Obesity and Diabetes: Pathophysiology of Obesity-Induced Hyperglycemia and Insulin Resistance

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

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Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

Journal of International Medical Research ◽

10.1177/03000605211048293 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110482

Author(s):

Xiaoqin Ha ◽

Xiaoling Cai ◽

Huizhe Cao ◽

Jie Li ◽

Bo Yang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Effective Means ◽

Model Assessment ◽

High Concentration ◽

Obesity And Diabetes ◽

Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

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Early Overnutrition Results in Early-Onset Arcuate Leptin Resistance and Increased Sensitivity to High-Fat Diet

Endocrinology ◽

10.1210/en.2009-1295 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1598-1610 ◽

Cited By ~ 104

Author(s):

Maria M. Glavas ◽

Melissa A. Kirigiti ◽

Xiao Q. Xiao ◽

Pablo J. Enriori ◽

Sarah K. Fisher ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

High Fat Diet ◽

Arcuate Nucleus ◽

Leptin Resistance ◽

Signal Transducer ◽

High Fat ◽

Insulin Tolerance ◽

Obesity And Diabetes ◽

Transcription 3

Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16–17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.

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Abstract 509: Myocardial Fatty Acid Oxidation Rates Remain Elevated in ob/ob Mice Despite Reversal of Obesity and Diabetes by Caloric Restriction

Circulation ◽

10.1161/circ.116.suppl_16.ii_89 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Crystal Sloan ◽

Joseph Tuinei ◽

E. Dale Abel

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Cardiac Hypertrophy ◽

Caloric Restriction ◽

Serum Triglyceride ◽

Palmitate Oxidation ◽

Oxidation Rates ◽

Leptin Deficiency ◽

Obesity And Diabetes ◽

Myocardial Substrate

Leptin deficient ob/ob mice are commonly used to study the effects of obesity and insulin resistance on myocardial substrate metabolism. However, it is difficult to discern the specific contribution of obesity, insulin resistance and diabetes versus leptin deficiency to the observed phenotypes. We therefore adopted a strategy using caloric restriction to normalize body weight and reverse insulin resistance to study the effect of leptin deficiency on myocardial metabolism in lean ob/ob mice. Male 4-week old ob/ob mice were “pair fed” to a leptin-treated group (3mg/kg/day by i.p. injection) for three weeks. Glucose tolerance, serum insulin, serum triglycerides and FA oxidation rates in hearts perfused with 0.4mM palmitate ± 1 nM insulin were determined. Leptin-treated ob/ob mice ate significantly less than non-treated ob/ob mice, and their weight returned to wild type levels. Hyperglycemia, hyperinsulinemia, hypertriglyceridemia and cardiac hypertrophy were also completely reversed in leptin-treated ob/ob mice. In contrast, cardiac hypertrophy persisted in pair fed ob/ob mice and despite normalization of glucose tolerance and insulin levels, serum triglyceride concentrations increased by 2 and 6 -fold in pair fed ob/ob mice relative to untreated ob/ob and wildtype mice respectively (p<0.05). As previously reported, palmitate oxidation rates were 2.1-fold increased in ob/ob hearts relative to controls (p<0.005) and were normalized with leptin treatment. In contrast, palmitate oxidation rates remained elevated in pair fed ob/ob mice relative to wildtype controls (1.9-fold, p<0.01). Insulin has a positive inotropic effect in perfused wildtype hearts, and this effect was absent in ob/ob hearts. The insulin-induced inotropic response was restored by leptin treatment in ob/ob mice but was not restored in pair fed ob/ob mice. These data support a direct antihypertrophic effect of leptin in the heart and suggest that leptin deficiency may directly contribute to myocardial insulin resistance and abnormal FA metabolism. Potential mechanisms include increased hepatic triglyceride production in leptin deficiency or direct effects of leptin signaling in the hypothalamus and/or the periphery on myocardial substrate utilization.

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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014868 ◽

2020 ◽

Vol 295 (51) ◽

pp. 17535-17548

Author(s):

Xanthe A. M. H. van Dierendonck ◽

Tiphaine Sancerni ◽

Marie-Clotilde Alves-Guerra ◽

Rinke Stienstra

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Macrophage Activation ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Obesity And Diabetes ◽

Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

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Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms20071658 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1658 ◽

Cited By ~ 29

Author(s):

Hatem Maamoun ◽

Shahenda Abdelsalam ◽

Asad Zeidan ◽

Hesham Korashy ◽

Abdelali Agouni

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Cardiovascular Disease ◽

Endoplasmic Reticulum ◽

Endothelial Cell ◽

Er Stress ◽

Cardiovascular Complications ◽

Endothelial Cell Dysfunction ◽

Cell Dysfunction ◽

Obesity And Diabetes

Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.

