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Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

ABSTRACT: Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis-at least in part-through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.

SUBMITTER: Ekim Ustunel B

PROVIDER: S-EPMC5105165 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other

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Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

Ekim Üstünel Bilgen B Friedrich Kilian K Maida Adriano A Wang Xiaoyue X Krones-Herzig Anja A Seibert Oksana O Sommerfeld Anke A Jones Allan A Sijmonsma Tjeerd P TP Sticht Carsten C Gretz Norbert N Fleming Thomas T Nawroth Peter P PP Stremmel Wolfgang W Rose Adam J AJ Berriel-Diaz Mauricio M Blüher Matthias M Herzig Stephan S

Nature communications 20161109

Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevent ...[more]

PMID: 27827363

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Project description:Aims/hypothesisThe present study compares the impact of endurance- vs resistance-type exercise on subsequent 24 h blood glucose homeostasis in individuals with impaired glucose tolerance (IGT) and type 2 diabetes.MethodsFifteen individuals with IGT, 15 type 2 diabetic patients treated with exogenous insulin (INS), and 15 type 2 diabetic patients treated with oral glucose-lowering medication (OGLM) participated in a randomised crossover experiment. Participants were studied on three occasions for 3 days under strict dietary standardisation, but otherwise free-living conditions. Blood glucose homeostasis was assessed by ambulatory continuous glucose monitoring over the 24 h period following a 45 min session of resistance-type exercise (75% one repetition maximum), endurance-type exercise (50% maximum workload capacity) or no exercise at all.ResultsAverage 24 h blood glucose concentrations were reduced from 7.4 ± 0.2, 9.6 ± 0.5 and 9.2 ± 0.7 mmol/l during the control experiment to 6.9 ± 0.2, 8.6 ± 0.4 and 8.1 ± 0.5 mmol/l (resistance-type exercise) and 6.8 ± 0.2, 8.6 ± 0.5 and 8.5 ± 0.5 mmol/l (endurance-type exercise) over the 24 h period following a single bout of exercise in the IGT, OGLM and INS groups, respectively (p < 0.001 for both treatments). The prevalence of hyperglycaemia (blood glucose >10 mmol/l) was reduced by 35 ± 7 and 33 ± 11% over the 24 h period following a single session of resistance- and endurance-type exercise, respectively (p < 0.001 for both treatments).Conclusions/interpretationA single session of resistance- or endurance-type exercise substantially reduces the prevalence of hyperglycaemia during the subsequent 24 h period in individuals with IGT, and in insulin-treated and non-insulin-treated type 2 diabetic patients. Both resistance- and endurance-type exercise can be integrated in exercise intervention programmes designed to improve glycaemic control.Trial registrationClinicaltrials.gov NCT00945165.FundingThe Netherlands Organization for Health Research and Development (ZonMw, the Netherlands).

Project description:BackgroundCancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process.MethodsWe used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15 mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability.ResultsThe animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR.ConclusionsDOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.

Project description:The safety and efficacy of dipeptidyl peptidase-4 inhibitors in patients newly diagnosed type 2 diabetes mellitus (T2DM) with severe hyperglycaemia have remained to be sufficiently demonstrated. The aim of the present study was to determine whether sitagliptin combined with metformin as an initial treatment had non-inferior outcomes with regards to glycaemic remission and ?-cell function recovery to those of standard insulin therapy in this patient group. A prospective observational study was performed comparing the effects of sitagliptin combined with metformin and insulin therapy in a real-world clinical setting. A total of 168 participants were enrolled and received sitagliptin combined with metformin (Sig) or insulin (Ins) for almost 4 weeks. In addition, each group was further stratified into three subgroups, according to glycosylated haemoglobin (HbA1c) levels (<10, 10-12 and >12%). The primary outcomes were ?-cell function and changes in fasting plasma glucose (FPG) and HbA1c at the 3-month follow-up. Both insulin and sitagliptin combined with metformin reduced hyperglycaemia and achieved similar glycaemic outcomes, and no significant differences in FPG and HbA1c levels were obtained. No significant changes were observed in ?-cell function concomitant with the glucose-lowering effects of the treatments. Of note, participants in the Ins group exhibited weight gain, whereas those in the Sig group had weight loss, with significant differences becoming evident after 1 month, particularly in the HbA1c <10% subgroup. As compared with insulin injection, early treatment with sitagliptin combined with metformin in newly diagnosed patients with T2DM and severe hyperglycaemia produced non-inferior outcomes with regards to glycaemic remission. Therefore, combination of sitagliptin and metformin may be a viable initial treatment option for patients who prefer an alternative to insulin injection. This study was registered with ClinicalTrials.gov under no. NCT03180281.

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Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

Publications

Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

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