Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats

Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.

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A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00573.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1358-E1363 ◽

Cited By ~ 47

Author(s):

Arvinder K. Dhalla ◽

Mei Yee Wong ◽

Peter J. Voshol ◽

Luiz Belardinelli ◽

Gerald M. Reaven

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Adenosine Receptor ◽

Infusion Rate ◽

Glucose Infusion ◽

Glucose Infusion Rate ◽

Oral Glucose ◽

Acute Administration ◽

High Fat ◽

Adenosine Receptor Agonist

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A1 adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly ( P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

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Abstract 17025: Myeloid Rage Protects From Insulin Resistance in Mice Fed High Fat Diet

Circulation ◽

10.1161/circ.142.suppl_3.17025 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Lakshmi Arivazhagan ◽

Henry Ruiz ◽

Robin Wilson ◽

Laura Frye ◽

Ravichandran Ramasamy ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Body Mass ◽

High Fat Diet ◽

Whole Body ◽

High Fat ◽

Double Knockout ◽

Euglycemic Clamp ◽

Insulin Resistant ◽

Hyperinsulinemic Euglycemic Clamp

Introduction: Obesity is a major global health problem, with over one third of adults in the US classified as obese. Obesity often leads to a state of insulin resistance (IR), type 2 diabetes (T2D) and its complications. We previously showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and IR, as whole body and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) were significantly protected from weight gain and IR. Here, we hypothesize that myeloid RAGE contributed to IR upon HFD feeding. Methods: We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager flox/flox and adipocyte and myeloid-specific (Double Knockouts) AdipoQCre(-/+)LyzMCre(+/+).Ager flox/flox deletion of Ager and LysMCre mice were used as control. Mice were fed either standard chow (LFD) or HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and composition, glucose and insulin sensitivity and whole body glucose metabolism by hyperinsulinemic-euglycemic clamp studies. Results: After 3 months HFD, there were no significant differences in body mass, body composition, food intake, energy expenditure and physical activity of the MDR mice vs. controls. Similar findings were observed in mice fed LFD. However, surprisingly, in HFD-fed mice, insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies showed decreased insulin sensitivity and insulin action in the MDR vs. control mice, indicating that the MDR mice were more insulin resistant. The Double Knockout (myeloid/adipocyte) Cre (+) mice were more glucose tolerant and insulin sensitive compared to MDR mice, showing that deletion of Ager in the adipocytes rescued the adverse effects of Ager deletion in myeloid cells. Conclusions: Myeloid Ager protects from IR in mice fed HFD. Furthermore, in MDR mice, concomitant adipocyte-specific deletion of Ager rescues these mice from IR and, at the same time, reduces HFD-induced adiposity. The mechanisms underlying these findings are under active investigation.

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Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance

Endocrinology ◽

10.1210/en.2012-1989 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1021-1028 ◽

Cited By ~ 104

Author(s):

João Paulo G. Camporez ◽

François R. Jornayvaz ◽

Hui-Young Lee ◽

Shoichi Kanda ◽

Blas A. Guigni ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Protein Kinase ◽

High Fat Diet ◽

Estrogen Replacement Therapy ◽

Whole Body ◽

Estrogen Replacement ◽

High Fat ◽

Muscle Insulin Resistance ◽

Body Energy

Abstract Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both SHAM and OVX mice. Increases in tissue DAG content were associated with increased protein kinase Cϵ activation in liver of SHAM and OVX mice compared with OVX+E2 and protein kinase Cθ activation in skeletal muscle of OVX mice compared with SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O2 consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic lipid (DAG) deposition and hepatic and muscle insulin resistance.

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High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00001.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. E764-E772 ◽

Cited By ~ 30

Author(s):

Amanda T. White ◽

Andrew Philp ◽

Heidi N. Fridolfsson ◽

Jan M. Schilling ◽

Anne N. Murphy ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Glucose Uptake ◽

High Fat Diet ◽

Sirtuin 1 ◽

Whole Body ◽

Oral Glucose ◽

High Fat

Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.

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Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0196 ◽

2017 ◽

Vol 58 (3) ◽

pp. 141-154 ◽

Cited By ~ 5

Author(s):

Yueting Dong ◽

Zhiye Xu ◽

Ziyi Zhang ◽

Xueyao Yin ◽

Xihua Lin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

High Fat Diet ◽

Insulin Response ◽

Receptor Activation ◽

Metabolic Effects ◽

Whole Body ◽

High Fat ◽

Epididymal Fat

Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.

