scholarly journals Mesenchymal Stem Cells Ameliorate Mitochondrial Dysfunction in α - cells and Hyperglucagonemia in type 2 Diabetes via SIRT1/FoxO3a Signaling

2021 ◽  
Author(s):  
Jia Song ◽  
Lingshu Wang ◽  
Xinghong Guo ◽  
Qin He ◽  
Chen Cui ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Glucagon Secretion ◽  
Sirtuin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Umbilical Cord ◽  
Therapeutic Effects

Abstract Background: Dysregulation of α-cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stem cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α- cell mitochondrial dysfunction remains unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSCs (hucMSCs) on α-cell mitochondrial function and glucagon secretion in T2DM.Methods: hucMSCs were used to treat two kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α-cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by western blotting analysis.Results: In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued islet structure and decreased α- to β-cell ratio. Consistently, glucagon secretion from αTC1-6 cells was inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion.Conclusions: Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α-cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.

scholarly journals Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

2008 ◽  
Vol 158 (5) ◽  
pp. 643-653 ◽  
Author(s):  
H M De Feyter ◽  
N M A van den Broek ◽  
S F E Praet ◽  
K Nicolay ◽  
L J C van Loon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Resonance Spectroscopy ◽  
Diabetes Patients

ObjectiveSeveral lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.MethodsTen long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using 31P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel 1H MRS.ResultsIMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The31P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.ConclusionsThe finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

scholarly journals THE ROLE OF SURVIVIN AND RAF-1 KINASE AGAINST ENHANCEMENT OF PANCREATIC BETA-CELL APOPTOSIS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

2018 ◽  
Vol 11 (11) ◽  
pp. 344
Author(s):  
Eva Decroli ◽  
Asman Manaf ◽  
Syafril Syahbuddin ◽  
Sarwono Waspadji ◽  
Dwisari Dillasamola
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Beta Cell ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Beta Cell Apoptosis

Objective: This study aimed to reveal differences in levels of survivin and Raf-1 kinase in prediabetes, controlled Type 2 diabetes mellitus (T2DM), uncontrolled T2DM, and their relationship with hemoglobin A1c (HbA1c) levels and serum triglyceride levels.Methods: This study was an observational study with a cross-sectional design. The study involved 60 people with T2DM who visited the endocrine and metabolic clinic and 30 prediabetes patients. The variables were survivin levels and Raf-1 kinase enzymes that examined using enzyme-linked immunosorbent assay techniques. HbA1c values are measured by high-performance liquid chromatography and triglyceride levels measured by enzymatic method.Results: Average levels of Raf-1 kinase were significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (11.6±1.4 pg mL, 9.9±1.1 pg/mL, and 9.1±1.5 pg/mL). Survivin was significantly higher in the prediabetes group, controlled T2DM, and uncontrolled T2DM (5.4±0.4 pg mL, 5.0±0.2 pg/mL, and 4.7±0.1 pg/mL). There was no correlation between HbA1c with Raf-1 kinase levels (R=−0.215, p=0.250), but there was a correlation between HbA1c with serum survivin levels (R=−0.6, *p<0.05). There was a correlation between the levels of triglycerides with survivin but not with Raf-1 kinase (R=−0.267, *p=0.039).Conclusion: Survivin and Raf-1 kinase levels are lower in uncontrolled T2DM. This explained the role of survivin and Raf-1 kinase against enhancement of pancreatic beta-cell apoptosis in patients with T2DM.

scholarly journals GCF Adrenomedullin Levels in Healthy and Periodontitis Patients with or without Type 2—Diabetes Mellitus: Clinicobiochemical Study

2014 ◽  
Vol 5 (1) ◽  
pp. 42-46
Author(s):  
SM Apoorva ◽  
Divya Bhat ◽  
Akanksha Garg ◽  
A Suchetha ◽  
N Sapna ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Gingival Crevicular Fluid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pocket Depth ◽  
Probing Pocket Depth ◽  
Crevicular Fluid

ABSTRACT Background The literature suggests that periodontal disease and diabetes mellitus share a two-way relationship. The aim of this study was to evaluate and compare the levels of adrenomedullin (ADM) in gingival crevicular fluid (GCF) of periodontally healthy and periodontitis patients with or without type 2 diabetes with different glycemic controls. Methods Ninety patients were included in the study and were divided into five groups based on CPI scores and ADA classification of diabetes. Probing pocket depth (PPD) and clinical attachment level (CAL) were measured in all the subjects. GCF was collected from all the participants using micropipettes. ADM levels were measured in GCF samples by enzyme-linked immunosorbent assay. Results The results showed higher levels of ADM in patients with periodontitis as compared to healthy group. Significant correlation was present between PPD and CAL and ADM levels in all periodontitis patients with or without type 2 diabetes. Conclusion Increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes with the worsening of glycemic control underlines the possible role of ADM in mounting a protective response to worsening disease state. How to cite this article Garg A, Suchetha A, Sapna N, Apoorva SM, Bhat D, Puzhankara L. GCF Adrenomedullin Levels in Healthy and Periodontitis Patients with or without Type 2—Diabetes Mellitus: Clinicobiochemical Study. World J Dent 2014;5(1):42-46.

