Insulin Resistance In Nondiabetic Subjects Research Articles

The biological variation of insulin resistance markers: data from the European Biological Variation Study (EuBIVAS).

An insulin resistant state is characteristic of patients with type 2 diabetes, polycystic ovary syndrome, and metabolic syndrome. Identification of insulin resistance (IR) is most readily achievable using formulae combining plasma insulin and glucose results. In this study, we have used data from the European Biological Variation Study (EuBIVAS) to examine the biological variability (BV) of IR using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and the Quantitative Insulin sensitivity Check Index (QUICKI). Ninety EuBIVAS non-diabetic subjects (52F, 38M) from five countries had fasting HOMA-IR and QUICKI calculated from plasma glucose and insulin samples collected concurrently on 10weekly occasions. The within-subject (CVI) and between-subject (CVG) BV estimates with 95 % CIs were obtained by CV-ANOVA after analysis of trends, variance homogeneity and outlier removal. The CVI of HOMA-IR was 26.7 % (95 % CI 25.5-28.3), driven largely by variability in plasma insulin and the CVI for QUICKI was 4.1 % (95 % CI 3.9-4.3), reflecting this formula's logarithmic transformation of glucose and insulin values. No differences in values or BV components were observed between subgroups of men or women below and above 50 years. The EuBIVAS, by utilising a rigorous experimental protocol, has produced robust BV estimates for two of the most commonly used markers of insulin resistance in non-diabetic subjects. This has shown that HOMA-IR, in particular, is highly variable in the same individual which limits the value of single measurements.

Taxonomic and Functional Fecal Microbiota Signatures Associated With Insulin Resistance in Non-Diabetic Subjects With Overweight/Obesity Within the Frame of the PREDIMED-Plus Study.

ObjectiveAn altered gut microbiota has been associated with insulin resistance, a metabolic dysfunction consisting of cellular insulin signaling impairment. The aim of the present study is to determine the taxonomic and functional fecal microbiota signatures associated with HOMA-IR index in a population with high cardiovascular risk.MethodsA total of 279 non-diabetic individuals (55–75 years aged) with overweight/obesity and metabolic syndrome were stratified according to tertiles of HOMA-IR index. Blood biochemical parameters, anthropometric measurements and fecal samples were collected at baseline. Fecal microbial DNA extraction, 16S amplicon sequencing and bioinformatics analysis were performed.Results Desulfovibrio, Odoribacter and Oscillospiraceae UCG-002 were negatively associated with HOMA-IR index, whereas predicted total functional abundances revealed gut metabolic modules mainly linked to amino acid degradation. Butyricicoccus, Erysipelotrichaceae UCG-003, Faecalibacterium were positively associated with HOMA-IR index, whereas predicted total functional abundances revealed gut metabolic modules mainly linked to saccharide degradation. These bacteria contribute differentially to the gut metabolic modules, being the degree of contribution dependent on insulin resistance. Both taxa and gut metabolic modules negatively associated to HOMA-IR index were linked to mechanisms involving sulfate reducing bacteria, improvement of intestinal gluconeogenesis and production of acetate. Furthermore, both taxa and gut metabolic modules positively associated to HOMA-IR index were linked to production and mechanisms of action of butyrate.ConclusionsSpecific taxonomic and functional fecal microbiota signatures associated with insulin resistance were identified in a non-diabetic population with overweight/obesity at high cardiovascular risk. These findings suggest that tailoring therapies based on specific fecal microbiota profiles could be a potential strategy to improve insulin sensitivity.

Vitamin D Deficiency Is Inversely Associated with Homeostatic Model Assessment of Insulin Resistance.

