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OBJECTIVE--Adverse effects of hypercaloric, high-fructose diets on insulin sensitivity and lipids in human subjects have been shown repeatedly. The implications of fructose in amounts dose to usual daily consumption, however, [...]

Background: High amounts of dietary fructose may contribute to dyslipidemia in adults, but there are few data in children. Childhood adiposity is associated with smaller LDL particle size, but the dietary predictors of LDL size in overweight children have not been studied. Objectives: We aimed to determine whether LDL particle size is associated with dietary factors and specifically with fructose intake in normal-weight and overweight children. Design: In a cross-sectional study of normal-weight and overweight 6-14 y-old Swiss children (n = 74), dietary intakes were assessed by using two 24-h-recalls and a 1-d dietary record. Body mass index (BMI) and waist-hip ratio (WHR) were measured, and plasma lipid profile and LDL particle size were determined. Results: Compared with the normal-weight group, overweight children had significantly higher plasma triacylglycerol concentrations, lower HDL-cholesterol concentrations, and smaller LDL particle size (P < 0.05). LDL particle size was inversely correlated to BMI SD scores and WHR (P = 0.007). Although there were no significant differences in total fructose intake, the overweight children consumed a significantly (P < 0.05) higher percentage of fructose from sweets and sweetened drinks than did the normal-weight children. After control for adiposity, the only dietary factor that was a significant predictor of LDL particle size was total fructose intake (P = 0.024). Conclusions: In school-age children, greater total and central adiposity are associated with smaller LDL particle size and lower HDL cholesterol. Overweight children consume more fructose from sweets and sweetened drinks than do normal-weight children, and higher fructose intake predicts smaller LDL particle size. KEY WORDS Fructose, children, diet, LDL particle size, overweight

Many factors influence the outcome of islet transplantation. As islets in the early posttransplant setting are supplied with oxygen by diffusion only and are in a hypoxic state in the portal system, we tested whether small human islets are superior to large islets both in vitro and in vivo. We assessed insulin secretion of large and small islets and quantified cell death during hypoxic conditions simulating the intraportal transplant environment. In the clinical setting, we analyzed the influence of transplanted islet size on insulin production in patients with type 1 diabetes. Our results provide evidence that small islets are superior to large islets with regard to in vitro insulin secretion and show a higher survival rate during both normoxic and hypoxic culture. Islet volume after 48 h of hypoxic culture decreased to 25% compared with normoxic culture at 24 h due to a preferential loss of large islets. In human islet transplantation, the isolation index (islet volume as expressed in islet equivalents/islet number), or more simply the islet number, proved to be more reliable to predict stimulated C-peptide response compared with islet volume. Thus, islet size seems to be a key factor determining human islet transplantation outcome., The field of clinical islet transplantation has slowly evolved during the past 3 decades (1). The success achieved with the Edmonton protocol (2,3) established islet transplantation as an alternative to [...]

The Per-ARNT-Sim (PAS) domain serine/threonine kinase PASKIN, or PAS kinase, links energy flux and protein synthesis in yeast and regulates glycogen synthase in mammals. A recent report suggested that PASKIN mRNA, protein, and kinase activity are increased in pancreatic islet β-cells under hyperglycemic conditions and that PASKIN is necessary for insulin gene expression. We previously generated Paskin knockout mice by targeted replacement of the kinase domain with the β-geo fusion gene encoding β-galactosidase reporter activity. Here we show that no 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining was observed in islet β-cells derived from Paskin knockout mice, irrespective of the ambient glucose concentration, whereas adenoviral expression of the lacZ gene in β-cells showed strong X-gal staining. No induction of PASKIN mRNA could be detected in insulinoma cell lines or in islet β-cells. Increasing glucose concentrations resulted in PASKIN-independent induction of insulin mRNA levels and insulin release. PASKIN mRNA levels were high in testes but undetectable in pancreas and in islet β-cells. Finally, blood glucose levels and glucose tolerance after intraperitoneal glucose injection were indistinguishable between Paskin wild-type and knockout mice. These results suggest that Paskin gene expression is not induced by glucose in pancreatic β-cells and that glucose-stimulated insulin production is independent of PASKIN., The Per-ARNT-Sim (PAS) domain proteins often serve as environment sensors, regulating the cellular metabolism and behavior of microorganisms in response to, among others, oxygen or light. In nitrogen-fixing Rhizobium species, [...]

