scholarly journals Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 313-323 ◽  
Author(s):  
Sophie R. Sayers ◽  
Rebecca L. Beavil ◽  
Nicholas H. F. Fine ◽  
Guo C. Huang ◽  
Pratik Choudhary ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Functional Changes ◽  
Cell Dysfunction

Abstract Aims/hypothesis Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes. Methods CD-1 mice and serum from obese humans who were without diabetes, with impaired fasting glucose (IFG) or with type 2 diabetes (from the Body Fat, Surgery and Hormone [BodyFatS&H] study) or with or at risk of developing type 2 diabetes (from the VaSera trial) were used in this study. We generated recombinant wild-type and monomeric eNAMPT to explore the effects of eNAMPT on functional beta cell mass in isolated mouse and human islets. Beta cell function was determined by static and dynamic insulin secretion and intracellular calcium microfluorimetry. NAD-biosynthetic capacity of eNAMPT was assessed by colorimetric and fluorescent assays and by native mass spectrometry. Islet cell number was determined by immunohistochemical staining for insulin, glucagon and somatostatin, with islet apoptosis determined by caspase 3/7 activity. Markers of inflammation and beta cell identity were determined by quantitative reverse transcription PCR. Total, monomeric and dimeric eNAMPT and nicotinamide mononucleotide (NMN) were evaluated by ELISA, western blot and fluorometric assay using serum from non-diabetic, glucose intolerant and type 2 diabetic individuals. Results eNAMPT exerts bimodal and concentration- and structure-functional-dependent effects on beta cell functional mass. At low physiological concentrations (~1 ng/ml), as seen in serum from humans without diabetes, eNAMPT enhances beta cell function through NAD-dependent mechanisms, consistent with eNAMPT being present as a dimer. However, as eNAMPT concentrations rise to ~5 ng/ml, as in type 2 diabetes, eNAMPT begins to adopt a monomeric form and mediates beta cell dysfunction, reduced beta cell identity and number, increased alpha cell number and increased apoptosis, through NAD-independent proinflammatory mechanisms. Conclusions/interpretation We have characterised a novel mechanism of beta cell dysfunction in type 2 diabetes. At low physiological levels, eNAMPT exists in dimer form and maintains beta cell function and identity through NAD-dependent mechanisms. However, as eNAMPT levels rise, as in type 2 diabetes, structure-functional changes occur resulting in marked elevation of monomeric eNAMPT, which induces a diabetic phenotype in pancreatic islets. Strategies to selectively target monomeric eNAMPT could represent promising therapeutic strategies for the treatment of type 2 diabetes.

scholarly journals Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3846
Author(s):  
Jun Inaishi ◽  
Yoshifumi Saisho
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Current Knowledge ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction ◽  
Pancreatic Fat

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

scholarly journals JOE DOUPE LECTURE: Emerging Strategies for the Preservation of Pancreatic Beta-cell Function in early Type 2 Diabetes

2014 ◽  
Vol 37 (6) ◽  
pp. 414 ◽  
Author(s):  
Ravi Retnakaran
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Fundamental Problem ◽  
Pancreatic Beta Cell ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction ◽  
Pancreatic Beta Cell Function

A fundamental problem in the clinical management of type 2 diabetes is the inability to prevent the ongoing deterioration of pancreatic beta-cell function over time that underlies the chronic progressive nature of this condition. Importantly, beta-cell dysfunction has both reversible and irreversible components. Furthermore, the amelioration of reversible beta-cell dysfunction through the early institution of short-term insulin-based therapy has emerged as a strategy that can yield temporary remission of type 2 diabetes. In this context, we have forwarded a novel therapeutic paradigm consisting of initial induction therapy to improve beta-cell function early in the course of diabetes followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. Ultimately, this approach may yield an optimized therapeutic strategy for the durable preservation of beta-cell function and consequent modification of the natural history of type 2 diabetes.

scholarly journals The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

2020 ◽  
Vol 27 (SP2) ◽  
pp. e22-e38
Author(s):  
Maximilian Andreas Storz
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood. The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function. Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction. Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels. All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

scholarly journals Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice

2021 ◽  
Author(s):  
Kazuno Omori ◽  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Yuki Yamauchi ◽  
Shinichiro Kawata ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Glucose Signalling ◽  
Excess Glucose

Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related with the excess glucose signalling by glucokinase activation towards beta-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as beta-cell function and mass using a mouse model of type 2 diabetes. Our results showed that <i>db/db</i> mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with <i>db/db</i> mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of <i>db/db</i> mice was associated with lower expression of stress-related genes, higher expression of transcription factors involved in the maintenance and maturation of beta-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve beta-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signalling in beta-cells by inhibiting glucokinase could prevent beta-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving beta-cell mass. Therefore, glucokinase inactivation in beta-cells could, paradoxically, be a potential strategy for the treatment of type 2 diabetes.

scholarly journals Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice

2021 ◽  
Author(s):  
Kazuno Omori ◽  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Yuki Yamauchi ◽  
Shinichiro Kawata ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Glucose Signalling ◽  
Excess Glucose

Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related with the excess glucose signalling by glucokinase activation towards beta-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as beta-cell function and mass using a mouse model of type 2 diabetes. Our results showed that <i>db/db</i> mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with <i>db/db</i> mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of <i>db/db</i> mice was associated with lower expression of stress-related genes, higher expression of transcription factors involved in the maintenance and maturation of beta-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve beta-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signalling in beta-cells by inhibiting glucokinase could prevent beta-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving beta-cell mass. Therefore, glucokinase inactivation in beta-cells could, paradoxically, be a potential strategy for the treatment of type 2 diabetes.

The Effects of Beta-cell Mass and Function, Intercellular Coupling, and islet Synchrony on Ca2+ Dynamics in Patients with Type 2 Diabetes Mellitus

2020 ◽  
Author(s):  
Maryam Saadati ◽  
Yousef Jamali
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Mass ◽  
Electrical Coupling ◽  
Beta Cell Mass ◽  
Intercellular Coupling ◽  
And Function

Abstract Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of beta-cell mass via progressive programmed cell death and alteration of beta-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in beta-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of beta-cell mass to beta-cell function in T2D, we make use of a comprehensive electrophysiological model from human beta-cell clusters. We find that defect in beta-cell mass causes a functional decline in single beta-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular Ca2+ concentration, which can lead to changes in insulin secretion dynamics and insulin levels. The model demonstrates good correspondence between suppression of synchronizing electrical activity and pulsatile insulin release, and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both beta-cell synchronization and metabolic coupling in the behavior of Ca2+ concentration dynamics within human islets. Our results indicate that inter-beta-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D. We further predict that varying the conductance gating of delayed rectifier K+ channels modifies oscillatory activity patterns of the beta-cell population lacking intercellular coupling, which significantly affects Ca2+ concentration and insulin secretion.

scholarly journals The Dynamic Roles of Visfatin and Obestatin Serum Concentration in Pancreatic Beta Cells Dysfunction (HOMA-beta) and Insulin Resistance (HOMA-IR) in Centrally Obese Men

2012 ◽  
Vol 4 (1) ◽  
pp. 43
Author(s):  
Bayu Winata Putera ◽  
Cynthia Retna Sartika ◽  
Andi Wijaya
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Cell Dysfunction ◽  
Pancreas Cell

BACKGROUND: Obesity is a major health problem in the world today. Obesity is closely associated with insulin resistance and type 2 diabetes. Epidemiological studies have shown that obese persons are in a state of insulin resistance, however, most of them do not progress to type 2 diabetes. This occurs because the beta cell function is still good enough for maintaining normal glucose level. Obestatin and visfatin are cytokines that are known to have a role in beta cell function. The aim of this study was to assess the relationship between visfatin and obestatin and Homeostasis Model Assessment of beta cell function (HOMA-β) and Homeostasis Model Assessment of insulin resistance (HOMA-IR).METHODS: This was a cross-sectional study involving 80 central obesity men with waist circumference >90 cm, age 30-65 years old. Visfatin and obestatin were measured by ELISA method. Beta pancreas cell dysfunction and insulin resistance were calculated by HOMA model.RESULTS: Our study showed a correlation between visfatin and HOMA-β (r=0.244 and p = 0.029) and visfatin with HOMA-IR (r=0.287 and p=0.001) and no correlation was found between obestatin with HOMA-β (r=0.010 and p=0.990) and obestatin with HOMA-IR (r=0.080 and p=0.480). We also found visfatin and obestatin concentrations were fluctuative depending on the measurements of the waist circumferences.CONCLUSIONS: High visfatin and low obestatin concentration were independently associated with increased beta pancreas cell dysfunction and insulin resistance.KEYWORDS: obesity. visfatin, obestatin, beta cell dysfunction (HOMA-β), insulin resistance (HOMA-IR)

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