Vaia Lambadiari

Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism

OBJECTIVE Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. DESIGN AND METHODS To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. RESULTS HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC(0)(-)(300) 32,190±1067 and 31,497±716,mg/dl min respectively) versus EU (27,119±1156 mg/dl min, P<0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC(0)(-)(300) 11,020±985 and 9565±904 mU/l min respectively) compared with EU subjects (AUC(0)(-)(300) 7588±743 mU/l min, P<0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81±0.3 and 2.43±0.38 respectively) compared with EU subjects (1.27±0.16, P<0.05), while Matsuda and Belfiore indices were decreased in HR (4.21±0.41 and 0.77±0.05 respectively, P<0.001) and SHR patients (4.47±0.33 and 0.85±0.05 respectively, P<0.05 versus EU (7.76±0.87 and 1 respectively). At 100 μU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8±7 mean fluorescence intensity (MFI)) and SHR patients (522.2±25 MFI) compared with EU subjects (407±18 MFI, P<0.01 and P<0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8±5%) versus EU subjects (61.26±10%, P<0.05). CONCLUSIONS Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

Insulin resistance in hyperthyroidism: the role of IL6 and TNFα

OBJECTIVE Although insulin resistance is a common finding in hyperthyroidism, the implicated mechanisms are obscure. The aim of this study was to investigate whether interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) are related to the development of insulin resistance in hyperthyroidism of nonautoimmune origin. DESIGN AND METHODS A meal was given to ten hyperthyroid (HR) and ten euthyroid (EU) women. Plasma samples were taken for 360 min from the radial artery for measurements of glucose, insulin, and nonesterified fatty acids (NEFA). IL6 and TNFalpha were measured preprandially from the superficial epigastric vein and from the radial artery. RESULTS i) In HR versus EU: (a) arterial glucose was similar (AUC(0-360) 2087+/-57 vs 2010+/-43 mM x min), but insulin was increased (AUC(0-360) 17 267+/-2447 vs 10 331+/-666 microU/ml x min, P=0.01), (b) homeostasis model assessment (HOMA) was increased (2.3+/-0.4 vs 1+/-0.1 kg/m(2), P=0.007), (c) arterial NEFA were increased (AUC(0-360) 136+/-18 vs 89+/-7 mmol/lxmin, P=0.03), (d) arterial IL6 (2+/-0.3 vs 0.9+/-0.1 pg/ml, P=0.0009) and TNFalpha (4.2+/-0.8 vs 1.5+/-0.2 pg/ml, P=0.003) were increased, and (e) IL6 production from the subcutaneous adipose tissue (AT) was increased (18+/-6 vs 5+/-1 pg/min per 100 ml tissue, P=0.04). ii) (a) Subcutaneous venous IL6 was positively associated with HOMA (beta-coefficient=1.7+/-0.7, P=0.049) and (b) although TNFalpha was not produced by the subcutaneous AT, arterial TNFalpha was positively associated with NEFA (AUC(0-360); beta-coefficient=0.045+/-0.01, P=0.005). CONCLUSIONS In hyperthyroidism: i) glucose and lipid metabolism are resistant to insulin, ii) subcutaneous AT releases IL6, which could then act as an endocrine mediator of insulin resistance, iii) although there is no net secretion of TNFalpha by the subcutaneous AT, increased systemic TNFalpha levels may be related to the development of insulin resistance in lipolysis.

Metabolic syndrome and cardiometabolic risk factors.

The metabolic syndrome (MetS) is a cluster of metabolic conditions associated to abdominal obesity, such as elevated blood pressure, impaired glucose tolerance, insulin resistance, elevated triglycerides, and low high-density lipoprotein cholesterol concentrations. Each of the associated conditions has an independent effect, but clustering together they become synergistic, making the risk of developing cardiovascular disease (CVD) greater. There is a big debate as to whether the MetS alone or its associated health conditions are more important for CVD incidence and mortality or whether prevention and/or treatment of the MetS will reduce CVD incidence and mortality. This article reviews the evidence that demonstrates that individuals with the MetS are at increased risk for CVD incidence and mortality and discusses these debated issues.

