scholarly journals Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

2006 ◽  
Vol 189 (3) ◽  
pp. 629-641 ◽  
Author(s):  
Helena A Walz ◽  
Linda Härndahl ◽  
Nils Wierup ◽  
Emilia Zmuda-Trzebiatowska ◽  
Fredrik Svennelid ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Rapid Development ◽  
Control Diet ◽  
Wild Type ◽  
High Fat ◽  
Β Cell ◽  
Phosphodiesterase 3B ◽  
Fat Feeding

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether β-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a β-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located α-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of β-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.

scholarly journals Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1441-1450 ◽  
Author(s):  
Isabel García-Tornadú ◽  
Ana M. Ornstein ◽  
Astrid Chamson-Reig ◽  
Michael B. Wheeler ◽  
David J. Hill ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Insulin Response ◽  
Wild Type ◽  
Β Cell ◽  
Insulin Response To Glucose

The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2−/−) mice and in isolated islets from wild-type and Drd2−/− mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2−/− male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2−/− mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2−/− mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic β-cell mass in Drd2−/− mice and decreased β-cell replication in 2-month-old Drd2−/− mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops.

scholarly journals Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

2016 ◽  
Vol 291 (33) ◽  
pp. 17066-17076 ◽  
Author(s):  
Carrie M. Elks ◽  
Peng Zhao ◽  
Ryan W. Grant ◽  
Hardy Hang ◽  
Jennifer L. Bailey ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Types ◽  
Oncostatin M ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Fat Feeding

Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMRFKO mice). The effects of OSM on gene expression were also assessed in vitro and in vivo. OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMRFKO mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMRFKO mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c. Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMRFKO mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

scholarly journals Palmitoleic Acid (N-7) Attenuates the Immunometabolic Disturbances Caused by a High-Fat Diet Independently of PPARα

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Camila O. Souza ◽  
Alexandre A. S. Teixeira ◽  
Edson A. Lima ◽  
Helena A. P. Batatinha ◽  
Lara M. Gomes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Oleic Acid ◽  
High Fat Diet ◽  
Palmitoleic Acid ◽  
Serum Levels ◽  
Standard Diet ◽  
Liver Inflammation ◽  
Wild Type ◽  
High Fat

Palmitoleic acid (PMA) has anti-inflammatory and antidiabetic activities. Here we tested whether these effects of PMA on glucose homeostasis and liver inflammation, in mice fed with high-fat diet (HFD), are PPAR-αdependent. C57BL6 wild-type (WT) and PPAR-α-knockout (KO) mice fed with a standard diet (SD) or HFD for 12 weeks were treated after the 10th week with oleic acid (OLA, 300 mg/kg of b.w.) or PMA 300 mg/kg of b.w. Steatosis induced by HFD was associated with liver inflammation only in the KO mice, as shown by the increased hepatic levels of IL1-beta, IL-12, and TNF-α; however, the HFD increased the expression of TLR4 and decreased the expression of IL1-Ra in both genotypes. Treatment with palmitoleate markedly attenuated the insulin resistance induced by the HFD, increased glucose uptake and incorporation into muscle in vitro, reduced the serum levels of AST in WT mice, decreased the hepatic levels of IL1-beta and IL-12 in KO mice, reduced the expression of TLR-4 and increased the expression of IL-1Ra in WT mice, and reduced the phosphorylation of NF𝜅B (p65) in the livers of KO mice. We conclude that palmitoleate attenuates diet-induced insulin resistance, liver inflammation, and damage through mechanisms that do not depend on PPAR-α.

Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart

2005 ◽  
Vol 289 (1) ◽  
pp. E30-E39 ◽  
Author(s):  
So-Young Park ◽  
Hyo-Jeong Kim ◽  
Shupei Wang ◽  
Takamasa Higashimori ◽  
Jianying Dong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Insulin Action ◽  
Hormone Sensitive Lipase ◽  
Wild Type ◽  
High Fat ◽  
Hormone Sensitive ◽  
Fat Feeding

Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50–80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.

scholarly journals Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet-Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1839-1851 ◽  
Author(s):  
Yoshihiko Kitada ◽  
Kazuo Kajita ◽  
Koichiro Taguchi ◽  
Ichiro Mori ◽  
Masahiro Yamauchi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Adipogenic Differentiation ◽  
Nuclear Antigen ◽  
Wild Type ◽  
High Fat ◽  
Insulin Tolerance ◽  
Sphingosine 1 Phosphate

Abstract Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic β-cells. Among its 5 cognate receptors (S1pr1–S1pr5), S1P seems to counteract insulin signaling and confer insulin resistance via S1pr2 in these cells. S1P may also regulate insulin resistance in adipocytes, but the S1pr subtype(s) involved remains unknown. Here, we investigated systemic glucose/insulin tolerance and phenotypes of epididymal adipocytes in high-fat diet (HFD)-fed wild-type and S1pr2-deficient (S1pr2−/−) mice. Adult S1pr2−/− mice displayed smaller body/epididymal fat tissue weights, but the differences became negligible after 4 weeks with HFD. However, HFD-fed S1pr2−/− mice displayed better scores in glucose/insulin tolerance tests and had smaller epididymal adipocytes that expressed higher levels of proliferating cell nuclear antigen than wild-type mice. Next, proliferation/differentiation of 3T3-L1 and 3T3-F442A preadipocytes were examined in the presence of various S1pr antagonists: JTE-013 (S1pr2 antagonist), VPC-23019 (S1pr1/S1pr3 antagonist), and CYM-50358 (S1pr4 antagonist). S1P or JTE-013 treatment of 3T3-L1 preadipocytes potently activated their proliferation and Erk phosphorylation, whereas VPC-23019 inhibited both of these processes, and CYM-50358 had no effects. In contrast, S1P or JTE-013 treatment inhibited adipogenic differentiation of 3T3-F442A preadipocytes, whereas VPC-23019 activated it. The small interfering RNA knockdown of S1pr2 promoted proliferation and inhibited differentiation of 3T3-F442A preadipocytes, whereas that of S1pr1 acted oppositely. Moreover, oral JTE-013 administration improved glucose tolerance/insulin sensitivity in ob/ob mice. Taken together, S1pr2 blockade induced proliferation but suppressed differentiation of (pre)adipocytes both in vivo and in vitro, highlighting a novel therapeutic approach for obesity/type 2 diabetes.

scholarly journals The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes

2021 ◽  
Vol 22 (15) ◽  
pp. 7995
Author(s):  
Jianfeng Du ◽  
Yu Tina Zhao ◽  
Hao Wang ◽  
Ling X. Zhang ◽  
Gangjian Qin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Function ◽  
Western Blot ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Wild Type ◽  
High Fat

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.

scholarly journals Access schedules mediate the impact of high fat diet on ethanol intake and insulin and glucose function in mice

2018 ◽  
Author(s):  
Caitlin R. Coker ◽  
Elizabeth A. Aguilar ◽  
Angela E. Snyder ◽  
Sarah S. Bingaman ◽  
Nicholas M. Graziane ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Binge Eating ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Control Diet ◽  
High Fat ◽  
Limited Access ◽  
Ad Libitum ◽  
The Impact

