Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance?

Insulin is a paramount anabolic hormone that promotes energy-storage in adipose tissue, skeletal muscle and liver, and these responses are significantly attenuated in insulin resistance leading to type 2 diabetes. Contrasting with insulin’s function, macroautophagy/autophagy is a physiological mechanism geared to the degradation of intracellular components for the purpose of energy production, building-block recycling or tissue remodeling. Given that both insulin action and autophagy are dynamic phenomena susceptible to the influence of nutrient availability, it is perhaps not surprising that there is significant interaction between these two major regulatory mechanisms. This review examines the crosstalk between autophagy and insulin action, with specific focus on dysregulated autophagy as a cause or consequence of insulin resistance.

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Insulin resistance: Impact on therapeutic developments in diabetes

Diabetes and Vascular Disease Research ◽

10.1177/1479164119827570 ◽

2019 ◽

Vol 16 (2) ◽

pp. 128-132 ◽

Cited By ~ 1

Author(s):

Clifford J Bailey

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Action ◽

Glucose Lowering ◽

Therapeutic Practice ◽

Improve Insulin Action ◽

Clinical Awareness

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies.

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Mitochondrial dysfunction and insulin resistance: an update

Endocrine Connections ◽

10.1530/ec-14-0092 ◽

2015 ◽

Vol 4 (1) ◽

pp. R1-R15 ◽

Cited By ~ 256

Author(s):

Magdalene K Montgomery ◽

Nigel Turner

Keyword(s):

Insulin Resistance ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Insulin Action ◽

Intervention Studies ◽

Human Populations ◽

Genetic Manipulations ◽

The Past ◽

Mitochondrial Capacity

Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR.

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Placental Restriction of Fetal Growth Increases Insulin Action, Growth, and Adiposity in the Young Lamb

Endocrinology ◽

10.1210/en.2006-0653 ◽

2007 ◽

Vol 148 (3) ◽

pp. 1350-1358 ◽

Cited By ~ 92

Author(s):

Miles J. De Blasio ◽

Kathryn L. Gatford ◽

I. Caroline McMillen ◽

Jeffrey S. Robinson ◽

Julie A. Owens

Keyword(s):

Insulin Sensitivity ◽

Fetal Growth ◽

Insulin Action ◽

Visceral Obesity ◽

Later Life ◽

Anabolic Hormone ◽

Increased Risk ◽

Catch Up ◽

Diabetes And Obesity

Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed “catch-up” growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.

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Inhibition of ADRP prevents diet-induced insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90204.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. G621-G628 ◽

Cited By ~ 75

Author(s):

Gladys M. Varela ◽

Daniel A. Antwi ◽

Ravindra Dhir ◽

Xiaoyan Yin ◽

Neel S. Singhal ◽

...

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Insulin Action ◽

Fatty Acyl ◽

High Fat ◽

Diet Induced Obesity ◽

Tracer Techniques ◽

Adipose Differentiation ◽

Lipid Droplet Protein

Diets with high fat content induce steatosis, insulin resistance, and type 2 diabetes. The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. We fed C57BL/6J mice a high-fat diet and simultaneously treated them with an antisense oligonucleotide (ASO) against ADRP for 4 wk. Glucose homeostasis was assessed with clamp and tracer techniques. ADRP ASO decreased the levels of triglycerides and diacylglycerol in the liver, but fatty acids, long-chain fatty acyl CoAs, ceramides, and cholesterol were unchanged. Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCε, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.

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Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00541.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. E537-E546 ◽

Cited By ~ 60

Author(s):

Sangeeta R. Kashyap ◽

Renata Belfort ◽

Rachele Berria ◽

Swangjit Suraamornkul ◽

Thongchai Pratipranawatr ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Family History ◽

Insulin Receptor ◽

Insulin Signaling ◽

Insulin Action ◽

Low Dose ◽

History Of ◽

Plasma Ffa

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (∼1,500–4,000 μmol/l). However, plasma FFA levels >1,000 μmol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (∼600–800 μmol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ∼1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

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θ-Defensin RTD-1 improves insulin action and normalizes plasma glucose and FFA levels in diet-induced obese rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00131.2015 ◽

2015 ◽

Vol 309 (2) ◽

pp. E154-E160 ◽

Cited By ~ 5

Author(s):

