Statins Are Associated With Increased Insulin Resistance and Secretion.

Objective: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01). Conclusions: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.

Cardiorespiratory Fitness, Body Mass Index, and Markers of Insulin Resistance in Apparently Healthy Women and Men.

BACKGROUND: Insulin resistance may be present in healthy adults and is associated with poor health outcomes. Obesity is a risk factor for insulin resistance, but most obese adults do not have insulin resistance. Fitness may be protective, but the association between fitness, weight, and insulin resistance has not been studied in a large population of healthy adults. METHODS: A cross-sectional analysis of cardiorespiratory fitness, body mass index, and markers of insulin resistance was performed. Study participants were enrolled at the Cooper Clinic in Dallas, Texas. The analysis included 19,263 women and 48,433 men with no history of diabetes or cardiovascular disease. Cardiorespiratory fitness was measured using exercise treadmill testing. Impaired fasting glucose (100-125 mg/dL) and elevated fasting triglycerides (≥150 mg/dL) were used as a markers of insulin resistance. RESULTS: Among individuals with normal weight, poor fitness was associated with 2.2-fold higher odds of insulin resistance in women (1.4-3.6; P = .001) and 2.8-fold higher odds in men (2.1-3.6; P <.001). The impact of fitness remained significant for overweight and obese individuals, with the highest risk group being the unfit obese. Among obese women, the odds ratio for insulin resistance was 11.0 for fit women (8.7-13.9; P <.001) and 20.3 for unfit women (15.5-26.5; P <.001). Among obese men, the odds ratio for insulin resistance was 7.4 for fit men (6.7-8.2; P < .001) and 12.9 for unfit men (11.4-14.6; P < .001). CONCLUSIONS: Independent of weight, poor fitness is associated with risk of insulin resistance. Obese individuals, particularly women, may benefit from the greatest absolute risk reduction by achieving moderate fitness.

Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia.

OBJECTIVE: Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups. RESEARCH DESIGN AND METHODS: In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance. RESULTS: Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations. CONCLUSION: Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

Plasma glucose concentration 60 min post oral glucose load and risk of type 2 diabetes and cardiovascular disease: Pathophysiological implications.

AIM: The aim of this study was to gain insight into the pathophysiological significance of elevated plasma glucose concentrations (mmol/L) 60 min post oral glucose load in apparently healthy individuals. METHODS: Comparison of resistance to insulin action and associated cardio-metabolic risk factors in 490 apparently healthy persons, subdivided into those with a plasma glucose concentration 60 min following a 75-g oral glucose challenge of <8.6 versus ⩾8.6. RESULTS: Insulin resistance was significantly greater in persons with normal glucose tolerance whose 60-min glucose concentration was ⩾8.6, associated with higher blood pressure, plasma concentrations of glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol concentrations. Similar differences were seen in persons with impaired fasting glucose, but not in those with impaired glucose tolerance or both impaired fasting glucose and impaired glucose tolerance. The group whose 60-min glucose was <8.6 (n = 318) contained primarily persons with normal glucose tolerance (88%), whereas the majority of those whose 60-min value was ⩾8.6 (n = 172) had prediabetes (59%) and in particular combined impaired fasting glucose and impaired glucose tolerance. CONCLUSION: Plasma glucose concentration of ⩾8.6 mmol/L 60 min post oral glucose identifies higher proportions of combined impaired fasting glucose and impaired glucose tolerance individuals as well as normal glucose tolerance and impaired fasting glucose individuals with a more adverse cardio-metabolic profile, contributing to observed increased overall risk of type 2 diabetes and other metabolic diseases.

Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?

BACKGROUND: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD). METHODS: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n = 576). RESULTS: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P < 0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P < 0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P < 0.001]. CONCLUSIONS: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.

Adapting to insulin resistance in obesity: role of insulin secretion and clearance.

