Adipocytokines, hepatic and inflammatory biomarkers and incidence of type 2 diabetes. the CoLaus study

Context There is contradictory information regarding the prognostic importance of adipocytokines, hepatic and inflammatory biomarkers on the incidence of type 2 diabetes. The objective was to assess the prognostic relevance of adipocytokine and inflammatory markers (C-reactive protein – CRP; interleukin-1beta – IL-1β; interleukin-6– IL-6; tumour necrosis factor-α – TNF-α; leptin and adiponectin) and gamma-glutamyl transpeptidase (γGT) on the incidence of type 2 diabetes. Methods Prospective, population-based study including 3,842 non-diabetic participants (43.3% men, age range 35 to 75 years), followed for an average of 5.5 years (2003–2008). The endpoint was the occurrence of type 2 diabetes. Results 208 participants (5.4%, 66 women) developed type 2 diabetes during follow-up. On univariate analysis, participants who developed type 2 diabetes had significantly higher baseline levels of IL-6, CRP, leptin and γGT, and lower levels of adiponectin than participants who remained free of type 2 diabetes. After adjusting for a validated type 2 diabetes risk score, only the associations with adiponectin: Odds Ratio and (95% confidence interval): 0.97 (0.64–1.47), 0.84 (0.55–1.30) and 0.64 (0.40–1.03) for the second, third and forth gender-specific quartiles respectively, remained significant (P-value for trend = 0.05). Adding each marker to a validated type 2 diabetes risk score (including age, family history of type 2 diabetes, height, waist circumference, resting heart rate, presence of hypertension, HDL cholesterol, triglycerides, fasting glucose and serum uric acid) did not improve the area under the ROC or the net reclassification index; similar findings were obtained when the markers were combined, when the markers were used as continuous (log-transformed) variables or when gender-specific quartiles were used. Conclusion Decreased adiponectin levels are associated with an increased risk for incident type 2 diabetes, but they seem to add little information regarding the risk of developing type 2 diabetes to a validated risk score.

Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia

Circumstantial evidence suggests that an increase in plasma glucose availability improves exercise capacity in subjects with type 1 diabetes mellitus. The aim of this study was to assess exercise capacity in eu- and hyperglycaemic conditions in subjects with type 1 diabetes.

Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes

The H(+) -coupled divalent metal-ion transporter DMT1 serves as both the primary entry point for iron into the body (intestinal brush-border uptake) and the route by which transferrin-associated iron is mobilized from endosomes to cytosol in erythroid precursors and other cells. Elucidating the molecular mechanisms of DMT1 will therefore increase our understanding of iron metabolism and the etiology of iron overload disorders. We expressed wild type and mutant DMT1 in Xenopus oocytes and monitored metal-ion uptake, currents and intracellular pH. DMT1 was activated in the presence of an inwardly directed H(+) electrochemical gradient. At low extracellular pH (pH(o)), H(+) binding preceded binding of Fe(2+) and its simultaneous translocation. However, DMT1 did not behave like a typical ion-coupled transporter at higher pH(o), and at pH(o) 7.4 we observed Fe(2+) transport that was not associated with H(+) influx. His(272) --> Ala substitution uncoupled the Fe(2+) and H(+) fluxes. At low pH(o), H272A mediated H(+) uniport that was inhibited by Fe(2+). Meanwhile H272A-mediated Fe(2+) transport was independent of pH(o). Our data indicate (i) that H(+) coupling in DMT1 serves to increase affinity for Fe(2+) and provide a thermodynamic driving force for Fe(2+) transport and (ii) that His-272 is critical in transducing the effects of H(+) coupling. Notably, our data also indicate that DMT1 can mediate facilitative Fe(2+) transport in the absence of a H(+) gradient. Since plasma membrane expression of DMT1 is upregulated in liver of hemochromatosis patients, this H(+) -uncoupled facilitative Fe(2+) transport via DMT1 can account for the uptake of nontransferrin-bound plasma iron characteristic of iron overload disorders.

Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study

Postprandial metabolism is impaired in patients with type 2 diabetes (T2Dm). Two thiazolidinediones pioglitazone (PGZ) and rosiglitazone (RGZ) have similar effects on glycaemic control but differ in their effects on fasting lipids. This study investigated the effects of RGZ and PGZ on postprandial metabolism in a prospective, randomized crossover trial.

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

AIMS/HYPOTHESIS: Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. METHODS: Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. RESULTS: RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA(1c) in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol. CONCLUSIONS/INTERPRETATION: RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.

