NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity.
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ABSTRACT:
SUBMITTER: Chen Y
PROVIDER: S-EPMC8111265 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mitochondrial dysfunction is both a contributing mechanism and complication of diabetes, and oxidative stress contributes to that dysfunction. Mitochondrial manganese-superoxide dismutase (MnSOD) is a metalloenzyme that provides antioxidant protection. We have previously shown in a mouse model of hereditary iron overload that cytosolic iron levels affected mitochondrial manganese availability, MnSOD activity, and insulin secretion. We therefore sought to determine the metallation status of MnSOD in wild-type mice and whether altering that status affected β-cell function. 129/SvEVTac mice given supplemental manganese exhibited a 73% increase in hepatic MnSOD activity and increased metallation of MnSOD. To determine whether manganese supplementation offered glucose homeostasis under a situation of β-cell stress, we challenged C57BL/6J mice, which are more susceptible to diet-induced diabetes, with a high-fat diet for 12 weeks. Manganese was supplemented or not for the final 8 weeks on that diet, after which we examined glucose tolerance and the function of isolated islets. Liver mitochondria from manganese-injected C57BL/6J mice had similar increases in MnSOD activity (81%) and metallation as were seen in 129/SvEVTac mice. The manganese-treated group fed high fat had improved glucose tolerance (24% decrease in fasting glucose and 41% decrease in area under the glucose curve), comparable with mice on normal chow and increased serum insulin levels. Isolated islets from the manganese-treated group exhibited improved insulin secretion, decreased lipid peroxidation, and improved mitochondrial function. In conclusion, MnSOD metallation and activity can be augmented with manganese supplementation in normal mice on normal chow, and manganese treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress.
| S-EPMC3578995 | biostudies-literature
Project description:Adult stem cells represent an invaluable resource that can be harnessed for therapeutic tissue repair. Gut stem cells are accessible by biopsy and grow indefinitely in culture as organoids or cell lines. Human fetal gut can generate rare insulin-secreting cells. However, the short lifespan of gut cells, amounting to only days in situ, calls into question the feasibility of producing stable and durable gut insulin-secreting cells as a potential engraftable therapeutic. Here, we show that cultured human stomach stem cells can be directed to generate pancreatic islet-like organoids containing long-lived gastric insulin-secreting (GINS) cells that resemble pancreatic b-cells in molecular hallmarks and function. After sequential activation of the inducing factors NGN3 and PDX1-MAFA, gastric stem cells passed through a SOX4High endocrine and a GalaninHigh precursor state before adopting the b-cell fate, at efficiencies exceeding 80%. GINS cells acquired glucose-stimulated insulin secretion 10 days post differentiation and restored glucose homeostasis for over 100 days in diabetic mice after transplantation. This study establishes a promising approach to procuring autologous human insulin producers for diabetes treatment, and further expands the already considerable therapeutic opportunities for gut stem cells.
2023-01-10 | GSE205766 | GEO
Project description:Aims/hypothesisZfp69 was previously identified by positional cloning as a candidate gene for obesity-associated diabetes. C57BL/6J and New Zealand obese (NZO) mice carry a loss-of-function mutation due to the integration of a retrotransposon. On the NZO background, the Zfp69 locus caused severe hyperglycaemia and loss of beta cells. To provide direct evidence for a causal role of Zfp69, we investigated the effects of its overexpression on both a lean [B6-Tg(Zfp69)] and an obese [NZO/B6-Tg(Zfp69)] background.MethodsZfp69 transgenic mice were generated by integrating the cDNA into the ROSA locus of the C57BL/6 genome and characterised.ResultsB6-Tg(Zfp69) mice were normoglycaemic, developed hyperinsulinaemia, and exhibited increased expression of G6pc and Pck1 and slightly reduced phospho-Akt levels in the liver. During OGTTs, glucose clearance was normal but insulin levels were significantly higher in the B6-Tg(Zfp69) than in control mice. The liver fat content and plasma triacylglycerol levels were significantly increased in B6-Tg(Zfp69) and NZO/B6-Tg(Zfp69) mice on a high-fat diet compared with controls. Liver transcriptome analysis of B6-Tg(Zfp69) mice revealed a downregulation of genes involved in glucose and lipid metabolism. Specifically, expression of Nampt, Lpin2, Map2k6, Gys2, Bnip3, Fitm2, Slc2a2, Ppargc1α and Insr was significantly decreased in the liver of B6-Tg(Zfp69) mice compared with wild-type animals. However, overexpression of Zfp69 did not induce overt diabetes with hyperglycaemia and beta cell loss.Conclusions/interpretationZfp69 mediates hyperlipidaemia, liver fat accumulation and mild insulin resistance. However, it does not induce type 2 diabetes, suggesting that the diabetogenic effect of the Zfp69 locus requires synergy with other as yet unidentified genes.
| S-EPMC4572078 | biostudies-literature
Project description:Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.
| S-EPMC4317319 | biostudies-literature
Project description:Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (? = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (? = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.
| S-EPMC4747453 | biostudies-literature
Project description:ContextType 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown.ObjectiveMeasure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes.DesignDouble-blind, placebo-controlled clinical trial.SettingMulti-center at eight sites of the T1D Exchange Clinic Network.ParticipantsA subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled.InterventionParticipants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment.Main outcome measuresPeripheral insulin sensitivity, endogenous glucose release, rate of lipolysis.ResultsBetween-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population.ConclusionsMetformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.
| S-EPMC6584133 | biostudies-literature
Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes. Microarray analysis was performed on abdominal subcutaneous white adipose tissue samples from human type 2 diabetic patients before, and after 10 days of cold acclimation. A total of 14 samples, from 7 subjects, were used for the microarray analysis.
2015-07-05 | E-GEOD-67297 | biostudies-arrayexpress
Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes.
2015-07-05 | GSE67297 | GEO
Project description:Brown adipocytes (BAs) play important roles in body temperature regulation, energy balance, and carbohydrate and lipid metabolism. Activities of BAs are remarkably diminished in obese and diabetic patients, providing possibilities of transplanting functional BAs resulting in therapeutic benefit. Here, we show generation of functional BAs by cellular reprogramming procedures. Transduction of the PRDM16 gene into iPSC-derived embryoid bodies induced BA phenotypes (iBAs). Moreover, normal human fibroblasts were directly converted into BAs (dBAs) by C/EBP-β and C-MYC gene transduction. Approximately 90% of the fibroblasts were successfully converted within 12 days. The dBAs were highly active in mitochondrial biogenesis and oxidative metabolism. Mouse dBAs were induced by Prdm16, C/ebp-β, and L-myc genes, and after transplantation, they significantly reduced diet-induced obesity and insulin resistance in an UCP1-dependent manner. Thus, highly functional BAs can be generated by cellular reprogramming, suggesting a promising tailor-made cell therapy against metabolic disorders including type 2 diabetes mellitus.
| S-EPMC4624936 | biostudies-literature
Project description:Recent genome-wide association studies (GWAS) identified DUSP8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes (T2D) risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8 KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of T2D.
2020-08-26 | GSE112688 | GEO