Sham feeding-induced cephalic phase insulin release in the rat

1982 ◽  
Vol 242 (4) ◽  
pp. E280-E285 ◽  
Author(s):  
H. R. Berthoud ◽  
B. Jeanrenaud
Keyword(s):  
Insulin Release ◽  
Intravenous Administration ◽  
Hepatic Glucose Production ◽  
Insulin Response ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Adrenergic Stimulation ◽  
Sham Feeding ◽  
Cephalic Phase ◽  
Atropine Methyl Nitrate

The effect of the cephalic phase of food ingestion on plasma insulin and glucagon concentration was assessed in the sham-feeding rat, bearing chronically implanted gastric drainage fistulas. It was found that continuous sham feeding produced a significant and phasic peripheral insulin response in the absence of any significant changes of glycemia. The response was almost completely blocked by prior intravenous administration of 2 mg/kg of atropine methyl nitrate and potentiated by prior intravenous administration of 1.0 or 2.5 mg/kg of phentolamine. In spite of the larger insulin response after phentolamine, there was no hypoglycemia detected. Furthermore, continuous sham feeding did not produce a significant glucagon response, whereas real feeling did. The results demonstrate that cholinergic insulin release is triggered phasically by continuous ingestion of familiar food and that this insulin response is inhibited by an alpha-adrenergic sympathetic tone. It is further concluded that the increased glucose disposal produced by the neurally released insulin is not counteracted by a concomitant glucagon response or by direct adrenergic stimulation of hepatic glucose production.

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

1993 ◽  
Vol 264 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
L. Rossetti ◽  
S. Farrace ◽  
S. B. Choi ◽  
A. Giaccari ◽  
L. Sloan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

1990 ◽  
Vol 259 (2) ◽  
pp. E210-E215 ◽  
Author(s):  
J. R. Lupien ◽  
M. F. Hirshman ◽  
E. S. Horton
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Glucose Turnover ◽  
Adrenergic Blockade ◽  
Sprague Dawley ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Peripheral Tissues

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

1994 ◽  
Vol 77 (2) ◽  
pp. 534-541 ◽  
Author(s):  
J. Gao ◽  
W. M. Sherman ◽  
S. A. McCune ◽  
K. Osei
Keyword(s):  
Heart Failure ◽  
Insulin Sensitivity ◽  
Acute Exercise ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

Contribution of central and peripheral adrenergic stimulation to IL-1 alpha-mediated glucoregulation

1994 ◽  
Vol 267 (1) ◽  
pp. E49-E56 ◽  
Author(s):  
F. Petit ◽  
A. Jarrous ◽  
R. D. Dickinson ◽  
P. E. Molina ◽  
N. N. Abumrad ◽  
...  
Keyword(s):  
Metabolic Response ◽  
Hepatic Glucose Production ◽  
Plasma Catecholamines ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Whole Body ◽  
Intracerebroventricular Injection ◽  
Central Administration ◽  
Adrenergic Stimulation ◽  
Sympathoadrenal Activity

The present study determined the contribution of central adrenoceptors and the peripheral sympathetic nervous system in regulating the hormonal and glucose metabolic response to intracerebroventricular injection of interleukin (IL)-1 alpha. After an overnight fast, hepatic glucose production (HGP) and peripheral glucose uptake (GU) were assessed in catheterized conscious unrestrained rats using [3-3H]glucose. Intracerebroventricular injection of IL-1 alpha (100 ng) produced a hyperglycemia that resulted from an early increase in HGP (108%) that exceeded a smaller elevation (82%) in GU. Intracerebroventricular injection of the alpha- and beta-adrenergic antagonists phentolamine and propranolol before IL-1 alpha blunted the glucose metabolic response 30-50%. This attenuated response was associated with normalization of the IL-1 alpha-induced hyperglucagonemia and hyperinsulinemia and a 50-60% reduction in the incremental increase in plasma catecholamines. In contrast to central administration, systemic infusion of adrenergic blockers completely prevented the IL-1 alpha-induced increases in plasma glucose, as well as HGP and GU. In these rats, the elevated plasma levels of insulin, glucagon, and corticosterone produced by intracerebroventricular injection of IL-1 alpha were still present. The results indicate that 1) the enhanced whole body glucose metabolism seen after central administration of IL-1 alpha is mediated by increased sympathoadrenal activity and 2) the IL-1 alpha-induced increase in pancreatic insulin and glucagon secretion as well as part of the peripheral catecholamine release is mediated by central adrenoreceptors.