The study was conducted to comprehensively assess the association of the concentration of vitamin D in the blood and insulin resistance in non-diabetic subjects. The objective was to pool the results from all observational studies from the beginning of 1980 to August 2021. PubMed, Medline and Embase were systematically searched for the observational studies. Filters were used for more focused results. A total of 2248 articles were found after raw search which were narrowed down to 32 articles by the systematic selection of related articles. Homeostatic Model Assessment of Insulin Resistance (HOMAIR) was used as the measure of insulin resistance and correlation coefficient was used as a measure of the relationship between vitamin D levels and the insulin resistance. Risk of bias tables and summary plots were built using Revman software version 5.3 while Comprehensive meta-analysis version 3 was used for the construction of forest plot. The results showed an inverse association between the status of vitamin D and insulin resistance (r = −0.217; 95% CI = −0.161 to −0.272; p = 0.000). A supplement of vitamin D can help reduce the risk of insulin resistance; however further studies, like randomized controlled trials are needed to confirm the results.

Concordance between Triglyceride Glucose Index and Admission Insulin Resistance Index in Non-diabetic Subjects of Acute Coronary Syndrome

BACKGROUND: Acute coronary syndrome (ACS) is the leading cause of death in the world and is closely related to insulin resistance (IR). The examination of the triglyceride glucose (TyG) Index and admission IR index (AIRI) can be an alternative examination to assess IR. AIM: The aim of the study was to analyze the concordance between the TyG index and AIRI in assessing IR in nondiabetic subjects of ACS. METHODS: This study was a cross-sectional study using secondary data from ACS patient medical records in Wahidin Sudirohusodo Hospital Makassar from September 2020 until April 2021. An examination of RBG, TyG, and fasting insulin was performed. The statistical test results were considered significant if the p < 0.05. RESULTS: This study included 67 subjects, of which 54 were male and 13 were female, there were 24 people aged <50 years, 43 people aged 50 years old, with a mean of 55.15 ± 12.71 years, a diagnosis of ST-elevation myocardial infarction (STEMI) 25 people, non STEMI 34 people and unstable angina pectoris 8 people, p < 0.05. The receiver operating characteristic curve showed that the cut-off value of the TyG index in predicting AIRI was 3141, with a sensitivity of 88.98% and specificity of 59.09%. The OR value revealed that subjects with a TyG index of >9.06 indicated an 11-time greater risk for IR than subjects with a TyG index ≤9.06. CONCLUSIONS: There was a significant concordance between the TyG index and the AIRI in non-diabetic acute coronary syndrome patient.

Elevated free fatty acid level is associated with insulin-resistant state in nondiabetic Chinese people

BackgroundFree fatty acids (FFAs) are associated with insulin secretion and insulin resistance. However, the associations among FFAs, obesity, and progression from a normal to a prediabetic state are unclear.MethodsNondiabetic subjects (5,952) were divided in two groups according to their body mass index (BMI): obese subjects (BMI ≥24 kg/m2) and nonobese subjects (BMI <24 kg/m2). Clinical and multiple glucolipid metabolism data were collected. The homeostasis model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) was used. HbA1c level between 5.7% and 6.4% was considered prediabetic. Nonparametric tests, one-way ANOVA, and linear correlation analysis were performed. R and SPSS 23.0 software programs were used to analyze the results.ResultsA U-shaped relationship between FFAs and HOMA-IR was observed. After adjusting for potential confounders, the turning points of FFA levels in the curves were 0.54 mmol/L in the nonobese group and 0.61 mmol/L in the obese group. HOMA-IR levels decreased with increasing FFA concentrations before the turning points (regression coefficient [β]= – 0.9, P=0.0111, for the nonobese group; β=0.2, P=0.5094, for the obese group) and then increased (β=0.9, P=0.0069, for the nonobese group; β=1.5, P=0.0263 for the obese group) after the points. Additionally, our study also identified that FFAs were associated with the prediabetes status in obese individuals.ConclusionFFA levels were associated with insulin resistance in nondiabetic subjects, and HOMA-IR in nonobese individuals was more sensitive to FFA changes. Monitoring and controlling plasma FFA levels in obese subjects is significant in decreasing insulin resistance and preventing diabetes.

High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson's Disease.

