What causes the insulin resistance underlying obesity?

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Current opinion in endocrinology, diabetes, and obesity (Impact Factor: 3.37). 04/2012; 19(2):81-7. DOI: 10.1097/MED.0b013e3283514e13
Source: PubMed


The association between obesity and insulin resistance is an area of much interest and enormous public health impact, with hundreds of articles being published in the last year focused on the possible mechanisms that underlie this association. The purpose to this review is to highlight some of the key recent literature with emphasis on emerging concepts.
The specific link between visceral adipose tissue accumulation and insulin resistance continues to be discerned. Visceral adiposity is correlated with accumulation of excess lipid in liver, and results in cell autonomous impairment in insulin signaling. Visceral adipose tissue is also prone to inflammation and inflammatory cytokine production, which also contribute to impairment in insulin signaling. The expansion of visceral adipose tissue and excess lipid accumulation in liver and muscle may result from limited expandability of subcutaneous adipose tissue, due to the properties of its extracellular matrix and capacity for capillary growth.
Recent studies underscore the need to better understand the mechanisms linking visceral adiposity with liver fat accumulation, the mechanisms by which ectopic fat accumulation cause insulin resistance, and the mechanisms by which the size of adipose tissue depots is determined.

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    • "BMI subgroup analyses revealed that associations between HOMA and red blood cells, hemoglobin and hematocrit remain statistically significant in lean and overweight but not in obese subjects. Since the obese individuals expectedly had markedly higher insulin resistance, it is likely that lack of associations in this group is due at least in part to a relevant negative impact on insulin action by non-hematological, obesity-associated alterations, that could include altered adipokine profiles, excess substrate availability, oxidative stress and inflammation [1]–[3]. The above observations have potentially relevant clinical implications since they suggest that: 1) although many important factors contribute to modulate insulin resistance, the current data suggest that, along with other parameters, higher hematological parameters may contribute to identify non-obese individuals at early stages of insulin resistance; 2) red blood cells, hemoglobin and hematocrit appear to have a less relevant metabolic impact and are unlikely to represent reliable biomarkers of insulin resistance in obese individuals. "
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    ABSTRACT: Objective Increments in red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) levels are reportedly associated with higher insulin resistance (IR). Obesity may cause IR, but underlying factors remain incompletely defined, and interactions between obesity, hematological parameters and IR are incompletely understood. We therefore determined whether: 1) BMI and obesity per se are independently associated with higher RBC, hemoglobin and hematocrit; 2) hematological parameters independently predict insulin resistance in obese individuals. Design and Methods We investigated the associations between BMI, hematological parameters and insulin resistance as reflected by homeostasis model assessment (HOMA) in a general population cohort from the North-East Italy MoMa epidemiological study (M/F = 865/971, age = 49±1). Results In all subjects, age-, sex- and smoking-adjusted hematological parameters were positively associated with BMI in linear regression (P<0.05), but not after adjustment for HOMA or waist circumference (WC) and potential metabolic confounders. No associations were found between hematological parameters and BMI in lean, overweight or obese subgroups. Associations between hematological parameters and HOMA were conversely independent of BMI in all subjects and in lean and overweight subgroups (P<0.01), but not in obese subjects alone. Conclusions In a North-East Italy general population cohort, obesity per se is not independently associated with altered RBC, Hb and Ht, and the association between BMI and hematological parameters is mediated by their associations with abdominal fat and insulin resistance markers. High hematological parameters could contribute to identify insulin resistance in non-obese individual, but they do not appear to be reliable insulin resistance biomarkers in obese subjects.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "As a consequence of the decreased fat accumulation in the organism, both HFD-Leu and HFD-pairfat animals had decreased triglycerides content in the liver, a finding that is in agreement with other published observations describing decreased hepatic lipid accumulation and expression of lipogenic enzymes in the liver of HFD mice supplemented with leucine [14]. Hepatic lipid deposition and consequent activation of inflammatory responses are known to play a critical role in the development of insulin resistance [2], [31]. Even though we did not assess inflammatory markers in liver or adipose tissue, it is likely that both HFD-Leu and HFD-pairfat mice were characterized by decreased inflammation and that these changes might ultimately have led to the improved insulin sensitivity. "
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    ABSTRACT: Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "While the mean values are comparable, the range and maximum values were lower in the current study. As obesity is the predominant underlying cause of insulin resistance [35], the lower HOMA-IR scores observed in the current study may be attributed to lower range of BMI values. The prevalence of obesity in Ireland is increasing steadily [36], albeit at a slower rate than observed in North America [37]. "
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    ABSTRACT: Breast cancer prognosis can be adversely influenced by obesity, physical inactivity and metabolic dysfunction. Interventions aimed at improving surrogate markers of breast cancer risk such as insulin resistance may result in improved breast cancer outcomes. The design of such interventions may be improved through increased understanding of metabolic presentation in this cohort. This cross-sectional study aimed to characterise the metabolic profile of breast cancer survivors relative to abdominal obesity and insulin resistance. A secondary aim was to compare measures of energy output across these groups. Sixty-nine women (mean (SD) age 53.43 (9.39)) who had completed adjuvant chemotherapy and radiotherapy for breast cancer were recruited. All measures were completed during one assessment conducted 3.1 (1.0) years post diagnosis. Body composition was measured by bioimpedance analysis and waist circumference (WC). Fasting (12 hour) blood samples were drawn to measure lipid profile, glucose, insulin, glycosylated haemoglobin A1c (HBA1c) and C-reactive protein (CRP). Insulin resistance was estimated by the homeostatic model assessment index (HOMA-IR)). Energy output was evaluated by resting metabolic rate (RMR) measured by indirect calorimetry and physical activity measured by accelerometry. Characteristics were compared across four groups (1. WC <80 cm, not insulin resistant; 2. WC 80--87.9 cm, not insulin resistant; 3. WC >88 cm, not insulin resistant; 4. WC >80 cm, insulin resistant) using ANOVA (p < 0.05). Group 4 was characterised by significant disturbances in measures of glucose metabolism (glucose, insulin, HOMA-IR and HBA1c) and raised CRP compared to other groups. Group 4 also displayed evidence of dyslipidemia and higher body composition values compared to Groups 1 and 2. Both absolute and adjusted RMR were significantly higher in the Group 4 versus all other groups. Physical activity levels were similar for all groups. The results from this study suggest that participants who were both centrally obese and insulin resistant showed evidence of dyslipidemia, low-grade inflammation and glucose dysregulation. Metabolic profiles of participants who were centrally obese only were not significantly different from lean participants. Consideration of baseline metabolic presentation may be useful when considering the therapeutic targets for future interventions in this cohort.
    Full-text · Article · Jul 2013 · Nutrition Journal
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