Insulin-stimulated glucose uptake is enhanced in sedentary and endurance-trained low insulin responders

1995 ◽  
Vol 268 (6) ◽  
pp. E1046-E1050 ◽  
Author(s):  
J. Pigon ◽  
S. Efendic ◽  
C. G. Ostenson ◽  
L. Lam ◽  
M. Vranic ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Insulin Response ◽  
Glucose Production ◽  
Normal Glucose Tolerance ◽  
Utilization Rate ◽  
Healthy Population ◽  
Appearance Rate ◽  
Normal Glucose ◽  
High Insulin

The mechanisms by which healthy sedentary subjects with low insulin response (LIR; 5-min insulin response to glucose load within lowest quartile of healthy population) maintain a normal glucose tolerance are not clear. We studied glucose uptake and hepatic glucose production in LIR, in healthy subjects with high insulin response (HIR; two highest quartiles of insulin response) matched for weight and physical fitness, and in endurance-trained subjects (ET). For this purpose, we performed hyperinsulinemic euglycemic clamps using the “hot-GINF” method with high-pressure liquid chromatography purified [6-3H]glucose. All groups had a similar basal glucose appearance rate (Ra). During clamps, plasma insulin levels were doubled to 169 +/- 9 pmol/l, whereas Ra decreased similarly in all groups. Glucose utilization rate increased more in LIR and ET than in HIR (to 20.9 +/- 1.5 mumol.kg-1.min-1 in LIR, P < 0.001 vs. HIR; 27.4 +/- 3.6 in ET, P < 0.01 vs. HIR and LIR; and 14.3 +/- 0.6 in HIR). In conclusion, the present study demonstrates increased insulin sensitivity in LIR and ET with respect to glucose uptake but not glucose production.

Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele

1997 ◽  
Vol 273 (4) ◽  
pp. E743-E750 ◽  
Author(s):  
Luciano Rossetti ◽  
Wei Chen ◽  
Meizhu Hu ◽  
Meredith Hawkins ◽  
Nir Barzilai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Relative Role ◽  
Β Cells ◽  
Plasma Insulin Concentration ◽  
Hyperglycemic Clamp ◽  
Human Diabetes ◽  
Hepatic Glucose

Glucokinase (GK) catalyzes the phosphorylation of glucose in β-cells and hepatocytes, and mutations in the GK gene have been implicated in a form of human diabetes. To investigate the relative role of partial deficiencies in the hepatic vs. pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic glucose production (HGP) in response to hyperglycemia in transgenic mice 1) with one disrupted GK allele, which manifest decreased GK activity in both liver and β-cells (GK+/−), and 2) with decreased GK activity selectively in β-cells (RIP-GKRZ). Liver GK activity was decreased by 35–50% in the GK+/− but not in the RIP-GKRZ compared with wild type (WT) mice. Hyperglycemic clamp studies were performed in conscious mice with or without concomitant pancreatic clamp. In all studies [3-3H]glucose was infused to measure the rate of appearance of glucose and HGP during 80 min of euglycemia (Glc ∼5 mM) followed by 90 min of hyperglycemia (Glc ∼17 mM). During hyperglycemic clamp studies, steady-state plasma insulin concentration, rate of glucose infusion, and rate of glucose disappearance (Rd) were decreased in both GK+/− and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged ∼22 mg ⋅ kg−1 ⋅ min−1in all groups, during hyperglycemia HGP was suppressed by only 48% in GK+/− compared with ∼70 and 65% in the WT and RIP-GKRZ mice, respectively. During the pancreatic clamp studies, the ability of hyperglycemia per se to increase Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/−, vs. 42 and 45%, respectively, in the WT and RIP-GKRZ mice. We conclude that, although impaired glucose-induced insulin secretion is common to both models of decreased pancreatic GK activity, the marked impairment in the ability of hyperglycemia to inhibit HGP is due to the specific decrease in hepatic GK activity.

