GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet

2010 ◽  
Vol 299 (2) ◽  
pp. E318-E324 ◽  
Author(s):  
Edwin T. Parlevliet ◽  
Judith E. de Leeuw van Weenen ◽  
Johannes A. Romijn ◽  
Hanno Pijl
Keyword(s):  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
High Fat ◽  
Insulin Resistant ◽  
Endogenous Insulin ◽  
Endogenous Glucose ◽  
Glucagon Like Peptide 1 ◽  
The Impact

Glucagon-like peptide-1 (GLP-1) improves insulin sensitivity in humans and rodents. It is currently unknown to what extent the (metabolic) effects of GLP-1 treatment are mediated by central GLP-1 receptors. We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fat-fed insulin-resistant C57Bl/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icv). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57Bl/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model.

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

2003 ◽  
Vol 285 (4) ◽  
pp. E701-E707 ◽  
Author(s):  
Ronald L. Prigeon ◽  
Shaista Quddusi ◽  
Breay Paty ◽  
David A. D'Alessio
Keyword(s):  
Plasma Glucose ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Preliminary Evidence ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Islet Hormones ◽  
Islet Hormone ◽  
Endogenous Glucose ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 ± 14 vs. 113 ± 11 pM; 0.153 ± 0.029 vs. 0.156 ± 0.026 nM; and 64.7 ± 11.5 vs. 65.8 ± 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 ± 0.2 to a nadir of 4.1 ± 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 ± 2.8 to 19.1 ± 2.8 μmol · kg–1 · min–1 ( P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.

Alterations in carbohydrate metabolism in response to short-term dietary carbohydrate restriction

2005 ◽  
Vol 289 (2) ◽  
pp. E306-E312 ◽  
Author(s):  
Matthew P. Harber ◽  
Simon Schenk ◽  
Ariel L. Barkan ◽  
Jeffrey F. Horowitz
Keyword(s):  
Glucose Uptake ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Carbohydrate Oxidation ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
Carbohydrate Restriction ◽  
Dietary Carbohydrate ◽  
Endogenous Glucose ◽  
Glucose Availability

Dietary carbohydrate restriction (CR) presents a challenge to glucose homeostasis. Despite the popularity of CR diets, little is known regarding the metabolic effects of CR. The purpose of this study was to examine changes in whole body carbohydrate oxidation, glucose availability, endogenous glucose production, and peripheral glucose uptake after dietary CR, without the confounding influence of a negative energy balance. Postabsorptive rates of glucose appearance in plasma (Ra; i.e., endogenous glucose production) and disappearance from plasma (Rd; i.e., glucose uptake) were measured using isotope dilution methods after a conventional diet [60% carbohydrate (CHO), 30% fat, and 10% protein; kcals = 1.3 × resting energy expenditure (REE)] and after 2 days and 7 days of CR (5% CHO, 60% fat, and 35% protein; kcals = 1.3 × REE) in eight subjects (means ± SE; 29 ± 4 yr; BMI 24 ± 1 kg/m2) during a 9-day hospital visit. Postabsorptive plasma glucose concentration was reduced ( P = 0.01) after 2 days but returned to prediet levels the next day and remained at euglycemic levels throughout the diet (5.1 ± 0.2, 4.3 ± 0.3, and 4.8 ± 0.4 mmol/l for prediet, 2 days and 7 days, respectively). Glucose Ra and glucose Rd were reduced to below prediet levels (9.8 ± 0.6 μmol·kg−1·min−1) after 2 days of CR (7.9 ± 0.3 μmol·kg−1·min−1) and remained suppressed after 7 days (8.3 ± 0.4 μmol·kg−1·min−1; both P < 0.001). A greater suppression in carbohydrate oxidation, compared with the reduction in glucose Rd, led to an increased (all P ≤ 0.05) rate of nonoxidative glucose disposal at 7 days (5.2 ± 0.5 μmol·kg−1·min−1), compared with 2 days (2.7 ± 0.5 μmol·kg−1·min−1) and prediet (1.6 ± 0.8 μmol·kg−1·min−1). In response to eucaloric CR, a marked increase in nonoxidative glucose disposal may help maintain systemic glucose availability.