Rates of lipid fluxes in adipose tissue in vivo after a mixed meal in morbid obesity

Objective:Although insulin resistance in obesity is established, information on insulin action on lipid fluxes, in morbid obesity, is limited. This study was undertaken in morbidly obese women to investigate insulin action on triacylglycerol fluxes and lipolysis across adipose tissue.Subjects and Design:A meal was given to 26 obese (age 35±1years, body mass index 46±1 kg m–2) and 11 non-obese women (age 38±2years, body mass index 24±1 kg m–2). Plasma samples for glucose, insulin, triglycerides and non-esterified fatty acids (NEFAs) were taken for 360 min from a vein draining the abdominal subcutaneous adipose tissue and from the radial artery. Adipose tissue blood flow was measured with 133Xe.Results:In obese vs non-obese: (1) Arterial glucose was similar, but insulin was increased (P=0.0001). (2) Adipose tissue blood flow was decreased (P=0.0001). (3) Arterial triglycerides (P=0.0001) and NEFAs (P=0.01) were increased. (4) Lipoprotein lipase was decreased (P=0.0009), although the arteriovenous triglyceride differences were similar. (5) Veno-arterial NEFA differences across the adipose tissue were similar. (6) NEFA fluxes and hormone-sensitive lipase-derived glycerol output from 100 g adipose tissue were not different. (7) Total adipose tissue NEFA release was increased (P=0.02).Conclusions:In morbid obesity: (a) hypertriglycerinemia could be attributed to a defect in the postprandial dynamic adjustment of triglyceride clearance across the adipose tissue, partly caused by blunted BF; and (b) postprandially, there is an impairment of adipose tissue to buffer NEFA excess, despite hyperinsulinemia.

Vinegar Decreases Postprandial Hyperglycemia in Patients With Type 1 Diabetes

Although previous studies show that vinegar improves insulin sensitivity in healthy or insulin-resistant subjects (1,2), information on the effect of vinegar in type 1 diabetes is absent. Given the beneficial effects of maintaining tight glycemic control on the development of complications, there is much interest in identifying diet patterns that could possibly reduce hyperglycemia. The aim of this study was to investigate the effect of vinegar in type 1 diabetes. Ten men with type 1 diabetes (aged 32 ± 3 years, BMI 24 ± 1 kg/m2, diabetes duration 14 ± 3 years, A1C 6.7 ± 0.2%) treated with rapid-acting insulin preprandially and long-acting insulin once daily were studied after an overnight fast. The study was approved by …

Skeletal muscle insulin resistance in morbid obesity: the role of interleukin-6 and leptin.

BACKGROUND Although insulin resistance in obesity is established, the link between excess body fat and skeletal muscle insulin resistance is obscure. The aim of this study was to investigate whether cytokines secreted from the subcutaneous adipose tissue are related to the sensitivity of glucose metabolism to insulin in skeletal muscle. METHODS A meal was given to 14 obese and 10 non-obese women. Plasma samples were taken for 360 min from a forearm vein and from the radial artery for glucose and insulin measurements. Interleukin-6, leptin, TNFα, resistin and adiponectin were measured preprandially from the radial artery and from the superficial epigastric vein. Forearm blood flow was measured with plethysmography. RESULTS (1) In obese vs non-obese: (a) Glucose uptake by skeletal muscle was decreased (AUC (0-360)369 ± 55 vs. 877 ± 146 μmol/100 g tissue, p=0.001) (b) arterial interleukin-6 (2.5 ± 0.5 vs. 1 ± 0.1 pg/ml, p=0.013) and subcutaneous venous interleukin-6 (5 ± 0.5 vs. 3.4 ± 0.5 pg/ml, p=0.027) were increased (c) arterial leptin (63 ± 7 vs. 5 ± 0.6 ng/ml, p<0.0001) and subcutaneous venous leptin 80 ± 8 vs. 6.5 ± 0.7 ng/ml, p<0.0001) were increased. (2) Arterial interleukin-6 (p=0.002) and subcutaneous venous interleukin-6 (p=0.014) were negatively associated with forearm glucose uptake in obese. (3) No association was found between leptin and forearm glucose uptake, after correcting with fat mass. CONCLUSIONS In morbid obesity: (1) Subcutaneous adipose tissue releases interleukin-6 which could then mediate insulin resistance in skeletal muscle. (2) Although there is increased secretion of leptin by the subcutaneous adipose tissue, leptin levels are not correlated to the sensitivity of glucose metabolism to insulin in muscle.