Islet cell responses to glucose in human transplanted pancreas

1991 ◽  
Vol 261 (6) ◽  
pp. E800-E808 ◽  
Author(s):  
D. Elahi ◽  
B. A. Clark ◽  
M. McAloon-Dyke ◽  
G. Wong ◽  
R. Brown ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Normal Subjects ◽  
Systemic Circulation ◽  
Glucose Disposal ◽  
Complete Suppression ◽  
Transplant Patients ◽  
Hyperglycemic Clamp ◽  
Hepatic Glucose ◽  
Glucose Output

Postsurgery, pancreas transplantation results in alterations of carbohydrate metabolism. Additionally, immunosuppressive therapy impacts on glucose regulation. We evaluated the hormonal and metabolic responses of pancreas allografts, utilizing the hyperglycemic clamp technique coupled with the tritiated glucose methodology, in 11 volunteers who had received simultaneous pancreas-kidney transplantation (P-K) with systemic drainage. Their responses were compared with seven volunteers who had received only a kidney (K) graft and with seven normal control (C) volunteers. Although basal glucose and hepatic glucose output were similar in all three groups, basal insulin, C-peptide, glucagon, and pancreatic polypeptide were highest in the P-K group and lowest in normal subjects. During hyperglycemia, all groups showed a similar characteristic, initial complete suppression of hepatic glucose production, with recovery followed by a later suppression. Peripheral glucose uptake was similar in P-K and C subjects but decreased in K patients. Systemic insulin levels were fourfold higher in the pancreas transplant patients than in healthy subjects. Thus, under basal and hyperglycemic stimulation, 1) hepatic glucose homeostasis is regulated normally, even with pancreatic drainage into the systemic circulation; 2) overall glucose disposal is normal in P-K patients because of marked hyperinsulinemia; and 3) there is loss of tonic inhibition of endocrine pancreatic function secondary to pancreatic denervation.

Effects of physiological hyperinsulinemia on the intracellular metabolic partition of plasma glucose

1993 ◽  
Vol 265 (6) ◽  
pp. E943-E953 ◽  
Author(s):  
R. C. Bonadonna ◽  
S. del Prato ◽  
E. Bonora ◽  
G. Gulli ◽  
A. Solini ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Healthy Subjects ◽  
Glucose Oxidation ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Glucose Recycling

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring 3H2O and 14CO2 rates of production during [3-3H]- and [U-14C]glucose infusion, was tested in healthy subjects. In study 1, during staircase 3H2O infusion in six subjects, calculated rates of 3H2O appearance agreed closely with 3H2O infusion rates. In study 2, when [2-3H]glucose and NaH14CO3 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 microU/ml) clamp, accurate estimates of the rates of [2-3H]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of NaH14CO3 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 microU/ml) clamp with [3-3H]- and [U-14C]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0.17 mg.min-1 x kg-1 of lean body mass (LBM), respectively, P < 0.01] and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.

scholarly journals Metabolic flexibility

2004 ◽  
Vol 63 (2) ◽  
pp. 363-368 ◽  
Author(s):  
Len Storlien ◽  
Nick D. Oakes ◽  
David E. Kelley
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Metabolic Flexibility ◽  
Disease States ◽  
The Metabolic Syndrome ◽  
Cephalic Phase ◽  
Metabolic Inflexibility

Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires ‘a clear capacity to utilize lipid and carbohydrate fuels and to transition between them’ ( Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed ‘metabolic flexibility’. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term ‘metabolic syndrome’. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained.

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

1988 ◽  
Vol 118 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Ole Schmitz
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

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