Neudesin in obesity and type 2 diabetes mellitus: the effect of acute fasting and weight reducing interventions.

CONTEXT: Neudesin has recently been identified as a novel regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored. OBJECTIVE: The aim of this study was to assess the effects of obesity and type 2 diabetes mellitus (T2DM) along with selected weight reducing interventions on serum neudesin levels and adipose tissue mRNA expression. PATIENTS AND METHODS: Fifteen obese subjects with T2DM undergoing endoscopic duodenal-jejunal bypass liner (DJBL) implantation, 17 obese subjects (11 with T2DM, 6 without T2DM) scheduled for gastric plication (GP), 15 subjects with functional hypoglycemia subjected to 72-hour acute fasting (AF), and 12 healthy controls were included in the study. RESULTS: Baseline neudesin levels were comparable between all groups. DJBL increased neudesin at 6 and 10 months after the procedure (1.77±0.86 vs 2.28±1.27 vs 2.13±1.02 ng/mL, P=0.001 for baseline vs 6 vs 10 months) along with reduction in body weight and improvement of HbA1c without any effect on neudesin mRNA expression in subcutaneous adipose tissue. Conversely, GP did not affect neudesin levels despite marked reduction in body weight and improvement of HbA1c. In contrast, AF decreased neudesin levels during the entire period (1.74±0.54 vs 1.46±0.48 ng/mL, P=0.001 for baseline vs 72 hours) with no impact of subsequent re-alimentation on neudesin concentrations. CONCLUSION: Neudesin levels are differentially regulated during AF and chronic weight reduction induced by DJBL or GP. Further studies are needed to assess its possible significance in energy homeostasis regulation in humans.

Endocrine effects of duodenal-jejunal exclusion in obese patients with type 2 diabetes mellitus.

Duodenal-jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.

Acute alcohol consumption downregulates lipoprotein lipase activity in vivo.

OBJECTIVE: Acute alcohol consumption can induce hypertriglyceridemia. Such an effect could be explained in part by the influence of alcohol on lipoprotein lipase (LPL) - the key enzyme responsible for triglyceride hydrolysis in circulation. Therefore, we have studied the effects of acute moderate alcohol consumption on LPL activity and on the concentrations of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4), which are known to inhibit LPL. METHODS: Two experiments were carried out in 8 healthy volunteers. They received 25 g of alcohol (vodka) in one experiment and water in the other (control). The in vivo function of LPL was estimated using intravenous fat tolerance tests (IVFTT) carried out before, 2 and 4 hours after alcohol administration. At the end of each experiment, LPL activity and mass were measured in post-heparin plasma (PHP). The concentrations of ANGPTL3 and ANGPTL4 in blood were measured before alcohol consumption and at the end of the experiments. RESULTS: LPL activity, as estimated using the IVFTT, was reduced by 25% and 24% two and four hours after the administration of alcohol, respectively, and was not affected in the control experiment. At the end of the experiment, LPL activity in PHP was 23% lower after alcohol consumption than in the controls. The concentrations of ANGPTL3 and ANGPTL4 had dropped to 67% and 86% of baseline values, respectively, at 280 min after alcohol consumption. These levels were not affected in the control experiment. The levels of ANGPTL4 but not those of ANGPTL3 were increased in PHP compared to both baseline values and values at 280 min. CONCLUSION: The capacity for triglyceride clearance seemed to be acutely reduced by alcohol consumption and the effect persisted for several hours. The levels of LPL activity in PHP were reduced to a similar extent. This reduction in LPL activity could not be explained by the changes in the levels of ANGPTL3 or ANGPTL4, which both decreased.

Metabolic characteristics of soleus muscle in relation to insulin action in the offspring of hypertensive parents.

Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

Insulin secretion, sensitivity, and metabolic profile of young healthy offspring of hypertensive parents.

