scholarly journals Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Tsvetelina V. Velikova ◽  
Plamena P. Kabakchieva ◽  
Yavor S. Assyov ◽  
Tsvetoslav А. Georgiev
Keyword(s):  
Type 2 Diabetes ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Option ◽  
Model Studies ◽  
Abnormal Immune Response ◽  
Islet Inflammation ◽  
Cytokine Dysregulation

Type 2 diabetes (T2D) is one of the most common chronic metabolic disorders in adulthood worldwide, whose pathophysiology includes an abnormal immune response accompanied by cytokine dysregulation and inflammation. As the T2D-related inflammation and its progression were associated with the balance between pro and anti-inflammatory cytokines, anticytokine treatments might represent an additional therapeutic option for T2D patients. This review focuses on existing evidence for antihyperglycemic properties of disease-modifying antirheumatic drugs (DMARDs) and anticytokine agents (anti-TNF-α, anti-interleukin-(IL-) 6, -IL-1, -IL-17, -IL-23, etc.). Emphasis is placed on their molecular mechanisms and on the biological rationale for clinical use. Finally, we briefly summarize the results from experimental model studies and promising clinical trials about the potential of anticytokine therapies in T2D, discussing the effects of these drugs on systemic and islet inflammation, beta-cell function, insulin secretion, and insulin sensitivity.

scholarly journals Selenoprotein P as a significant regulator of pancreatic β cell function

2019 ◽  
Author(s):  
Yoshiro Saito
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Insulin Signalling ◽  
Selenoprotein P ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Abstract Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.

scholarly journals Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

2017 ◽  
Author(s):  
Anne Raimondo ◽  
Soren K. Thomsen ◽  
Benoit Hastoy ◽  
Mahesh M. Umapathysivam ◽  
Xiao-Qing Dai ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Model ◽  
Catalytic Function ◽  
Risk Alleles ◽  
Human Beta Cells

ABSTRACTMolecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants in Peptidylglycine Alpha-amidating Monooxygenase (PAM) associated with T2D risk and measures of beta cell dysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cell model, PAM silencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cell function, and uncover a novel mechanism for T2D-associated PAM alleles.

scholarly journals Recovery of human type 2 diabetes beta cell function associates with transcriptomic signatures that point to novel therapeutic targets

2021 ◽  
Author(s):  
Mara Suleiman ◽  
Xiaoyan Yi ◽  
Emanuele Bosi ◽  
Frederic Burdet ◽  
Carmela De Luca ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Targets ◽  
Glucose Stimulated Insulin Secretion ◽  
Novel Therapeutic

Abstract Remission of type 2 diabetes (T2D) may occur after very low-calorie diets or bariatric surgery, and is associated with improved pancreatic beta cell function. Here, we evaluated if T2D beta cell dysfunction can be rescued ex-vivo and which are the molecular mechanisms involved. Islets from 19 T2D donors were studied after isolation (“basal”) and following culture at 5.5 or 11.1 mmol/l glucose (“cultured”). We evaluated glucose-stimulated insulin secretion (GSIS) and transcriptomes by RNA sequencing, correlated insulin secretion changes (“cultured” vs “basal”) to global gene expression, and searched for potential therapeutic gene targets and compounds that mimic gene signatures of recovered beta cell function in T2D islets. GSIS improved in 12 out of 19 islet preparations from T2D donors after culture at 5.5 mmol/l glucose (insulin stimulation index increased from 1.4±0.1 to 2.3±0.2, p<0.01), mainly due to greater insulin response to high glucose. No improvement was seen in islets cultured at 11.1 mmol/l glucose. Functional improvement was accompanied by changes in expression of 438 genes, many of which involved in functional and inflammatory processes. Of them, 123 were significantly correlated with changes in glucose-stimulated insulin secretion. Drug repurposing and target identification analyses for beta cell functional recovery predicted several chemical (including Src inhibitors and anti-inflammatory drugs) and genetic hits in pathways such as chemokine, MAPK, ERBB signaling, and autophagy. In conclusion, defective insulin secretion in T2D can be rescued, at least in part, by a “non-diabetic” milieu, demonstrating important T2D beta cell functional plasticity. This recovery associates with specific transcriptomic traits, pointing to known as well as novel therapeutic targets to induce T2D remission.

scholarly journals Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

2015 ◽  
Vol 112 (20) ◽  
pp. E2611-E2619 ◽  
Author(s):  
Karin Åvall ◽  
Yusuf Ali ◽  
Ingo B. Leibiger ◽  
Barbara Leibiger ◽  
Tilo Moede ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Β Cell ◽  
Apolipoprotein Ciii

Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.

Blood intact incretin levels are related to beta-cell function and glycemia in patients with type 2 diabetes

2019 ◽  
Author(s):  
Yeekyoung Ko ◽  
Soyeon Yoo ◽  
Gwanpyo Koh
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function

1561-P: Associations between ß-Cell Function and Cognitive Measures Differ in Youth vs. Adults with Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes (T2D)

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1561-P
Author(s):  
SUZANNE CRAFT ◽  
AMY CLAXTON ◽  
MARK TRIPPUTI ◽  
SHARON EDELSTEIN ◽  
SILVA A. ARSLANIAN ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Early Type ◽  
Cognitive Measures

1782-P: Impact of Treatment with Medication vs. Laparoscopic Gastric Banding (GB) on ß-Cell Function in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D) in the Restoring Insulin Secretion (RISE) Study

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1782-P
Author(s):  
DAVID A. EHRMANN ◽  
SHARON EDELSTEIN ◽  
ANNY XIANG ◽  
THOMAS A. BUCHANAN ◽  
SILVA A. ARSLANIAN ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Gastric Banding ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Laparoscopic Gastric Banding

1780-P: Differential Effects of Medications and Gastric Banding on OGTT-Modeled Measures of ß-Cell Function in Adults with IGT or Recent-Onset Type 2 Diabetes (T2D)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1780-P
Author(s):  
KRISTINA UTZSCHNEIDER ◽  
LAURE EL GHORMLI ◽  
SUSAN SAM ◽  
DAVID A. EHRMANN ◽  
KIEREN J. MATHER ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Banding ◽  
Cell Function ◽  
Differential Effects ◽  
Recent Onset ◽  
Onset Type

970-P: Comparative Assessment of the Effect of Vildagliptin and Metformin on Pancreatic Beta-Cell Function and Insulin Sensitivity in Newly Diagnosed Asian Indians with Type 2 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 970-P
Author(s):  
KRISHNAMOORTHY SATHEESH ◽  
CHAMUKUTTAN SNEHALATHA ◽  
ARUN NANDITHA ◽  
ARUN RAGHAVAN ◽  
RAMACHANDRAN VINITHA ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Beta Cell Function ◽  
Asian Indians ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Comparative Assessment ◽  
Newly Diagnosed ◽  
Pancreatic Beta Cell Function

78-OR: Glycaemia, Beta-Cell Function, and Incretin Hormones Post-OGTT One Year after Gastric Bypass and Sleeve Gastrectomy in Patients with Morbid Obesity and Type 2 Diabetes: An RCT (Oseberg Study)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 78-OR
Author(s):  
FARHAT FATIMA ◽  
JØRAN HJELMESÆTH ◽  
KARE I. BIRKELAND ◽  
HANNE L. GULSETH ◽  
JENS K. HERTEL ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Morbid Obesity ◽  
Gastric Bypass ◽  
Sleeve Gastrectomy ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Incretin Hormones ◽  
One Year
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