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A deficient brain serotonin function has been demonstrated in psychiatric disorders and increases in brain serotonin ameliorate emotional and behavioural abnormalities found in depression. The uptake of the serotonin precursor tryptophan into the brain is dependent on nutrients that influence the cerebral availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp/LNAA). In the present study, we investigated the time- and dose dependent effects of α-lactalbumin enriched whey protein with a high tryptophan content in combination with two doses of glucose on plasma Trp/LNAA. Twelve healthy subjects participated in a double-blind cross-over study and ingested 200 ml orange juice added with glucose alone or mixed with either 5, 10, and 20 g α-lactalbumin or 20 g α-lactalbumin hydrolysate. One half of the subjects received the orange juice with 25 g glucose, whereas the other half of the subjects received the juice with 50 g glucose. Results revealed a relationship between α-lactalbumin dosage and increases in plasma Trp/LNAA [P < 0.001]. Different doses interacted with time-dependent changes in plasma Trp/LNAA [P < 0.0001] such that the most prolonged increase was found with 20 g α-lactalbumin [P < 0.0001]. Changes in plasma Trp/LNAA were not affected by glucose dose. Since increases in plasma Trp/LNAA are indicative of increased serotonin concentrations in the brain, this study shows that ingestion of 20 g α-lactalbumin may be a suitable dietary method to investigate the effect of alterations in brain serotonin.

Initiation of therapy in a life-long disease such as insulin-dependent (type I) diabetes mellitus (IDDM) represents a dramatic event for the child and his family. Epidemiologic surveys in the Netherlands over the past 15 years show a marked increase in the incidence of IDDM among children 0 to 19 years of age, contrasting with a reduction by more than 50% in all admission days for IDDM between 1980 and 1991. This reflects improved initial diagnosis by primary care physicians and improved self management by their families at home. Accordingly, out-patient initial management has been increasing. Given appropiate facilities, there is room for extension of non-admission for these children. The conditions for doing so are outlined in this article.

Insulin is an important regulator of hepatic carbohydrate, lipid, and protein metabolism, and the regulation of these processes by insulin is disturbed under conditions of insulin resistance and type 2 diabetes. Despite these alterations, the impact of insulin resistance on insulin signalling in the liver is not well defined. Variations in time and dose of insulin stimulation as well as plasma glucose levels may underlie this. The present study aimed at determining the dynamics of activation of hepatic insulin signalling in vivo at insulin concentrations resembling those achieved after a meal, and addressing the effects of high-fat feeding. An unexpected finding of this study was the biphasic activation pattern of the IRS-PI3K-PKB/Akt pathway. Our findings indicate that the first burst of activation contributes to regulation of glucose metabolism. The physiological function of the second peak is still unknown, but may involve regulation of protein synthesis. Finally, high-fat feeding caused hepatic insulin resistance, as illustrated by a reduced suppression of hepatic glucose production. A sustained increased phosphorylation of the serine/threonine kinases p70S6kinase and Jun N-terminal kinase in the absence of insulin may underlie the abrogated phosphorylation of the IRS proteins and their downstream targets.

This study examined postprandial plasma insulin and glucose responses after co-ingestion of an insulinotropic protein (Pro) hydrolysate with and without additional free leucine with a single bolus of carbohydrate (Cho). Male patients with long-standing Type 2 diabetes (n = 10) and healthy controls (n = 10) participated in 3 trials in which plasma glucose, insulin, and amino acid responses were determined after the ingestion of beverages of different composition (Cho: 0.7 g/kg carbohydrate, Cho+Pro: 0.7 g/kg carbohydrate with 0.3 g/kg protein hydrolysate, or Cho+Pro+Leu: 0.7 g/kg carbohydrate, 0.3 g/kg protein hydrolysate and 0.1 g/kg free leucine). Plasma insulin responses [expressed as area under the curve (AUC)] were 141 and 204% greater in patients with Type 2 diabetes and 66 and 221% greater in the controls in the Cho+Pro and Cho+Pro+Leu trials, respectively, compared with those in the Cho trial (P < 0.05). The concomitant plasma glucose responses were 15 and 12% lower in the patients with Type 2 diabetes and 92 and 97% lower in the control group in the Cho+Pro and Cho+Pro+Leu trials, respectively, compared with those in the Cho trial (P < 0.05). Plasma leucine concentrations correlated with the insulin response in all subjects (r = 0.43, P < 0.001). We conclude that co-ingestion of a protein hydrolysate with or without additional free leucine strongly augments the insulin response after ingestion of a single bolus of carbohydrate, thereby significantly reducing postprandial blood glucose excursions in patients with long-standing Type 2 diabetes. © 2006 American Society for Nutrition.