Young Taek Oh ◽

Dat Tran ◽

Thomas A. Buchanan ◽

Michael E. Selsted ◽

Jang H. Youn

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Plasma Glucose ◽

Insulin Action ◽

Calorie Intake ◽

Model Assessment ◽

Hepatic Expression ◽

Glucose Clamp Technique ◽

Metabolic Conditions

Inflammation is implicated in metabolic abnormalities in obesity and type 2 diabetes. Because θ-defensins have anti-inflammatory activities, we tested whether RTD-1, a θ-defensin, improves metabolic conditions in diet-induced obesity (DIO). DIO was induced by high-fat feeding in obese-prone CD rats from 4 wk of age. Starting at age 10 wk, the DIO rats were treated with saline or RTD-1 for 4 or 8 wk. DIO rats gained more weight than low-fat-fed controls. RTD-1 treatment did not alter body weight or calorie intake in DIO rats. Plasma glucose, FFA, triglyceride (TG), and insulin levels increased in DIO rats; RTD-1 normalized plasma glucose and FFA levels and showed tendencies to lower plasma insulin and TG levels. Hepatic and skeletal muscle TG contents increased in DIO rats; RTD-1 decreased muscle, but not hepatic, TG content. Insulin sensitivity, estimated using homeostasis model assessment of insulin resistance and the glucose clamp technique, decreased in DIO rats, but this change was markedly reversed by RTD-1. RTD-1 had no significant effects on plasma cytokine/chemokine levels or IL-1β and TNF-α expression in liver or adipose tissues. RTD-1 treatment decreased hepatic expression of phospho enolpyruvate carboxykinase and glucose-6-phosphatase, suggesting that the effect of RTD-1 on plasma glucose (or insulin action) might be mediated by its effect to decrease hepatic gluconeogenesis. Thus, RTD-1 ameliorated insulin resistance and normalized plasma glucose and FFA levels in DIO rats, supporting the potential of RTD-1 as a novel therapeutic agent for insulin resistance, metabolic syndrome, or type 2 diabetes.

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Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00376.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E327-E336 ◽

Cited By ~ 37

Author(s):

You-Ree Cho ◽

Hyo-Jeong Kim ◽

So-Young Park ◽

Hwi Jin Ko ◽

Eun-Gyoung Hong ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mouse Model ◽

Lipid Content ◽

Insulin Action ◽

Plasma Insulin ◽

Glut4 Expression ◽

Organ Specific

As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes.

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Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/379024 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 53

Author(s):

Sandro M. Hirabara ◽

Renata Gorjão ◽

Marco A. Vinolo ◽

Alice C. Rodrigues ◽

Renato T. Nachbar ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Cardiovascular Diseases ◽

Molecular Basis ◽

Insulin Action ◽

Molecular Targets ◽

Two Factors ◽

Molecular Aspects

Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions.

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Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice

Endocrinology ◽

10.1210/en.2013-1191 ◽

2013 ◽

Vol 154 (9) ◽

pp. 3099-3109 ◽

Cited By ~ 117

Author(s):

João Paulo G. Camporez ◽

François R. Jornayvaz ◽

Max C. Petersen ◽

Dominik Pesta ◽

Blas A. Guigni ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Protein Kinase ◽

Insulin Action ◽

Fibroblast Growth Factor 21 ◽

Cellular Mechanisms ◽

Novel Therapy

Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid metabolism and is currently being pursued as a therapeutic agent for insulin resistance and type 2 diabetes. However, the cellular mechanisms by which FGF21 modifies insulin action in vivo are unclear. To address this question, we assessed insulin action in regular chow– and high-fat diet (HFD)–fed wild-type mice chronically infused with FGF21 or vehicle. Here, we show that FGF21 administration results in improvements in both hepatic and peripheral insulin sensitivity in both regular chow– and HFD-fed mice. This improvement in insulin responsiveness in FGF21-treated HFD-fed mice was associated with decreased hepatocellular and myocellular diacylglycerol content and reduced protein kinase Cϵ activation in liver and protein kinase Cθ in skeletal muscle. In contrast, there were no effects of FGF21 on liver or muscle ceramide content. These effects may be attributed, in part, to increased energy expenditure in the liver and white adipose tissue. Taken together, these data provide a mechanism by which FGF21 protects mice from lipid-induced liver and muscle insulin resistance and support its development as a novel therapy for the treatment of nonalcoholic fatty liver disease, insulin resistance, and type 2 diabetes.

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