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Objective: Insulin resistance is common in individuals with chronic kidney disease (CKD) and may be partly explained by modifiable risk factors. In the general population, vitamin E supplementation has been suggested to improve both insulin sensitivity and secretion. We here explore the potential role of vitamin E as a modifiable risk factor for insulin resistance among individuals with CKD., Design: Observational study., Setting: A total of 273 nondiabetic men aged 70 to 71 years with CKD defined as either cystatin C estimated glomerular filtration rate < 60 mL/minute/1.73 m(2) or urinary albumin excretion rate ≥ 20 mg/minute from the third examination cycle of Uppsala Longitudinal Study of Adult Men., Subjects: A total of 273 nondiabetic men aged 70 to 71 years with CKD defined as either cystatin C estimated glomerular filtration rate < 60 mL/minute/1.73 m(2) or urinary albumin excretion rate ≥ 20 μg/minute., Methods: Serum α-, β-, and γ-tocopherol concentrations were measured by high-performance liquid chromatography and expressed as μmol/total serum cholesterol and triglycerides (in mmol). Dietary vitamin E intake was estimated from 7-day food records., Main Outcome Measure: Insulin sensitivity index (M/I ratio) was measured by hyperinsulinemic-euglycemic glucose clamps. Univariate and multivariate regression models were fitted to assess the association between M/I and circulating concentrations of tocopherols., Results: The mean serum concentration of α-, β-, and γ- was 37.4 ± 6.58, 0.89 ± 0.23, and 4.32 ± 1.69 μmol/mmol, respectively. Median dietary vitamin E intake was 6.14 (interquartile range, 5.48-6.82) mg/day. In crude and fully-adjusted multivariate regression analyses, serum α-tocopherol levels were directly and strongly associated with M/I (standard β = 0.17, P = .003). No such association was observed for dietary vitamin E, serum β-, and γ-tocopherol concentrations., Conclusions: Serum α-tocopherol concentration associates with insulin sensitivity in nondiabetic older men with CKD., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Context: Kidney dysfunction induces insulin resistance, but it is unknown if β cell function is affected., Objective: To investigate insulin release (β cell function) and glucose tolerance following a standardized oral glucose tolerance test (OGTT) across kidney function strata., Setting and Design: Community-based cohort study from the Uppsala Longitudinal Study of Adult Men (ULSAM). PARTICIPANTS AND MAIN OUTCOME MEASURE: Included were 1015 nondiabetic Swedish men aged 70-71 years. All participants underwent OGTT and euglycaemic hyperinsulinaemic clamp (HEGC) tests, allowing determination of insulin sensitivity, β cell function, and glucose tolerance. Kidney function was estimated by cystatin C-algorithms. Mixed models were used to identify determinants of insulin secretion after the hyperglycemic load., Results: As many as 466 (46%) of participants presented moderate-advanced kidney disease. Insulin sensitivity (by HEGC) decreased across decreasing kidney function quartiles. After the OGTT challenge, however, β cell function indices (area under the curve for insulin release, the estimated first phase insulin release, and the insulinogenic index) were incrementally higher. Neither the oral disposition index nor the 2-h postload glucose tolerance differed across the kidney function strata. Mixed models showed that dynamic insulin release during the OGTT was inversely associated with kidney function, despite the correction for each individual's insulin sensitivity or its risk factors., Conclusions: In older men, β cell function after a hyperglycemic load appropriately compensated the loss in insulin sensitivity that accompanies kidney dysfunction. As a result, the net balance between insulin sensitivity and β cell function was preserved.

