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: 3.77). 04/2012; 19(2):81-7. DOI: 10.1097/MED.0b013e3283514e13
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma.
    BioMed Research International 09/2014; DOI:10.1155/2014/120179 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background An inactive lifestyle is a risk factor for several types of cancer. A proposed pathway through which exercise influences cancer risk is via insulin. We aim to investigate the effect of a one-year exercise intervention on insulin sensitivity, and the role of body fat in this association, in healthy, normal to overweight/obese, postmenopausal women. Methods In the SHAPE study, 189 healthy, inactive and postmenopausal women (aged 50-69, BMI 22-40 kg/m2) were randomly assigned to a one-year aerobic and strength exercise intervention (150 min/week), or a control group. Between group differences in fasting insulin, glucose and homeostatic model assessment of insulin resistance (HOMA2) over time were estimated using linear mixed models. Results Follow-up measurements of insulin sensitivity were available for 181 (95.8%) and 182 (96.3%) women at 4 and 12 months, respectively. The intention to treat analysis showed no significant differences between the two study groups (treatment effect ratio of the exercise group versus control (β) [95% confidence interval]): insulin, β=1.07 [0.96-1.19]; glucose, β=1.01 [0.99-1.02]; HOMA2, β=1.07 [0.96-1.20]). Similar results were found in a per protocol analysis in compliant women, and in a subgroup of women who lost >2% body fat (measured by DEXA). Conclusions Participation in a one-year aerobic and strength exercise intervention programme did not result in changes in insulin sensitivity in healthy postmenopausal and inactive women. Impact Our findings suggest that 150 minutes/week of exercise, as recommended by current guidelines, is not enough to achieve improvements in insulin sensitivity and subsequent cancer risk, in healthy postmenopausal women.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24(1). DOI:10.1158/1055-9965.EPI-14-0722 · 4.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Obesity is a known risk factor for colorectal cancer (CRC), and emerging data suggest that this association is mediated by visceral fat rather than total body fat. However, there is a lack of studies evaluating the association between visceral fat area and the prevalence of CRC. Methods: To investigate the relationship between visceral adiposity and prevalence of CRC, data of 497 women diagnosed with CRC and 318 apparently healthy women were analysed and data of well-balanced 191 pairs of women with CRC and healthy women matched based on propensity scores were additionally analysed. Diagnosis of CRC was confirmed by colonoscopy and histology. Metabolic parameters were assessed, along with body composition, using computed tomography. Results: The median visceral fat area was significantly higher in the CRC group compared with the control group before and after matching. The prevalence of CRC increased significantly with increasing visceral fat tertiles after matching (p for trend <0.01). A multivariate analysis showed that mean visceral fat area of individuals in the 67th percentile or greater group was associated with an increased prevalence of CRC (adjusted odds ratio: 1.80; 95% confidence interval: 1.12-2.91 before matching and adjusted odds ratio: 2.96; 95% confidence interval: 1.38-6.33) compared with that of individuals in the 33th percentile or lower group. Conclusion: Thus, we conclude that visceral fat area is positively associated with the prevalence of CRC. Although we could not determine the causality, visceral adiposity may be associated with the risk of CRC. Further prospective studies are required to determine the benefits of controlling visceral obesity for reducing CRC risk.
    PLoS ONE 11/2014; 9(11):e110587. DOI:10.1371/journal.pone.0110587 · 3.53 Impact Factor