Sleep-associated fall in glucose disposal and hepatic glucose output in normal humans. Putative signaling mechanism linking peripheral and hepatic events

The effect of pressor doses of angiotensin II infused intravenously on insulin-mediated glucose uptake was determined in normotensive men. A 3-h hyperinsulinemic euglycemic clamp was employed in 14 normotensive subjects to determine insulin-mediated glucose uptake with or without an infusion of angiotensin II (approximately 15 ng.kg-1.min-1), which increased blood pressure by 20/15 mmHg (systolic/diastolic). Addition of angiotensin II increased whole body glucose uptake by 15% (9.2 +/- 0.5 vs. 10.8 +/- 0.8 mg.kg-1 x min-1; P = 0.011), and glucose oxidation (determined by indirect calorimetry) by 25% (4.0 +/- 0.3 vs. 4.9 +/- 0.4 mg.kg-1 x min-1; P < 0.05) over insulin alone. There was no significant increase in hepatic glucose output during angiotensin II infusion (2.2 +/- 0.1 vs. 2.4 +/- 0.1 mg.kg-1 x min-1; P = NS). We conclude that angiotensin II in pressor doses increases insulin-mediated glucose disposal and oxidation. The mechanism for this may involve a redirection of blood flow into skeletal muscle during angiotensin II infusion or a direct biochemical action of angiotensin II. Although performed in lean normotensive subjects, these results cast doubt on a significant role for angiotensin II in the insulin resistance associated with essential hypertension.

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Selective suppression of hepatic glucose output by human proinsulin in the dog

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.252.2.e230 ◽

1987 ◽

Vol 252 (2) ◽

pp. E230-E236 ◽

Cited By ~ 1

Author(s):

M. Lavelle-Jones ◽

M. H. Scott ◽

O. Kolterman ◽

A. H. Rubenstein ◽

J. M. Olefsky ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Hormone Secretion ◽

Glucose Production ◽

Glucose Disposal ◽

Glucose Turnover ◽

Hepatic Glucose Output ◽

Glucose Clamp Technique ◽

Hepatic Glucose ◽

The Mean ◽

Glucose Output

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.

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Glucagon-cortisol interactions on glucose turnover and lactate gluconeogenesis in normal humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.4.e569 ◽

1990 ◽

Vol 258 (4) ◽

pp. E569-E575 ◽

Cited By ~ 7

Author(s):

L. Lecavalier ◽

G. Bolli ◽

J. Gerich

Keyword(s):

Glucose Utilization ◽

Glucose Turnover ◽

Hepatic Glucose Output ◽

Experimental Conditions ◽

Peripheral Tissues ◽

Persistent Effect ◽

Lactate Turnover ◽

Hepatic Glucose ◽

Normal Humans ◽

Glucose Output

To determine the mechanism for cortisol enhancement of glucagon-stimulated overall hepatic glucose output (OHGO), we employed the glucose-insulin clamp technique with infusions of [6-3H]glucose and [U-14C]lactate and measured OHGO, glucose utilization, and the turnover and incorporation of lactate in plasma glucose in normal volunteers under four experimental conditions: 1) normoglucagonemia (approximately 150 pg/ml)- normocortisolemia (approximately 14 micrograms/dl); 2) isolated hyperglucagonemia (approximately 550 pg/ml); 3) isolated hypercortisolemia (approximately 32 micrograms/dl); and 4) combined hyperglucagonemia-hypercortisolemia. Isolated hyperglucagonemia caused initial increases in OHGO and lactate gluconeogenesis, which were maximal at 1 h (23.9 +/- 1 and 2.7 +/- 0.4 mumol.kg-1.min-1, respectively) but remained significantly above values in control experiments through 5 h (10.3 +/- 0.7 vs. 8.2 +/- 1.1, P less than 0.03; 2.2 +/- 0.4 vs. 1.2 +/- 0.3, mumol.kg-1.min-1, P less than 0.04, respectively). Hypercortisolemia has no effect on OHGO but increased lactate gluconeogenesis after 3 h. Superimposition of hypercortisolemia on hyperglucagonemia did not further increase OHGO (11.1 +/- 0.7 vs. 10.3 +/- 0.7 mumol.kg-1.min-1, P = NS) but augmented lactate gluconeogenesis additively (isolated hyperglucagonemia = 0.96, isolated hypercortisolemia = 0.98; combined = 2.02 mumol.kg-1.min-1). Neither glucagon nor cortisol affected lactate turnover or glucose utilization. We conclude that glucagon has a persistent effect on OHGO largely accounted for by increased gluconeogenesis. Cortisol augments glucagon-stimulated gluconeogenesis in an additive manner best explained by changes in gluconeogenic enzymes rather than in substrate availability. Finally, the fact that cortisol increased gluconeogenesis without affecting glucose utilization suggests that the liver is more sensitive to the diabetogenic effects of cortisol than are peripheral tissues.

