Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells

2020 ◽  
Author(s):  
Hayat Aljaibeji ◽  
Noha Mousaad Elemam ◽  
Abdul Khader Mohammed ◽  
Hind Hasswan ◽  
Mahammad Al Thahyabat ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Cell Function ◽  
Serum Levels ◽  
Insulin Content ◽  
Β Cell ◽  
Control Subjects ◽  
Β Cell Function

Abstract Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.

scholarly journals A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 624-635 ◽  
Author(s):  
Joon Ha ◽  
Leslie S. Satin ◽  
Arthur S. Sherman
Keyword(s):  
Mathematical Model ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Metabolic Defects ◽  
Normal Individuals ◽  
Β Cell Function

Abstract Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing β-cell mass. We add to that model regulation of 2 aspects of β-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into “Starling's Law of the Pancreas,” whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass

2015 ◽  
Vol 308 (6) ◽  
pp. E535-E544 ◽  
Author(s):  
Christoffer Martinussen ◽  
Kirstine N. Bojsen-Møller ◽  
Carsten Dirksen ◽  
Siv H. Jacobsen ◽  
Nils B. Jørgensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Β Cell ◽  
Glucose Effectiveness ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

scholarly journals Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

2020 ◽  
Author(s):  
Rong Huang ◽  
Songping Yin ◽  
Yongxin Ye ◽  
Nixuan Chen ◽  
Shiyun Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Retinol Binding Protein ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Β Cell Function ◽  
Oral Minimal Model

<p>OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.</p>

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

2009 ◽  
Vol 296 (2) ◽  
pp. C346-C354 ◽  
Author(s):  
Fan Zhang ◽  
Deben Dey ◽  
Robert Bränström ◽  
Lars Forsberg ◽  
Ming Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic β-cells. We have investigated the influence of the drug on β-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+]i) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the β-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in β-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+]i mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

scholarly journals Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

2016 ◽  
Vol 175 (4) ◽  
pp. 345-352 ◽  
Author(s):  
Daniël H van Raalte ◽  
Mathijs C Bunck ◽  
Mark M Smits ◽  
T Hoekstra ◽  
Anja Cornér ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Treatment Period ◽  
Receptor Agonist ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

Objective Glucagon-like peptide (GLP)-1 receptor agonist treatment improves β-cell function. In this study, we investigated whether the improvements are sustained during a 3-year treatment period. Research design and methods Sixty-nine metformin-treated type 2 diabetes patients were randomised to the GLP1 receptor agonist, exenatide (EXE) twice daily (BID) or to insulin glargine (GLAR). β-cell function parameters were derived using the Mari model from standardised breakfast and lunch meals that were administered before treatment, and after 1 and 3 years of treatment. EXE was administered before breakfast. Results Fifty-nine (EXE: n = 30; GLAR: n = 29) and thirty-six (EXE: n = 16; GLAR: n = 20) patients completed the meal at 1- and 3-year treatment respectively. After 3 years, groups had comparable glycaemic control (HbA1c: EXE 6.6 ± 0.2% and GLAR 6.9 ± 0.2%; P = 0.216). Compared with GLAR, at 1 and 3 years, EXE induced a stronger reduction in post-breakfast glucose concentrations (P < 0.001), with lower C-peptide levels (P < 0.001). Compared with GLAR, EXE increased insulin secretion at 8 mmol/L glucose throughout the study period (P < 0.01). Both treatments improved β-cell glucose sensitivity after 1-year treatment. However, only EXE treatment sustained this improvement for 3 years. No consistent changes in other β-cell parameters including rate sensitivity and potentiation were observed. Conclusions Compared with GLAR, EXE improved the parameters of β-cell function, especially insulin secretion at 8 mmol/L glucose and β-cell glucose sensitivity, which was sustained during the 3-year treatment period.

scholarly journals Association of Insulin Resistance, β-Cell Function Impairment and Calcium, Magnesium, and Fetuin-A Concentrations in Women with Type 2 Diabetes Mellitus

2016 ◽  
Vol 33 (3) ◽  
pp. 187-197
Author(s):  
Shatha Rouf Moustafa
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cell Function ◽  
Serum Levels ◽  
Control Group ◽  
Β Cell ◽  
Fetuin A ◽  
Function Impairment ◽  
Β Cell Function

SummaryInsulin resistance and β-cell function impairment play a role in the pathogenesis of type 2 diabetes (T2DM). Insulin signaling is inhibited by fetuin-A, an abundant plasma protein. Fetuin-A is also a candidate marker of the T2DM risk. This case-control study aimed to determine whether fetuin-A serum level is related to insulin resistance, β-cell function impairment, and total and ionized Ca and Mg serum levels in Erbil patients with T2DM.A total of 60 patients with T2DM were recruited, and 30 healthy persons were included in the control group. Fetuin-A and insulin concentrations were measured through ELISA. Other biochemical parameters were determined spectrophotometrically. Insulin resistance (HOMA2IR), insulin sensitivity (HOMA2%S), and β-cell function were examined by using a homeostatic model assessment 2 (HOMA2).Fasting serum insulin, fetuin-A serum levels, and HOMA2IR were significantly increased. HOMA2%S of the patients with diabetes was significantly lower than that of the control group. The total serum and ionized Ca and Mg contents and the Ca/Mg ratio were reduced in the patients.Therefore, fetuin-A is related to T2DM pathogenesis and is strongly associated with insulin resistance and glycemic control in T2DM patients. Future large-scale studies are necessary to validate fetuin-A as an indicator of IR in T2DM patients.

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

2011 ◽  
Vol 300 (2) ◽  
pp. E255-E262 ◽  
Author(s):  
Adria Giacca ◽  
Changting Xiao ◽  
Andrei I. Oprescu ◽  
Andre C. Carpentier ◽  
Gary F. Lewis
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

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