Short Term, Low Dose Thyroxin Treatment of Euthyroid Patients with Type 2 Diabetes improves Peripheral Blood Flow and Overall Insulin Sensitivity

Purpose: Variation of plasma thyroid hormone levels influences insulin sensitivity and peripheral glucose disposal. High thyroxin dose administration to healthy humans induces insulin resistance, whereas moderate doses increase peripheral glucose disposal. An open-labeled, randomized and placebo-controlled intervention was performed in euthyroid type 2-diabetic patients, to examine the effect of a small thyroxin dose within the euthyroid range on postprandial forearm muscle glucose uptake, insulin sensitivity, in vitro glucose uptake and GLUT4 recruitment in the plasma membrane of monocytes. Methods: A meal was given to eleven euthyroid, treatment-naive, type-2 diabetic patients (aged 43 ± 3.8 yrs, BMI 27.48 ± 1.39 kg/m2, T3 119 ± 5.7 ng/dl, T4 8,13 ± 0.46 μg/dl, TSH 1.51 ± 0.14 μU/ml, FT4 1.272 ± 0.047 ng/dl) before and after administration of 50 μg of thyroxin once daily for 2 months. Similarly, a placebo was given to eleven age, sex and BMI-matched euthyroid, type-2 diabetic patients. Blood was drawn for 300 min from a forearm deep vein and the radial artery for measurements of glucose, insulin, and GLUT4 abundance in peripheral monocytes. Forearm blood flow (BF) was measured with strain-gauge-plethysmography. Forearm glucose-uptake, and insulin sensitivity were assessed. After the first meal-tolerance-test, daily treatment with 50 μg of thyroxin or placebo was initiated for a 2-month period. Then a second identical test was repeated. Results: TSH, glucose, insulin levels and HbA1c reduced significantly in the treatment group. Peak-baseline BF and Glucose-uptake (AUC0-300 min) increased significantly (1.685 ± 0.3 vs. 3.07 ± 0.15 ml/min per 100 cc tissue, p=0.0018) and (587 ± 68 vs. 1015 ± 131 μmol per 100 cc tissue, p=0.0051), respectively. All insulin-sensitivity indices improved post-treatment. Glucose uptake and GLUT4 abundance in monocytes also improved. The placebo group exhibited no change in all variables. Conclusion: Administration of small, subthyrotoxic doses of thyroxin to euthyroid diabetic patients improves peripheral glucose disposal, blood flow responses and overall insulin sensitivity. This could be of therapeutic importance by reducing the burden of hyperglycaemia and possibly the long term complications of diabetes.

Insulin action in muscle and adipose tissue in type 2 diabetes: The significance of blood flow

Under normal metabolic conditions insulin stimulates microvascular perfusion (capillary recruitment) of skeletal muscle and subcutaneous adipose tissue and thus increases blood flow mainly after meal ingestion or physical exercise. This helps the delivery of insulin itself but also that of substrates and of other signalling molecules to multiple tissues beds and facilitates glucose disposal and lipid kinetics. This effect is impaired in insulin resistance and type 2 diabetes early in the development of metabolic dysregulation and reflects early-onset endothelial dysfunction. Failure of insulin to increase muscle and adipose tissue blood flow results in decreased glucose handling. In fat depots, a blunted postprandial blood flow response will result in an insufficient suppression of lipolysis and an increased spill over of fatty acids in the circulation, leading to a more pronounced insulin resistant state in skeletal muscle. This defect in blood flow response is apparent even in the prediabetic state, implying that it is a facet of insulin resistance and exists long before overt hyperglycaemia develops. The following review intends to summarize the contribution of blood flow impairment to the development of the atherogenic dysglycemia and dyslipidaemia.