Background: In obese children, subclinical inflammation is often present and is correlated with the metabolic syndrome. Dietary factors, such as fatty acids and antioxidants, potentially modulate the association between adiposity and subclinical inflammation, but few data are available in children. Objective: The aim of the study was to determine whether dietary fat or antioxidant intakes influence circulating tumor necrosis factor [alpha] (TNF-[alpha]), interleukin 6 (IL-6), C-reactive protein (CRP), and leptin concentrations in overweight children. Design: In a cross-sectional study of 6-14-y-old normal-weight (n = 33), overweight (n = 19), and obese (n = 27) Swiss children, nutritional intakes were assessed from two 24-h dietary recalls and a 1-d dietary record. Percentage body fat from skinfold thicknesses, waist-hip ratio, and blood pressure were measured. Fasting blood samples were collected for the measurement of insulin, glucose, HDL-cholesterol, triacylglycerol, CRP, IL-6, TNF-[alpha], and leptin concentrations. Results: CRP, IL-6, and leptin increased significantly (P < 0.02) with increasing adiposity, independent of age; TNF-[alpha] did not increase. Total dietary fat and the percentage of energy from fat were significant predictors of CRP concentration, independent of body mass index (P < 0.05). Meat intake was a significant predictor of IL-6 and leptin, independent of body mass index (P < 0.05). Intakes of antioxidant vitamins (vitamins E and C and [beta]-carotene) were significant predictors of leptin (P < 0.05) but not of CRP, IL-6, or TNF-[alpha]. Conclusions: Overweight Swiss children as young as 6 y have elevated concentrations of inflammatory markers. Intakes of total fat and antioxidant vitamins are determinants of subclinical inflammation in this age group. KEY WORDS Children, obesity, inflammation, diet, C-reactive protein, interleukin 6, leptin, tumor necrosis factor [alpha] fat, antioxidants

OBJECTIVE--To compare the effect of acute psychosocial stress on glucose concentrations in the fasting state and following food intake in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS--In study, [...]

Increasing evidence indicates that a progressive decrease in the functional [beta]-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, [beta]-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1[beta] and/or high-glucose-induced p-cell production of IL-1[beta] Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the [beta]-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1[beta]-induced apoptosis and impaired function in human [beta]-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1[beta], or 10 and 100 [micro]mol/l of the sulfonylurea tolbutamide induced [beta]-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1[beta] were blocked by 200 [micro]mol/l diazoxide as well as by 3 and 30 [micro]mol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1[beta] were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 [micro]mol/l NN414. Similarly, 1 [micro]mol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 [micro]mol/l of the L-type [Ca.sup.2+] channel blocker nimodipine prevented glucose- and IL-1[beta]-induced ERK activation, [beta]-cell apoptosis, and impaired function. Finally, islet release of IL-1[beta] in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1[beta]-induced [beta]-cell secretory dysfunction and apoptosis are [Ca.sup.2+] influx and ERK dependent and can be prevented by the [beta]-cell selective potassium channel opener NN414., There is now general agreement that both impaired [beta]-cell function and decreased [beta]-cell mass contribute to the insulin deficiency observed in patients with type 2 diabetes (1-11). Therefore, in the [...]

Background: Magnesium deficiency has been associated with type 2 diabetes and may reduce insulin sensitivity and impair glucose tolerance. The etiology of magnesium depletion in diabetes is unclear. Animal studies suggest that diabetes may impair magnesium absorption; however, there are no published data on magnesium absorption in humans with diabetes. Objective: Magnesium absorption from a test meal and the excretion and retention of magnesium were compared between patients with type 2 diabetes and healthy control subjects. Design: A meal labeled with 10 mg [.sup.26]Mg isotopic label was administered, and stool and urine samples were collected for 10 and 6 d, respectively. Apparent absorption was calculated as the difference between the oral dose of [.sup.26]Mg isotopic label and the total amount of the isotopic label excreted in the feces. Magnesium retention was calculated from the apparent absorption and urinary excretion of [.sup.26]Mg isotopic label in the 6 d after administration. Results: Mean ([+ or -] SD) values for fractional magnesium absorption in the diabetic patients and the control subjects were 59.3 [+ or -] 7.0% and 57.6 [+ or -] 8.5%, respectively (NS). Mean ([+ or -] SD) urinary magnesium excretion values in the diabetic patients and the control subjects were 11.2 [+ or -] 2.6% and 11.7 [+ or -] 3.8%, respectively (NS); retention values were 54.2 [+ or -] 7.1% and 51.4 [+ or -] 6.1%, respectively (NS). Conclusion: Dietary magnesium absorption and retention are not impaired in patients with reasonably well-controlled type 2 diabetes. KEY WORDS Magnesium, absorption, excretion, retention, diabetes, stable isotopes, fecal monitoring