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Short-Term High-Fat Diet Alters Substrate Utilization during Exercise but Not Glucose Tolerance in Highly Trained Athletes

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.11.3.273 ◽

2001 ◽

Vol 11 (3) ◽

pp. 273-286 ◽

Cited By ~ 10

Author(s):

Heidi M. Staudacher ◽

Andrew L. Carey ◽

Nicola K. Cummings ◽

John A. Hawley ◽

Louise M. Burke

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

High Fat Diet ◽

Dietary Intervention ◽

Substrate Oxidation ◽

Whole Body ◽

Oral Glucose ◽

High Fat ◽

Short Term ◽

Time Curve

We determined the effect of a high-fat diet and carbohydrate (CHO) restoration on substrate oxidation and glucose tolerance in 7 competitive ultra-endurance athletes (peak oxygen uptake [V̇O2peak] 68 ± 1 ml · kg−1 · min−1; mean±SEM). For 6 days, subjects consumed a random order of a high-fat (69% fat; FAT-adapt) or a high-CHO (70% CHO; HCHO) diet, each followed by 1 day of a high-CHO diet. Treatments were separated by an 18-day wash out. Substrate oxidation was determined during submaximal cycling (20 min at 65% V̇O2peak) prior to and following the 6 day dietary interventions. Fat oxidation at baseline was not different between treatments (17.4 ± 2.1 vs. 16.1 ± 1.3 g · 20 min−1 for FAT-adapt and HCHO, respectively) but increased 34% after 6 days of FAT-adapt (to 23.3 ± 0.9 g · 20 min−1, p < .05) and decreased 30% after HCHO (to 11.3±1.4 g · 20 min−1, p < .05). Glucose tolerance, determined by the area under the plasma [glucose] versus time curve during an oral glucose tolerance (OGTT) test, was similar at baseline (545±21 vs. 520±28 mmol · L−1 · 90 min−1), after 5-d of dietary intervention (563 ± 26 vs. 520 ± 18 mmol · L−1 · 90 min−1) and after 1 d of high-CHO (491 ± 28 vs. 489 ± 22 mmol · L−1 · 90min−1 for FAT- adapt and HCHO, respectively). An index of whole-body insulin sensitivity (SI 10000/÷fasting [glucose] × fasting [insulin] × mean [glucose] during OGTT × mean [insulin] during OGTT) was similar at baseline (15 ± 2 vs. 17 ± 5 arbitrary units), after 5-d of dietary intervention (15 ± 2 vs. 15 ± 2) and after 24 h of CHO loading (17 ± 3 vs. 18 ± 2 for FAT- adapt and HCHO, respectively). We conclude that despite marked changes in the pattern of substrate oxidation during submaximal exercise, short-term adaptation to a high-fat diet does not alter whole-body glucose tolerance or an index of insulin sensitivity in highly-trained individuals.

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Antisense oligonucleotides against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1

10.1101/2020.08.05.238535 ◽

2020 ◽

Author(s):

