Increased Gluconeogenesis Is Not an Early Feature of Whole-Body Insulin Resistance in Black Women—The Federal Women Study

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

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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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Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E654-E667 ◽

Cited By ~ 70

Author(s):

Dake Qi ◽

Brian Rodrigues

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Glucose Utilization ◽

Experimental Studies ◽

Cardiac Metabolism ◽

Multiple Organ ◽

Whole Body ◽

Metabolic Abnormalities ◽

Organ Systems ◽

Per Se

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in “lipotoxicity”. In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

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Whole body insulin resistance in rat offspring of mothers consuming alcohol during pregnancy or lactation: comparing prenatal and postnatal exposure

Journal of Applied Physiology ◽

10.1152/japplphysiol.00751.2003 ◽

2004 ◽

Vol 96 (1) ◽

pp. 167-172 ◽

Cited By ~ 41

Author(s):

Li Chen ◽

B. L. Grégoire Nyomba

Keyword(s):

Insulin Resistance ◽

Birth Weight ◽

Glucose Tolerance ◽

The Body ◽

Whole Body ◽

Glucose Disposal ◽

Tolerance Index ◽

Sensitivity Index ◽

Intravenous Glucose ◽

Rat Offspring

This study examined the effects of maternal ethanol (EtOH) consumption during pregnancy or lactation on glucose homeostasis in the adult rat offspring. Glucose disposal was determined by minimal model during an intravenous glucose tolerance test in rats that had a small or normal birth weight after EtOH exposure in utero and in rats whose mothers were given EtOH during lactation only. All three EtOH groups had decreased glucose tolerance index and insulin sensitivity index, but their glucose effectiveness was not different from that of controls. In addition, EtOH rat offspring that were small at birth had elevated plasma, liver, and muscle triglyceride levels. The data show that EtOH exposure during pregnancy programs the body to insulin resistance later in life, regardless of birth weight, but that this effect also results in dyslipidemia in growth-restricted rats. In addition, insulin resistance is also evident after EtOH exposure during lactation.

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The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance

Biochemical Journal ◽

10.1042/bj2430549 ◽

1987 ◽

Vol 243 (2) ◽

pp. 549-553 ◽

Cited By ~ 7

Author(s):

I D Caterson ◽

L D Astbury ◽

P F Williams ◽

M A Vanner ◽

G J Cooney ◽

...

Keyword(s):

Insulin Resistance ◽

Pyruvate Dehydrogenase ◽

Serum Insulin ◽

Pyruvate Dehydrogenase Complex ◽

Active Form ◽

Whole Body ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Gold Thioglucose ◽

Mitochondrial Fatty Acid

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.

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Abstract 15813: Loss-of-Function Mutation in Toll-Like Receptor 4 Partially Protects Against Peripheral and Cardiac Insulin Resistance During a Long-Term High-Fat Diet

Circulation ◽

10.1161/circ.130.suppl_2.15813 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ellen Jackson ◽

Elizabeth Rendina-Ruedy ◽

Matt Priest ◽

Brenda Smith ◽

Veronique Lacombe

Keyword(s):

Insulin Resistance ◽

Protein Content ◽

Glucose Transport ◽

High Fat Diet ◽

Whole Body ◽

Toll Like Receptor ◽

Loss Of Function ◽

High Fat ◽

The Face ◽

Tlr4 Activation

Diabetes mellitus is an epidemic disease characterized by alterations in glucose transport, which is tightly regulated by a family of specialized proteins called the glucose transporters (GLUTs). Although diabetic cardiomyopathy is a common complication in diabetic patients, its pathogenesis is still not well understood. Toll-like receptor (TLR) 4, which plays a central role in pathogen recognition by the innate immune system, may also play a critical role in linking inflammation and metabolic disease. We hypothesized that TLR4 activation triggers cardiac insulin resistance. We used mice with a loss-of function mutation in TLR4 (C3H/HeJ) and age-matched wild-type (WT, C57BL/6N) mice (n=8/group) to investigate how feeding a high-fat diet (HFD, 60% kcal from fat) for 16 weeks affected whole-body and cardiac glucose metabolism. After 16 weeks, WT mice fed a HFD were obese and developed hyperglycemia and insulin resistance compared to WT mice on a control diet (10% kcal from fat). The C3H/HeJ mice were partially protected against HFD-induced obesity and insulin resistance. In the heart, WT mice fed a HFD had a 30% decrease (P<0.05) in GLUT4 protein content as measured by Western Blot of cardiac crude membrane protein extracts. In contrast, the loss-of-function point mutation in TLR4 partially rescued cardiac GLUT4 content in the face of a HFD. Interestingly, there was a 40% increase (P<0.05) in the novel GLUT isoform, GLUT8, in the heart when mice of either genotype were fed a HFD. Additionally, GLUT4 protein content was negatively (P<0.05) correlated with GLUT8 content in the myocardium, suggesting that GLUT8 may act as a compensatory mechanism in the face of HFD-induced GLUT4 downregulation. Phosphorylated Akt, a key protein of the insulin signaling pathway, was positively (P<0.05) correlated with GLUT4 content, while the basal/inactive form was negatively correlated. In conclusion, these data suggest that activation of TLR4 activation during diabetes and obesity alters glucose transport by an Akt mechanism, and as such is a pathogenic factor during peripheral and cardiac insulin resistance. Overall, TLR4 appears to be a key modulator in the cross-talk between inflammatory and metabolic pathways, as well as a potential therapeutic target for diabetes.