Reduced glucose tolerance has been long recognized as a potential risk factor for Parkinson's disease (PD), and increasing scrutiny is currently being placed on insulin resistance (IR) as a pathologic driver of neurodegeneration. However, the prevalence of IR in PD is unknown. To determine IR prevalence in non-diabetic patients with PD and to correlate IR with other metabolic indicators, motor and non-motor symptoms (NMS) of PD, and quality of life (QoL). Non-diabetic patients with a diagnosis of PD were identified and tested for fasting insulin, fasting glucose, and HbA1c. Patients were also offered to take a battery of clinical tests (MoCA, NMSQ, and PDQ-39) and had their PD medications, height, weight, and other demographic features recorded. IR was defined as HOMA-IR≥2.0 and/or HbA1c≥5.7. IR abnormalities were correlated with BMI and demographic features, in addition to motor and NMS. 154 subjects (109 M, 45F, mean age 67.7±10.5) were included in this study. Mean HOMA-IR was 2.3±1.8. Ninety out of 154 (58.4%) subjects had abnormal IR. IR was more frequent in overweight and obese subjects (61.1% and 82.8% respectively) than normal weight subjects (41.5%). Multivariate analysis showed that BMI was the only significant predictor of IR (p < 0.0001). There was no significant correlation between HOMA-IR and MoCA, PDQ-39, and NMSQ scores. IR is prevalent in PD and it correlates with BMI. A correlation between IR with cognitive and QoL measures cannot be determined on the basis of this sample.

“It Takes Two To Tango”, Exercise Modifies Skeletal Muscle Mitochondria And Lipid Droplets Closeness

PURPOSE: Intramyocellular lipids (IMCL), stored in lipid droplets (LD), are known to be a hallmark of skeletal muscle insulin resistance. Chronic exercise (training) increases IMCL while also increasing insulin sensitivity (IS), a paradigm known as the athlete’s paradox. Mitochondria (M), the powerhouse of the cells, are responsible to transform LD content into energy. The closeness of these 2 organelles in the different subcellular compartments (intramyofribrillar (IMF) and subsarcolemmal (SSL)) and how they change with training are not yet known. The purpose of this study was to examine exercise induced changes in LD and M closeness in insulin resistant non-diabetic subjects. METHODS: In a nested case-control study, 12 cases (6F/6M) underwent a 4-months supervised endurance exercise intervention. 12 insulin sensitive subjects matched by age and gender served as controls (C). LD, M and the surface in contact with each other, were assessed in muscle biopsies with electron microscopy. IS was measured by hyperinsulinemic euglycemic clamp. VO2peak was measured by GXT and body composition by DEXA. RESULTS: Although training improved IS by 45±8% (P<0.05), increased VO2peak by 13.2±4.4% (P<0.05), reduced body fat by 3.9±1.2% (P<0.05), cases remained significantly different from C. M increased in IMF and SSL (54.7±15.1% and 78.2±20.5% respectively, P<0.05). LD increased in IMF (51.8±18.1%) and decreased in (SSL 20.7±8.3%, both P<0.05). Contact between M and LD increased significantly only in IMF (65.1±26.3%, P<0.05). While SSL LD were negatively correlated with IS at baseline, changes in overall LD with intervention were related with improvements in IS. SSL LD correlated with body adiposity, but not IMF LD. CONCLUSIONS: With endurance training, the closeness of M and LD increased only in the contractile region, i.e. the IMF compartment. At the same time, the amount of M and LD increased in this compartment. This observation confirms what is observed in healthy and athletic individuals, which suggests that IMCL are used for fuel. At the contrary, LD decreased in the SSL region while M increased in this compartment. Our observations are of interest, as IMCL are known to be involved in the mechanisms leading to insulin resistance in sedentary muscle, possibly explaining the observation in the SSL region.

