Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.

Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus.

Background: According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM).

Transport within the interstitial space, rather than membrane permeability, determines norepinephrine recovery in microdialysis.

Microdialysis is a sampling method that permits measurement of hormones, drugs, and other lower molecular weight compounds present in interstitial fluid. We developed a straightforward mathematical model that predicts a linear relationship between the reciprocal dialysate concentration of the analyte from the interstitium and perfusion rate, permitting estimation of the interstitial concentration by extrapolation to zero perfusion rate. Conversely, linearity between the reciprocal dialysate concentration of internal standard added to the perfusion medium (retrodialysis), and the reciprocal perfusion rate, is predicted.

Thiazolidinedione derivatives in type 2 diabetes mellitus.

In Europe, the thiazolidinedione derivatives pioglitazone and rosiglitazone have been approved for the treatment of type 2 diabetes mellitus either as monotherapy for patients with intolerance or contraindications to metformin or in combination therapy. This class of drugs seems particularly suited for obese patients, but is currently not considered as a first choice for monotherapy. The efficacy with respect to blood glucose lowering is comparable with sulphonylurea (SU) derivatives and with metformin.

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia.

Student evaluation of a problem-oriented module of clinical medicine within a revised dental curriculum.

As part of a revised dental curriculum, a 3(rd) year module on medical subjects was developed based on a mixture of self-study and problem-oriented approach using cases. Pairs of students had to select a specific medical problem and solve a paper patient case using a problem-solving cycle. Results were presented in working groups and by writing an essay.

Sympathetic nervous system function in HIV-associated adipose redistribution syndrome.

It was recently suggested that HIV-associated adipose redistribution syndrome (HARS) results from an autonomic dysbalance. We investigated the local and global sympathetic nervous system function of patients with HIV-1 infection and HARS. Interstitial noradrenaline concentrations in skeletal muscle and subcutaneous adipose tissue were increased in the absence of changes in global sympathetic nerve activity, consistent with locally increased sympathetic activity.

Fluid retention and vascular effects of rosiglitazone in obese, insulin-resistant, nondiabetic subjects.

Objective: The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.

Effects of pioglitazone in familial combined hyperlipidaemia.

Objectives: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function.

Design: Double blind, randomized, cross-over study.

Energy and fibre intake in a group of captive giraffe (Giraffa camelopardalis) offered increasing amounts of browse.

We investigated the effect of diet on intake of energy and fibre in a group of three captive adult giraffe by weighing offered diet items and leftovers for 7 days after an adaptation period of 7 days. Digestion coefficients were calculated using, as internal marker, the acid detergent lignin content of a faecal sample pooled from subsamples taken during the last 5 days of intake measurement. Two lucerne hay-only diets of differing quality (L1, L2) were fed, as well as the regular diet of lucerne hay and concentrates (L2C), and the regular diet supplemented with 3 or 6 kg of edible, fresh browse material (L2CB3, L2CB6).

Effects of rosuvastatin on endothelial function in patients with familial combined hyperlipidaemia (FCH).

Objective: Although several studies have reported a positive effect of statins on endothelial vasoreactivity, most studies performed in subjects with type 2 diabetes mellitus report no effect at all. This lack of effect may be related to the existence of insulin resistance, or to insufficient lowering of atherogenic (apo)lipoproteins. Therefore, we tested in this study whether treatment of insulin resistant familial combined hyperlipidaemia (FCH) patients with a high dose (40 mg/day) of the potent rosuvastatin was able to improve endothelial function, without necessarily improving insulin sensitivity.

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.

Background: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity.

Methods: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks.

Anti-inflammatory effects of troglitazone in nondiabetic obese subjects independent of changes in insulin sensitivity.

Background: Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers. We investigated whether, in the absence of changes in glucose, thiazolidinediones (TZDs) have anti-inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers.

Methods: We performed a randomised double-blind placebo-controlled crossover study with troglitazone (400 mg daily for eight weeks) in 15 normoglycaemic obese subjects.

Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation.

Activation of the sympathetic nervous system inhibits insulin-stimulated glucose uptake. However, the underlying mechanisms are incompletely understood. Therefore, we studied the effects of catecholamines on insulin-stimulated glucose uptake and insulin-stimulated translocation of GLUT4 to the plasma membrane in 3T3-L1 adipocytes.

Glycogen synthesis in human gastrocnemius muscle is not representative of whole-body muscle glycogen synthesis.

The introduction of 13C magnetic resonance spectroscopy (MRS) has enabled noninvasive measurement of muscle glycogen synthesis in humans. Conclusions based on measurements by the MRS technique assume that glucose metabolism in gastrocnemius muscle is representative for all skeletal muscles and thus can be extrapolated to whole-body muscle glucose metabolism. An alternative method to assess whole-body muscle glycogen synthesis is the use of [3-(3)H]glucose.

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

Aims/hypothesis: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection.

Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans.

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.

A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy.

Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660), and the PPARG form is called FPLD3 (MIM 604367). We now report a 21-yr-old female with FPLD and no coding sequence mutations in either LMNA or PPARG.

Role of hexosamines in insulin resistance and nutrient sensing in human adipose and muscle tissue.

It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations.

Compared to glibenclamide, repaglinide treatment results in a more rapid fall in glucose level and beta-cell secretion after glucose stimulation.

Background: The more rapid onset of action and the shorter half-life of repaglinide may reduce the post-load glucose excursion and limit sustained insulin secretion compared to sulphonylurea (SU) derivatives.

Methods: We studied 12 patients with type 2 diabetes (age 62 +/- 2 years, BMI 28.3 +/- 1.

Regulation of GLUT1-mediated glucose uptake by PKClambda-PKCbeta(II) interactions in 3T3-L1 adipocytes.

Members of the PKC (protein kinase C) superfamily play key regulatory roles in glucose transport. How the different PKC isotypes are involved in the regulation of glucose transport is still poorly defined. PMA is a potent activator of conventional and novel PKCs and PMA increases the rate of glucose uptake in many different cell systems.

Plasma metanephrine levels are decreased in type 1 diabetic patients with a severely impaired epinephrine response to hypoglycemia, indicating reduced adrenomedullary stores of epinephrine.

A defective epinephrine response to hypoglycemia is a common disorder in type 1 diabetes. We assessed the role of the adrenomedullary capacity to secrete epinephrine in this disorder by measuring plasma metanephrine levels in affected type 1 diabetic patients compared with those in matched nondiabetic controls. Metanephrine is formed from epinephrine that leaks from adrenomedullary storage vesicles by catechol-O-methyl transferase (COMT) and is continuously released into the circulation.

Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment.

Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations.

F-18-fluorodeoxyglucose positron emission tomography leading to a diagnosis of septic thrombophlebitis of the portal vein: description of a case history and review of the literature.

Pylephlebitis or septic thrombophlebitis of the portal vein is a serious infectious disorder. Early diagnosis is difficult, due to nonspecific symptoms and signs, limitations of diagnostic modalities and the lack of familiarity of physicians with this entity. We report the history of a 73-year-old man with fever of unknown origin (FUO) in whom laboratory tests, blood and urine cultures, chest X-ray, abdominal ultrasound, and Indium-111-leucocyte scintigraphy did not reveal the cause of the fever.