AIMS/HYPOTHESIS: The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes. METHODS: Obese (BMI ≥30 kg/m2) individuals without diabetes (n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant). RESULTS: There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8-36.3] mmol/l × h) and insulin responses (1711 [1476-2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8-32.9] mmol/l × h, p = 0.04, and 851 [600-1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41-0.59]; SSPG-2, 0.43 [0.39-0.50]; SSPG-3, 0.34 [0.31-0.40]). CONCLUSIONS/INTERPRETATION: While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.

Relationship between several surrogate estimates of insulin resistance and a direct measure of insulin-mediated glucose disposal: Comparison of fasting versus post-glucose load measurements.

AIMS: The study aim was to determine the correlation of several surrogate estimates of insulin resistance with a direct measure of insulin action and the ability of these estimates to identify insulin resistant persons. METHODS: Retrospective analysis of 454 apparently healthy individuals studied in a clinical research center. The correlations between 11 surrogate estimates of insulin resistance, using either fasting or post-oral glucose challenge values, and a direct measure of insulin-mediated glucose uptake (SSPG concentration during the Insulin Suppression Test) were determined as well as the ability of the surrogate estimates to identify insulin resistant individuals. RESULTS: All surrogate estimates were significantly (P < .001) correlated with SSPG concentrations and successfully identified insulin resistant persons. These relationships were of lesser magnitude when estimates were based on fasting data, with the exception of the McAuley index-derived from fasting data, but resembling post-glucose challenge estimates. Moreover, correlation with SSPG concentration, and positive identification of insulin resistance, varied considerably among estimates. CONCLUSION: All 11 surrogate estimates of insulin resistance significantly correlated with insulin-mediated glucose disposal and identified insulin resistant persons with a reasonable degree of sensitivity and specificity. For identification of insulin resistant individuals, indices based on post-glucose challenge measurements performed better than those based on fasting measurements, with the exception of McAuley index. The quantitative information derived from this analysis should help investigators select the surrogate marker of insulin resistance best suited for their study.

Relationship between simple markers of insulin resistance and coronary artery calcification.

BACKGROUND: Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information. OBJECTIVE: We hypothesized that combining 2 simple markers of insulin resistance, prediabetes (PreDM) and triglyceride (TG) concentration ≥150 mg/dL, would identify apparently healthy persons with adverse cardiometabolic risk profiles and increased coronary artery calcium (CAC) compared with those with neither or only 1 abnormality. METHODS: A cross-sectional analysis was performed using data from 25,886 apparently healthy individuals (18,453 men and 7433 women) evaluated at the Cooper Clinic from 1998 to 2015. Participants were divided into those with a normal fasting glucose concentrations (<100 mg/dL = normal fasting glucose) or PreDM (fasting plasma glucose ≥100 and <126 mg/dL) and further subdivided into those with a plasma TG concentration <150 or ≥150 mg/dL. These 4 groups were compared on the basis of multiple coronary artery disease risk factors and the presence of CAC determined during their evaluation. RESULTS: Participants with PreDM and a TG concentration ≥150 mg/dL had a significantly more adverse coronary artery disease risk profile than individuals with either abnormality or only 1 abnormality (PreDM or TG concentration ≥150 mg/dL). Furthermore, the odds of detectable CAC were higher in participants with PreDM and a TG ≥ 150 mg/dL than in participants with neither or only 1 abnormality. CONCLUSION: The presence of 2 markers of insulin resistance, PreDM and TG concentration ≥150 mg/dL, is associated with increased cardiometabolic risk and detectable CAC within a population of apparently healthy individuals.

Relationship among age, insulin resistance, and blood pressure.

The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (<52 vs. ≥52 years), and comparisons were made of metabolic characteristics, including steady-state plasma glucose (SSPG) concentrations measured during the insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged <52 years, whereas in those aged ≥52 years, prevalence of hypertension was increased approximately fivefold compared with those with normal BP. Multivariate regression analysis demonstrated significant interaction between age and SSPG in predicting systolic BP (P = .023). In stratified analysis, SSPG, but not age, was an independent predictor of systolic BP and diastolic BP in ≥52 years group, whereas the reverse was true in the younger group. The adverse impact of insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging.