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Loss of CTRP5 improves insulin action and hepatic steatosis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00010.2016 ◽

2016 ◽

Vol 310 (11) ◽

pp. E1036-E1052 ◽

Cited By ~ 18

Author(s):

Xia Lei ◽

Susana Rodriguez ◽

Pia S. Petersen ◽

Marcus M. Seldin ◽

Caitlyn E. Bowman ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Insulin Action ◽

Subcutaneous Fat ◽

Physiological Role ◽

Negative Regulator ◽

Chow Diet ◽

High Fat ◽

Peripheral Tissues ◽

Obesity And Diabetes

The gene that encodes C1q/TNF-related protein 5 (CTRP5), a secreted protein of the C1q family, is mutated in individuals with late-onset retinal degeneration. CTRP5 is widely expressed outside the eye and also circulates in plasma. Its physiological role in peripheral tissues, however, has yet to be elucidated. Here, we show that Ctrp5 expression is modulated by fasting and refeeding, and by different diets, in mice. Adipose expression of CTRP5 was markedly upregulated in obese and diabetic humans and in genetic and dietary models of obesity in rodents. Furthermore, human CTRP5 expression in the subcutaneous fat depot positively correlated with BMI. A genetic loss-of-function mouse model was used to address the metabolic function of CTRP5 in vivo. On a standard chow diet, CTRP5-deficient mice had reduced fasting insulin but were otherwise comparable with wild-type littermate controls in body weight and adiposity. However, when fed a high-fat diet, CTRP5-deficient animals had attenuated hepatic steatosis and improved insulin action. Loss of CTRP5 also improved the capacity of chow-fed aged mice to respond to subsequent high-fat feeding, as evidenced by decreased insulin resistance. In cultured adipocytes and myotubes, recombinant CTRP5 treatment attenuated insulin-stimulated Akt phosphorylation. Our results provide the first genetic and physiological evidence for CTRP5 as a negative regulator of glucose metabolism and insulin sensitivity. Inhibition of CTRP5 action may result in the alleviation of insulin resistance associated with obesity and diabetes.

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CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00344.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. E309-E325 ◽

Cited By ~ 18

Author(s):

Pia S. Petersen ◽

Xia Lei ◽

Risa M. Wolf ◽

Susana Rodriguez ◽

Stefanie Y. Tan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Resistance Index ◽

Activity Level ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Metabolic Role ◽

Obesity And Diabetes

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

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Artificial selection for high-capacity endurance running is protective against high-fat diet-induced insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00500.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E31-E41 ◽

Cited By ~ 90

Author(s):

Robert C. Noland ◽

John P. Thyfault ◽

Sarah T. Henes ◽

Brian R. Whitfield ◽

Tracey L. Woodlief ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Weight Gain ◽

High Fat Diet ◽

Oxidative Capacity ◽

Male Rats ◽

High Fat ◽

Endurance Running ◽

Muscle Oxidative Capacity ◽

Obesity And Diabetes

Elevated oxidative capacity, such as occurs via endurance exercise training, is believed to protect against the development of obesity and diabetes. Rats bred both for low (LCR)- and high (HCR)-capacity endurance running provide a genetic model with inherent differences in aerobic capacity that allows for the testing of this supposition without the confounding effects of a training stimulus. The purpose of this investigation was to determine the effects of a high-fat diet (HFD) on weight gain patterns, insulin sensitivity, and fatty acid oxidative capacity in LCR and HCR male rats in the untrained state. Results indicate chow-fed LCR rats were heavier, hypertriglyceridemic, less insulin sensitive, and had lower skeletal muscle oxidative capacity compared with HCR rats. Upon exposure to an HFD, LCR rats gained more weight and fat mass, and their insulin resistant condition was exacerbated, despite consuming similar amounts of metabolizable energy as chow-fed controls. These metabolic variables remained unaltered in HCR rats. The HFD increased skeletal muscle oxidative capacity similarly in both strains, whereas hepatic oxidative capacity was diminished only in LCR rats. These results suggest that LCR rats are predisposed to obesity and that expansion of skeletal muscle oxidative capacity does not prevent excess weight gain or the exacerbation of insulin resistance on an HFD. Elevated basal skeletal muscle oxidative capacity and the ability to preserve liver oxidative capacity may protect HCR rats from HFD-induced obesity and insulin resistance.

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Ketogenic Diets as Highly Effective Treatments for Diabetes Mellitus and Obesity

10.1093/med/9780190497996.003.0037 ◽

2016 ◽

Author(s):

Eric C. Westman ◽

Emily Maguire ◽

William S. Yancy

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Modern Medicine ◽

Carbohydrate Restriction ◽

Abdominal Adiposity ◽

Ketogenic Diets ◽

Chronic Hyperglycemia ◽

Obesity And Diabetes ◽

Low Carbohydrate

Obesity and type 2 diabetes mellitus (T2DM) have reached epidemic proportions worldwide. While characterized by chronic hyperglycemia, the underlying cause of T2DM is insulin resistance—most often related to an increase in abdominal adiposity caused by obesity. The goal of treatment of T2DM is to put the disease into remission by targeting the underlying insulin resistance. The observation that dietary carbohydrate is the major factor to cause glycosuria and hyperglycemia, has been known since the early days of modern medicine. As a result, low-carbohydrate, ketogenic diets were employed to treat obesity and diabetes in the nineteenth and early twentieth centuries. This chapter reviews the rationale and recent clinical research supporting the use of a low-carbohydrate, ketogenic diet in individuals with obesity and diabetes. For individuals affected by obesity-related T2DM, clinical studies have shown that carbohydrate restriction and weight loss can improve hyperglycemia, obesity, and T2DM.

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