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Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease mainly characterized by the hepatic accumulation of lipid inducing a deregulation of β-oxidation. Its advanced form is non-alcoholic steatohepatitis (NASH), which, in addition to lipid accumulation, induces hepatocellular damage, oxidative stress and fibrosis that can progress to cirrhosis and to its final stage: hepatocellular carcinoma (HCC). To date, no specific therapeutic treatment exists. The implications of organ crosstalk have been highlighted in many metabolic disorders, such as diabetes, metabolic-associated liver diseases and obesity. Skeletal muscle, in addition to its role as a reservoir and consumer of energy and carbohydrate metabolism, is involved in this inter-organs' communication through different secreted products: myokines, exosomes and enzymes, for example. Interestingly, resistance exercise has been shown to have a beneficial impact on different metabolic pathways, such as lipid oxidation in different organs through their secreted products. In this review, we will mainly focus on myokines and their effects on non-alcoholic fatty liver disease, and their complication: non-alcoholic steatohepatitis and HCC. [ABSTRACT FROM AUTHOR]

Background: The aim was to identify fall predictors in elderly suffering from chronic pain (CP) and to test their applicability among patients with other chronic conditions. Methods: 1,379 non-institutionalized patients aged 65 years and older who were suffering from CP (S.AGE CP sub-cohort) were monitored every 6 months for 1 year. Socio-demographic, clinical and pain data and medication use were assessed at baseline for the association with falls in the following year. Falls were assessed retrospectively at each study visit. Logistic regression analyses were performed to identify fall predictors. The derived model was applied to two additional S.AGE sub-cohorts: atrial fibrillation (AF) ( n = 1,072) and type-2 diabetes mellitus (T2DM) ( n = 983). Results: Four factors predicted falls in the CP sub-cohort: fall history (OR: 4.03, 95 % CI 2.79-5.82), dependency in daily activities (OR: 1.81, 95 % CI 1.27-2.59), age ≥75 (OR: 1.53, 95 % CI 1.04-2.25) and living alone (OR: 1.73, 95 % CI 1.24-2.41) (Area Under the Curve: AUC = 0.71, 95 % CI 0.67-0.75). These factors were relevant in AF (AUC = 0.71, 95 % CI 0.66-0.75) and T2DM (AUC = 0.67, 95 % CI 0.59-0.73) sub-cohorts. Fall predicted probability in CP, AF and T2DM sub-cohorts increased from 7, 7 and 6 % in patients with no risk factors to 59, 66 and 45 % respectively, in those with the four predictors. Fall history was the strongest predictor in the three sub-cohorts. Conclusion: Fall history, dependency in daily activities, age ≥75 and living alone are independent fall predictors in CP, AF and T2DM patients. [ABSTRACT FROM AUTHOR]

Intraperitoneal insulin allows physiological portal insulin administration and first-pass hepatic insulin extraction, but the impact on liver metabolism and inflammation is unknown. Our objective was to compare the impact, on metabolic control and liver function, of the same dose of insulin administered either intraperitoneally or subcutaneously during continuous infusion in diabetic rats. Wistar rats were randomly divided into 4 groups: control (C), untreated diabetic (streptozotocin, 100 mg/kg) and diabetic rats treated by continual subcutaneous Insuplant® infusion ( CSII) and continual intraperitoneal Insuplant® infusion ( CPII) of 2 UI/200 g/day (via an osmotic mini-pump for 1-4 weeks). Insulin signalling pathways were analysed through hepatic expression of growth hormone receptor and phosphorylated insulin receptor substrate 1. Metabolic control was determined by measurement of body weight, blood glucose and fructosamine. Liver function was assessed by measuring insulin-like growth factor-1 ( IGF-1), with global inflammation assessed by levels of alpha-2-macroglobulin (α2M) and lipid peroxidation in plasma. Liver inflammation was evaluated by quantification of hepatic macrophage infiltration and reactive oxygen species production. CPII induced a better improvement in metabolic control and liver function than CSII, producing a significant decrease in blood glucose and fructosamine, coupled with increased IGF-1 and hepatic glycogen storage. Moreover, liver oxidative stress and liver inflammation were reduced. Such observations indicate that the same insulin level in CPII improves glucose control and hepatic glucose metabolism and function, attenuating the hepatic inflammatory response to diabetes. These data demonstrate the importance of focusing on therapeutics to allow first-pass hepatic insulin extraction or prevent diabetic complications. [ABSTRACT FROM AUTHOR]