Abstract P041: New Biomarkers for Detecting and Subtyping Insulin Resistance

Introduction: The metabolic abnormalities that precede type 2 diabetes progress slowly and in stages. Current evidence-based diabetes prevention programs target individuals in Stage 2 (impaired glucose tolerance or prediabetes). However, by that stage, 70% of pancreatic beta-cell insulin secretory capacity has been lost irreversibly. Thus, it is imperative to identify individuals in Stage I (early insulin resistance syndrome) in order to preserve pancreatic insulin secretion and prevent both diabetes and prediabetes. Early insulin resistance syndrome is characterized by compensatory hyperinsulinemia, dyslipidemia, sub-clinical inflammation and acid-base abnormalities. The nature of the association between these elements is unclear, and different subtypes of insulin resistance syndrome may exist. Hypothesis: We have developed two novel and unconventional biomarkers for characterizing insulin resistance in non-diabetic subjects. One approach is based on dynamic light scattering (DLS) of human serum. The second approach measures the T 2 relaxation time of water in human plasma using compact time-domain NMR relaxometry (TD-NMR). We hypothesize that these methods can detect subtypes, i.e. , insulin resistance with or without inflammation, hypercholesterolemia, or acid-base abnormalities. Methods: Seventy-two asymptomatic non-diabetic human subjects were recruited through an IRB-approved biomarker discovery protocol. Medical histories, anthropomorphic measurements and fasting blood samples were obtained, and over 1300 blood biomarkers were measured on each subject along with DLS and TD-NMR parameters. Bi-variate correlation analyses and multiple regression models were used to analyze continuous variables, and categorical variables were established for insulin resistance, inflammation, acid-base abnormalities and lipid abnormalities. Multiple means comparisons were performed using one-way ANOVA and Tukey-Kramer testing. Results: Plasma water T 2 from TD-NMR was strongly correlated with markers of early insulin resistance syndrome. Multiple regression analysis showed independent contributions from markers of hyperinsulinemia, hypercholesterolemia and inflammation. Multiple means comparisons showed significant differences for insulin resistance with and without inflammation. By contrast, DLS parameters were strongly correlated with insulin markers, but could not distinguish the inflammatory subtypes. Conclusions: Both TD-NMR and DLS are able to detect early insulin resistance in individuals who do not meet the criteria for prediabetes or metabolic syndrome. However, TD-NMR has the unique ability to distinguish inflammatory vs. non-inflammatory subtypes of insulin resistance. Subtyping and risk stratification are important for the design of personalized interventions to prevent diabetes, prediabetes and cardiovascular disease.

The independent relationship between hemoglobin A1c and homeostasis model assessment of insulin resistance in non-diabetic subjects

Abstract Introduction Determining the factors affecting hemoglobin A1c (HbA1c) levels may help better interpretation of HbA1c values. In this study, we investigated if insulin resistance is a significant parameter contributing to the variability of HbA1c values. Methods We retrospectively analyzed serum fasting glucose, fasting insulin, 2 h glucose and HbA1c records of 18–85 years aged outpatients who underwent a 75 g oral glucose tolerance test (OGTT) in our hospital during the period January 2010–May 2014. Homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 was defined as insulin resistant. Results Insulin resistant subjects with normal glucose tolerance had significantly higher HbA1c and fasting glucose levels compared to insulin sensitive subjects with normal glucose tolerance (p=0.002, p&lt;0.001, respectively). Similarly, insulin resistant subjects with pre-diabetes had significantly higher HbA1c and 2-h glucose levels compared to insulin sensitive subjects with pre-diabetes (p=0.016, p=0.013, respectively). Regression analysis showed that HOMA-IR(log) is associated with HbA1c levels independent of fasting and 2h glucose concentrations (p&lt;0.001). Age was the variable with highest standardized β coefficient in regression model. Conclusion Our data showed that HOMA-IR is associated with glycated hemoglobin values independent of glycemic status and the effect of age on HbA1c values should not be ignored in non-diabetic subjects.

High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report.

Objective Advanced glycation end products (AGEs) are important in the pathophysiology of type 2 diabetes mellitus (T2DM). They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Methods Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL), carboxymethyllysine (CML), and methyl-glyoxal-hydro-imidazolone (MG-H1). Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. Results CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. Conclusions These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.