Previous studies have shown that energy restriction (ER) or low-fat (LF) diets have beneficial effects on high-fat (HF) diet-induced obesity and non-insulin-dependent diabetes. However, comparison between ER and low-fat diet regarding the effect on insulin resistance and lipid metabolism has not been reported. After inducing insulin resistance by HF feeding for 20 weeks, male C57BL/6J mice were divided into 3 groups. For a period of 12 weeks, group 1 received energy restriction (70% of ad libitum, HF diet), group 2 LF diet, and group 3 maintained on HF diet. Body weight and energy intake were reduced equally in ER and LF feeding. Plasma insulin levels were decreased on LF feeding, but were unchanged on ER, when compared with HF feeding. Glucose tolerance and insulin sensitivity tests revealed that insulin sensitivity was improved more efficiently by LF feeding than on ER. Plasma triglyceride (TG) levels were lower on LF feeding compared with ER and HF feeding. Measurement of hepatic very-low-density lipoprotein (VLDL)-TG production revealed a lower production after LF diet feeding or ER compared with HF diet feeding. In summary, our data show that LF diet has a higher potential than ER to improve HF diet-induced insulin resistance, and that there is an association between improvement of insulin resistance and decrease of TG levels. Copyright 2002, Elsevier Science (USA). All rights reserved.

Obesity is associated with insulin resistance, disturbed glucose homeostasis, low grade inflammation, and comorbidities such as type 2 diabetes and cardiovascular disease. The cytokine macrophage migration inhibitory factor (MIF) is an ubiquitously expressed protein that plays a crucial role in many inflammatory and autoimmune disorders. Increasing evidence suggests that MIF also controls metabolic and inflammatory processes underlying the development of metabolic pathologies associated with obesity. This is a comprehensive summary of our current knowledge on the role of MIF in obesity and obesity-associated comorbidities, based on human clinical data as well as animal models of disease.

Light to moderate alcohol consumption is associated with a reduced risk for cardiovascular diseases. Epidemiologic studies, like our analysis of the European Prospective Investigation into Cancer and Nutrition study, suggest that moderate alcohol consumption is also associated with a reduced risk of type 2 diabetes, reported for various populations. This risk reduction may be explained by an increase in insulin sensitivity after moderate alcohol consumption. Indeed, a positive association between alcohol consumption and insulin sensitivity is consistently reported in cross-sectional studies. Mechanisms for the effect of alcohol on insulin sensitivity may include modulation of changes in the endocrine functioning of fat tissue, modulation of the inflammatory status of several organs, and/or modulation of glucose and fatty acid metabolism. © 2007 Elsevier Inc. All rights reserved.

Insulin resistance is a characteristic of type-2 diabetes and its development is associated with an increased fat consumption. Muscle is one of the tissues that becomes insulin resistant after high fat (HF) feeding. The aim of the present study is to identify processes involved in the development of HF-induced insulin resistance in muscle of ApOE3*Leiden mice by using microarrays. These mice are known to become insulin resistant on a HF diet. Differential gene expression was measured in muscle using the Affymetrix mouse plus 2.0 array. To get more insight in the processes, affected pathway analysis was performed with a new tool, PathVisio. PathVisio is a pathway editor customized with plug-ins (1) to visualize microarray data on pathways and (2) to perform statistical analysis to select pathways of interest. The present study demonstrated that with pathway analysis, using PathVisio, a large variety of processes can be investigated. The significantly regulated genes in muscle of ApOE3*Leiden mice after 12 weeks of HF feeding were involved in several biological pathways including fatty acid beta oxidation, fatty acid biosynthesis, insulin signaling, oxidative stress and inflammation. © 2008 The Author(s).