Effect of Pioglitazone on Cardiometabolic Risk in Patients With Obstructive Sleep Apnea.

Prevalence of insulin resistance is increased in patients with obstructive sleep apnea (OSA). Because insulin resistance is an independent predictor of cardiovascular disease (CVD), this study was initiated to see if pioglitazone administration would improve insulin sensitivity and thereby decrease risk of CVD in overweight/obese, nondiabetic, insulin-resistant patients with untreated OSA. Patients (n = 30) were administered pioglitazone (45 mg/day) for 8 weeks, and measurements were made before and after intervention of insulin action (insulin-mediated glucose uptake by the insulin suppression test), C-reactive protein, lipid/lipoprotein profile, and gene expression profile of periumbilical subcutaneous fat tissue. Insulin sensitivity increased 31% (p <0.001) among pioglitazone-treated subjects, associated with a decrease in C-reactive protein concentration (p ≤0.001), a decrease in plasma triglyceride, and increase in high-density lipoprotein cholesterol concentrations (p ≤0.001), accompanied by significant changes in apolipoprotein A1 and B concentrations and lipoprotein subclasses known to decrease CVD risk. In addition, subcutaneous adipose tissue gene expression profile showed a 1.6-fold (p <0.01) increase in GLUT4 expression and decreased expression in 5 of 9 inflammatory genes (p <0.05). In conclusion, enhanced insulin sensitivity can significantly decrease multiple cardiometabolic risk factors in patients with untreated OSA, consistent with the view that coexisting insulin resistance plays an important role in the association between OSA and increased risk of CVD.

Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance.

OBJECTIVE: The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. METHODS: Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m2 , and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. RESULTS: Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. CONCLUSIONS: Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR.

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity.

Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study.

BACKGROUND: High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures. PATIENTS/METHODS: Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test). RESULTS: A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed. CONCLUSIONS: Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.

Hypertriglyceridemia: A simple approach to identify insulin resistance and enhanced cardio-metabolic risk in patients with prediabetes.

AIMS: Prediabetes (PreDM) is a metabolically heterogeneous condition, differing in degree of insulin resistance and risk of type 2 diabetes mellitus and coronary heart disease (CHD). This study was initiated to evaluate the hypothesis that a fasting plasma triglyceride (TG) concentration ⩾1.7mmol/L can aid in identifying the subset of individuals with PreDM who are most insulin resistant and at greatest risk to develop CHD as well as type 2 diabetes mellitus. METHODS: In this cross-sectional study, measurements were made of: (1) steady-state plasma glucose (SSPG) concentration during the insulin suppression test to ascertain degree of insulin resistance and (2) conventional CHD risk factors in 587 apparently healthy individuals with normal fasting plasma glucose (NFG, n=370) or PreDM (n=217). RESULTS: Subjects with PreDM were significantly (P<0.001) more insulin resistant (higher SSPG concentrations) and had a more adverse CHD risk profile than those with NFG. A TG concentration ⩾1.7mmol/L identified a subset of individuals with PreDM (38%) who had a higher mean SSPG concentration (11.3±3.5mmol/L vs. 9.3±3.9mmol/L, P<0.001), were more likely to be insulin resistant (66% vs. 39%, P<0.001), and had a more adverse CHD risk factor profile. CONCLUSIONS: Measurement of fasting TG concentration in individuals with PreDM may provide a simple clinical approach to identify those who are insulin resistant, at enhanced risk of CHD, and more likely to develop type 2 diabetes mellitus.

Insulin clearance: an underappreciated modulator of plasma insulin concentration.

Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic ß-cells to modify insulin secretion rate (ISR), thus preventing wide-swings in plasma glucose concentrations. As a consequence, and in contrast to plasma glucose concentrations, plasma insulin concentrations vary substantially in non-diabetic individuals. Although differences in ISR are primarily responsible for the variability in plasma insulin concentration, there is increasing evidence that differences in insulin clearance rate (ICR) also play a role in regulation of plasma insulin concentration. The goal of this mini-review is to highlight situations that demonstrate the important role of ICR in both insulin and glucose homeostasis.

Cardiometabolic Risk in South Asian Inhabitants of California: Hypertriglyceridemic Waist vs Hypertriglyceridemic Body Mass Index.

OBJECTIVE: Hypertriglyceridemic waist (HTG-waist), an increased waist circumference (WC) with an elevated triglyceride (TG) concentration, can identify increased cardiometabolic risk in apparently healthy individuals. Since WC and BMI are highly correlated, we examined whether an HTG-BMI would be as effective as an HTG-waist in identifying cardiometabolic risk in apparently healthy South Asians. DESIGN SETTING AND PARTICIPANTS: In this cross-sectional study, we classified South Asian women (n=1156) and men (n=1842) without diabetes mellitus as having an HTG-waist (TG ≥150 mg/dL and a WC ≥80 cm in women or ≥ 90 cm in men) and an HTG-BMI (TG ≥150 mg/dL and a BMI ≥23 kg/m²). OUTCOME MEASURES: We measured cardiometabolic risk factors, including blood pressure and fasting lipid profile, glucose, insulin, fibrinogen, and high-sensitivity C-reactive protein. RESULTS: An HTG-waist was present in 670 individuals, of whom 648 (97%) had an HTG-BMI. The cardiometabolic profile was significantly more adverse in those in whom an HTG-waist was present vs absent; and the same was true when individuals with an HTG-BMI were compared with those without. CONCLUSIONS: Essentially every individual with an HTG-waist also had an HTG-BMI. An HTG-BMI identified cardiometabolic risk as effectively as an HTG-waist in a population composed entirely of South Asians.

Insulin resistance: The linchpin between prediabetes and cardiovascular disease.

The aim of this study was to test the hypothesis that cardiovascular disease occurs to the greatest extent in persons with prediabetes mellitus who are also insulin resistant. In 2003, 664 non-diabetic women (n = 457) and men (n = 207), aged 52 ± 16 and 53 ± 15 years, were surveyed during a programme for cardiovascular disease prevention. Fasting plasma glucose concentrations defined participants as having normal fasting plasma glucose (fasting plasma glucose <5.6 mmol/L) or prediabetes mellitus (fasting plasma glucose ⩾ 5.6 and <7.0 mmol/L). The tertile of prediabetes mellitus subjects with the highest fasting plasma insulin concentration was classified as insulin resistant. Baseline cardiovascular disease risk factors were accentuated in prediabetes mellitus versus normal fasting glucose, particularly in prediabetes mellitus/insulin resistant. In 2012, 86% of the sample were surveyed again, and the crude incidence for cardiovascular disease was higher in subjects with prediabetes mellitus versus normal fasting glucose (13.7 vs 6.0/100 persons/10 years; age- and sex-adjusted hazard ratio = 1.88, p = 0.052). In prediabetes mellitus, the crude incidences were 22.9 versus 9.6/100 persons/10 years in insulin resistant versus non-insulin resistant persons (age- and sex-adjusted hazard ratio = 2.36, p = 0.040). In conclusion, cardiovascular disease risk was accentuated in prediabetes mellitus/insulin resistant individuals, with a relative risk approximately twice as high compared to prediabetes mellitus/non-insulin resistant subjects.

Hyperinsulinemia in individuals with obesity: Role of insulin clearance.

OBJECTIVE: Several studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. This study aimed to clarify the complex interrelationship that exists between obesity, IR, and ICR. METHODS: Healthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into four dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m(2) , and IR was defined as SSPG ≥ 150 mg/dL. RESULTS: Individuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in insulin resistant individuals compared with insulin-sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR. CONCLUSIONS: Reduced ICR in obesity is secondary to IR, not excess adiposity.