Higher plasma betatrophin/ANGPTL8 level in Type 2 Diabetes subjects does not correlate with blood glucose or insulin resistance.

Betatrophin/ANGPTL8 is a newly identified hormone produced in liver and adipose tissue that has been shown to be induced as a result of insulin resistance and regulates lipid metabolism. Little is known about betatrophin level in humans and its association with T2D and metabolic risk factors. Plasma level of betatrophin was measured by ELISA in 1603 subjects: 1047 non-diabetic and 556 T2D subjects and its associations with metabolic risk factors in both non-diabetic and T2D were also studied. Our data show a significant difference in betatrophin levels between non-diabetic (731.3 (59.5–10625.0) pg/ml) and T2D (1710.5 (197.4–12361.1) p < 0.001. Betatrophin was positively correlated with age, BMI, waist/hip ratio, FBG, HbA1C, HOMA-IR and TG in the non-diabetic subjects. However, no association was observed with BMI, FBG, HbA1C or HOMA-IR in T2D subjects. TC and LDL showed negative association with betatrophin in T2D subjects. Multivariate analysis showed that subjects in the highest tertile of betatrophin had higher odds of having T2D (odd ratio [OR] = 6.15, 95% confidence interval [CI] = (3.15 – 12.01). Our data show strong positive associations between betatrophin and FBG and insulin resistance in non-diabetic subjects. However, correlations with FBG and insulin resistance were diminished in T2D subjects.

Dyslipidemia and Insulin Resistance in Nondiabetic Subjects with Fatty Liver Disease

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Is There a Relation Between Triglyceride Concentrations in Very Low Density Lipoprotein and the Index of Insulin Resistance in Nondiabetic Subjects?

Serum very low density lipoprotein (VLDL) levels increase during the early stages of insulin resistance; therefore, determination of VLDL levels would be useful for evaluating the progression of metabolic syndrome and diabetes mellitus. The aim of this study was to clarify the clinical utility of triglyceride in VLDL (VLDL-TG) level, determined using a homogeneous assay kit (Shino-test Corporation, Tokyo, Japan), as an index of insulin resistance. We enrolled 74 subjects in this study (diabetic subjects, n = 42; nondiabetic subjects, n = 32). The levels of VLDL-TG, remnant-like lipoprotein particle cholesterol, preheparin lipoprotein lipase mass, and other biochemical markers were determined. VLDL-TG levels were significantly higher in the diabetic group (1.04 ± 0.84 mmol/l vs. 0.64 ± 0.42 mmol/l, P < 0.01) than in the nondiabetic group. In the nondiabetic group, VLDL-TG was significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), the index for insulin resistance (r = 0.513, P = 0.003). VLDL-TG levels, but not TG levels, were higher in the highest quartile (HOMA-IR) of the nondiabetic group. VLDL-TG level was a useful early marker for insulin resistance, especially in nondiabetic subjects. The homogeneous VLDL-TG assay is a simple, low-cost method for determining insulin resistance.

Serum Levels of Advanced Glycation End Products (AGEs) are Independent Correlates of Insulin Resistance in Nondiabetic Subjects

Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans. Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay. Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females. The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.

Depression and Insulin Resistance in Non-Diabetic Subjects: An Intervention Study with Insulin Clamp Technique

Aims: To clarify the relationship between depression and glucose metabolism using sensitive measures of insulin resistance, and to assess if remission of depression results in enhanced insulin sensitivity. Methods: An intervention study to quantify changes in insulin sensitivity before and after treatment of depression was carried out. Twenty six Pakistani women with newly diagnosed depression underwent euglycemic insulin clamp to measure insulin sensitivity at inclusion and again after treatment of depression 6 - 8 weeks later. Twenty-three individuals completed both tests. Results: Significant improvement of insulin sensitivity was observed following the treatment of depression. The improved insulin sensitivity remained statistically significant after controlling for confounding factors. Conclusions: This study establishes a relationship between depression and insulin resistance. It demonstrated that insulin sensitivity can be improved by treating depression.