Background: Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity.Objective:To study the effect of dietary supplementation with PS on cholesterol and glucose metabolism in humans. Methods: Twelve men with the metabolic syndrome (MetS) (according to the International Diabetes Federation (IDF) criteria; age 512 years (means.e.m.); body mass index (BMI) 321 kg/m 2) were randomly assigned to 4 weeks of PS (500 mg twice daily) and 4 weeks of placebo (P) in a double-blind cross-over study, with a 4-week wash-out period between both interventions. At the end of each intervention anthropometric measures and serum lipids were measured and an intravenous glucose tolerance test (IVGTT) was performed. Results: Phytosphingosine did not affect body weight and fat mass compared with P. PS decreased serum total cholesterol (5.10.3 (PS) vs 5.40.3 (P) mmol/l; P0.05) and low-density lipoprotein (LDL)-cholesterol levels (3.10.3 (PS) vs 3.40.3 (P) mmol/l; P0.05), whereas it did not alter serum triglyceride and high-density lipoprotein (HDL)-cholesterol levels. In addition, PS lowered fasting plasma glucose levels (6.20.3 (PS) vs 6.50.3 (P) mmol/l; P0.05). PS increased the glucose disappearance rate (K-value) by 9.9% during the IVGTT (0.910.06 (PS) vs 0.820.05 (P) %/min; P0.05) at similar insulin levels, compared with P, thus implying enhanced insulin sensitivity. PS induced only minor gastrointestinal side effects. Conclusion: Dietary supplementation of PS decreases plasma cholesterol levels and enhances insulin sensitivity in men with the MetS. © 2010 Macmillan Publishers Limited All rights reserved.

To optimize the postexercise insulin response and to increase plasma amino acid availability, we studied postexercise insulin levels after the ingestion of carbohydrate and wheat protein hydrolysate with and without free leucine and phenylalanine. After an overnight fast, eight male cyclists visited our laboratory on five occasions, during which a control drink and two different beverage compositions in two different doses were tested. After they performed a glycogen-depletion protocol, subjects received a beverage (3.5 mL · kg-1) every 30 min to ensure an intake of 1.2 g · kg-1 · h-1 carbohydrate and 0, 0.2 or 0.4 g · kg-1 · h-1 protein hydrolysate (and amino acid) mixture. After the insulin response was expressed as the area under the curve, only the ingestion of the beverages containing wheat protein hydrolysate, leucine and phenylalanine resulted in a marked increase in insulin response (+52 and + 107% for the 0.2 and 0.4 g · kg-1 · h-1 mixtures, respectively; P < 0.05) compared with the carbohydrate-only trial). A dose-related effect existed because doubling the dose (0.2-0.4 g · kg-1 · h-1) led to an additional rise in insulin response (P < 0.05). Plasma leucine, phenylalanine and tyrosine concentrations showed strong correlations with the insulin response (P < 0.0001). This study provides a practical tool to markedly elevate insulin levels and plasma amino acid availability through dietary manipulation, which may be of great value in clinical nutrition, (recovery) sports drinks and metabolic research. Chemicals/CAS: Amino Acids; Blood Glucose; Dietary Carbohydrates; Dietary Proteins; Insulin, 11061-68-0; Leucine, 61-90-5; Phenylalanine, 63-91-2; Protein Hydrolysates; Tyrosine, 55520-40-6