Aims/hypothesis: We tested the hypothesis that dietary acid load may increase the risk of type 2 diabetes, and studied the association between acid load and insulin sensitivity as a possible mechanism involved., Methods: An observational survey with prospective follow-up including 911 non-diabetic Swedish men aged 70-71 years was carried out. The gold standard euglycaemic-hyperinsulinaemic clamp technique and the OGTT were used to determine insulin sensitivity and beta cell function, respectively. Diabetes incidence was assessed during 18 years of follow-up. Renal function was estimated from serum cystatin C concentrations. Dietary acid load was calculated as potential renal acid load (PRAL) and net endogenous acid production (NEAP) algorithms from 7 day food records. Adequate dietary reporters were identified by Goldberg cut-offs., Results: PRAL and NEAP were not associated with insulin sensitivity or beta cell function. Underlying kidney function or consideration of dietary adequate reporters did not modify these null findings. During follow-up, 115 new cases of diabetes were validated. Neither PRAL nor NEAP was associated with diabetes incidence., Conclusions/interpretation: Our results do not support the hypothesis that dietary acid load influences insulin sensitivity, beta cell function or diabetes risk. Interventional studies modifying acid-base dietary intake are needed to further elucidate a possible role of acid load in the development of type 2 diabetes.

Aims: The relation between selenium status and risk of Type 2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes., Methods: We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50 years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20 years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted., Results: At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) μg/l. During 20 years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio 1.06; 95% CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized β -0.08; 95% CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of β-cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account., Conclusions: Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Objectives: The causes of the multiple metabolic disorders of individuals with chronic kidney disease (CKD) are not fully known. We investigated the relationships between dietary fat quality, the metabolic syndrome (MetS), insulin sensitivity and inflammation in individuals with CKD., Subjects: Two population-based surveys were conducted in elderly Swedish individuals (aged 70 years) with serum cystatin C-estimated glomerular filtration rate <60 mL min(-1) /1.73 m2: the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) surveys. The present population comprised 274 men and 187 subjects (63% women) from the ULSAM and PIVUS cohorts, respectively., Design: Factor analyses of serum fatty acids were used to evaluate dietary fat quality. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance (IR) and, in ULSAM, also by euglycaemic clamp., Results: Factor analyses generated two fatty acid patterns of (i) low linoleic acid (LA)/high saturated fatty acid (SFA) or (ii) high n-3 polyunsaturated fatty acid (n-3 PUFA) levels. In both surveys, the low LA/high SFA pattern increased the odds of having MetS [adjusted odds ratio 0.60 [95% confidence interval (CI) 0.44-0.81] and 0.45 (95% CI 0.30-0.67) per SD decrease in factor score in the ULSAM and PIVUS surveys, respectively] and was directly associated with both IR and C-reactive protein. The n-3 PUFA pattern was not consistently associated with these risk factors., Conclusions: A serum fatty acid pattern reflecting low LA and high SFA was strongly associated with MetS, IR and inflammation in two independent surveys of elderly individuals with CKD. At present, there are no specific dietary guidelines for individuals with CKD; however, these findings indirectly support current recommendations to replace SFAs with PUFAs from vegetable oils., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

Aims/hypothesis: Dietary fatty acids may affect insulin sensitivity. Adipose tissue fatty acid composition partly reflects long-term dietary intake, but data from large studies regarding relationships with insulin sensitivity are lacking. We aimed to determine the association between adipose tissue fatty acids and insulin sensitivity in elderly Swedish men., Methods: In a cross-sectional analysis of the community-based Uppsala Longitudinal Study of Adult Men (n = 795, mean age 71 years), adipose tissue biopsies were obtained and fatty acid composition was determined by gas-liquid chromatography. Insulin sensitivity was measured directly by a euglycaemic clamp., Results: Palmitic acid (16:0), the major saturated fatty acid (SFA) in the diet and in adipose tissue, was negatively correlated with insulin sensitivity (r = -0.14), as were 16:1 n-7 (r = -0.15), 20:3 n-6 (r = -0.31), 20:4 n-6 (r = -0.38), 22:4 n-6 (r = -0.37) and 22:5 n-3 (r = -0.24; p < 0.001 for all). Some minor SFAs were positively correlated; 12:0 (r = 0.46), 14:0 (r = 0.32), 17:0 (r = 0.21) and 18:0 (r = 0.41; p < 0.001 for all), as were essential polyunsaturated fatty acids (PUFAs) 18:2 n-6 (r = 0.10, p < 0.01) and 18:3 n-3 (r = 0.16, p < 0.001). Docosahexaenoic acid (22:6 n-3) was negatively correlated (r = -0.11, p < 0.01), whereas eicosapentaenoic acid (20:5 n-3) was not (r = -0.02, NS). Most associations diminished or disappeared in lean individuals, indicating an effect of obesity., Conclusions/interpretation: Adipose tissue enriched with palmitic acid and depleted of essential PUFAs is associated with insulin resistance. The positive association between minor SFAs and insulin sensitivity merits further investigation.

