Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk

Despite significant progress by genome-wide association studies, the ability of genetic variants to conduce to the prediction or prognosis of type-2 diabetes (T2D) is weak. Expression analysis of the corresponding genes may suggest possible links between single-nucleotide polymorphisms and T2D phenotype and/or risk. Herein, we investigated the expression patterns of 24 T2D-susceptibility genes, and their individual transcript variants (tv), in peripheral blood of T2D patients and controls (CTs), applying RNA-seq and real-time qPCR methodologies, and explore possible associations with disease features. Our data revealed the deregulation of certain transcripts in T2D patients. Among them, the down-regulation of CAPN10 tv3 was confirmed as an independent predictor for T2D. In patients, increased expression of CDK5 tv2, CDKN2A tv3 or THADA tv5 correlated positively with serum insulin levels, of CDK5 tv1 positively with % HbA1c levels, while in controls, elevated levels of TSPAN8 were associated positively with the presence of T2D family history. Herein, a T2D-specific expression profile of specific transcripts of disease-susceptibility genes is for the first time described in human peripheral blood. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers

Insulin action in morbid obesity: a focus on muscle and adipose tissue

The aim of this review is to summarize the mechanisms underlying insulin resistance in morbid obesity. Glucose regulation by insulin depends on the suppression of endogenous glucose production and stimulation of glucose disposal. In morbid obesity, glucose production by the liver is increased. Moreover, the sensitivity of glucose metabolism to insulin is impaired both in muscle (due to defects in insulin-stimulated glucose utilization and decreased blood flow) and in adipose tissue (due to decreased blood flow). However, recent studies suggest that expanded total fat mass becomes a major consumer of glucose providing a sink for glucose and compensating for insulin resistance. Metabolism and immunity are closely linked. Bearing in mind the crosstalk between inflammatory pathways and the insulin signaling cascade, adipose tissue derived cytokines may represent a link between inflammation and metabolic signals and mediate, at least in part, insulin resistance. Adipose tissue plays a crucial role by buffering daily influx of dietary fat, suppressing the release of non-esterified fatty acids into the circulation and increasing triacylglycerol clearance. However, in morbid obesity there is an impairment of the normal ability of adipose tissue to buffer fatty acids, despite hyperinsulinemia. Lipotoxicity gradually impairs insulin action in the liver and muscle, aggravating insulin resistance

Thyroid disease in older people

Several changes in thyroid hormone secretion, metabolism, and action occur with the increase in age. Aging is often associated with a decrease in serum thyroid stimulating hormone and 13 levels, whereas serum free T4 levels usually remain unchanged. The prevalence of thyroid dysfunction is higher in the elderly as compared to the younger population. In elderly individuals the non-specific clinical manifestations of thyroid hormone excess or deprivation can cause confusion in the clinical setup: while some of the symptoms of thyroid disease are similar to those in younger patients, it is not uncommon for both hyperthyroidism and hypothyroidism to be manifested in subtle ways in older patients, often mimicking symptoms of aging or masquerading as diseases of the cardiovascular, gastrointestinal, or nervous system. In addition, diagnosis of thyroid disorders is commonly complicated, due to chronic, non-thyroidal illness or medication therapy. Early diagnosis and treatment of overt thyroid disorders is crucial, since these disorders are associated with increased morbidity and mortality in the elderly, usually due to common coexistent diseases such as diminished cardiovascular reserve. Treatment of subclinical thyroid disease should also be considered, based on a combination of age, symptoms and risk factors in the individual patients. In addition, both prevalence and aggressiveness of thyroid cancer increase with age. This review summarizes the changes of thyroid function, as well as the clinical manifestations and treatment of thyroid disorders with advancing age. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Insulin Action in Hyperthyroidism: A Focus on Muscle and Adipose Tissue