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

2002 ◽  
Vol 282 (6) ◽  
pp. E1360-E1368 ◽  
Author(s):  
Thongchai Pratipanawatr ◽  
Wilailak Pratipanawatr ◽  
Clifford Rosen ◽  
Rachele Berria ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Control Subjects ◽  
Igf I ◽  
Plasma Ffa ◽  
Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

Enteral infusion of glucose at rates approximating EGP enhances glucose disposal but does not cause hypoglycemia

2003 ◽  
Vol 285 (2) ◽  
pp. E280-E286 ◽  
Author(s):  
Farhad Zangeneh ◽  
Rita Basu ◽  
Pankaj Shah ◽  
Puneet Arora ◽  
Michael Camilleri ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Glucose Sensor ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Wild Type ◽  
Glucose Disappearance ◽  
Endogenous Glucose ◽  
Glucose Plasma ◽  
Portal Infusion

Portal infusion of glucose at rates approximating endogenous glucose production (EGP) causes paradoxical hypoglycemia in wild-type but not GLUT2 null mice, implying activation of a specific portal glucose sensor. To determine whether this occurs in humans, glucose containing [3-3H]glucose was infused intraduodenally at rates of 3.1 mg · kg-1 · min-1 ( n = 5), 1.55 mg · kg-1 · min-1 ( n = 9), or 0/0.1 mg · kg-1 · min-1 ( n = 9) for 7 h in healthy nondiabetic subjects. [6,6-2H2]glucose was infused intravenously to enable simultaneous measurement of EGP, glucose disappearance, and the rate of appearance of the intraduodenally infused glucose. Plasma glucose concentrations fell ( P < 0.01) from 90 ± 1 to 84 ± 2 mg/dl during the 0/0.1 mg · kg-1 · min-1 id infusions but increased ( P < 0.001) to 104 ± 5 and 107 ± 3 mg/dl, respectively, during the 1.55 and 3.1 mg · kg-1 · min-1 id infusions. In contrast, insulin increased ( P < 0.05) during the 1.55 and 3.0 mg · kg-1 · min-1 infusions, reaching a peak of 10 ± 2 and 18 ± 5 μU/ml, respectively, by 2 h. Insulin concentrations then fell back to concentrations that no longer differed by study end (7 ± 1 vs. 8 ± 1 μU/ml). This resulted in comparable suppression of EGP by study end (0.84 ± 0.2 and 0.63 ± 0.1 mg · kg-1 · min-1). Glucose disappearance was higher ( P < 0.01) during the final hour of the 3.1 than 1.55 mg · kg-1 · min-1 id infusion (4.47 ± 0.2 vs. 2.6 ± 0.1 mg · kg-1 · min-1), likely because of the slightly, but not significantly, higher glucose and insulin concentrations. We conclude that, in contrast to mice, selective portal glucose delivery at rates approximating EGP does not cause hypoglycemia in humans.

scholarly journals Insulin action and glucose metabolism in sheep fed on dried-grass or ground, maize-based diets

1985 ◽  
Vol 54 (2) ◽  
pp. 459-471 ◽  
Author(s):  
A. N. Janes ◽  
T. E. C. Weekes ◽  
D. G. Armstrong
Keyword(s):  
Glucose Metabolism ◽  
Insulin Action ◽  
Plasma Insulin ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Metabolic Clearance ◽  
Endogenous Glucose

1. The effect of an exogenous supply of glucose, provided by the digestion of maize starch in the small intestine, on endogenous glucose metabolism and insulin action was studied in sheep using the euglycaemic insulin clamp procedure.2. Insulin was infused intravenously at rates of 0.2, 0.5, 1.0 and 6.0 mU/min per kg live weight for four consecutive periods in each of four sheep fed on dried-grass and maize-based diets. Glucose was also infused intravenously at a variable rate, sufficient to maintain the plasma glucose concentration at basal levels. Whole-body rates of glucose metabolism were determined using a continuous infusion of [6-3H]glucose.3. From the resultinginsulin dose-response curves, it was observed that, when the sheep were fed on the dried-grass diet, the responsiveness of glucose metabolism to insulin was less than that reported for non-ruminants.4. When fed the maize-based diet, the glucose metabolic clearance rates (MCR) observed during insulin infusions were significantly greater (P < 0.05) than those observed for the dried-grass diet. However, after correcting for the non-insulin-mediated glucose disposal, differences between diets were not significant.5. The sensitivity of glucose utilization to insulin was not affected by diet. The plasma insulin concentrations causing half-maximal insulin-mediated glucose MCR were 103 (SE 21) and 85 (SE 11) mU/l for the dried-grass and maize-based diets respectively.6. The sensitivity of endogenous glucose production to insulin was also unaffected by diet. The plasma insulin concentrations resulting in the suppression of endogenous glucose production to half the basal level were 80 (SE 26) and 89 (SE 29) mU/l for the dried-grass and maize-based diets respectively.7. It is concluded that the observed increase in glucose utilization on the maize-based diet was due partly to a slight change in responsiveness to insulin and also partly to a change in the rate of non-insulin-mediated glucose disposal.