Hyperinsulinemia and insulin resistance are commonly observed in essential hypertension, which is part of the metabolic syndrome. The aim of this study was to examine whether insulin secretion abnormalities or alterations in insulin sensitivity and glucose tolerance are also present in healthy men, offspring of patients with essential hypertension. Twelve young (27 +/- 3.6 years), lean normotensive offspring were compared with 14 age-, sex-, and body mass index (BMI)-matched controls without a family history of hypertension, diabetes mellitus, and coronary heart disease. We studied glucose tolerance, insulin secretion, and sensitivity using 10-hour hyperglycemic and 10-hour hyperinsulinemic-euglycemic clamps (HIC). Glucose tolerance was comparable in the offspring and controls. However, the offspring had higher insulin and C-peptide levels during the hyperglycemic clamp (HGC) compared with controls (P <.05). There was no difference in the early phase of insulin secretion between the groups. The insulin sensitivity index (glucose infusion rate/serum insulin) was significantly lower in the offspring during both clamps. Moreover, the offspring had higher systolic (P <.001) and diastolic (P <.001) blood pressure and had higher serum cholesterol (P <.01) and triglyceride (P <.05) levels. Apparently healthy, young, lean individuals with a genetic predisposition to essential hypertension and with normal glucose tolerance had higher insulin secretion and lower insulin sensitivity than controls. These abnormalities, together with higher blood pressure and altered lipid metabolism, may play a role in the development of hypertension and an increased risk of cardiovascular morbidity and mortality in these individuals.

Effect of acute hyperglycemia on erythrocyte membrane ion transport in offspring of hypertensive parents.

OBJECTIVE: Patients with essential hypertension exhibit several red blood cell (RBC) ion transport abnormalities, insulin resistance (IR) and increased risk of developing type 2 diabetes. The aims of this study were to assess RBC ion transport activities under basal conditions and to test the in vivo effect of acute hyperglycemia on RBC ion transport in the offspring of hypertensive parents (OHP) and healthy controls (C). DESIGN AND METHODS: Activities of Na+-K+ pump, Na+-K+ cotransport, Na+-Li+ countertransport (SLC) and Na+, Rb+ and Li+ leaks were measured before and after a 5-h hyperglycemic (12 mmol/l) clamp (HGC) and compared to values found under euglycemic isovolumic conditions in OHP (n = 12) and C (n = 14). Insulin action was calculated as insulin sensitivity index (M/I) during HGC. RESULTS: The offspring of hypertensive parents were characterized by lower M/I (0.07 +/- 0.03 versus 0.12 +/- 0.07 mg/kg per min per microU per ml; P < 0.05) and elevated SLC (0.080 +/- 0.004 versus 0.068 +/- 0.003 mmol/h per litre; P < 0.05), as well as by higher Li+ (0.106 +/- 0.004 versus 0.093 +/- 0.003 mmol/h per litre; P < 0.05) and Rb+ leaks (0.160 +/- 0.014 versus 0.120 +/- 0.007 mmol/h per litre; P < 0.05) compared to controls. Acute hyperglycemia did not cause significant changes in any investigated RBC ion transport parameters. CONCLUSIONS: The offspring of hypertensive parents displayed higher insulin resistance, enhanced activity of SLC and formerly undocumented augmented Li+ and Rb+ leaks. Acute hyperglycemia did not modify any RBC ion transport activities in either offspring of hypertensive parents or controls.

Erythrocyte membrane ion transport in offspring of hypertensive parents: effect of acute hyperinsulinemia and relation to insulin action.

Some patients with essential hypertension exhibit insulin resistance (IR) and several red blood cell (RBC) ion transport abnormalities. The aims of the study were to assess RBC ion transport acitivities under basal conditions, to test in vivo the effect of acute hyperinsulinemia, and to evaluate the relationship to IR in the offspring of hypertensive parents (n = 12; OHP) and healthy controls (n = 14; C). Activities of the Na+-K+ pump, Na+-K+ cotransport, Na+-Li+ countertransport (SLC), and Na+, Rb+, and Li+ leaks (passive membrane permeability) were measured before and after a hyperinsulinemic (75 microU/mL) euglycemic clamp (HIC) and compared to those found under isoinsulinemic isovolumic conditions in OHP and C. An insulin action was calculated as glucose disposal and insulin sensitivity index (M/I) after HIC. OHP were characterized by lower M/I (0.12+/-0.07 vs. 0.20+/-0.09 mg/kg/min/microU/mL; p < 0.05) and elevated SLC and Li+ and Rb+ leaks (p < 0.05) compared with C. Although acute hyperinsulinemia did not modify significantly any ion transport parameter studied, negative correlation was observed between insulin action and membrane cation leaks. Glucose disposal correlated with an Li+ leak in C (r = -0.736; p < 0.01) and all subjects (r = -0.424; p < 0.05) after HIC and in OHP with an Na+ leak (r = -0.727; p < 0.05) before HIC. In conclusion, OHP displayed higher insulin resistance, enhanced activity of SLC, and augmented Li+ and Rb+ leaks. Acute hyperinsulinemia did not modify any ion transport parameter studied, although negative correlation was observed between insulin action and membrane leaks.