OBJECTIVE-To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls. RESEARCH DESIGN AND METHODS-Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m(2)/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 +/- 8 years; 55% female). RESULTS-Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 +/- 0.72 vs. 12.71 +/- 0.66, mean +/- SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (mu M) during 8 mU/m(2)/min insulin infusion = 370 +/- 27 vs. 185 +/- 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = -0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22-0.93, P = 0.03; OR = 2.4, 95% CI = 1.08-5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters. CONCLUSIONS-Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes. Diabetes 60:306-314, 2011
The relationship between insulin sensitivity and overall obesity is well established. However, there remains debate as to which of the fat depots, visceral abdominal tissue (VAT) or subcutaneous abdominal tissue (SAT), is of greater importance. Also, the relationship between fat distribution and insulin secretion is largely unknown. We studied S, acute insulin response (AIR), and disposition index (DI), as obtained by minimal model analysis, in 999 Hispanic and 458 African-American men and women as part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. VAT and, SAT were measured from computed tomography scans performed at the. L4/L5 vertebral region. A mixed-model approach was used to determine the relationship between each of the glucose homeostasis measures (SI, AIR, and DI) versus Abdominal fat measures. Mean values were as follows: age, 41 years; S-I, 1.98 min (.) muU(-1) (.) ml(-1); AIR, 840 pmol (.) ml(-1) (.) min(-1) BMI, 28.5 kg/m(2); VAT, 100 cm 2; and SAT, 333 cm(2). SAT, VAT, and their joint interaction were each inversely and significantly associated with S-I, adjusting for age, sex, ethnicity, and BMI. SAT, but not VAT, was positively associated with AIR, except when additionally adjusting for S-I, in which case VAT was inversely associated with AIR. VAT and the joint interaction of VAT and SAT were inversely associated with DI. The fat measures explained 27% of R-2 the model. for S-I, 16% for AIR, and 16% for DI. Thus, fat distribution is an important determinant of both insulin resistance and insulin secretion.
OBJECTIVE - Insulin resistance and beta-cell function are major predictors Of type 2 diabetes, but studies using direct methods of insulin resistance and secretion are few and relatively small. Furthermore, the strength of these associations has not been tested in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity. RESEARCH DESIGN AND METHODS - Predictors of incident diabetes were evaluated in Hispanic, non-Hispanic white, and African American participants in the Insulin Resistance Atherosclerosis Study (aged 40-69 years). In 557 participants with normal glucose tolerance and 269 with impaired glucose tolerance (IGT), insulin sensitivity (insulin sensitivity index [S-L]) and first-phase insulin secretion (acute insulin response [AIR]) were directly measured using the frequently sampled intravenous glucose tolerance test. RESULTS - At the 5-year follow-up examination, 128 (15.5%) individuals had developed diabetes. Both S-1 (odds ratio X 1 SD 0.50 [95% CI 0.37-0.681) and AIR(0.51. [0.40-0.65]) were independent predictors of incident diabetes even after adjustment for age, sex, ethnicity, center, IGT, family history of diabetes, and BMI. The strength of the relation of S-I and AIR to incident diabetes was not significantly affected by potential interactions of age, sex, ethnicity, glucose tolerance, BMI, or family history of diabetes (P >= 0.15). CONCLUSIONS - Both insulin sensitivity and beta-cell function predict conversion to diabetes in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity. The prevention of type 2 diabetes should focus on interventions that improve both insulin resistance and insulin secretion.
Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and andinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using andinflammatory strategies to correct the metabolic consequences of excess adiposity.
Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D). Patients with diabetes and/or the metabolic syndrome have a significantly increased risk of heart attack and stroke compared with people with normal insulin sensitivity. Decreased insulin sensitivity in cardiovascular tissues as well as in traditional targets of insulin metabolic signaling, such as skeletal muscle, is an underlying abnormality in obesity, hypertension, and T2D. In the vasculature, insulin signaling plays a critical role in normal vascular function via endothelial cell nitric oxide production and modulation of Ca2+ handling and sensitivity in vascular smooth muscle cells. Available evidence suggests that impaired vascular insulin sensitivity may be an early, perhaps principal, defect of vascular function and contributor to the pathogenesis of vascular disease in persons with obesity, hypertension, and T2D. In the overweight and obese individual, as well as in persons with hypertension, systemic and vascular insulin resistance often occur in concert with elevations in plasma aldosterone. Indeed, basic and clinical studies have demonstrated that elevated plasma aldosterone levels predict the development of insulin resistance and that aldosterone directly interferes with insulin signaling in vascular tissues. Furthermore, elevated plasma aldosterone levels are associated with increased heart attack and stroke risk. Conversely, renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone-mediated interruption of downstream vascular insulin signaling. Prevention or restoration of these changes via blockade of aldosterone action in the vascular wall with MR antagonists (i.e., spironolactone, eplerenone) may therefore account for the clinical benefit of these compounds in obese and diabetic patients with cardiovascular disease. This review will highlight recent evidence supporting the hypothesis that aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease. Diabetes 62:313-319, 2013
Insulin resistance OR), the hallmark of type 2 diabetes, may be under epigenetic control. This study examines the association between global DNA methylation and IR using 84 monozygotic twin pairs. IR was estimated using homeostasis model assessment (HOMA). Global DNA methylation of Alu repeats in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between global DNA methylation and IR was examined using generalized estimating equation (GEE) and within-twin pair analyses, adjusting for potential confounders. Results show that methylation levels at all four CpG sites were individually associated with IR by GEE (all false discovery rate-adjusted P values <= 0.026). A 10% increase in mean Alu methylation was associated with an increase of 4.55 units (95% CI 2.38-6.73) in HOMA. Intrapair difference in IR was significantly associated with intrapair difference in global methylation level. A 10% increase in the difference in mean Alu rnethylation was associated with an increase of 4.54 units (0.34-8.71; P = 0.036) in the difference in HOMA. Confirmation of the results by intrapair analyses suggests that genetic factors do not confound the association between global DNA methylation and IR. Exclusion of twins taking diabetes medication (n = 17) did not change our results. Diabetes 61:542-546, 2012
OBJECTIVE-Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions. RESEARCH DESIGN AND METHODS-We fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity. RESULTS-In wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD. CONCLUSIONS-These data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload. Diabetes 60:2474-2483, 2011
OBJECTIVE-Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score > 0), independently of cardiovascular risk factors and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS-Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) >= 75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score > 0 were estimated using logistic regression. RESULTS-There were 915 people with a CAC score > 0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score > 0 (all comparisons against CAC score 0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01-1.45]; P = 0.04) and HOMA-IR (1.10 [1.02-1.18]; P = 0.02) were associated with CAC score > 0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score > 0 (1.53 [1.20-1.95]; P = 0.001). CONCLUSIONS-Fatty liver and HOMA-IR are both associated with a CAC score > 0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD.