Non-diabetic Insulin Resistance Research Articles

Probing the Relationship Between Declining Renal Glomerular Filtration Over the Life Span and General Biological Aging: Does the Former Provide Means to Estimate the Latter?

Background: While a consistent, gradual decline in the renal glomerular filtration rate (GFR) is a characteristic occurrence over the human life span, the exact pathophysiology behind this event remains unresolved. Evidence to date suggests that the endogenous glucose-insulin system could be involved at some level. Diabetic-induced nephropathy, one of the most prevalent chronic renal diseases, is closely linked to a severe form of insulin resistance (IR). Nevertheless, it is less certain that the ubiquitous milder forms of IR in nondiabetics ascribed customarily to routine, poor choices in diet and exercise management can over time diminish GFR and adversely influence other renal functions to any perceptible extent. Methodology: Baseline data for cross-sectional analyses were obtained from a cohort of healthy, nondiabetic volunteers (fasting blood glucose [FBG] ≤ 125 mg/dL) involved in prior clinical studies. Slope-based rather than threshold analyses were mainly employed. These measurements were applied for the most part to correlate age, FBG levels used as an estimate of IR activity, and systolic blood pressure (SBP) to a variety of metabolic parameters during aging with a primary focus on GFR. Results: Considering cause and effect, FBG and SBP correlate positively with the diminishing GFR over a major part of the life span. The decline in GFR begins somewhere around the mid-20s and coincides with key temporal increases in FBG and SBP levels. Conclusions: A close time-based setting suggests that IR plays a prominent role in the declining GFR that occurs over the life span. This is perhaps due in part through deleterious effects of rising levels of insulin, glucose, and SBP individually or combined that are also popular proposed causative factors for human aging in general. On the philosophical side, the latter fact suggests that the declining GFR might provide a practical way to estimate the rate of overall human biological aging.

Plasma metabolites predict both insulin resistance and incident type 2 diabetes: a metabolomics approach within the Prevención con Dieta Mediterránea (PREDIMED) study

Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D). The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D. We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models. We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors. The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.

GLP-1 response to sequential mixed meals: influence of insulin resistance.

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

Urinary chromium is associated with changes in leukocyte miRNA expression in obese subjects

Background/Objectives:Epidemiological studies suggest a link between chromium (Cr) status and cardiovascular disease. Increased urinary excretion of Cr was reported in subjects with diabetes compared with non-diabetic controls and those with non-diabetic insulin resistance. Epigenetic alterations have been linked to the presence of Cr, and microRNA (miRNA) expression has been implicated in the pathogenesis of metabolic diseases and cardiovascular diseases (CVDs). We investigated the association between Cr excretion and miRNA expression in leukocytes from obese subjects. We also examined the relationship between altered miRNA expression and selected clinical parameters to further investigate mechanisms linking Cr to metabolic diseases and CVDs.Subjects/Methods:We analyzed urinary Cr in 90 Italian subjects using inductively coupled plasma-mass spectrometry. Peripheral blood miRNA levels were screened with TaqMan Low-Density Array Human MicroRNA A. Cr level-associated expression of miRNAs was detected with multivariate regression analyses, and the top 10 candidate miRNAs were selected for validation. We also used multivariate regression analyses to assess possible associations between validated miRNAs and glycated hemoglobin (A1c) and blood pressure (BP). The validated miRNAs were further investigated by functional analysis with Ingenuity Pathway Analysis software.Results:Urinary Cr levels (mean: 0.35 μg/l; s.d.=0.24) ranged from 0.05 to 1.27 μg/l. In the screening phase, 43 miRNAs were negatively associated with Cr. Of the top 10 miRNAs selected for validation, nine (miR-451, miR-301, miR-15b, miR-21, miR-26a, miR-362-3p, miR-182, miR-183 and miR-486-3p) were downregulated in association with Cr (P-false discovery rate (FDR)<0.10). miR-451 expression was associated with A1c (β=–0.06; P=0.0416), whereas miR-486-3p expression was associated both with diastolic (β=2.1; P=0.004) and systolic BP (β=3.3; P=0.003).Conclusions:These results indicate that miR-451 and miR-486-3p are involved in the link between Cr levels and metabolic diseases and CVDs.

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population

BackgroundInsulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. ObjectiveThe goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. MethodsWe conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m2/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. ResultsCompared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43–2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17–0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. ConclusionsSignificant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

Insulin Resistance Increases the Risk of Contrast-Induced Nephropathy in Patients Undergoing Elective Coronary Intervention.