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57Bl/6 mice. By extrapolation, we estimated that half-maximal inhibition of hepatic glucose output and hepatic VLDL-TG production by insulin were obtained at plasma insulin levels of ∼3.6 and ∼6.8 ng/ml, respectively. In the same experiments, we measured that half-maximal decrease of plasma free fatty acid levels and half-maximal stimulation of peripheral glucose uptake were reached at plasma insulin levels of ∼3.0 and ∼6.0 ng/ml, respectively. We conclude that, compared with insulin sensitivity of hepatic glucose output, peripheral glucose uptake and hepatic VLDL-TG production are less sensitive to insulin. Copyright © 2006 the American Physiological Society. Chemicals / CAS: insulin, 9004-10-8; Blood Glucose; Fatty Acids, Nonesterified; Glucose, 50-99-7; Hypoglycemic Agents; Insulin, 11061-68-0; Lipoproteins, VLDL; Triglycerides

OBJECTIVE - Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sensitivity. Moderate alcohol consumption may increase adiponectin, which in turn causes a decrease of tumor necrosis factor (TNF)-α. A decreased TNF-α level may consequently increase insulin sensitivity. RESEARCH DESIGN AND METHODS - To test this hypothesis, we performed a randomized crossover partially diet-controlled study. A total of 23 healthy middle-aged male subjects consumed daily four glasses of whisky (40 g ethanol) or tap water with dinner during two successive periods of 17 days. RESULTS - Moderate alcohol consumption increased plasma adiponectin level (11%; P = 0.002) but did not affect plasma TNF-α level. An increase in insulin sensitivity index was observed in an insulin-resistant subgroup (21%; P = 0.11), which positively correlated with the relative alcohol-induced increase in plasma adiponectin level (r = 0.73, P = 0.02). CONCLUSIONS - The experimental results are in agreement with observational data. Moderate alcohol consumption improved insulin sensitivity in relatively insulin-resistant middle-aged men, an effect that may be mediated through alcohol-induced increases in adiponectin.

Postprandial high glucose and insulin responses after starchy food consumption, associated with an increased risk of developing several metabolic diseases, could possibly be improved by altering food structure. We investigated the influence of a compact food structure; different wheat products with a similar composition were created using different processing conditions. The postprandial glucose kinetics and metabolic response to bread with a compact structure (flat bread, FB) was compared to bread with a porous structure (control bread, CB) in a randomized, crossover study with ten healthy male volunteers. Pasta (PA), with a very compact structure, was used as the control. The rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR) was calculated using stable isotopes. Furthermore, postprandial plasma concentrations of glucose, insulin, several intestinal hormones and bile acids were analyzed. The structure of FB was considerably more compact compared to CB, as confirmed by microscopy, XRT analysis (porosity) and density measurements. Consumption of FB resulted in lower peak glucose, insulin and glucose-dependent insulinotropic polypeptide (ns) responses and a slower initial RaE compared to CB. These variables were similar to the PA response, except for RaE which remained slower over a longer period after PA consumption. Interestingly, the GCR after FB was higher than expected based on the insulin response, indicating increased insulin sensitivity or insulin-independent glucose disposal. These results demonstrate that the structure of wheat bread can influence the postprandial metabolic response, with a more compact structure being more beneficial for health. Bread-making technology should be further explored to create healthier products.

Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance syndrome. We analyzed this association in young, nonobese transsexual men and women before and after administration of cross-sex steroids, which potentially influence many elements of the insulin resistance syndrome, including PAI-1 levels and visceral fat accumulation. We assessed the visceral fat area (by MRI); total body fat; insulin sensitivity (with a glucose clamp technique); and plasma levels of PAI-l, insulin, and triglycerides in young (<37 years old), nonobese (body mass index <28 kg/m2), healthy men (n= 18) and women (n= 15) before and after 12 months of cross-sex hormone administration. Men were treated with ethinyl estradiol 100 μg/d plus cyproterone acetate 100 mg/d, and women were treated with testosterone esters 250 mg IM every 2 weeks. At baseline, only visceral fat area was significantly correlated with plasma PAI-1 levels in both men (r=0.57, P=0.03) and women (r=0.59, P=0.03). In multivariate linear regression analysis, this association was independent of total body fat, insulin sensitivity, and plasma levels of triglycerides and insulin. After 12 months of cross-sex hormone administration, the plasma PAI-1 levels were no longer correlated with visceral fat (which had increased). We conclude that in young, nonobese men and women, visceral fat area is an important determinant of plasma PAI-1 levels. After cross-sex hormone administration, this association was no longer demonstrable.