Glucotoxicity and lipotoxicity contribute to the impaired β-cell function observed in type 2 diabetes. Here we examine the effect of saturated and monounsaturated fatty acids at different glucose concentrations on human β-cell turnover and secretory function. Exposure of cultured human islets to saturated fatty acid and/or to an elevated glucose concentration for 4 days increased β-cell DNA fragmentation and decreased β-cell proliferation. In contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA fragmentation and induced β-cell proliferation. Moreover, each monounsaturated fatty acid prevented the deleterious effects of both palmitic acid and high glucose concentration. The cell-permeable ceramide analogue [C.sub.2]-ceramide mimicked both the palmitic acid-induced β-cell apoptosis and decrease in proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on β-cell turnover. In addition, palmitic acid decreased Bcl-2 expression and induced release of cytochrome c from the mitochondria into the cytosol, which was prevented by fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved β-cell secretory function that was reduced by palmitic acid and by high glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose concentration induce β-cell apoptosis, decrease β-cell proliferation, and impair β-cell function, which can be prevented by monounsaturated fatty acids. The deleterious effect of palmitic acid is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute to the protective effect of monounsaturated fatty acids., Normoglycemia is maintained in the face of insulin resistance until the pancreatic β-cells become unable to produce sufficient quantities of insulin, at which point type 2 diabetes begins. A major [...]

Several studies support the concept of a diabetic cardiomyopathy in the absence of discernible coronary artery disease, although its mechanism remains poorly understood. We investigated the role of glucose and [...]

In autoimmune type 1 diabetes, Fas-to-Fas-ligand (FasL) interaction may represent one of the essential pro-apoptotic pathways leading to a loss of pancreatic β-cells. In the advanced stages of type 2 [...]

Acute endotoxinemia is an infection that results when poisons are released throughout the body as bacteria break down. It causes several effects on the body, including fever, headache, and an increase in the numbers of white blood cells (which fight infection.) These changes are moderated by the action of a number of cytokines (substances released by cells to regulate other cells), including interleukin-1 (IL-1), tumor necrosis factor- (TNF-alpha), and interleukin-6 (IL-6). A number of studies have shown that cytokines can be detected in the blood of patients with acute endotoxinemia, and there appears to be a correlation between the level of cytokines and the severity of infection. The highest levels are found in patients with fatal illness. Twenty men aged 20-42 years were assigned to one of three groups. They were administered either Escherichia coli endotoxin alone, ibuprofen (a non-steroidal anti-inflammatory drug) and then the endotoxin, or saline (a salt and water solution; the control group). It was found that those given ibuprofen had greater cytokine levels in their blood and few or no symptoms of acute endotoxinemia. These results suggest that ibuprofen blunts the clinical response to endotoxin and increases cytokine levels, enabling the body to combat the infection better than it could alone. (Consumer Summary produced by Reliance Medical Information, Inc.)

There is growing evidence that insulin-dependent diabetes mellitus (IDDM) is caused by an immunemediated destruction of the pancreatic Β-cells [1,2]. Recent studies of immunosuppression with cyclosporin in patients and experimental [...]

* We conducted a controlled trial to determine frequency and severity of autonomic neuropathy in patients infected with the human immunodeficiency virus (HIV). We studied 25 HIV-seropositive patients and 10 seronegative controls in HIV risk groups by means of five cardiovascular tests, and autonomic neuropathy was graded with a scoring system. The overall autonomic test score differed between patients and controls and was higher in patients with advanced (Centers for Disease Control class IV) disease than in those with earlier (class 11 or 111) HIV disease. Of the patients, 60% had findings of autonomic dysfunction. Our data demonstrate a high prevalence of autonomic neuropathy in HIV-infected patients. Advanced HIV disease is associated with more severe involvement than earlier disease states. (Arch Intern Med. 1991;151:2441-2443)

MICHAEL BRANDLE [1] ROGER LEHMANN [1] FRIEDRICH E. MALY [2] CHRISTOPH SCHMID [1] GIATGEN A. SPINAS [1] OBJECTIVE -- The effects of glucose, arginine, and glucagon on β-cell function as [...]

OBJECTIVE: The results of the metformin sub-study of the United Kingdom Prospective Diabetes Study (UKPDS) were applied, through modeling techniques, to the USA, UK and Swiss settings, allowing a cost-effectiveness [...]

The aim of this study was to assess the effects of regular moderate physical activity on lipolytic enzymes and plasma lipid concentrations in patients with type 2 diabetes mellitus. Ten [...]

Abstract Objective To evaluate whether measuring fasting plasma glucose concentration is an easier screening procedure for gestational diabetes mellitus than the 1 hour 50 g glucose challenge test. Design Prospective [...]

The pathophysiological mechanisms leading to mitochondrial diabetes are complex and may involve insulin secretion, glucose toxicity, and insulin resistance. Since mitochondrial oxidative phosphorylation plays a major role in glucose induced [...]

Interaction of Β-Cell Activity and IL-1 Concentration and Exposure Time in Isolated Rat Islets of Langerhans This study was designed to test the hypothesis that target-cell activity influences the degree [...]