Fetal haemoglobin levels in adult type 1 (insulin-dependent) diabetic patients

Glycated haemoglobin levels (HbA1 and HbA1c) are established parameters of long-term glycaemic control in diabetic patients. Depending on the method used, fetal haemoglobin interferes with the assays for glycated haemoglobin. If present in high amounts, fetal haemoglobin may lead to overestimation of glycated haemoglobin levels, and therefore, of average blood glucose concentration in diabetic patients. Glycated (HbA1c) and fetal haemoglobin levels were measured by high pressure liquid chromatography in 60 (30 female) adult Type 1 (insulin-dependent) diabetic patients of Swiss descent, and were compared with levels obtained from 60 normal, non-diabetic control subjects matched for age and sex. Fetal haemoglobin levels were significantly higher in the diabetic patients (0.6 +/- 0.1%, mean +/- SEM; range: 0-3.6%) than in the control subjects (0.4 +/- 0.1%, p < 0.001). Elevated fetal haemoglobin levels (> or = 0.6%) were found in 23 of 60 diabetic patients (38%) compared to 9 of 60 control subjects (15%; chi 2 = 8.35, p < 0.01). In addition, fetal haemoglobin levels in diabetic patients are weakly correlated with glycated haemoglobin (HbA1c) (r = 0.38, p < 0.01). Fetal haemoglobin results were confirmed with the alkali denaturation procedure, and by immunocytochemistry using a polyclonal rabbit anti-fetal haemoglobin antibody. A significant proportion of adult patients with Type 1 diabetes has elevated fetal haemoglobin levels. In certain patients this may lead to a substantial over-estimation of glycated haemoglobin levels, and consequently of estimated, average blood glucose levels. The reason for this increased prevalence of elevated fetal haemoglobin remains unclear, but it may be associated with poor glycaemic control.

Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients

To evaluate the metabolic consequences of pancreas transplantation with systemic venous drainage on beta-cell function, we examined insulin and C-peptide responses to glucose and arginine in type I (insulin-dependent) diabetic pancreas recipients (n = 30), nondiabetic kidney recipients (n = 8), and nondiabetic control subjects (n = 28). Basal insulin levels were 66 +/- 5 pM in control subjects, 204 +/- 18 pM in pancreas recipients (P less than 0.0001 vs. control), and 77 +/- 17 pM in kidney recipients. Acute insulin responses to glucose were 416 +/- 44 pM in control subjects, 763 +/- 91 pM in pancreas recipients (P less than 0.01 vs. control), and 589 +/- 113 pM in kidney recipients (NS vs. control). Basal and stimulated insulin levels in two pancreas recipients with portal venous drainage were normal. Integrated acute C-peptide responses were not statistically different (25.3 +/- 4.3 nM/min in pancreas recipients, 34.2 +/- 5.5 nM/min in kidney recipients, and 23.7 +/- 2.1 nM/min in control subjects). Similar insulin and C-peptide results were obtained with arginine stimulation, and both basal and glucose-stimulated insulin-C-peptide ratios in pancreas recipients were significantly greater than in control subjects. We conclude that recipients of pancreas allografts with systemic venous drainage have elevated basal and stimulated insulin levels and that these alterations are primarily due to alterations of first-pass hepatic insulin clearance, although insulin resistance secondary to immunosuppressive therapy (including prednisone) probably plays a contributing role. To avoid hyperinsulinemia and its possible long-term adverse consequences, transplantation of pancreas allografts into sites with portal rather than systemic venous drainage should be considered.

Self-monitoring of blood glucose in non-insulin treated patients with type 2 diabetes: a systematic review and meta-analysis

To assess the effect of self-monitoring of blood glucose (SMBG) on glycaemic control in non-insulin treated patients with type 2 diabetes by means of a systematic review and meta-analysis.

Mucosal maltase-glucoamylase plays a crucial role in starch digestion and prandial glucose homeostasis of mice

Starch is the major source of food glucose and its digestion requires small intestinal alpha-glucosidic activities provided by the 2 soluble amylases and 4 enzymes bound to the mucosal surface of enterocytes. Two of these mucosal activities are associated with sucrase-isomaltase complex, while another 2 are named maltase-glucoamylase (Mgam) in mice. Because the role of Mgam in alpha-glucogenic digestion of starch is not well understood, the Mgam gene was ablated in mice to determine its role in the digestion of diets with a high content of normal corn starch (CS) and resulting glucose homeostasis. Four days of unrestricted ingestion of CS increased intestinal alpha-glucosidic activities in wild-type (WT) mice but did not affect the activities of Mgam-null mice. The blood glucose responses to CS ingestion did not differ between null and WT mice; however, insulinemic responses elicited in WT mice by CS consumption were undetectable in null mice. Studies of the metabolic route followed by glucose derived from intestinal digestion of (13)C-labeled and amylase-predigested algal starch performed by gastric infusion showed that, in null mice, the capacity for starch digestion and its contribution to blood glucose was reduced by 40% compared with WT mice. The reduced alpha-glucogenesis of null mice was most probably compensated for by increased hepatic gluconeogenesis, maintaining prandial glucose concentration and total flux at levels comparable to those of WT mice. In conclusion, mucosal alpha-glucogenic activity of Mgam plays a crucial role in the regulation of prandial glucose homeostasis.

