Insulin-degrading enzyme higher in subjects with metabolic syndrome.

Metabolic syndrome (MS) is comprised of a cluster of abnormalities in glucose, lipid, and vascular homeostasis, which is most commonly linked to abdominal obesity. MS heralds increased risk for development of diabetes and is linked to impairment in insulin signaling. Insulin-degrading enzyme (IDE) is one of the mechanisms through which insulin blood levels are maintained. It has been previously suggested that controlling IDE levels could provide yet another potential therapeutic approach in diabetes. Here we aim to investigate whether changes in serum IDE levels correlate with the severity of MS. Using a highly sensitive ELISA assay of active IDE in human serum, we found a strong correlation between circulating IDE levels and circulating levels of triglycerides, insulin, and c-peptide and an inverse correlation with HDL cholesterol (HDLc). Serum IDE levels were higher in MS subjects than in control subjects. Hence, circulating IDE may serve as a tool to identify subjects with abnormal insulin metabolism, possibly those with MS that are at risk to develop diabetes.

Effects of a typical acute oral calcium load on arterial properties and endothelial function in healthy subjects.

BACKGROUND/OBJECTIVES: Often recommended, calcium supplements have been incriminated as increasing the risk of cardiovascular events, whereas dietary calcium has generally been exonerated. As a first step to address the vascular safety of such dietary measures at the clinical nutritionist toolbox, we sought to determine and compare the acute effects of a typical oral calcium load, provided either as a supplement or as food, on vascular parameters assessed noninvasively in healthy subjects. SUBJECTS/METHODS: In this acute, cross-over, random-order intervention, 11 young and healthy vitamin D-sufficient volunteers (8 women/3 men, 33±6.1 years, body mass index 22.6±2.3 kg/m(2)), ingested 600 mg of calcium twice, once as calcium citrate and the other time from dairy products. Biochemical, vascular and hemodynamic parameters, before and 2 h after each challenge, were compared. Arterial stiffness was studied by measuring pulse wave velocity, augmentation index and large (C1) and small (C2) arterial compliance. Endothelial function was assessed by flow-mediated dilation (FMD). RESULTS: Despite effective calcium loading accompanied by a significant 60% parathyroid hormone level reduction on both occasions, there were no clinically significant changes in the vascular parameters neither in comparison with baseline, nor between the studies. A decrease in heart rate with no change in cardiac output was noticed after the supplement. CONCLUSIONS: An effective calcium load has no clinically significant untoward effect on the vascular properties of young healthy subjects, regardless of its source. Additional studies should determine whether this holds true for chronic calcium supplementation, particularly in subjects with a priori vascular impairment.

Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation.

We report on a case of a man with familial, X-linked, partial androgen insensitivity, in whom a new point mutation in the androgen receptor (AR) ligand-binding domain (causing a valine-to-alanine substitution at codon 686) was identified. High-dose prolonged testosterone therapy resulted in marked progression in patient's appearance and great improvement in sperm count and characteristics. In combination with intracytoplasmic microinjection, treatment resulted in fertility. This is believed to be the first report of such a case. This case supports high-dose testosterone therapeutic trial in this condition. Furthermore, it underscores the possibility of achieving fertility with current endocrine and assisted reproduction modalities, making some of these X-linked AR mutations paternally transmissible.

Differential regulation of the HepG2 and adipocyte/muscle glucose transporters in 3T3L1 adipocytes. Effect of chronic glucose deprivation.