We assessed the influence of insulin resistance (IR) on the development of contrast-induced nephropathy (CIN) in patients (n = 719) undergoing elective percutaneous coronary intervention (PCI). Patients were divided into diabetes mellitus (DM = 242), nondiabetic IR (IR = 120), and nondiabetic insulin sensitivity (IS = 357) groups according to medical history and homeostasis model assessment insulin resistance index. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were measured before and 72 hours after PCI. There were no differences in SCr and eGFR among the groups before PCI; SCr increased and eGFR decreased significantly in the DM and IR groups post-PCI (P < .001). The incidence of CIN in the IR group was as high as in the DM group and were both significantly higher than in the IS group (6.7% vs 8.7% vs 2.2%, P < .05). Multivariate logistic regression analysis showed DM (odds ratio [OR] = 1.19, 95%CI = 1.08-1.510, P < .001), HOMA-IR (OR = 1.39, 95%CI = 1.23-1.58, P < 0.001), and eGFR (OR = 0.88, 95%CI = 0.84-0.92, P < .001) were independent risk factors in predicting CIN. Screening IR patients and taking appropriate prophylactic strategy before PCI may reduce the incidence of CIN.

Vitamin D deficiency is associated with insulin resistance in nondiabetics and reduced insulin production in type 2 diabetics.

It is not known whether the association of serum 25-hydroxyvitamin D [25(OH)D] with glycemic measurements of individuals without diabetes is similar to those with diabetes or not. This study is aimed to investigate the association of serum 25(OH)D with glycemic markers of diabetics, nondiabetics, and prediabetics. A case-control study was conducted on age and sex matched 1,195 patients with type 2 DM, 121 prediabetics, and 209 healthy controls. Anthropometric variables, lipid profile, glycemic measurements, and serum 25(OH)D levels were recorded. Serum insulin and C-peptide levels were also measured. All glycemic measurements were compared between diabetics and nondiabetics and prediabetics at different vitamin D status. Patients with DM had lower serum 25(OH)D compared to prediabetics and healthy controls. Endogenous insulin production in response to food intake and in fasting was significantly lower in vitamin D deficient patients with DM compared to those with serum 25(OH)D>40 ng/ml. Diabetic women with serum 25(OH)D<20 ng/ml had lower beta cell function as estimated by lower HOMA-B compared to their counterparts with serum 25(OH)D>40 ng/ml. Healthy individuals with serum 25(OH)D<20 ng/ml had signs of insulin resistance as estimated by significant increase of HOMA-IR, HbA1c, and fasting plasma glucose (FPG). In addition, we found that serum 25(OH)D was inversely associated with insulin resistance. Vitamin D deficiency is associated with insulin resistance in nondiabetics, which is independent of obesity. Furthermore, vitamin D deficiency is associated with reduced insulin production in type 2 diabetics, which was mainly observed in men. Accordingly, a gender disparity also exists in association of serum 25(OH)D with glycemic measurements.

Diagnostic criteria for sarcopenia relate differently to insulin resistance

Skeletal muscle is important in insulin-stimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in relation to insulin resistance in nondiabetics. This cross-sectional study included 301 nondiabetics, mean age 65.9 years. Area under curve (AUC) calculations of insulin and glucose from a 2-h oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used as measures of insulin resistance. Muscle characteristics were relative muscle mass (total or appendicular lean mass (ALM) as percentage of body mass), absolute muscle mass (ALM/height(2) and total lean mass), handgrip strength, and walking speed. All muscle characteristics were standardized and analyzed in linear regression models, stratified by gender. For both males and females, relative muscle mass was inversely associated with AUC insulin, AUC glucose, and HOMA-IR (ALM percentage all p ≤ 0.004). Absolute muscle mass was positively associated with AUC insulin and HOMA-IR (ALM/height(2) all p < 0.001) but not with AUC glucose. Adjustments for fat mass attenuated aforementioned associations. There were no associations between handgrip strength and insulin resistance. Walking speed was inversely associated with AUC insulin in males (p = 0.032). The association between muscle characteristics and insulin resistance was strongest for relative muscle mass. Diagnostic criteria for sarcopenia relate differently to insulin resistance. The role of muscle tissue as an internal glucose-regulating organ is better reflected by relative muscle mass than by absolute muscle mass, muscle strength, or walking speed.

The effect of metformin on insulin resistance and exercise parameters in patients with heart failure

Chronic heart failure (CHF) is an insulin-resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non-diabetic CHF patients identified to have IR. In a double-blind, placebo-controlled study, 62 non-diabetic IR CHF patients (mean age, 65.2 ± 8.0 years; male, 90%; left ventricular ejection fraction, 32.6 ± 8.3%; New York Heart Association class I/II/III/IV, 11/45/6/0) were randomized to receive either 4 months of metformin (n = 39, 2 g/day) or matching placebo (n = 23). IR was defined by a fasting insulin resistance index (FIRI) ≥2.7. Cardiopulmonary exercise testing and FIRI were assessed at baseline and after 4 months of intervention. Compared with placebo, metformin decreased FIRI (from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) and resulted in a weight loss of 1.9 kg (P < 0.001). The primary endpoint of the study, peak oxygen uptake (VO(2)), did not differ between treatment groups. However, metformin improved the secondary endpoint of the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO(2) slope), from 32.9 ± 15.9 to 28.1 ± 8.8 (P = 0.034). In the metformin-treated group, FIRI was significantly related to the reduction of the VE/VCO(2) slope (R = 0.41, P = 0.036). Metformin treatment significantly improved IR but had no effect on peak VO(2), the primary endpoint of our study. However, metformin treatment did result in a significant improvement in VE/VCO(2) slope. NCT00473876.