scholarly journals Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight

2008 ◽  
Vol 93 (10) ◽  
pp. 3885-3892 ◽  
Author(s):  
Charlotte Brøns ◽  
Christine B. Jensen ◽  
Heidi Storgaard ◽  
Amra Alibegovic ◽  
Stine Jacobsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Young Men ◽  
Hepatic Insulin Resistance

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

scholarly journals Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

Diabetologia ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 2218-2234
Author(s):  
Christian Stern ◽  
Barbara Schreier ◽  
Alexander Nolze ◽  
Sindy Rabe ◽  
Sigrid Mildenberger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Smooth Muscle ◽  
Mitochondrial Dysfunction ◽  
Renal Damage ◽  
Egf Receptor ◽  
Vascular Dysfunction ◽  
Cellular Level

Abstract Aims/hypothesis Obesity causes type 2 diabetes leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesity-induced renovascular dysfunction, as well as EGFR–hyperglycaemia crosstalk. Methods The role of VSM-EGFR during high-fat diet (HFD)-induced type 2 diabetes was investigated in a mouse model with inducible, VSM-specific EGFR-knockout (KO). Various structural and functional variables as well as transcriptome changes, in vivo and ex vivo, were assessed. The impact of hyperglycaemia on EGFR-induced signalling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results We show that VSM-EGFR mediates obesity/type 2 diabetes-induced vascular dysfunction, remodelling and transcriptome dysregulation preceding renal damage and identify an EGFR–glucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR deletion protects the animals from HFD-induced endothelial dysfunction, creatininaemia and albuminuria. Furthermore, we show that HFD leads to marked changes of the aortic transcriptome in wild-type but not in KO animals, indicative of EGFR-dependent SRF activation, matrix dysregulation and mitochondrial dysfunction, the latter confirmed at the cellular level. Studies at the cellular level revealed that high glucose potentiated EGFR/EGF receptor 2 (ErbB2)-induced stimulation of SRF activity, enhancing the graded signalling responses to EGF, via the EGFR/ErbB2–ROCK–actin–MRTF pathway and promoted mitochondrial dysfunction. Conclusions/interpretation VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations. We propose that a potentiated EGFR/ErbB2–ROCK–MRTF–SRF signalling axis and mitochondrial dysfunction underlie the role of EGFR. This advanced working hypothesis will be investigated in mechanistic depth in future studies. VSM-EGFR may be a therapeutic target in cases of type 2 diabetes-induced renovascular disease. Data availability The datasets generated during and/or analysed during the current study are available in: (1) share_it, the data repository of the academic libraries of Saxony-Anhalt (10.25673/32049.2); and (2) in the gene expression omnibus database with the study identity GSE144838 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144838).

scholarly journals Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes

2013 ◽  
Vol 18 (6) ◽  
pp. 871-882 ◽  
Author(s):  
Quan Zhang ◽  
Reshma Ramracheya ◽  
Carolina Lahmann ◽  
Andrei Tarasov ◽  
Martin Bengtsson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucagon Secretion ◽  
Katp Channels

scholarly journals Potential Prognostic Role of Immune System Activation Marker Neopterin in Patients with Type 2 Diabetes

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Songül Ünüvar ◽  
Zübeyde Tanrıverdi ◽  
Hamza Aslanhan
Keyword(s):  
Type 2 Diabetes ◽  
Bacterial Infections ◽  
Metabolic Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Serum Neopterin ◽  
Immune System Activation ◽  
Study Results

Summary Background: An increase in neopterin concentrations is known in some pathologies due to interferon-gamma (INF-γ) activation. These include viral and bacterial infections, auto immune diseases, metabolic diseases, psychiatric disorders, tissue and organ rejections, and different malignancies. The aim of this study was to evaluate the role of neopterin as a prognostic biomarker in type 2 diabetes, which is a metabolic disease with a high worldwide prevalence. Methods: The study included a total of one hundred thirty-nine individuals including one hundred and six patients admitted to a family medicine outpatient clinic and diagnosed with type 2 diabetes and thirty-three healthy volunteers. Serum neopterin concentrations were measured using the enzyme-linked immunosorbent assay. Results: Serum neopterin levels significantly increased in type 2 diabetes patients, compared to the control group (p<0.00001). Conclusions: Early diagnosis of diabetes and determination of the appropriate therapeutic options are of utmost importance, as diabetes is also associated with other systemic diseases. The risk of developing secondary diseases is high in untreated patients. Our study results suggest that serum neopterin may be a useful biomarker in patients with type 2 diabetes.

scholarly journals Can resveratrol help to maintain metabolic health?

2014 ◽  
Vol 73 (2) ◽  
pp. 271-277 ◽  
Author(s):  
Patrick Schrauwen ◽  
Silvie Timmers
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Function ◽  
Therapeutic Strategy ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Metabolic Health ◽  
Sirtuin 1 ◽  
Cellular Energy ◽  
Cellular Energy Metabolism

The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4′-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic.

scholarly journals An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Alessandra Puddu ◽  
François Mach ◽  
Alessio Nencioni ◽  
Giorgio Luciano Viviani ◽  
Fabrizio Montecucco
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Advanced Glycation ◽  
Chronic Hyperglycemia ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreaticβ-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

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