AbstractAlcoholism and high fat diet (HFD)-induced obesity individually promote insulin resistance and glucose intolerance in clinical populations, increasing risk for metabolic diseases. Conversely, animal studies, typically utilizing forced/continuous alcohol (EtOH) access, tend to show that EtOH intake mitigates HFD-induced effects on insulin and glucose function, while HFD decreases voluntary EtOH intake in continuous access models. However, the impact of HFD on intermittent EtOH intake and resultant changes to metabolic function are not well characterized. The present studies sought to determine if HFD alters EtOH intake in male C57Bl/6J mice given differing two-bottle choice EtOH access schedules, and to assess resultant impact on insulin sensitivity and glucose tolerance. In the first experiment, mice had Unlimited Access EtOH (UAE)+HFD (n=15; HFD=60% calories from fat, 10% EtOH v/v, ad libitum) or UAE+Chow (n=15; control diet=16% calories from fat, ad libitum) for 6 weeks. UAE+HFD mice had lower EtOH preference, consumed significantly less EtOH, and were insulin resistant and hyperglycemic compared with UAE+Chow mice. In the second experiment, mice had Limited Access EtOH (LAE, 4 hrs/d; 3 d/wk)+HFD (n=15) or LAE+Chow (n=15) with increasing EtOH concentrations (10%, 15%, 20%). LAE+HFD mice had no difference in total EtOH consumption compared to LAE+Chow mice, but exhibited hyperglycemia, insulin resistance, and glucose intolerance. In the third experiment, mice had intermittent HFD access (single 24 hr session/week) with limited access to EtOH (iHFD-E, 4hrs/d; 4 d/wk) (n=10). iHFD-E mice displayed binge eating behaviors and consumed significantly more EtOH than mice given ad libitum chow or HFD, suggesting transfer of binge eating to binge drinking behaviors. Although iHFD-E mice did not have significantly altered body composition, they developed insulin insensitivity and glucose intolerance. These results suggest that access schedules determine the impact of HFD on EtOH consumption and resultant metabolic dysfunction.

Long-term high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats

2002 ◽  
Vol 282 (6) ◽  
pp. E1231-E1238 ◽  
Author(s):  
Simon M. Chalkley ◽  
Manthinda Hettiarachchi ◽  
Donald J. Chisholm ◽  
Edward W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Wistar Rats ◽  
Cell Function ◽  
Insulin Response ◽  
High Fat ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Severe Insulin Resistance ◽  
Fat Feeding

Although lipid excess can impair β-cell function in vitro, short-term high-fat feeding in normal rats produces insulin resistance but not hyperglycemia. This study examines the effect of long-term (10-mo) high polyunsaturated fat feeding on glucose tolerance in Wistar rats. The high fat-fed compared with the chow-fed group was 30% heavier and 60% fatter, with approximately doubled fasting hyperinsulinemia ( P < 0.001) but only marginal fasting hyperglycemia (7.5 ± 0.1 vs. 7.2 ± 0.1 mmol/l, P < 0.01). Insulin sensitivity was ∼67% lower in the high-fat group ( P < 0.01). The acute insulin response to intravenous arginine was approximately double in the insulin-resistant high-fat group ( P < 0.001), but that to intravenous glucose was similar in the two groups. After the intravenous glucose bolus, plasma glucose decline was slower in the high fat-fed group, confirming mild glucose intolerance. Therefore, despite severe insulin resistance, there was only a mildly elevated fasting glucose level and a relative deficiency in glucose-stimulated insulin secretion; this suggests that a genetic or congenital susceptibility to β-cell impairment is required for overt hyperglycemia to develop in the presence of severe insulin resistance.

Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding

1999 ◽  
Vol 277 (4) ◽  
pp. E659-E667 ◽  
Author(s):  
Karl J. Kaiyala ◽  
Ronald L. Prigeon ◽  
Steven E. Kahn ◽  
Stephen C. Woods ◽  
Daniel Porte ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Chow Diet ◽  
High Fat ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Β Cell Function ◽  
Fat Feeding

The ability to increase β-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces β-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance ( K g), insulin sensitivity (SI), and the acute insulin response to glucose (AIRg) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, SI decreased by 57% ( P = 0.003) but AIRg was unchanged. This absence of β-cell compensation to insulin resistance contributed to a 41% reduction of K g( P = 0.003) and abolished the normal hyperbolic relationship between AIRg and SI observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level ( P = 0.004) in association with an 8% reduction of glucose ( P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.

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