The role of acetic acid on glucose uptake and blood flow rates in the skeletal muscle in humans with impaired glucose tolerance

Background/Objectives:Previous studies support the glucose-lowering effect of vinegar. However, the effect of vinegar on muscle glucose metabolism and endothelial function has not been studied in humans. This open, randomized, crossover, placebo-controlled study aims to investigate the effects of vinegar on muscle glucose metabolism, endothelial function and circulating lipid levels in subjects with impaired glucose tolerance (IGT) using the arteriovenous difference technique.Subjects/Methods:Eight subjects with IGT (4 males, age 46±10 years, body mass index 30±5) were randomised to consume 0.50 mmol vinegar (6% acetic acid) or placebo before a mixed meal. Plasma samples were taken for 300 min from the radial artery and the forearm vein for measurements of glucose, insulin, triglycerides, non-esterified fatty acids (NEFAs) and glycerol. Muscle blood flow was measured with strain gauge plethysmography. Glucose flux was calculated as the arteriovenous difference of glucose multiplied by the blood flow rates.Results:Vinegar compared with placebo: (1) decreased arterial plasma insulin (Poverall<0.001; P75 min=0.014, β=−42), (2) increased forearm blood flow (Poverall<0.001; P240 min=0.011, β=1.53; P300 min=0.023, β=1.37), (3) increased muscle glucose uptake (Poverall<0.001; P60 min=0.029, β=2.78) and (4) decreased arterial plasma triglycerides (Poverall=0.005; P240 min<0.001, β=−344; P300 min<0.001, β=−373), without changing NEFA and glycerol.Conclusions:In individuals with IGT, vinegar ingestion before a mixed meal results in an enhancement of muscle blood flow, an improvement of glucose uptake by the forearm muscle and a reduction of postprandial hyperinsulinaemia and hypertriglyceridaemia. From this point of view, vinegar may be considered beneficial for improving insulin resistance and metabolic abnormalities in the atherogenic prediabetic state.

Vinegar Consumption Increases Insulin-Stimulated Glucose Uptake by the Forearm Muscle in Humans with Type 2 Diabetes

Background and Aims. Vinegar has been shown to have a glucose-lowering effect in patients with glucose abnormalities. However, the mechanisms of this effect are still obscure. The aim of this randomised, crossover study was to investigate the effect of vinegar on glucose metabolism in muscle which is the most important tissue for insulin-stimulated glucose disposal. Materials and Methods. Eleven subjects with DM2 consumed vinegar or placebo (at random order on two separate days, a week apart), before a mixed meal. Plasma glucose, insulin, triglycerides, nonesterified fatty acids (NEFA), and glycerol were measured preprandially and at 30–60 min for 300 min postprandially from the radial artery and from a forearm vein. Muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake was calculated as the arteriovenous difference of glucose multiplied by blood flow. Results. Vinegar compared to placebo (1) increased forearm glucose uptake (p = 0.0357), (2) decreased plasma glucose (p = 0.0279), insulin (p = 0.0457), and triglycerides (p = 0.0439), and (3) did not change NEFA and glycerol. Conclusions. In DM2 vinegar reduces postprandial hyperglycaemia, hyperinsulinaemia, and hypertriglyceridaemia without affecting lipolysis. Vinegars effect on carbohydrate metabolism may be partly accounted for by an increase in glucose uptake, demonstrating an improvement in insulin action in skeletal muscle. This trial is registered with Clinicaltrials.gov NCT02309424.