Glucose transport in 3T3L1 adipocytes is mediated by two facilitated diffusion transport systems. We examined the effect of chronic glucose deprivation on transport activity and on the expression of the HepG2 (GLUT 1) and adipocyte/muscle (GLUT 4) glucose transporter gene products in this insulin-sensitive cell line. Glucose deprivation resulted in a maximal increase in 2-deoxyglucose uptake of 3.6-fold by 24 h. Transport activity declined thereafter but was still 2.4-fold greater than the control by 72 h. GLUT 1 mRNA and protein increased progressively during starvation to values respectively 2.4- and 7.0-fold greater than the control by 72 h. Much of the increase in total immunoreactive GLUT 1 protein observed later in starvation was the result of the accumulation of a non-functional or mistargeted 38 kDa polypeptide. Immunofluorescence microscopy indicated that increases in GLUT 1 protein occurred in presumptive plasma membrane (PM) and Golgi-like compartments during prolonged starvation. The steady-state level of GLUT 4 protein did not change during 72 h of glucose deprivation despite a greater than 10-fold decrease in the mRNA. Subcellular fractionation experiments indicated that the increased transport activity observed after 24 h of starvation was principally the result of an increase in the 45-50 kDa GLUT 1 transporter protein in the PM. The level of the GLUT 1 transporter in the PM and low-density microsomes (LDM) was increased by 3.9- and 1.4-fold respectively, and the GLUT 4 transporter content of the PM and LDM was 1.7- and 0.6-fold respectively greater than that of the control after 24 h of glucose deprivation. These data indicate that newly synthesized GLUT 1 transporters are selectively shuttled to the PM and that GLUT 4 transporters undergo translocation from an intracellular compartment to the PM during 24 h of glucose starvation. Thus glucose starvation results in an increase in glucose transport in 3T3L1 adipocytes via a complex series of events involving increased biosynthesis, decreased turnover and subcellular redistribution of transporter proteins.

Differential regulation of two distinct glucose transporter species expressed in 3T3-L1 adipocytes: effect of chronic insulin and tolbutamide treatment.

The HepG2-type glucose transporter (HepG2-GT) is expressed in 3T3-L1 fibroblasts and adipocytes. In contrast, the acutely insulin-regulatable glucose transporter (IRGT) is expressed only in the adipocytes. In the present study, the expression of the IRGT was shown to increase in parallel with the acquisition of acutely insulin-stimulated glucose uptake during differentiation of these cells, whereas the level of the HepG2-GT decreased during the course of differentiation in parallel with a decline in basal glucose uptake. We examined the effects of chronic insulin and tolbutamide treatment on glucose transporter activity in conjunction with the expression of these two glucose transporter species in 3T3-L1 adipocytes. Treatment of adipocytes with insulin, tolbutamide, or both agents in combination increased 2-deoxyglucose uptake, HepG2-GT protein, and HepG2-GT mRNA levels in parallel. The effect of combined insulin/tolbutamide administration on these three parameters was greater than the effect of either treatment alone. In contrast, these treatments either had no significant effect or decreased levels of IRGT protein and mRNA. We conclude that chronic treatment of 3T3-L1 adipocytes with insulin or tolbutamide increases glucose uptake primarily by means of a selective increase in the expression of the HepG2-GT. We suggest that part of the in vivo hypoglycemic effect of insulin and sulfonylureas may involve an increased expression of the HepG2-GT.

Failure of nocturnal hypoglycemia to cause fasting hyperglycemia in patients with insulin-dependent diabetes mellitus.

To test the hypothesis that nocturnal hypoglycemia causes fasting hyperglycemia (the Somogyi phenomenon) in patients with insulin-dependent diabetes mellitus, we studied 10 patients, who were on their usual therapeutic regimens, from 10 p.m. through 8 a.m. on three nights. On the first night, only a control procedure was performed (blood sampling only); on the second night, hypoglycemia was prevented (by intravenous glucose infusion, if necessary, to keep plasma glucose levels above 100 mg per deciliter [5.6 mmol per liter]); and on the third night, hypoglycemia was induced (by stepped intravenous insulin infusions between midnight and 4 a.m. to keep plasma glucose levels below 50 mg per deciliter [2.8 mmol per liter]). After nocturnal hypoglycemia was induced (36 +/- 2 mg per deciliter [2.0 +/- 0.1 mmol per liter] [mean +/- SE] from 2 to 4:30 a.m.), 8 a.m. plasma glucose concentrations (113 +/- 18 mg per deciliter [6.3 +/- 1.0 mmol per liter]) were not higher than values obtained after hypoglycemia was prevented (182 +/- 14 mg per deciliter [10.1 +/- 0.8 mmol per liter]) or those obtained after blood sampling only (149 +/- 20 mg per deciliter [8.3 +/- 1.1 mmol per liter]). Indeed, regression analysis of data obtained on the control night indicated that the 8 a.m. plasma glucose concentration was directly related to the nocturnal glucose nadir (r = 0.761, P = 0.011). None of the patients was awakened by hypoglycemia. Scores for symptoms of hypoglycemia, which were determined at 8 a.m., did not differ significantly among the three studies. We conclude that asymptomatic nocturnal hypoglycemia does not appear to cause clinically important fasting hyperglycemia in patients with insulin-dependent diabetes mellitus on their usual therapeutic regimens.