Plasma phospholipid transfer protein activity is independently determined by obesity and insulin resistance in non-diabetic subjects

BackgroundPhospholipid transfer protein (PLTP) is an emerging cardio-metabolic risk factor which is intricately involved in lipoprotein metabolism. Elevated plasma PLTP activity levels are reported in obesity and diabetes mellitus, but the relative contributions of obesity and insulin resistance to plasma PLTP activity remain unclear. We tested whether plasma PLTP activity is independently related to (central) obesity and insulin resistance in non-diabetic subjects. MethodsThe relationships of plasma PLTP activity levels (phospholipid vesicles–HDL system) with waist circumference, waist/hip ratio, body mass index (BMI) and insulin resistance (homeostasis model assessment (HOMAir)) were determined in 313 non-diabetic subjects (273 men). ResultsPLTP activity was higher in 67 subjects with enlarged waist circumference (NCEP-ATP-III criteria; 102±11AU) compared to 246 subjects with normal waist (98±11AU, P=0.027). In univariate analysis PLTP activity correlated positively with waist (r=0.188), waist/hip ratio (r=0.143), BMI (r=0.125) and HOMAir (r=0.192) (P<0.05 to P<0.001). The relationship of PLTP with HOMAir was confined to subjects with the highest waist circumference and waist/hip ratio. In age- and sex-adjusted multiple linear regression models, waist circumference (β=0.158, P=0.025), but not BMI, predicted PLTP activity independently of HOMAir (β=0.126, P=0.047). Furthermore, both waist and waist/hip ratio interacted positively with HOMAir on PLTP activity (β=0.109, P=0.056 and β=0.156, P=0.034, respectively). ConclusionsIn non-diabetic subjects, both obesity and insulin resistance influence plasma PLTP activity, resulting in elevated plasma PLTP activity particularly with combined increases in obesity and insulin resistance. Higher PLTP activity could contribute to elevated cardiovascular risk in the presence of obesity and insulin resistance.

Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial

The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects. Subjects were tested for eligibility using oral glucose tolerance test (OGTT) and subsequently randomized to receive either Mg-aspartate-hydrochloride (n = 27) or placebo (n = 25) for 6 months. As trial endpoints, several indices of insulin sensitivity, plasma glucose, serum insulin, blood pressure and lipid profile were determined. Mg supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices (ISIs) compared to placebo. Blood pressure and lipid profile did not show significant changes. The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of Mg status to prevent insulin resistance and subsequently type 2 diabetes.

Skeletal Muscle 11βHSD1 Activity of Nondiabetic Subjects is Unaltered in Central Obesity-associated Insulin Resistance

Local activation of glucocorticoids in insulin target tissues by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) has been implicated in the etiology of the metabolic syndrome. In obesity, adipose tissue 11βHSD1 is upregulated, leading to the generation of higher tissue levels of cortisol, which may increase insulin resistance. However, skeletal muscle is the predominant site of insulin-mediated glucose disposal, which is known to be reduced in obesity. We aimed to determine if there is any relationship between skeletal muscle 11βHSD1 and markers of central adiposity and insulin resistance in nondiabetic subjects. 20 nondiabetic volunteers (8 males and 12 females, mean age 55 ± 13 years, body mass index 21.5-47.6, mean 30.4 ± 1.6 kg/m (2)) underwent a single fasting blood sample followed by a muscle biopsy of vastus lateralis under local anesthetic. Fasting glucose, insulin and adiponectin were measured in serum. Skeletal muscle 11βHSD1 oxoreductase activity was determined by measuring the conversion of radiolabelled (3)H-cortisone to cortisol by thin layer chromatography. When subjects were categorised according to abdominal obesity (waist circumference ≥ 102 cm in men, ≥ 88 cm in women), there was no difference between the groups in skeletal muscle 11βHSD1 activity. There was no correlation between body mass index or waist circumference and 11βHSD1 activity or between HOMA and 11βHSD1 activity. Skeletal muscle 11βHSD1 oxoreductase activity is not altered in nondiabetic subjects with central obesity-associated insulin resistance. It is therefore unlikely that the in vivo insulin resistance observed in skeletal muscle of centrally obese subjects is mediated by alterations in 11βHSD1.