OBJECTIVE — To study the effect of systemic hyperbaric oxygenation (HBO) therapy on the healing course of nonischemic chronic diabetic foot ulcers. RESEARCH DESIGN AND METHODS — From 1999 to 2000, 28 patients (average age 60.2 ± 9.7 years, diabetes duration 18.2 ± 6.6 years), of whorn 87% had type 2 diabetes, demonstrating chronic Wagner grades I-III foot ulcers without clinical symptoms of arteriopathy, were studied. They were randomized to undergo HBO because their ulcers did not improve over 3 months of full standard treatment. All the patients demonstrated signs of neuropathy. HBO was applied twice a day, 5 days a week for 2 weeks; each session lasted 90 min at 2.5 ATA (absolute temperature air). The main parameter studied was the size of the foot ulcer measured on tracing graphs with a computer. It was evaluated before HBO and at day 15 and 30 after the baseline. RESULTS — HBO was well tolerated in all but one patient (barotraumatic otitis). The transcutaneous oxygen pressure (TcPo[sub 2]) measured on the dorsum of the feet et the patients was 45.6 ± 18.1 mmHg (room air). During HBO, the TcPo[sub 2] measured around the ulcer increased significantly from 21.9 ± 12.1 to 454.2 ± 128.1 mmHg (P < 0.001). At day 15 (i.e., after completion of HBO), the size of ulcers decreased significantly in the HBO group (41.8 ± 25.5 vs. 21.7 ± 16.0% in the control group [P = 0.037]). Such a difference could no longer be observed at day 30 (48.1 ± 30.3 vs. 41.7 ± 27.3%). Four weeks later, complete healing was observed in two patients having undergone HBO and none in the control group. CONCLUSIONS — In addition to standard muhidisciplinary management, HBO doubles the mean healing rate of nonischemic chronic foot ulcers in selected diabetic patients. The time dependence of the effect of HBO warrants further investigations. [ABSTRACT FROM AUTHOR]

We investigated the effects of increasing concentrations of cholecystokinin octapeptide (CCK-8) on the exocrine pancreas of a new model of type 2 diabetic rats due to the partial protection exerted by nicotinamide against the β-cytotoxic effect of streptozotocin. CCK-8, administered for 8 successive days, exerted a biphasic action on the growth of the pancreas in non-diabetic and type 2 diabetic rats; however, the latter were less sensitive to CCK-8. Similar results were obtained in vitro by measuring the uptake of 5-bromo-2′-deoxyuridine (BrdU) in cultured isolated acinar cells. This effect was completely blocked by 3S(−)(N′-2,3-dihydro-1-methyl-2-oxo5-phenyl-1H-1,4-benzo-diazepin-3-yl)-1H-indole-2-carboxamide (L 364,718; a CCK1 receptor antagonist) but not by (3R)-3[N′-(3-methylphenyl)ureido]-1,3-dihydro-1-methyl-5-phenyl-2H1,4-benzo-diazepin-2-one (L 365,260; a CCK2 receptor antagonist), suggesting a direct effect via CCK1 receptors. Binding studies showed that these effects were mediated by a single class of low-affinity CCK1 receptors in diabetic rats and two classes of CCK-8 binding sites (with high and low affinity) in non-diabetic rats. Thus, in our new type 2 diabetes model, the loss of sensitivity of the pancreas to CCK-8 could be attributed to the loss of CCK1 receptors of high affinity. [Copyright &y& Elsevier]

Studies markers for risk of type 1 diabetes in relatives of Alsacian patients with type 1 diabetes. Encoding of T cell receptor involved in the control of T cell proliferation; Mediation of T cell apoptosis.