The degree of coronary atherosclerosis as a marker of insulin resistance in non-diabetics

The metabolic syndrome and its influence on coronary artery disease development and progression remains in focus of international research debates, while insulin resistance, which represents its core, is the key component of hypertension, dyslipidaemias, glucose intolerance and obesity. The aim of this study was to establish relationship between basal glucose and insulin levels, insulin sensitivity and lipid panel and the degree of coronary atherosclerosis in nondiabetic patients. The coronary angiograms were evaluated for the presence of significant stenosis, insulin sensitivity was assessed using the intravenous glucose tolerance test with a minimal model according to Bergman, while baseline glucose (GO), insulin (10) and lipid panel measurements (TC, HDL, LDL, TG) were taken after a 12-hour fasting. The protocol encompassed 40 patients (19 men and 21 women) treated at the Institute for Cardiovascular Diseases of the Clinical Centre of Serbia, Belgrade. All were non-diabetics who were divided into 3 groups based on their angios: Group A (6 patients, 15%, with no significant stenosis), Group B (18 patients, 45%, with a single-vessel disease) and Group C (16 patients, 40%, with multi-vessel disease). Presence of lower insulin sensitivity, higher 10 and TC in the group of patients with a more severe degree of coronary atherosclerosis (insulin sensitivity: F = 4.279, p = 0.023, A vs. C p = 0.012, B vs. C p = 0.038; 10: F = 3.461 p = 0.042, A vs. B p = 0.045, A vs. C p = 0.013; TC: F = 2.572, p = 0.09), while no significant difference was found for GO, LDL, HDL and TG. Baseline insulinaemia, more precisely, fasting hyperinsulinaemia could be a good predictor of significant coronary atherosclerosis in non-diabetic patients, which enables a more elegant cardiometabolic risk assessment in the setting of everyday clinical practice.

More Sugar, Less Blood Vessels

Patients with diabetes have a several-fold higher risk of cardiovascular events than people without diabetes. The susceptibility to heart failure, lower limb amputations, and other manifestations of tissue ischemia in diabetes is attributable to an increased risk of atherothrombotic disease as well as impaired neovascularization and collateral formation through arteriogenesis or angiogenesis.1,2 Abnormal angiogenesis in diabetes, however, is complex because increased neovascularization is the hallmark of proliferative diabetic retinopathy, another major complication of the disease. See accompanying article on page 651 The mechanisms responsible for this range of abnormal angiogenesis in different tissues in patients with diabetes are poorly understood, but relate at least in part to differential expression of hypoxia-induced angiogenic factors like vascular endothelial growth factor (VEGF). Cardiac expression of VEGF and its receptors are decreased in diabetic rats3,4 and in patients with diabetes,3 whereas VEGF and its receptors, paradoxically, are increased in the diabetic retina, even in animal models where proliferative diabetic retinopathy does not occur.3,5 Both insulin resistance and hyperglycemia, present in most patients with diabetes, may affect angiogenic potential. Insulin action is necessary for appropriate expression of VEGF6 (see Figure), and rats with obesity-associated nondiabetic insulin resistance have decreased expression of VEGF and VEGF receptors3 and decreased capillary density in the heart.6 Hyperglycemia itself may inhibit angiogenesis, for example through formation of advanced glycation end-products (AGE). As an example modification of (basic) fibroblast growth factor-2 (FGF2) by AGE,7 as shown by several independent groups, inhibits its angiogenic action. Even though many studies have shown that AGE increase proangiogenic functions of cultured endothelial cells, the compound effect …

Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.

Up-regulation of IGF binding protein-1 as an anticarcinogenic strategy: relevance to caloric restriction, exercise, and insulin sensitivity

The mitotic rate of stem cells is a major determinant of cancer risk. Insulin-like growth factors (IGFs) are virtually obligate stimulants of cell turnover in nearly every tissue. IGF activity is subject to rapid modulation by hepatic release of IGF binding protein-1 (IGFBP-1), a factor whose synthesis is suppressed by insulin and increased by glucagon. Up-regulation of IGFBP-1 production can be expected to decrease IGF activity and thereby diminish cancer risk. Measures that sensitize peripheral tissues to insulin, and thereby down-regulate insulin secretion, can be expected to increase IGFBP-1 synthesis, provided that they do not unduly sensitize hepatocytes as well. Prolonged aerobic exercise and caloric restriction also increase IGFBP-1 production. Since IGF-I suppresses hepatic synthesis of sex hormone binding globulin (SHBG), down-regulation of IGF activity will increase SHBG levels and thus diminish the availability of free sex hormones - an effect that should further decrease cancer risk in sex hormone-responsive tissues. These considerations rationalize many findings in animal and epidemiologic studies, and suggest that non-diabetic insulin resistance may be a significant cancer risk factor. Increased IGF activity associated with insulin resistance may also promote benign hyperplasias - most notably atherosclerosis. Hyperinsulinemia stimulates intimal hyperplasia indirectly, via IGF.