Skeletal Muscle Mitochondria in Insulin Resistance: Differences in Intermyofibrillar Versus Subsarcolemmal Subpopulations and Relationship to Metabolic Flexibility

Insulin resistance is accompanied by lower lipid oxidation during fasting and metabolic inflexibility. Whether these abnormalities correlate with mitochondrial content in skeletal muscle is unknown. The objective of the study was to investigate whether decreased fasting lipid oxidation, metabolic inflexibility, and impaired glucose disposal correlate with reduced mitochondrial content in intermyofibrillar vs. subsarcolemmal (SS) subpopulations. Forty sedentary adults with a wide spectrum of insulin sensitivity were studied: insulin-sensitive lean subjects, insulin-resistant nondiabetic subjects, and subjects with type 2 diabetes mellitus. Glucose disposal was measured by euglycemic clamp and [6,6-D(2)]-glucose methodology. Fuel oxidation and metabolic flexibility (during clamps) were assessed by indirect calorimetry. Maximum aerobic capacity was assessed by treadmill testing. Intermyofibrillar and SS mitochondrial content were measured by quantitative electron microscopy of muscle biopsy samples. Intermyofibrillar mitochondrial content was lower in the insulin-resistant nondiabetic subjects and type 2 diabetes mellitus groups, significantly correlating with glucose disposal in both men (R = 0.72, P < 0.01) and women (R = 0.53, P < 0.01). In contrast, SS mitochondrial content was similar among groups. Lower intermyofibrillar mitochondrial content was not explained by mitochondrial size, altered fiber-type distribution, or differences in maximum aerobic capacity. Intermyofibrillar mitochondrial content was significantly correlated with fasting respiratory quotient (R = -0.46, P = 0.003) and metabolic flexibility (R = 0.38, P = 0.02). In obese-insulin-resistant subjects with or without diabetes, intermyofibrillar mitochondrial content is decreased. This is not entirely explained by fitness status or fiber-type composition. SS mitochondrial content is unaffected, suggesting independent mitochondrial pool regulation. Lower mitochondrial content correlates with lower fasting lipid oxidation and metabolic inflexibility, suggesting it may be intrinsically linked to abnormal fuel utilization patterns of obesity-associated insulin resistance.

Elevated serum γ-glutamyltransferase levels are independently associated with insulin resistance in non-diabetic subjects

We investigated the associations of γ-glutamyltransferase (GGT) with visceral obesity, adiponectin and retinol binding protein 4 (RBP4), and insulin resistance (IR) and compared these associations with other liver enzymes in non-diabetes. We enrolled 94 healthy subjects 30–69 years old. Clinical and biochemical metabolic parameters were measured. Adiponectin and RBP4 were determined by ELISA. IR was examined by HOMA-IR. Visceral fat was determined by computed tomography scan. GGT and alanine aminotransferase (ALT) were positively correlated with waist circumference (WC), waist-to-hip ratio (WHR), visceral fat area (VFA), visceral-to-subcutaneous fat area ratio (VSR), HOMA-IR, and RBP4, but was negatively correlated with adiponectin ( p < 0.05). In multivariate regression, GGT was associated with male sex, HOMA-IR, and RBP4 ( R 2 = 0.48, p < 0.05) and ALT was associated with HOMA-IR ( R 2 = 0.22, p < 0.05). By logistic regression after adjusted for age and sex, the odds ratio (OR) for IR in the highest tertile of sex-specific GGT and ALT were significantly increased compared to those in the lowest [OR (95% CI); 6.90 (2.08–22.82), 3.38 (1.08–10.57), respectively]. However, these relationships after further adjustments for RBP4, adiponectin, VFA, VSR, WHR, WC, TG, and HDL remained significant in only GGT. In conclusions, GGT may be a useful marker of IR in non-diabetes.