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Contributions of gluconeogenesis and glycogenolysis during glucose counterregulation in normal humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.6.e844 ◽

1989 ◽

Vol 256 (6) ◽

pp. E844-E851 ◽

Cited By ~ 10

Author(s):

L. Lecavalier ◽

G. Bolli ◽

P. Cryer ◽

J. Gerich

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Output ◽

Insulin Hypoglycemia ◽

Isotopic Method ◽

Exogenous Glucose ◽

Primary Mechanism ◽

Hepatic Glucose ◽

Normal Humans ◽

Predominant Factor ◽

Glucose Output

To estimate the relative contributions of gluconeogenesis and glycogenolysis to the increase in hepatic glucose output (HGO) during glucose counterregulation under conditions simulating clinical insulin hypoglycemia, we induced moderate hypoglycemia (approximately 55 mg/dl) with a continuous infusion of insulin that resulted in physiological hyperinsulinemia (approximately 20 microU/ml) in eight normal volunteers and estimated gluconeogenesis by two methods: an isotopic approach in which appearance of plasma glucose derived from lactate was determined and another approach in which we infused alcohol along with insulin to block gluconeogenesis and used the exogenous glucose required to prevent greater hypoglycemia as an index of gluconeogenesis. Both methods gave similar results. Initially glycogenolysis accounted for approximately 85% of HGO; however, once hypoglycemia became established, the contribution of gluconeogenesis increased progressively to 77 +/- 10 (isotopic method) and 94 +/- 10% (alcohol method) of overall HGO. We conclude that in normal humans during moderate protracted hypoglycemia induced by physiological hyperinsulinemia, gluconeogenesis is the predominant factor responsible for the counterregulatory increase in HGO and that increased gluconeogenesis rather than increased glycogenolysis is the primary mechanism preventing development of greater hypoglycemia.

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Pressor doses of angiotensin II increase hepatic glucose output and decrease insulin sensitivity in rats

Journal of Endocrinology ◽

10.1677/joe.0.1480311 ◽

1996 ◽

Vol 148 (2) ◽

pp. 311-318 ◽

Cited By ~ 26

Author(s):

R H Rao

Keyword(s):

Angiotensin Ii ◽

Pressor Response ◽

Metabolic Effects ◽

Glucose Disposal ◽

Glucose Turnover ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Anaesthetized Rats ◽

Glucose Output

Abstract The metabolic effects of angiotensin II (AII) were studied under steady-state conditions of euglycaemic hyperinsulinaemia in anaesthetized rats. Pressor doses of AII (50 and 400 ng/kg per min) had dose-dependent hypertensive and hyperglycaemic effects during glucose clamp studies. Glucose turnover measurements showed that hepatic glucose output (HGO) increased equally at both pressor doses compared with either saline infusion or AII infusion at a dose without a pressor effect (20 ng/kg per min); however, glucose disposal increased significantly only at 50 ng/kg per min. Infusion of the AII receptor antagonist, saralasin, did not itself alter glucose output or disposal significantly, but it abolished the effects of a simultaneous infusion of All. It is concluded that pressor doses of AII increase HGO by a receptor-mediated mechanism that is not related to the pressor response to the hormone. The hyperglycaemic reaction to this metabolic effect of AII is partially offset by increased glucose disposal at lower doses. The physiological significance of these metabolic actions of AII remains to be established, but they raise the possibility that AII could potentially play a role in glucose homeostasis in vivo. Journal of Endocrinology (1996) 148, 311–318

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Liraglutide Enhances Insulin Sensitivity by Activating AMP-Activated Protein Kinase in Male Wistar Rats

Endocrinology ◽

10.1210/en.2013-2157 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3288-3301 ◽

Cited By ~ 26

Author(s):

Satoru Yamazaki ◽

Hiroaki Satoh ◽

Tsuyoshi Watanabe

Keyword(s):

Insulin Sensitivity ◽

Skeletal Muscles ◽

Glucose Disposal ◽

Control Group ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Male Wistar Rats ◽

Glucose Output ◽

Amp Activated Protein Kinase ◽

Glucose Disposal Rate

Abstract We investigated the effects of liraglutide on insulin sensitivity and glucose metabolism in male Wistar rats. The rats were fed a normal chow diet (NCD) or a 60% high-fat diet (HFD) for a total of 4 weeks. After 3 weeks of feeding, they were injected with liraglutide once a day for 7 days. Subsequently, euglycemic-hyperinsulinemic clamp studies were performed after fasting the animals for 8 hours. During the clamp studies on the NCD-fed rats, the glucose infusion rate required for euglycemia was significantly higher in the liraglutide group than in the control group. The clamp hepatic glucose output was significantly lower in the liraglutide group than in the control group, but the insulin-stimulated glucose disposal rate did not change significantly in the liraglutide groups. The clamp studies on the HFD-fed rats revealed that the glucose infusion rate required to achieve euglycemia was significantly higher in the liraglutide group than in the control HFD group, and the insulin-stimulated glucose disposal rate increased significantly in the liraglutide groups. The clamp hepatic glucose output decreased significantly in the liraglutide groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMP-activated protein kinase was enhanced in the livers of the NCD- and HFD-fed rats and in the skeletal muscles of the HFD-fed rats. Oil red O staining indicated that liraglutide also improved hepatic steatosis. In summary, our studies suggest that in normal glucose tolerance states, liraglutide enhances insulin sensitivity in the liver but not in skeletal muscles. However, in insulin-resistant states, liraglutide improves insulin resistance in the liver and muscles and improves fatty liver.

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