scholarly journals Effects of fasting on hepatic and peripheral glucose metabolism in conscious rats with near-total fat depletion

1995 ◽  
Vol 310 (3) ◽  
pp. 819-826 ◽  
Author(s):  
N Barzilai ◽  
D Massillon ◽  
L Rossetti
Keyword(s):  
Glucose Metabolism ◽  
Experimental Diabetes ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Fold Increase ◽  
Whole Body ◽  
Conscious Rats ◽  
Hepatic Glucose ◽  
Total Fat

Experimental diabetes and fasting are both associated with hypoinsulinaemia and share several other metabolic features. We investigated hepatic and peripheral glucose metabolism in young rats after near-total depletion of their fat mass. Conscious rats were fasted for 72 h (n = 13), while 6 h-fasted animals (n = 14) served as controls. Rats were studied either during saline infusion or insulin (18 m-units/kg per min)-clamp studies. In fasting, despite a 2-fold increase in hepatic glucose-6-phosphatase (Glc-6-Pase) Vmax. (from 16 +/- 2 mumol/g of liver per min in control; P < 0.001), the basal hepatic glucose production (HGP) decreased by 47% [from 88 +/- 3 mumol/kg lean body mass (LBM) per min in control; P < 0.01]. The decreased HGP in fasting was associated with a 70% decrease in the hepatic levels of glucose 6-phosphate (Glc-6-P) (from 366 +/- 53 nmol/g wet wt. in control; P < 0.01). Thus Glc-6-Pase activity assayed in the presence of the Glc-6-P levels found in vivo was decreased by 44%. During hyperinsulinaemia, peripheral glucose uptake was decreased by 15% with 3 days of fasting (from 272 +/- 17 mumol/kg LBM per min in control; P < 0.01). This was completely accounted for by a 42% decrease in whole-body glycolysis (P < 0.01), while the rate of glycogen synthesis was unchanged. Thus fasting (after near-total fat depletion) differs from experimental diabetes because: (1) despite markedly increased Glc-6-Pase, HGP is decreased in fasting, due to a marked decrease in the substrate level (Glc-6-P) in vivo; and (2) the impairment in peripheral insulin sensitivity in fasting is due to a decrease in the glycolytic, and not the glycogen-synthetic, pathway.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

scholarly journals Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
Author(s):  
Thiago M. Batista ◽  
Sezin Dagdeviren ◽  
Shannon H. Carroll ◽  
Weikang Cai ◽  
Veronika Y. Melnik ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Glycogen Accumulation ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

Acute effects of insulin-like growth factor I and insulin on glucose metabolism in vivo

1990 ◽  
Vol 259 (4) ◽  
pp. E561-E567 ◽  
Author(s):  
R. T. Moxley ◽  
P. Arner ◽  
A. Moss ◽  
A. Skottner ◽  
M. Fox ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Metabolism ◽  
Metabolic Rate ◽  
Glucose Uptake ◽  
Whole Body ◽  
Hepatic Glucose ◽  
Igf I ◽  
Glucose Metabolic Rate ◽  
Stimulation Of

We have compared the actions of insulin-like growth factor (IGF-I) and insulin on glucose metabolism in vivo, using the glucose clamp technique in rats. Both hormones caused dose-dependent inhibition of hepatic glucose production, stimulation of whole body glucose disposal, and an increase in the glucose metabolic rate of specific muscles. Infusion of IGF-I also decreased the plasma concentration of insulin. An an infusion rate of 0.57 nmol.kg-1.min-1, IGF-I led to stimulation of whole body glucose uptake that was similar to the glucose uptake produced by infusion of 0.01 nmol.kg-1.min-1 insulin. The glucose metabolic rate, as measured by 2-deoxy-D-glucose uptake, was comparable in quadriceps femoris, soleus, and diaphragm muscles during the infusion of 0.57 nmol.kg-1.min-1 IGF-I and 0.01 nmol.kg-1.min-1 insulin. However, at these rates of infusion, IGF-I caused only a 38 +/- 6% inhibition of hepatic glucose output compared with 66 +/- 12% inhibition by insulin (P less than 0.05). Thus, under these conditions, muscle is more responsive than liver to IGF-I, which agrees with the complement of IGF-I receptors in the two tissues.

In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions

1986 ◽  
Vol 250 (6) ◽  
pp. E662-E668 ◽  
Author(s):  
L. Penicaud ◽  
F. Rohner-Jeanrenaud ◽  
B. Jeanrenaud
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Tissue Response ◽  
Insulin Concentration ◽  
Insulin Resistant ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Total Glucose

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.

