- 9.5 pmol/1 and 5.8 +/- 0.4 to 16.2 +/- 2.0 mmol/l, respectively), (mean +/- SEM), while insulin concentrations were either undetectable or very low. After pancreatectomy, however, glucagon concentrations no longer increased during arginine infusion. Gut type glucagon levels were not affected by pancreatectomy, and did not change during arginine infusion. When examined by gel filtration, plasma from unoperated pigs contained two components of pancreatic type glucagon, one coeluting with the glucagon marker, the other eluting earlier, probably reflecting larger molecular size. After pancreatectomy only this larger component was found in the plasma. The role of this component in the control of blood glucose is unknown.
Basal (medicine)
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The acute effects of bovine growth hormone (bGH) upon the release of glucagon and insulin from the isolated perfused rat pancreas were investigated in the presence of 5.6 niM glucose. Glucagon and insulin release occurred in response to 10−9, 10-8 and 10-7M bGH within 1–2 min and dissipated within 4 min; a significant increase was seen at 24 sec for glucagon and at 48 sec for insulin. In this concentration range, a dose-response relationship was established for both islet hormones. Upon the addition of 5 mM fumarate, glutamate, and pyruvate, glucagon and insulin release occurred also in response to 10-11 and 10-10M bGH. In the absence of glucose, in response to 10-7M bGH, the magnitude of glucagon release was similar to that seen with 5.6 mM glucose; but the release of insulin failed to occur. In the presence of 16.7 mM glucose, the release of glucagon was blunted and that of insulin augmented. The data indicate that growth hormone can stimulate acutely the release of glucagon and insulin at physiological as well as pharmacological concentrations. These rapid and short-lived effects are likely to be direct and not mediated through the generation of somatomedin. The stimulatory effect of growth hormone appears to favor the release of glucagon under conditions of glucose lack, and of insulin under conditions of glucose abundance. These results indicate that growth hormone may have a tonic effect on islet hormone release.
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The antagonistic effects of insulin and glucagon on glycogen formation and mobilization were studied in cultured 18-day foetal rat hepatocytes with regard to different modes of exposure. Hormone combinations were achieved with a constant dose of 10 nM-insulin (maximal for the glycogenic effect of this hormone) and increasing doses of glucagon [from 0.03 to 10 nM: concn. causing half-maximal response (ED50) = 0.3 nM)]. When insulin and glucagon were added simultaneously, increasing glucagon concentrations progressively depressed the glycogenic effect of insulin and 0.3 nM-glucagon antagonized the insulin effect completely. The maximal glycogenolytic effect of glucagon was observed at concentrations greater than 1 nM. When the two hormones were introduced successively, with an interval of 4 h between additions, the effect of the second hormone was always fully expressed between 4 and 8 h. at which time the effect of the first hormone had ceased; the dominance of glucagon over insulin was also lost, due to cell desensitization to glucagon. Both continuous or intermittent (10 min on/10 min off periods) exposure to insulin and/or glucagon gave similar antagonistic effects, while in cells exposed to insulin plus glucagon alternating with exposure to insulin or glucagon alone, the glycogenic effect of insulin was less or more antagonized respectively by glucagon. Whatever the situation, the results obtained could not be related to antagonism by a glucagon-induced rise in either cyclic AMP levels (ED50 = 3 nM) or cell-surface hormone binding. Thus, depending on the hormonal state and the mode of hormone administration, regulation of glycogenesis in cultured foetal hepatocytes appears to be different from that predicted by the insulin/glucagon molar ratio, which is strikingly altered in the perinatal period.
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The dynamics and interrelationships of glucagon and insulin secretion were studied in the isolated perfused rat pancreas by utilizing a series of compounds that stimulate the release of both hormone. Leucine, arginine, prostaglandins F2α and E2, bovine growth hormone, and isoproterenol were administered individually over 60-second intervals. The release of glucagon preceded that of insulin in response to all compounds tested. The rapidity of glucagon release varied in response to different secretagogues; the time course of insulin release was fairly constant. The timing and the magnitude of glucagon and insulin release did not correlate statistically. Conclusions: (1) pancreatic alpha cells respond more rapidly than beta cells to the same stimulus; (2) antecedent release of glucagon is not the principal mediator of insulin release in response to stimuli common to both hormones; and (3) endogenous glucagon may at best modify the release of insulin evoked by certain secretagogues.
Insulin oscillation
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