scholarly journals Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

2006 ◽  
Vol 190 (2) ◽  
pp. 471-482 ◽  
Author(s):  
Soo Bong Choi ◽  
Jin Sun Jang ◽  
Sang Mee Hong ◽  
Dong Wha Jun ◽  
Sunmin Park
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Signaling Cascade ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
Igf I ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Long-term dexamethasone (DEX) treatment is well known for its ability to increase insulin resistance in liver and adipose tissues leading to hyperinsulinemia. On the other hand, exercise enhances peripheral insulin sensitivity. However, it is not clear whether DEX and/or exercise affect β-cell mass and function in diabetic rats, and whether their effects can be associated with the modulation of the insulin/IGF-I signaling cascade in pancreatic β-cells. After an 8-week study, whole body glucose disposal rates in 90% pancreatectomized (Px) and sham-operated male rats decreased with a high dose treatment of DEX (0.1mg DEX/kg body weight/day)(HDEX) treatment, while disposal rates increased with exercise. First-phase insulin secretion was decreased and delayed by DEX via the impairment of the glucose-sensing mechanism in β-cells, while exercise reversed the impairment of first-phase insulin secretion caused by DEX, suggesting ameliorated β-cell functions. However, exercise and DEX did not alter second-phase insulin secretion except for the fact that HDEX decreased insulin secretion at 120 min during hyperglycemic clamp in Px rats. Unlike β-cell functions, DEX and exercise exhibited increased pancreatic β-cell mass in two different pathways. Only exercise, through increased proliferation and decreased apoptosis, increased β-cell mass via hyperplasia, which resulted from an enhanced insulin/IGF-I signaling cascade by insulin receptor substrate 2 induction. By contrast, DEX expanded β-cell mass via hypertrophy and neogenesis from precursor cells, rather than increasing proliferation and decreasing apoptosis. In conclusion, the improvement of β-cell function and survival via the activation of an insulin/IGF-I signaling cascade due to exercise has a crucial role in preventing the development and progression of type 2 diabetes.

scholarly journals Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats

2021 ◽  
Vol 22 (1) ◽  
pp. 421
Author(s):  
Hui Huang ◽  
Bradi R. Lorenz ◽  
Paula Horn Zelmanovitz ◽  
Catherine B. Chan
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Metformin Treatment ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Output ◽  
Mass Expansion

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress β-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.

scholarly journals A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

2021 ◽  
Author(s):  
Cyril Bourouh ◽  
Emilie Courty ◽  
Gianni Pasquetti ◽  
Xavier Gromada ◽  
Nabil Rabhi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Signaling Pathways ◽  
Glucose Homeostasis ◽  
Transcriptional Activity ◽  
Cell Function ◽  
Cell Mass ◽  
Mass Function ◽  
Β Cell ◽  
Cell Functions ◽  
Β Cell Function

AbstractCompromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice (E2f1β−/−) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1β−/− pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival

2017 ◽  
Vol 399 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Dawood Khan ◽  
Srividya Vasu ◽  
R. Charlotte Moffett ◽  
Victor A. Gault ◽  
Peter R. Flatt ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Glucose Disposal ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Mouse Islets ◽  
Receptor Modulators

AbstractModulation of neuropeptide receptors is important for pancreatic β-cell function. Here, islet distribution and effects of the neurotensin (NT) receptor modulators, xenin and NT, was examined. Xenin, but not NT, significantly improved glucose disposal and insulin secretion, in mice. However, both peptides stimulated insulin secretion from rodent β-cells at 5.6 mmglucose, with xenin having similar insulinotropic actions at 16.7 mmglucose. In contrast, NT inhibited glucose-induced insulin secretion. Similar observations were made in human 1.1B4 β-cells and isolated mouse islets. Interestingly, similar xenin levels were recorded in pancreatic and small intestinal tissue. Arginine and glucose stimulated xenin release from islets. Streptozotocin treatment decreased and hydrocortisone treatment increased β-cell mass in mice. Xenin co-localisation with glucagon was increased by streptozotocin, but unaltered in hydrocortisone mice. This corresponded to elevated plasma xenin levels in streptozotocin mice. In addition, co-localisation of xenin with insulin was increased by hydrocortisone, and decreased by streptozotocin. Furtherin vitroinvestigations revealed that xenin and NT protected β-cells against streptozotocin-induced cytotoxicity. Xenin augmented rodent and human β-cell proliferation, whereas NT displayed proliferative actions only in human β-cells. These data highlight the involvement of NT signalling pathways for the possible modulation of β-cell function.

Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

2019 ◽  
Author(s):  
Chao Yang ◽  
Hua Qu ◽  
Xiaolan Zhao ◽  
Yingru Hu ◽  
Jiayao Xiong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Abstract Objective Secretagogin, a Ca2+ binding protein, is one of the most abundant proteins in pancreatic β-cells and is critical for maintaining the structural integrity and signaling competence of β-cells. This study seeks to assess the concentrations of plasma secretagogin in participants with prediabetes (pre-DM) and newly diagnosed type 2 diabetes (T2DM) and to explore its relationship to parameters of glucose and lipid metabolism, first-phase insulin secretion, insulin resistance and pancreatic β-cell function. Materials and Methods A total of 126 eligible subjects were divided into three groups: a normal glucose tolerance (NGT, n=45), a pre-DM (n=30), and a T2DM (n=51) group. An intravenous glucose tolerance test (IVGTT) was performed, and clinical and biochemical parameters were measured for all subjects. Results Plasma secretagogin levels were significantly higher in both pre-DM and T2DM patients compared with NGT subjects and were highest in the T2DM group. Correlation analysis showed that plasma secretagogin levels were positively correlated with fasting plasma glucose, postchallenge plasma glucose (2hPG), HbA1c and body mass index (BMI) but were not correlated with waist-hip ratio, blood pressure, lipid profiles, fasting serum insulin, homeostasis model assessment for insulin resistance, homeostasis model assessment for β-cell function and first-phase insulin secretion indicators. Multiple logistic regression analysis revealed that 2hPG and BMI were independent predictors for elevation of plasma secretagogin concentrations. Conclusions Increased circulating secretagogin might be a molecular predictor for early diagnosis of diabetes. Further studies are needed to confirm this finding and explore the role of secretagogin in obesity.

scholarly journals The impact of IUGR on pancreatic islet development and β-cell function

2017 ◽  
Vol 235 (2) ◽  
pp. R63-R76 ◽  
Author(s):  
Brit H Boehmer ◽  
Sean W Limesand ◽  
Paul J Rozance
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Perinatal Period ◽  
Placental Insufficiency ◽  
Β Cells ◽  
Β Cell ◽  
Islet Development ◽  
Β Cell Function ◽  
The Impact

Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.

scholarly journals Herbal Medicines Targeting the Improved β-Cell Functions and β-Cell Regeneration for the Management of Diabetes Mellitus

2021 ◽  
Vol 2021 ◽  
pp. 1-32
Author(s):  
Akurange Sujeevi Dammadinna Wickramasinghe ◽  
Pabasara Kalansuriya ◽  
Anoja Priyadarshani Attanayake
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Herbal Medicines ◽  
Cell Regeneration ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
Glucose Transporter 2 ◽  
Β Cell Function

There is an increasing trend of investigating natural bioactive compounds targeting pancreatic β-cells for the prevention/treatment of diabetes mellitus (DM). With the exploration of multiple mechanisms by which β-cells involve in the pathogenesis of DM, herbal medicines are gaining attention due to their multitasking ability as evidenced by traditional medicine practices. This review attempts to summarize herbal medicines with the potential for improvement of β-cell functions and regeneration as scientifically proven by in vivo/in vitro investigations. Furthermore, attempts have been made to identify the mechanisms of improving the function and regeneration of β-cells by herbal medicines. Relevant data published from January 2009 to March 2020 were collected by searching electronic databases “PubMed,” “ScienceDirect,” and “Google Scholar” and studied for this review. Single herbal extracts, polyherbal mixtures, and isolated compounds derived from approximately 110 medicinal plants belonging to 51 different plant families had been investigated in recent years and found to be targeting β-cells. Many herbal medicines showed improvement of β-cell function as observed through homeostatic model assessment-β-cell function (HOMA-β). Pancreatic β-cell regeneration as observed in histopathological and immunohistochemical studies in terms of increase of size and number of functional β-cells was also prominent. Increasing β-cell mass via expression of genes/proteins related to antiapoptotic actions and β-cell neogenesis/proliferation, increasing glucose-stimulated insulin secretion via activating glucose transporter-2 (GLUT-2) receptors, and/or increasing intracellular Ca2+ levels were observed upon treatment of some herbal medicines. Some herbal medicines acted on various insulin signaling pathways. Furthermore, many herbal medicines showed protective effects on β-cells via reduction of oxidative stress and inflammation. However, there are many unexplored avenues. Thus, further investigations are warranted in elucidating mechanisms of improving β-cell function and mass by herbal medicines, their structure-activity relationship (SAR), and toxicities of these herbal medicines.

scholarly journals NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

scholarly journals Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

2008 ◽  
Vol 28 (9) ◽  
pp. 2971-2979 ◽  
Author(s):  
Yutaka Shigeyama ◽  
Toshiyuki Kobayashi ◽  
Yoshiaki Kido ◽  
Naoko Hashimoto ◽  
Shun-ichiro Asahara ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cell Function ◽  
Cell Mass ◽  
Mammalian Target Of Rapamycin ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass ◽  
Β Cell Function

ABSTRACT Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.

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.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

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