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.

Inhibition by insulin of hepatic glucose production in the normal dog

1965 ◽  
Vol 208 (2) ◽  
pp. 301-306 ◽  
Author(s):  
R. Steele ◽  
J. S. Bishop ◽  
A. Dunn ◽  
N. Altszuler ◽  
I. Rathgeb ◽  
...  
Keyword(s):  
Production Rate ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Release ◽  
Endogenous Insulin ◽  
Intravenous Insulin ◽  
Hepatic Glucose ◽  
Endogenous Glucose

Glucose-C14 was given intravenously in trace amount as an initial dose followed by continuous infusion to tag the circulating glucose of normal unanesthetized dogs in the post-absorptive state. The rate of dilution of this circulating tagged glucose by new (C12) glucose produced endogenously was measured. The release to the blood of such new glucose, presumably almost entirely from liver, was reduced by half during the 1st hr of intravenous insulin infusion at 0.1 U/kg per hr or more, provided that enough glucose was also infused to limit hypoglycemia. During the 2nd hr new glucose release was reduced by three-quarters or more. Insulin infusion at lower rates (02–.04 U/kg per hr), along with glucose, produced smaller effects. Glucose alone, infused intravenously in amounts sufficient to raise plasma glucose concentration, and hence presumed to enhance endogenous insulin secretion, reduced new glucose release by half during the 1st hr of infusion at one-half to one and one-half times the resting endogenous glucose production rate In the 2nd or 3rd hr, with glucose infusion increased to two to five times the resting endogenous glucose production rate, new glucose release was reduced by three-fourths or more.

scholarly journals Effects of maternal undernutrition and exercise on glucose kinetics in fetal sheep

1990 ◽  
Vol 64 (2) ◽  
pp. 463-472 ◽  
Author(s):  
B. J. Leury ◽  
K. D. Chandler ◽  
A. R. Bird ◽  
A. W. Bell
Keyword(s):  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Utilization Rate ◽  
Glucose Kinetics ◽  
Arterial Blood ◽  
Net Uptake ◽  
Endogenous Glucose ◽  
Total Glucose ◽  
Glucose Disposal Rate

Fetal glucose kinetics were measured using a combination of isotope-dilution and Fick-principle methodology in single-pregnant ewes which were either well-fed throughout, or fed at 0.3–0.4 predicted energy requirement for 7–21 d during late pregnancy. All ewes were studied while standing at rest and then while walking on a treadmill at 0.7 m/s on a 10° slope for 60 min. Underfed ewes suffered major decreases in fetal total disposal rate, fetal-placental transfer and umbilical net uptake of glucose, each of which were significantly related to declines in maternal and fetal blood glucose concentrations respectively. In well-fed ewes, fetal endogenous glucose production was negligible, as indicated by the similarity between fetal utilization rate (total glucose disposal rate minus placental uptake of fetal glucose) and umbilical net uptake of glucose, and by nearly identical fetal and maternal arterial blood specific radioactivities of maternally infused D-[2-3H]glucose. By contrast, in underfed ewes, fetal utilization rate greatly exceeded umbilical net uptake of glucose, and the fetal:maternal [3H]glucose specific activity ratio declined significantly, suggesting induction of a substantial rate of fetal endogenous glucogenesis. Exercise caused increases in fetal total glucose disposal rate and glycaemia in fed and underfed ewes. In underfed ewes only, this was accompanied by increased placental uptake of fetal glucose and umbilical net glucose uptake, unchanged fetal glucose utilization and decreased fetal endogenous glucose production. It is concluded that fetal gluconeogenesis makes a major contribution to fetal glucose requirements in undernourished ewes. Increased maternal supply of fetal glucose during exercise substitutes for rather than adds to fetal endogenous glucogenesis.

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