Mechanism by which calcitonin gene-related peptide antagonizes insulin action in vivo

1991 ◽  
Vol 260 (2) ◽  
pp. E321-E325 ◽  
Author(s):  
S. B. Choi ◽  
S. Frontoni ◽  
L. Rossetti
Keyword(s):  
Skeletal Muscle ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Calcitonin Gene Related Peptide ◽  
Whole Body ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Clamp Study

Calcitonin gene-related peptide (CGRP) is a peptide with structural homology to amylin, which is present in nerve terminals of skeletal muscle and intestine. The effect of this peptide on in vivo insulin action was studied in conscious rats. All rats received 180 min euglycemic (5.6 mM) insulin (21.5 pmol.kg-1.min-1) clamp study in combination with [3-3H]- and [U-14C]glucose infusions. In the basal state, the plasma CGRP concentration was 36 +/- 5 pM, and the skeletal muscle CGRP concentration was 376 +/- 88 pmol/kg wet wt. CGRP was infused at 100 pmol.kg-1.min-1 during the last 90 min of the insulin clamp study and determined a rise in plasma concentration to 781 +/- 34 pM. Hepatic glucose production was stimulated by the infusion of CGRP (35.6 +/- 6.1 vs. 24.4 +/- 4.4 mumol.kg-1.min-1). During infusion in insulin alone, glucose uptake was 133.3 +/- 8.9 mumol.kg-1.min-1 and decreased to 105.5 +/- 12.2 mumol.kg-1.min-1 with CGRP. However, the whole body rates of glycolysis (3H2O generation) were higher during the infusion of CGRP (83.9 +/- 6.1 mumol.kg-1.min-1) compared with insulin alone (72.2 +/- 7.8 mumol.kg-1.min-1). By contrast, CGRP determined a severe impairment in muscle glycogen synthesis (11.7 +/- 3.9 vs. 47.8 +/- 5.0 mumol.kg-1.min-1). Skeletal muscle glucose 6-phosphate concentration was significantly increased after CGRP infusion compared with insulin alone (0.540 +/- 0.052 vs. 0.219 +/- 0.038 mumol/g wet wt; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Epinephrine-induced changes in hepatic glucose production after ethanol

1994 ◽  
Vol 266 (6) ◽  
pp. E863-E869
Author(s):  
C. H. Lang ◽  
P. E. Molina ◽  
N. Skrepnick ◽  
G. J. Bagby ◽  
J. J. Spitzer
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Response ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Plasma Catecholamines ◽  
Glucose Production ◽  
Whole Body ◽  
Metabolic Clearance ◽  
Hepatic Glucose ◽  
Acute Ethanol

Previous studies indicate that catecholamines play an important role in mediating the glucose metabolic response to endotoxin. Because acute ethanol (EtOH) intoxication impairs this response, the present study was initiated to ascertain whether EtOH attenuates the lipopolysaccharide response by decreasing the increment in plasma catecholamines after endotoxin or by decreasing the responsiveness of rats to epinephrine. All studies were performed on chronically catheterized fasted rats infused intravenously with either EtOH or an equal volume of saline. In the first series of experiments, intravenous administration of Escherichia coli endotoxin increased, to the same extent, the plasma concentrations of epinephrine and norepinephrine in both saline- and EtOH-infused rats. In the second study, rats were infused with [3-3H]glucose to assess whole body glucose metabolism and the ability of EtOH to alter the glucose metabolic response to epinephrine. The exogenous infusion of a maximally stimulating dose of epinephrine (1 microgram.min-1.kg-1) into saline-infused control animals for 3 h produced a marked hyperglycemia that resulted from a sustained increase in the rate of hepatic glucose production and a reduction in the metabolic clearance rate for glucose. EtOH infusion did not prevent the epinephrine-induced hyperglycemia but blunted the stimulatory effect of epinephrine on glucose production. The differences in glucose metabolism between saline- and EtOH-treated rats could not be explained by changes in plasma insulin or glucagon concentrations. Furthermore, the ability of EtOH to impair the epinephrine-induced increase in glucose production was still evident in rats treated with 4-methylpyrazole, an inhibitor of alcohol dehydrogenase.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Ling Wu ◽  
Yang Jiao ◽  
Yao Li ◽  
Jingjing Jiang ◽  
Lin Zhao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Mouse Models ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dna Demethylation ◽  
Diabetic Patients ◽  
Functional Studies ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose

Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible β (Gadd45β)–dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet– or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.

scholarly journals Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

2013 ◽  
Vol 305 (1) ◽  
pp. E132-E139 ◽  
Author(s):  
Dale S. Edgerton ◽  
Zhibo An ◽  
Kathryn M. S. Johnson ◽  
Tiffany Farmer ◽  
Ben Farmer ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Glucose Production ◽  
Area Under The Curve ◽  
Glucose Production ◽  
Experimental Period ◽  
Whole Body ◽  
Saline Control ◽  
Hepatic Glucose Metabolism ◽  
Hyperglycemic Clamp ◽  
Hepatic Glucose

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg−1·min−1, Ex-4-low; n = 5) or high (0.9 pmol·kg−1·min−1, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg−1·min−1between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg−1·min−1), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver.

scholarly journals The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis—Dysregulation by the Liver

2021 ◽  
Vol 10 (3) ◽  
pp. 390
Author(s):  
Amalie London ◽  
Anne-Marie Lundsgaard ◽  
Bente Kiens ◽  
Kirstine Nyvold Bojsen-Møller
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Liver Fat ◽  
Whole Body ◽  
Insulin Metabolism ◽  
Fat Accumulation ◽  
Hepatic Glucose

Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes.

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.

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