scholarly journals Ciliary Neurotrophic Factor Prevents Acute Lipid-Induced Insulin Resistance by Attenuating Ceramide Accumulation and Phosphorylation of c-Jun N-Terminal Kinase in Peripheral Tissues

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2077-2085 ◽  
Author(s):  
Matthew J. Watt ◽  
Andrea Hevener ◽  
Graeme I. Lancaster ◽  
Mark A. Febbraio
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Ciliary Neurotrophic Factor ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Ceramide Accumulation ◽  
Glucose Disposal Rate

Ciliary neurotrophic factor (CNTF) is a member of the gp130 receptor cytokine family recently identified as an antiobesity agent in rodents and humans by mechanisms that remain unclear. We investigated the impact of acute CNTF treatment on insulin action in the presence of lipid oversupply. To avoid confounding effects of long-term high-fat feeding or genetic manipulation on whole-body insulin sensitivity, we performed a 2-h Intralipid infusion (20% heparinized Intralipid) with or without recombinant CNTF pretreatment (Axokine 0.3 mg/kg), followed by a 2-h hyperinsulinemic-euglycemic clamp (12 mU/kg·min) in fasted, male Wistar rats. Acute Intralipid infusion increased plasma free fatty acid levels from 1.0 ± 0.1 to 2.5 ± 0.3 mm, which subsequently caused reductions in skeletal muscle (insulin-stimulated glucose disposal rate) and liver (hepatic glucose production) insulin sensitivity by 30 and 45%, respectively. CNTF pretreatment completely prevented the lipid-mediated reduction in insulin-stimulated glucose disposal rate and the blunted suppression of hepatic glucose production by insulin. Although lipid infusion increased triacylglycerol and ceramide accumulation and phosphorylation of mixed linage kinase 3 and c-Jun N-terminal kinase 1 in skeletal muscle, CNTF pretreatment prevented these lipid-induced effects. Alterations in hepatic and muscle insulin signal transduction as well as phosphorylation of c-Jun N-terminal kinase 1/2 paralleled alterations in insulin sensitivity. These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance.

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 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.

scholarly journals Systemic benefits of Gc inhibition to preserve insulin sensitivity

2020 ◽  
Author(s):  
Taiyi Kuo ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Fat ◽  
Β Cell ◽  
Hepatic Glucose ◽  
Β Cell Function

ABSTRACTType 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues.RESEARCH IN CONTEXT▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously.▪ Gc ablation preserves β-cell insulin secretion ex vivo and in vivo.▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose.▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.

Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits

1993 ◽  
Vol 264 (4) ◽  
pp. E576-E582 ◽  
Author(s):  
M. Gilbert ◽  
S. Basile ◽  
A. Baudelin ◽  
M. C. Pere
Keyword(s):  
Insulin Resistance ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Pregnancy ◽  
Plasma Free Fatty Acid ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Total Glucose ◽  
Control Study

Acute elevation in plasma free fatty acid (FFA) levels in nonpregnant rabbits simulates some aspects of insulin resistance observed in late pregnancy. The aim of this study was therefore to evaluate whether lowered FFA induced by nicotinic acid (NA) infusion can improve insulin action in pregnant rabbits. To assess insulin sensitivity we applied euglycemic hyperinsulinemic clamp without (control study) or with concomitant NA infusion (NA study; infusion started 150 min before the glucose clamp) in conscious virgin and pregnant rabbits after an 18-h fast. A primed constant infusion of [3-3H]glucose was used to measure total glucose disposal and hepatic glucose production. Hyperinsulinemia, in association with NA infusion (NA study) brings about a significantly greater stimulation of total glucose disposal in both pregnant (approximately 30%) and nonpregnant (approximately 35%) rabbits compared with the control study. A more pronounced inhibition of hepatic glucose production occurred in NA study in pregnant rabbits (approximately 30 vs. approximately 10%) but it did not reach a statistical significance, whereas there was a total inhibition in nonpregnant rabbits. We conclude that acute decrease in plasma FFA levels mainly improves insulin action at the site of glucose utilization. These results therefore suggest that elevated FFA would contribute to the peripheral insulin resistance in late pregnancy.

scholarly journals Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

2009 ◽  
Vol 297 (6) ◽  
pp. R1785-R1794 ◽  
Author(s):  
Elisabeth L. Raab ◽  
Patricia M. Vuguin ◽  
Doris A. Stoffers ◽  
Rebecca A. Simmons
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Intrauterine Growth ◽  
Hepatic Glucose ◽  
Neonatal Hepatocytes

Intrauterine growth retardation (IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagon-like-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1–6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance.

scholarly journals Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

2016 ◽  
Vol 311 (3) ◽  
pp. E620-E627 ◽  
Author(s):  
Tianru Jin ◽  
Jianping Weng
Keyword(s):  
Insulin Resistance ◽  
Degradation Products ◽  
Hepatic Glucose Production ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Beneficial Effects ◽  
Metabolic Functions ◽  
Pathway Activation ◽  
Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

Hepatic glucose production and insulin sensitivity and responsiveness in iron-deficient anemic rats

1993 ◽  
Vol 264 (3) ◽  
pp. E380-E390 ◽  
Author(s):  
M. J. Borel ◽  
J. L. Beard ◽  
P. A. Farrell
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Insulin Dose ◽  
Glucose Production ◽  
Deficiency Anemia ◽  
Response Curves ◽  
Iron Deficient ◽  
Hepatic Glucose ◽  
Basal Plasma ◽  
Insulin Responsiveness

We performed euglycemic hyperinsulinemic glucose clamps at insulin infusion rates of 1.9, 4.0, 9.3, and 19.3 mU.kg-1 x min-1 in rats with varying severities of iron deficiency anemia (IDA; mean hemoglobin concentrations of 59, 79, 107, and 137 g/l) to assess the effect of IDA on insulin sensitivity and responsiveness. Glucose appearance and disappearance (Rd) rates were determined using a primed continuous infusion of [3-3H]glucose. Basal plasma glucose and insulin concentrations were similar between the IDA and control rats. Basal hepatic glucose production was significantly (P = 0.0001) elevated in the two most anemic groups (13.6 +/- 2.4 and 12.6 +/- 3.1 vs. 10.6 +/- 2.2 and 10.2 +/- 2.0 mg.kg-1 x min-1). A significant upward shift in the insulin dose-response curves for Rd indicated an increase in peripheral insulin responsiveness in the two most anemic groups while a slight leftward shift was suggestive of an increase in insulin sensitivity in all three anemic groups. Hepatic insulin sensitivity and responsiveness were unaffected by IDA. We conclude that increased glucose utilization rates in IDA rats are due primarily to an increase in peripheral insulin responsiveness.

scholarly journals Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

2014 ◽  
Vol 307 (10) ◽  
pp. E928-E934 ◽  
Author(s):  
Jose Cordoba-Chacon ◽  
Manuel D. Gahete ◽  
Owen P. McGuinness ◽  
Rhonda D. Kineman
Keyword(s):  
Insulin Sensitivity ◽  
Gh Deficiency ◽  
Hepatic Glucose Production ◽  
Insulin Receptors ◽  
Glucose Production ◽  
Reciprocal Relationship ◽  
Hepatic Insulin Resistance ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Glucose ◽  
Gh Excess

A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulin-mediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency.

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.

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