Hyperthyroidism leads to an enhanced demand for glucose, which is primarily provided by increased rates of hepatic glucose production due to increased gluconeogenesis (in the fasting state) and increased Cori cycle activity (in the late postprandial and fasting state). Adipose tissue lipolysis is increased in the fasting state, resulting in increased production of glycerol and nonesterified fatty acids. Under these conditions, increased glycerol generated by lipolysis and increased amino acids generated by proteolysis are used as substrates for gluconeogenesis. Increased nonesterified fatty acid levels are necessary to stimulate gluconeogenesis and provide substrate for oxidation in other tissues (such as muscle). In the postprandial period, insulin-stimulated glucose uptake by the skeletal muscle has been found to be normal or increased, mainly due to increased blood flow. Under hyperthyroid conditions, insulin-stimulated rates of glycogen synthesis in skeletal muscle are decreased, whereas there is a preferential increase in the rates of lactate formation vs. glucose oxidation leading to increased Cori cycle activity. In hyperthyroidism, the Cori cycle could be considered as a large substrate cycle; by maintaining a high flux through it, a dynamic buffer of glucose and lactate is provided, which can be used by other tissues as required. Moreover, lipolysis is rapidly suppressed to normal after the meal to facilitate the disposal of glucose by the insulin-resistant muscle. This ensures the preferential use of glucose when available and helps to preserve fat stores. (Endocrine Reviews 31: 663-679, 2010

Insulin effects in muscle and adipose tissue

The major effects of insulin on muscle and adipose tissue are: (1) Carbohydrate metabolism: (a) it increases the rate of glucose transport across the cell membrane, (b) it increases the rate of glycolysis by increasing hexokinase and 6-phosphofructokinase activity, (c) it stimulates the rate of glycogen synthesis and decreases the rate of glycogen breakdown. (2) Lipid metabolism: (a) it decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level, (b) it stimulates fatty acid and triacylglycerol synthesis in tissues, (c) it increases the uptake of triglycerides from the blood into adipose tissue and muscle, (d) it decreases the rate of fatty acid oxidation in muscle and liver. (3) Protein metabolism: (a) it increases the rate of transport of some amino acids into tissues, (b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other tissues, (c) it decreases the rate of protein degradation in muscle (and perhaps other tissues). These insulin effects serve to encourage the synthesis of carbohydrate, fat and protein, therefore, insulin can be considered to be an anabolic hormone. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Increases in muscle blood flow after a mixed meal are impaired at all stages of type 2 diabetes

Objective In type 2 diabetes, although the impairment of postprandial muscle blood flow response is well established, information on the effect of this impairment on glucose uptake and lipid metabolism is controversial. Design Postprandial forearm blood flow responses and metabolic parameters were assessed in a cross-sectional study of subjects at various stages of insulin resistance. Patients Eleven healthy subjects (CONTROLS), 11 first-degree relatives of type-2 diabetics (RELATIVES), 10 patients with impaired glucose tolerance (IGT), 10 diabetic patients with postprandial hyperglycaemia (DMA), and 13 diabetic patients with both fasting and postprandial hyperglycaemia (DMB). Measurements All subjects received a meal. Blood was drawn from a forearm deep vein and the radial artery at specific time-points during a period of 360 min for measurements of glucose, insulin, triglycerides and nonesterified-fatty acids. Forearm muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake and ISI Index were calculated. Results Peak-baseline muscle blood flow was higher in CONTROLS (3.32 +/- 0.4) than in RELATIVES (0.53 +/- 0.29), IGT (0.82 +/- 0.2), DMA (1.44 +/- 0.34), DMB (1.23 +/- 0.35 ml/min/100 ml tissue), P < 0.001. Glucose uptake (AUC0-360,mu mol/100 ml tissue) was higher in CONTROLS (1023 +/- 132) than in RELATIVES (488 +/- 42), IGT (458 +/- 43), DMA (347 +/- 63), DMB (543 +/- 53), P < 0.001. ISI index, postprandial triglycerides and nonesterified-fatty acids behaved in a similar way. Peak-baseline muscle blood flow correlated positively with glucose uptake (r = 0.440, P = 0.001) and ISI index (r = 0.397, P = 0.003), and negatively with postprandial triglycerides (r = -0.434, P = 0.001) and nonesterified-fatty acids (r = -0.370, P = 0.005). Conclusions These results suggest that increase in muscle blood flow after a meal is impaired at all stages of type-2 diabetes. This defect influences glucose uptake and is associated with impaired lipid metabolism in the postprandial 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. Vinegar’s 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