The incidence of childhood diabetes (0-19 years of age) in The Netherlands, where there is no nationalized health-care system, was investigated retrospectively in the years 1978 to 1980 inclusive. The method chosen was a questionnaire among all Dutch paediatricians and internal physicians acting as consultants. Ascertainment was by the same questionnaire held separately among the large Dutch membership of the Dutch Diabetes Association, employing the capture-recapture census method for calculation. For paediatricians the ascertainment was 94%, for specialists in internal medicine 75%. Before correction for ascertainment 1271 children were registered in the two surveys. The ascertainment-corrected annual incidence was 10.95/100,000 for 0-19-year-old children, lower than in any other ascertained survey in north-western Europe published so far. The male:female ratio was the same as in other studies and no local geographical differences were found. Seasonal variation was absent in children 0-10 years old in the month the first insulin injection was administered. The data support the influence of unknown exogenous factors associated with the clinical onset of childhood diabetes.

Chemicals/CAS: Autoantibodies; islet cell antibody; Mumps Vaccine

Raised plasma lipoprotein(a) (lp(a)) concentrations have been reported in patients with Type I (insulin-dependent) diabetes mellitus, which were lowered by insulin therapy. To investigate the biochemical background of these changes, we studied the effect of insulin on apolipoprotein(a) (apo(a)) synthesis and mRNA levels in primary cultures of cynomolgus monkey hepatocytes. Low concentrations of insulin (10 nmol/l) had a small but significant decreasing effect (p < 0.046) on apolipoprotein(a) secretion (- 16%). Maximum inhibition (-33%) was obtained after incubation for 72 h with 1000 nmol/l insulin. Apolipoprotein B-100 secretion was 30%-36% decreased when using 10-1000 nmol/l and no change was observed for the secretion of apolipoprotein A-1 and albumin which were measured as control proteins. Steady state apolipoprotein(a) mRNA concentrations paralleled the decrease in apolipoprotein(a) synthesis (-29% after incubating the cells for 48 h with 100 nmol/l insulin) indicating that the decreased synthesis is regulated at the (post)-transcriptional level. Concentrations of apolipoprotein B-100 and apolipoprotein A-1 mRNA were not changed after incubation with insulin. We conclude that high concentrations of insulin suppress apolipoprotein(a) synthesis in monkey hepatocytes at the (post)-transcriptional level. These data may provide an explanation for the increased plasma concentrations of lipoprotein(a) as found in patients with insulin dependent diabetes mellitus. Chemicals/CAS: Apolipoprotein B-100; Apolipoproteins B; Apolipoproteins; Apoprotein(a), EC 3.4.21.-; Insulin, 11061-68-0; Lipoprotein(a); RNA, Messenger

OBJECTIVE - A nationwide retrospective study was conducted to assess the incidence of type 1 diabetes in The Netherlands among children <20 years of age in 1988-1990. The first study with a similar design covered 1978-1980. RESEARCH DESIGN AND METHODS - The capture-recapture census method was chosen for analysis of the data. A questionnaire was sent to all Dutch pediatricians and internists, and for the ascertainment, a similar questionnaire was sent out separately to members of the Dutch Diabetes Association, which is the national patient association. RESULTS - The average achieved ascertainment rate was 81%. The ascertainment-adjusted annual incidence was 13.2/100,000 for 0- to 19-year-old children, indicating an increase of 23% compared with the 1978-1980 survey; for 0- to 14-year-olds, the increase amounted to 17%. CONCLUSIONS - This study suggests a sustained increase of type 1 diabetes in The Netherlands because the cumulative incidence studied previously in the 1960-1970 birth cohorts of male army conscripts 18 years of age was also found to rise. In contrast to Northern European countries, an increase in incidence for the age category 0-4 years could not be found.