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      Hyperinsulinemia in Individuals with obesity: Role of Insulin Clearance

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          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. We aimed to clarify the complex interrelationship that exists between obesity, IR and ICR.


          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 4 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.


          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 IR 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.


          Reduced ICR in obesity is secondary to IR, not excess adiposity.

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          Most cited references 19

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          Insulin resistance as a predictor of age-related diseases.

           N Hua,  F Abbasi,  G M Reaven (2001)
          The current study was initiated to evaluate the ability of insulin resistance to predict a variety of age-related diseases. Baseline measurements of insulin resistance and related variables were made between 1988-1995 in 208 apparently healthy, nonobese (body mass index < 30 kg/m2) individuals, who were then evaluated 4-11 yr later (mean +/- SEM = 6.3 +/- 0.2 yr) for the appearance of the following age-related diseases: hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. The effect of insulin resistance on the development of clinical events was evaluated by dividing the study group into tertiles of insulin resistance at baseline and comparing the events in these 3 groups. Clinical endpoints (n = 40) were identified in 37 individuals (18%) of those evaluated, including 12 with hypertension, 3 with hypertension + type 2 diabetes, 9 with cancer, 7 with coronary heart disease, 4 with stroke, and 2 with type 2 diabetes. Twenty-eight out of the total 40 clinical events were seen in 25 individuals (36%) in the most insulin-resistant tertile, with the other 12 occurring in the group with an intermediate degree of insulin resistance. Furthermore, insulin resistance was an independent predictor of all clinical events, using both multiple logistic regression and Cox's proportional hazards analysis. The fact that an age-related clinical event developed in approximately 1 out of 3 healthy individuals in the upper tertile of insulin resistance at baseline, followed for an average of 6 yr, whereas no clinical events were observed in the most insulin-sensitive tertile, should serve as a strong stimulus to further efforts to define the role of insulin resistance in the genesis of age-related diseases.
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            Effect of liver fat on insulin clearance.

            A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 +/- 1 yr, body mass index (BMI) 26.3 +/- 0.5 kg/m(2)]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU.kg(-1).min(-1) for 240 min) clamp technique combined with the infusion of [3-(3)H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained approximately 40% higher (P < 0.0001) in the high (15.0 +/- 1.5%) compared with the low (1.8 +/- 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml.kg fat free mass(-1).min(-1)) was inversely related to liver fat content (r = -0.52, P < 0.0001), independent of age, sex, and BMI (r = -0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0-41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance (r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity (r = -0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.
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              Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease.

               J Yip,  G M Reaven,  F Facchini (1998)
              Resistance to insulin-mediated glucose disposal has been postulated to predispose individuals to a cluster of associated abnormalities (Syndrome X) known to increase risk of cardiovascular disease (CVD). Although several abnormalities subsumed under the rubric of Syndrome X have been shown to predict CVD, there has been no prospective study evaluating the power of insulin resistance, the putative fundamental defect in the syndrome, in this context. Therefore, this study was initiated to evaluate the hypothesis that resistance to insulin-mediated glucose disposal would predict the development of CVD in healthy volunteers. To accomplish this goal, 147 normal, healthy, nonobese, volunteers were evaluated [4.7 +/- 0.1 yr (mean +/- SEM)] after baseline measurements of steady state plasma glucose concentration (an estimate of insulin-mediated glucose disposal), as well as other CVD risk factors. Clinical end points developed in 13 subjects during the follow-up period; hypertension in 5, coronary artery disease in 4, cerebrovascular accident in 3, and peripheral vascular disease in 1. There was a significant univariate relationship between SSPG and CVD (P < 0.002), with the majority of the events taking place in the tertile of subjects with the highest SSPG concentration, i.e. the greatest degree of insulin resistance. In contrast, no CVD events were observed in the tertile with the lowest SSPG concentrations; the most insulin sensitive. SSPG was also related significantly to diastolic blood pressure, triglyceride, and low-density lipoprotein and high-density lipoprotein cholesterol concentrations, and the glucose and insulin responses to oral glucose. All of these relationships were independent of age, gender, body mass index, estimates of physical activity, and smoking history. When SSPG was paired with each of the other variables in a series of multiple regression models, only SSPG, or insulin response, were independent predictors of CVD events. In conclusion, approximately one of every five healthy, nonobese subjects in the most insulin-resistant tertile, followed for approximately 5 yr, had a serious clinical event. These data highlight the importance of insulin resistance as a predictor of CVD.

                Author and article information

                Obesity (Silver Spring)
                Obesity (Silver Spring)
                Obesity (Silver Spring, Md.)
                5 August 2015
                02 November 2015
                December 2015
                01 December 2016
                : 23
                : 12
                : 2430-2434
                [1 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
                [2 ]Department of Medicine, Stanford University School of Medicine, Standford, California, USA
                [3 ]Department of Pediatrics and Medicine, UCLA School of Medicine, Institute for Translational Genomics and Population Sciences, LAbiomedical Research Institute, Harbor-UCLA Medical Center, Los Angeles, USA
                Author notes
                Address correspondence to: Sun H. Kim, MD, MS, Department of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Room S025, Stanford, California 94305-5103. sunhkim@ 123456stanford.edu

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                hyperinsulinemia, insulin clearance, insulin resistance, obesity


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