Pancreatic β-Cell Rest Replenishes Insulin Secretory Capacity and Attenuates Diabetes in an Extreme Model of Obese Type 2 Diabetes

Increased apoptosis of pancreatic β-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic β-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg·kg−1·d−1, administered ip) inhibited β-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet β-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38β MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting β-cell apoptosis via increasing p38β MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

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The relationship between serum uric acid within the normal range and β-cell function in Chinese patients with type 2 diabetes: differences by body mass index and gender

PeerJ ◽

10.7717/peerj.6666 ◽

2019 ◽

Vol 7 ◽

pp. e6666 ◽

Cited By ~ 2

Author(s):

Xing Zhong ◽

Deyuan Zhang ◽

Lina Yang ◽

Yijun Du ◽

Tianrong Pan

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Normal Weight ◽

Normal Range ◽

Β Cell ◽

C Peptide ◽

Β Cell Function ◽

Insulin Secretory Capacity ◽

Secretory Capacity

Background Elevated serum uric acid (SUA) has a positive correlation with insulin secretion and insulin resistance indexes. However, whether weight- and gender-specific differences regarding the relationship between SUA within the normal range and β-cell function and insulin resistance exist is unknown in type 2 diabetes mellitus (T2DM) patients. Methods A total of 380 patients with type 2 diabetes were divided into two groups as overweight/obesity (n = 268) and normal weight (n = 112). Each group were again divided into low (LSUA) and high normal SUA (HSUA). The HbA1c, C-peptide, SUA, creatinine, and lipids profiles were measured. HOMA2IR and HOMA%2B were estimated using fasting glucose and C-peptide by homeostasis model assessment (HOMA). Pearson’s correlations and multiple linear regression analyses were conducted to assess the associations between SUA levels and islet function indexes. Results In overweight/obesity subgroup, the levels of body mass index, fasting C-peptide (FCP), P2hCP, fasting CPI (FCPI), postprandial CPI (PPCPI), ΔC-peptide, HOMA2%B, and HOMA2IR were higher in HSUA group than in LSUA group. In contrast, the HbA1c, FBS, and P2hBS were lower in HSUA than in LSUA. In normal weight subgroup, there were no differences between the HSUA than LSUA group in terms of clinical characteristics. Pearson’s correlations indicated that there were no significant correlations between SUA and insulin secretory capacity in normal weight group, but in overweight/obesity group, SUA had positive significant correlations with P2hCP, FCPI, PPCPI, ΔC-peptide, and HOMA2%B. In the female group, there were no significant correlations between SUA and insulin secretory capacity. However, in the male group, SUA had positive significant correlations with insulin secretory capacity include P2hCP, FCPI, PPCPI, ΔC-peptide, and HOMA2%B. Multiple linear regression showed that SUA was significantly associated with HOMA2%B, but not with HOMA2IR in overweight/obesity and male group. Conclusions Our study shows that SUA levels within normal range were associated with β-cell function in T2DM patients with overweight/obesity or male. This finding supports that the association between SUA within normal range and insulin secretion ability differs by weight and sex.

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INCRETIN AND DIABETES

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2011.3.1 ◽

2011 ◽

pp. 5-10

Author(s):

Huu Dang Tran

Keyword(s):

Type 2 Diabetes ◽

Cell Proliferation ◽

Glycaemic Control ◽

Animal Studies ◽

Dipeptidyl Peptidase ◽

Pancreatic Β Cell ◽

Β Cell ◽

Glucose Sensitivity ◽

Cell Glucose

The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase. Studies have identified other actions including improvement in pancreatic β cell glucose sensitivity and, in animal studies, promotion of pancreatic β cell proliferation and reduction in β cell apoptosis.

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Comment on Retnakaran et al. Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes: The LIBRA Trial. Diabetes Care 2014;37:3270–3278

Diabetes Care ◽

10.2337/dc14-2418 ◽

2015 ◽

Vol 38 (2) ◽

pp. e25-e25 ◽

Cited By ~ 1

Author(s):

Sabine Arnolds ◽

Peter T. Sawicki

Keyword(s):

Type 2 Diabetes ◽

Diabetes Care ◽

Cell Function ◽

Pancreatic Β Cell ◽

Early Type ◽

Β Cell ◽

Β Cell Function

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Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽

10.1152/physiol.00032.2009 ◽

2009 ◽

Vol 24 (6) ◽

pp. 325-331 ◽

Cited By ~ 171

Author(s):

Marc Y. Donath ◽

Marianne Böni-Schnetzler ◽

Helga Ellingsgaard ◽

Jan A. Ehses

Keyword(s):

Type 2 Diabetes ◽

Cell Mass ◽

Metabolic Stress ◽

Innate Immune ◽

Pancreatic Β Cell ◽

Β Cell ◽

Amyloid Deposits ◽

Impaired Insulin ◽

Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction

iScience ◽

10.1016/j.isci.2020.101566 ◽

2020 ◽

Vol 23 (10) ◽

pp. 101566

Author(s):

Saifur R. Khan ◽

Yousef Manialawy ◽

Andreea Obersterescu ◽

Brian J. Cox ◽

Erica P. Gunderson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Sphingolipid Metabolism ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction

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Association between Pancreatic Atrophy and Loss of Insulin Secretory Capacity in Patients with Type 2 Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2019/6371231 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Jun Lu ◽

Meixiang Guo ◽

Hongtao Wang ◽

Haibin Pan ◽

Liang Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Multiple Logistic Regression Analysis ◽

Insulin Deficiency ◽

Cross Sectional ◽

Pancreatic Atrophy ◽

Insulin Secretory Capacity ◽

Absolute Insulin Deficiency ◽

Secretory Capacity

Aims. To examine pancreatic volume (PV) changes among patients with different duration of type 2 diabetes and whether pancreatic atrophy was associated with loss of insulin secretory capacity. Methods. This cross-sectional study (203 patients with type 2 diabetes, 93 controls without diabetes) was conducted from January 2016 to December 2017. Patients with type 2 diabetes were divided into 3 groups: recently diagnosed (duration≤2 years), midterm (duration 3-9 years), and long term (duration≥10 years). All the patients were scanned with upper abdominal computerized tomography; PV was then calculated by an experienced technician. Absolute insulin deficiency was defined as fasting C−peptide<0.9 ng/mL. Results. Compared with PV (cm3) in the controls, the mean PV was similar in patients with recently diagnosed type 2 diabetes (68.8 versus 71.0, P=0.56) but significantly reduced in patients with midterm (68.8 versus 60.8, P<0.05) and long-term (68.8 versus 53.1, P<0.001) type 2 diabetes. A similar trend was observed for the PV index (PV adjusted for body surface area and body mass index). Furthermore, rates of pancreatic atrophy and absolute insulin deficiency increased with duration of diabetes. Multiple logistic regression analysis indicated that pancreatic atrophy was associated with higher likelihood of absolute insulin deficiency (odds ratio=4.47, 95%confidence interval=1.45‐13.8). Conclusions. PV was reduced in those with midterm and long-term type 2 diabetes compared to individuals without type 2 diabetes. Overall, pancreatic atrophy was associated with the loss of insulin secretory capacity in patients with type 2 diabetes.

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