[Role of complementary medicine in type 1 diabetes mellitus in two Swiss centres]

Insulin replacement is the only effective treatment of type 1 Diabetes mellitus (T1DM). Nevertheless, many complementary treatments are in use for T1DM. In this study we assessed by questionnaire that out of 342 patients with T1DM, 48 (14%; 13.4% adult, 18.5% paediatric; 20 male, 28 female) used complementary medicine (CM) in addition to their insulin therapy. The purpose of the use of CM was to improve general well-being, ameliorate glucose homeostasis, reduce blood glucose levels as well as insulin doses, improve physical fitness, reduce the frequency of hypoglycaemia, and control appetite. The modalities most frequently used are cinnamon, homeopathy, magnesium and special beverages (mainly teas). Thus, good collaboration between health care professionals will allow optimal patient care.

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

Neural network based glucose - insulin metabolism models for children with Type 1 diabetes

In this paper two models for the simulation of glucose-insulin metabolism of children with Type 1 diabetes are presented. The models are based on the combined use of Compartmental Models (CMs) and artificial Neural Networks (NNs). Data from children with Type 1 diabetes, stored in a database, have been used as input to the models. The data are taken from four children with Type 1 diabetes and contain information about glucose levels taken from continuous glucose monitoring system, insulin intake and food intake, along with corresponding time. The influences of taken insulin on plasma insulin concentration, as well as the effect of food intake on glucose input into the blood from the gut, are estimated from the CMs. The outputs of CMs, along with previous glucose measurements, are fed to a NN, which provides short-term prediction of glucose values. For comparative reasons two different NN architectures have been tested: a Feed-Forward NN (FFNN) trained with the back-propagation algorithm with adaptive learning rate and momentum, and a Recurrent NN (RNN), trained with the Real Time Recurrent Learning (RTRL) algorithm. The results indicate that the best prediction performance can be achieved by the use of RNN.

A real time simulation model of glucose-insulin metabolism for type 1 diabetes patients

In this paper, a simulation model of glucose-insulin metabolism for Type 1 diabetes patients is presented. The proposed system is based on the combination of Compartmental Models (CMs) and artificial Neural Networks (NNs). This model aims at the development of an accurate system, in order to assist Type 1 diabetes patients to handle their blood glucose profile and recognize dangerous metabolic states. Data from a Type 1 diabetes patient, stored in a database, have been used as input to the hybrid system. The data contain information about measured blood glucose levels, insulin intake, and description of food intake, along with the corresponding time. The data are passed to three separate CMs, which produce estimations about (i) the effect of Short Acting (SA) insulin intake on blood insulin concentration, (ii) the effect of Intermediate Acting (IA) insulin intake on blood insulin concentration, and (iii) the effect of carbohydrate intake on blood glucose absorption from the gut. The outputs of the three CMs are passed to a Recurrent NN (RNN) in order to predict subsequent blood glucose levels. The RNN is trained with the Real Time Recurrent Learning (RTRL) algorithm. The resulted blood glucose predictions are promising for the use of the proposed model for blood glucose level estimation for Type 1 diabetes patients.

Determinants of phosphatidylinositol-4-phosphate 5-kinase type Iγ90 uropod location in T-lymphocytes and its role in uropod formation

We have previously identified phosphatidylinositol-4-phosphate 5-kinase type I (PIPKI)γ90 as a T cell uropod component. However, the molecular determinants and functional consequences of its localization remain unknown. In this report, we seek to better understand the mechanisms involved in PIPKIγ90 uropod targeting and the role that PIPKIγ90 plays in T cell uropod formation. During T cell activation, PIPKIγ90 cocaps with the membrane microdomain-associated proteins flotillin-1 and -2 and accumulates in the uropod. We report that the C-terminal 26 amino acid extension of PIPKIγ90 is required for its localization to the uropod. We further use T cells from PIPKIγ90(-/-) mice and human T cells expressing a kinase-dead PIPKIγ90 mutant to examine the role of PIPKIγ90 in a T cell uropod formation. We find that PIPKIγ90 deficient T cells have elongated uropods on ICAM-1. Moreover, in human T cells overexpression of PIPKIγ87, a naturally occurring isoform lacking the last 26 amino acids, suppresses uropod formation and impairs capping of uropod proteins such as flotillins. Transfection of human T cells with a dominant-negative mutant of flotillin-2 in turn attenuates capping of PIPKIγ90. Our data contribute to the understanding of the molecular mechanisms that regulate T cell uropod formation.