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Insulin Resistance and Inflammation in Black Women with and without Breast Cancer: Cause for Concern

Ethnicity & Disease ◽

10.18865/ed.26.4.513 ◽

2016 ◽

Vol 26 (4) ◽

pp. 513 ◽

Cited By ~ 2

Author(s):

Kathleen A. Griffith ◽

Seon Yoon Chung ◽

Shijun Zhu ◽

Alice S. Ryan

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Black Women ◽

White Women ◽

Cancer Recurrence ◽

Control Group ◽

Study Objective ◽

Increased Risk ◽

Tnf Α ◽

History Of

Objective: After chemotherapy for breast cancer, Black women gain more weight and have an increased mortality rate compared with White women. Our study objective was to compare biomarkers associated with obesity in Black women with and without a history of breast cancer.Design: Case-controlSetting: Academic/federal institutionParticipants: Black women with a history of breast cancer (cases) and age-matched controls.Methods: We compared insulin resistance, inflammation, and lipids in overweight and obese Black women with a history of breast cancer (n=19), age similar controls (n=25), and older controls (n=32). Groups did not differ on mean body mass index (BMI), which was 35.4 kg/m2, 36.0 kg/m2, and 33.0 kg/m2, respectively.Main Outcome Measures: Insulin resistance (HOMA-IR); inflammation (TNF-α, IL-1b, IL-6, IL-8, CRP); lipids (cholesterol, triglycerides).Results: Cases had 1.6 and 1.38 times higher HOMA-IR values compared with age similar and older controls, respectively (P≤.001 for both). TNF-α and IL-1b were significantly higher in cases compared with both control groups (P<.001 for both). IL-6 was also higher in cases compared with age-similar controls (P=.007), and IL-8 was lower in cases compared with older controls (P<.05). Lipids did not differ between cases and either control group.Conclusions: Black women with breast cancer were significantly more insulin resistant with increased inflammation compared not only with age similar controls but with women who were, on average, a decade older. These biomarkers of insulin resistance and inflammation may be associated with increased risk of breast cancer recurrence and require ongoing evaluation, especially given the relatively abnormal findings compared with the controls in this underserved group. Ethn Dis. 2016;26(4):513-520; doi:10.18865/ed.26.4.513

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Proposed trial: safety and efficacy of resveratrol for the treatment of non-alcoholic fatty liver disease (NAFLD) and associated insulin resistance in adolescents who are overweight or obese adolescents — rationale and protocol

Biochemistry and Cell Biology ◽

10.1139/bcb-2014-0136 ◽

2015 ◽

Vol 93 (5) ◽

pp. 522-530 ◽

Cited By ~ 10

Author(s):

Brandy Wicklow ◽

Kristy Wittmeier ◽

Geert W. t’ Jong ◽

Jonathon McGavock ◽

Marni Robert ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Liver ◽

Outcome Measures ◽

Side Effect ◽

Controlled Trial ◽

Whole Body ◽

Secondary Outcome ◽

Side Effect Profile ◽

Obese Adolescent ◽

Alcoholic Fatty Liver

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to <18 years of age) with NAFL. Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity. Adolescents in the intervention arm (n = 10) will receive oral supplementation of resveratrol 75 mg twice daily (with breakfast and dinner) for a total daily dose of 150 mg for the duration of 30 days. The comparison group (n = 10) will receive a placebo twice daily for 30 days. Both cases and controls will receive a standardized lifestyle intervention program. Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days. Primary outcome measures include a primary side effect profile determined by participant interview, a side effect profile determined by serum biochemistry and vital signs. Secondary outcome measures include an oral glucose tolerance test, liver and cardiac fat content measured by magnetic resonance spectroscopy, anthropometric measures of overweight/obesity, inflammatory markers, and cardiac function and morphology measured with ultrasonography. Additional outcome measures include serum concentrations of resveratrol, compliance to protocol, physical activity, and nutritional assessment. This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger randomized controlled trial.

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Inflammation and impaired adipogenesis in hypertrophic obesity in man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E999-E1003 ◽

Cited By ~ 162

Author(s):

Birgit Gustafson ◽

Silvia Gogg ◽

Shahram Hedjazifar ◽

Lachmi Jenndahl ◽

Ann Hammarstedt ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Molecular Mechanisms ◽

Whole Body ◽

Preadipocyte Differentiation ◽

Metabolic Complications ◽

Adipose Cell ◽

Subcutaneous Adipose ◽

Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

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