Objective: Proteins involved in cellular fatty acid (FA) uptake and metabolism may be of relevance in the context of disturbed FA metabolism associated with insulin resistance. Therefore this study investigated relationships between FA handling protein mRNA expression in adipose tissue, FA composition of adipose tissue and serum, and markers of insulin resistance., Subjects: 75 subjects with a range of insulin sensitivities recruited from a cohort of 294 healthy 63-year-old Swedish men., Measurements: Anthropometric and biochemical variables (e.g. waist-hip-ratio (WHR) and homeostasis model assessment (HOMA) index of insulin sensitivity), FA composition of the subcutaneous (s.c.) gluteal adipose tissue, serum nonesterified FA (NEFA) and serum phospholipid compartments (by gas-liquid chromatography; n = 294), and mRNA levels of FA handling proteins (adipocyte and keratinocyte lipid binding proteins, fatty acid transport protein (FATP) -1 and -4, CD36/fatty acid translocase, plasma membrane fatty acid binding protein, and acyl-CoA synthase-1 (ACS1)) in s.c. gluteal adipose tissue (by quantitative real-time polymerase chain reaction; n = 75)., Results: ACS1 expression was negatively correlated with measures of insulin resistance and central obesity (ACS1 versus HOMA: r = -0.28, P<0.05; ACS1 versus WHR: r = -0.23, P<0.05), with an opposite trend for FATP4. Further analysis of ACS1 expression levels revealed correlations with adipose tissue 16:0 (r = -0.27, P<0.05) and NEFA 16:1 (r = 0.29, P<0.05), FA composition variables which in turn correlated with HOMA index (r = 0.39, P<0.001 and r = -0.23, P<0.05, respectively, n = 75). Moreover, NEFA 16:1 predicted ACS1 expression independently of HOMA, WHR and adipose tissue 16:0 in multiple regression analysis (standardized coefficient = 0.27, P<0.05)., Conclusion: Significant associations were found between measures of insulin sensitivity, adipose tissue FA handling protein expression, and specific FA composition variables. Although causal relationships could not be identified these findings suggest a role of FA handling proteins in relation to insulin sensitivity, via their involvement in FA trafficking and metabolism. In particular they indicate links between ACS1 activity, the distribution of 16:0 and 16:1, and insulin sensitivity, which may be of physiological relevance.

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Abstract: Insulin resistance develops rapidly during critical illness. The release of adipokines from adipose tissue is thought to play a key role in the development of insulin resistance, as are elevated levels of acute-phase proteins. The aim of this study was to identify changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins during critical illness. From 8 patients with subarachnoidal hemorrhage, consecutive blood samples and adipose tissue biopsies were obtained at 3 time points, twice during intensive care (1-2 days [IC1] and 7-9 days after subarachnoidal hemorrhage) and once after 8 months (recovery). The patients received a continuous insulin infusion to maintain normal glucose levels reflecting insulin resistance. The DNA microarray analysis showed increased zink-alpha2 glycoprotein (ZAG) and phospholipase A2, group IIA messenger RNA levels during intensive care compared with recovery (P < .05). Real-time polymerase chain reaction confirmed the increased expression of ZAG and phospholipase A2, group IIA. Plasma levels of ZAG, serum amyloid A, and C-reactive protein were higher at 7 to 9 days after subarachnoidal hemorrhage compared with either IC1 or recovery (P = .0001); and plasma levels of retinol-binding protein 4 and adiponectin were lower at IC1 compared with recovery (P = .05). The described changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins may influence the development of insulin resistance during critical illness. [Copyright &y& Elsevier]