Aims: Nicotinamide adenine dinucleotide phosphate oxidases (NOX-es) produce reactive oxygen species and modulate β-cell insulin secretion. Islets of type 2 diabetic subjects present elevated expression of NOX5. Here, we sought to characterize regulation of NOX5 expression in human islets in vitro and to uncover the relevance of NOX5 in islet function in vivo using a novel mouse model expressing NOX5 in doxycycline-inducible, β-cell-specific manner (RIP/rtTA/NOX5 mice). Results:In situ hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 messenger ribonucleic acid (mRNA) and protein expressions in human islets. In cultures of dispersed islets, NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8 mM glucose) conditions. Small interfering ribonucleic acid (siRNA)-mediated knockdown of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion (GIIS) in vitro. However, when islets were preincubated in high (16.7 mM) glucose media for 12 h, NOX5 appeared also in insulin-positive (β) cells. In vivo, mice with β-cell NOX5 expression developed aggravated impairment of GIIS compared with control mice when challenged with 14 weeks of high-fat diet. Similarly, in vitro palmitate preincubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared with their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation, suggesting impaired cyclic adenosine monophosphate (cAMP)-mediated signaling due to increased phosphodiesterase activation. Innovation and Conclusions: Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell-mediated intraislet crosstalk in physiological circumstances but also identifying it as an aggravating factor in β-cell failure in diabetic conditions. [ABSTRACT FROM AUTHOR]

Oral administration of insulin increases patient comfort and could improve glycemic control thanks to the hepatic first passage. However, challenges remain. The current approach uses poly ( d , lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), an effective drug carrier system with a long acting profile. However, this system presents a bioavailability of less than 20% for insulin encapsulation. In this context, physico-chemical parameters like surface charge could play a critical role in NP uptake by the intestinal barrier. Therefore, we developed a simple method to modulate NP surface charge to test its impact on uptake in vitro and finally on NP efficiency in vivo . Various NPs were prepared in the presence (+) or absence (−) of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and/or coated with chitosan chloride. In vitro internalization was tested using epithelial culture of Caco-2 or using a co-culture (Caco-2/RevHT29MTX) by flow cytometry. NPs were then administered by oral route using a pharmaceutical complex vector (100 or 250 UI/kg) in a diabetic rat model. SDS-NPs (−42 ± 2 mV) were more negatively charged than −PVA-NPs (–22 ± 1 mV) and chitosan-coated NPs were highly positively charged (56 ± 2 mV) compared to +PVA particles (−2 ± 1 mV), which were uncharged. In the Caco-2 model, NP internalization was significantly improved by using negatively charged NPs (SDS NPs) compared to using classical NPs (+PVA NPs) and chitosan-coated NPs . Finally, the efficacy of insulin SDS-NPs was demonstrated in vivo (100 or 250 UI insulin/kg) with a reduction of blood glucose levels in diabetic rats. Formulation of negatively charged NPs represents a promising approach to improve NP uptake and insulin bioavailability for oral delivery. [ABSTRACT FROM AUTHOR]

Background: The Asia-Pacific region is thought to be severely affected by diabetes. However, reliable, standardised data on prevalence and characteristics of glucose intolerance in Asian populations remain sparse. We describe the results of two field surveys undertaken in Cambodia in 2004. Methods: 2246 randomly selected adults aged 25 years and older were examined in two communities, one rural (Siemreap) and one semi-urban (Kampong Cham). The diagnosis of diabetes and impaired glucose tolerance was based on 2-h blood glucose estimation using criteria recommended by the latest report of a WHO Expert Group. Blood pressure, anthropometry, habitual diet, and other relevant characteristics were also recorded. Findings: Prevalence of diabetes was 5% in Siemreap and 11% in Kampong Cham. Prevalence of impaired glucose tolerance was 10% in Siemreap and 15% in Kampong Cham. About two-thirds of all cases of diabetes were undiagnosed before the survey. Prevalence of hypertension was 12% at Siemreap and 25% at Kampong Cham. People in Kampong Cham had higher estimates of central obesity than those in Siemreap. Interpretation: Diabetes and hypertension are not uncommon in Cambodia. A quarter of all adults in the chosen suburban community had some degree of glucose intolerance. Since Cambodian society is relatively poor, and lifestyle is fairly traditional by international standards, these findings are unexpected. [ABSTRACT FROM AUTHOR]