Andrew J. Lutkewitte ◽

Jason M. Singer ◽

Trevor M. Shew ◽

Michael R. Martino ◽

Angela M. Hall ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

High Fat Diet ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

High Fat ◽

Target Effects ◽

Monoacylglycerol Acyltransferase

ABSTRACTObjectiveMonoacylglycerol acyltransferase (MGAT) enzymes catalyze the synthesis of diacylglycerol from monoacylglycerol. Previous work has suggested the importance of MGAT activity in the development of obesity-related hepatic insulin resistance. Indeed, antisense oligonucleotide (ASO)-mediated knockdown of the gene encoding MGAT1, Mogat1, reduced hepatic MGAT activity and improved glucose tolerance and insulin resistance in high fat diet (HFD) fed mice. However, recent work has suggested that some ASOs may have off-target effects on body weight and metabolic parameters via activation of the interferon alpha/beta receptor 1 (IFNAR-1) pathway.MethodsMice with whole-body Mogat1 knockout or a floxed allele for Mogat1 to allow for liver-specific Mogat1-knockout (by either a liver-specific transgenic or adeno-associated virus-driven Cre recombinase) were generated. These mice were placed on a high fat diet and glucose metabolism and insulin sensitivity was assessed after 16 weeks on diet. In some experiments, mice were treated with control or Mogat1 or control ASOs in the presence or absence of IFNAR-1 neutralizing antibody.ResultsGenetic deletion of hepatic Mogat1, either acutely or chronically, did not improve hepatic steatosis, glucose tolerance, or insulin sensitivity in HFD-fed mice. Furthermore, constitutive Mogat1 knockout in all tissues actually exacerbated HFD-induced weight gain, insulin resistance, and glucose intolerance on a HFD. Despite markedly reduced Mogat1 expression, liver MGAT activity was unaffected in all knockout mouse models. Mogat1 overexpression hepatocytes increased liver MGAT activity and TAG content in low-fat fed mice, but did not cause insulin resistance. Interestingly, Mogat1 ASO treatment improved glucose tolerance in both wild-type and Mogat1 null mice, suggesting an off target effect. Inhibition of IFNAR-1 did not block the effect of Mogat1 ASO on glucose homeostasis.ConclusionThese results indicate that genetic loss of Mogat1 does not affect hepatic MGAT activity or metabolic homeostasis on HFD and show that Mogat1 ASOs improve glucose metabolism through effects independent of targeting Mogat1 or activation of IFNAR-1 signaling.Abstract FigureHighlightsMogat1 liver-specific KO or KD does not improve metabolism in HFD fed mice.Whole-body Mogat1-deletion impairs insulin tolerance in HFD fed mice.Mogat1 ASOs improves whole body metabolism independently of gene knockdown.Blockade of the INFR response does not prevent off-target effects of Mogat1 ASOs.

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Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet (Running Title: Sdc4 Deficiency Affects Metabolic Phenotypes)

Nutrients ◽

10.3390/nu11112810 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2810 ◽

Cited By ~ 1

Author(s):

Maria De Luca ◽

Denise Vecchie’ ◽

Baskaran Athmanathan ◽

Sreejit Gopalkrishna ◽

Jennifer A. Valcin ◽

...

Keyword(s):

Insulin Sensitivity ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Serum Triglyceride ◽

Independent Study ◽

Whole Body ◽

Elderly Subjects ◽

Sensitivity Index ◽

High Fat ◽

Metabolic Phenotypes

Syndecans are transmembrane proteoglycans that, like integrins, bind to components of the extracellular matrix. Previously, we showed significant associations of genetic variants in the Syndecan-4 (SDC4) gene with intra-abdominal fat, fasting plasma glucose levels, and insulin sensitivity index in children, and with fasting serum triglyceride levels in healthy elderly subjects. An independent study also reported a correlation between SDC4 and the risk of coronary artery disease in middle-aged patients. Here, we investigated whether deletion of Sdc4 promotes metabolic derangements associated with diet-induced obesity by feeding homozygous male and female Sdc4-deficient (Sdc4-/-) mice and their age-matched wild-type (WT) mice a high-fat diet (HFD). We found that WT and Sdc4-/- mice gained similar weight. However, while no differences were observed in males, HFD-fed female Sdc4-/- mice exhibited a higher percentage of body fat mass than controls and displayed increased levels of plasma total cholesterol, triglyceride, and glucose, as well as reduced whole-body insulin sensitivity. Additionally, they had an increased adipocyte size and macrophage infiltration in the visceral adipose tissue, and higher triglyceride and fatty acid synthase levels in the liver. Together with our previous human genetic findings, these results provide evidence of an evolutionarily conserved role of SDC4 in adiposity and its complications.

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Time course of insulin resistance associated with feeding dogs a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.1.e147 ◽

1997 ◽

Vol 272 (1) ◽

pp. E147-E154 ◽

Cited By ~ 13

Author(s):

A. P. Rocchini ◽

P. Marker ◽

T. Cervenka

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Glucose Uptake ◽

Dose Response ◽

High Fat Diet ◽

Time Course ◽

Rapid Development ◽

Diet Group ◽

Whole Body ◽

High Fat

The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.

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Whole body metabolism is improved by hemin added to high fat diet while counteracted by nitrite: a mouse model of processed meat consumption.

Food & Function ◽

10.1039/d1fo01199e ◽

2021 ◽

Author(s):

Diana Abu Halaka ◽

Ofer Gover ◽

Einat Rauchbach ◽

Shira Zelber-Sagi ◽

Betty Schwartz ◽

...

Keyword(s):

High Fat Diet ◽

Food Industry ◽

Food Additives ◽

Whole Body ◽

Processed Meat ◽

Traditional Food ◽

High Fat ◽

Curing Agents ◽

Whole Body Metabolism ◽

Processed Meat Consumption

Nitrites and nitrates are traditional food additives used as curing agents in the food industry. They inhibit the growth of microorganisms and convey a typical pink color to the meat....

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