Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons

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 db/db mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with db/db mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db 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.

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The Current State of Beta-Cell-Mass PET Imaging for Diabetes Research and Therapies

Biomedicines ◽

10.3390/biomedicines9121824 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1824

Author(s):

Pierre Cheung ◽

Olof Eriksson

Keyword(s):

Positron Emission Tomography ◽

Beta Cell ◽

Disease Progression ◽

Beta Cell Function ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Emission Tomography ◽

Diabetes Research ◽

Positron Emission

Diabetes is a chronic metabolic disease affecting over 400 million people worldwide and one of the leading causes of death, especially in developing nations. The disease is characterized by chronic hyperglycemia, caused by defects in the insulin secretion or action pathway. Current diagnostic methods measure metabolic byproducts of the disease such as glucose level, glycated hemoglobin (HbA1c), insulin or C-peptide levels, which are indicators of the beta-cell function. However, they inaccurately reflect the disease progression and provide poor longitudinal information. Beta-cell mass has been suggested as an alternative approach to study disease progression in correlation to beta-cell function, as it behaves differently in the diabetes physiopathology. Study of the beta-cell mass, however, requires highly invasive and potentially harmful procedures such as pancreatic biopsies, making diagnosis and monitoring of the disease tedious. Nuclear medical imaging techniques using radiation emitting tracers have been suggested as strong non-invasive tools for beta-cell mass. A highly sensitive and high-resolution technique, such as positron emission tomography, provides an ideal solution for the visualization of beta-cell mass, which is particularly essential for better characterization of a disease such as diabetes, and for estimating treatment effects towards regeneration of the beta-cell mass. Development of novel, validated biomarkers that are aimed at beta-cell mass imaging are thus highly necessary and would contribute to invaluable breakthroughs in the field of diabetes research and therapies. This review aims to describe the various biomarkers and radioactive probes currently available for positron emission tomography imaging of beta-cell mass, as well as highlight the need for precise quantification and visualization of the beta-cell mass for designing new therapy strategies and monitoring changes in the beta-cell mass during the progression of diabetes.

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Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas

F1000Research ◽

10.12688/f1000research.9129.1 ◽

2016 ◽

Vol 5 ◽

pp. 1851 ◽

Cited By ~ 5

Author(s):

Ahmed Abbas ◽

Christine Beamish ◽

Rebecca McGirr ◽

John Demarco ◽

Neil Cockburn ◽

...

Keyword(s):

Beta Cell ◽

Er Stress ◽

Beta Cell Function ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Wild Type ◽

Time Activity ◽

System L ◽

Akita Mice

Purpose: In diabetes, pancreatic beta cell mass declines significantly prior to onset of fasting hyperglycemia. This decline may be due to endoplasmic reticulum (ER) stress, and the system L amino acid transporter LAT1 may be a biomarker of this process. In this study, we used 5-(2-18F-fluoroethoxy)-L-tryptophan (18F-L-FEHTP) to target LAT1 as a potential biomarker of beta cell function in diabetes. Procedures: Uptake of 18F-L-FEHTP was determined in wild-type C57BL/6 mice by ex vivo biodistribution. Both dynamic and static positron emission tomography (PET) images were acquired in wild-type and Akita mice, a model of ER stress-induced diabetes, as well as in mice treated with streptozotocin (STZ). LAT1 expression in both groups of mice was evaluated by immunofluorescence microscopy. Results: Uptake of 18F-L-FEHTP was highest in the pancreas, and static PET images showed highly specific pancreatic signal. Time-activity curves showed significantly reduced 18F-L-FEHTP uptake in Akita mice, and LAT1 expression was also reduced. However, mice treated with STZ, in which beta cell mass was reduced by 62%, showed no differences in 18F-L-FEHTP uptake in the pancreas, and there was no significant correlation of 18F-L-FEHTP uptake with beta cell mass. Conclusions: 18F-L-FEHTP is highly specific for the pancreas with little background uptake in kidney or liver. We were able to detect changes in LAT1 in a mouse model of diabetes, but these changes did not correlate with beta cell function or mass. Therefore, 18F-L-FEHTP PET is not a suitable method for the noninvasive imaging of changes in beta cell function during the progression of diabetes.

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Stereological assessment of pancreatic beta-cell mass development in male Zucker Diabetic Fatty (ZDF) rats: correlation with pancreatic beta-cell function

Journal of Anatomy ◽

10.1111/j.1469-7580.2010.01285.x ◽

2010 ◽

Vol 217 (5) ◽

pp. 624-630 ◽

Cited By ~ 21

Author(s):

Sarah Juel Paulsen ◽

Niels Vrang ◽

Leif Kongskov Larsen ◽

Philip Just Larsen ◽

Jacob Jelsing

Keyword(s):

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Zdf Rats ◽

Mass Development ◽

Pancreatic Beta Cell Mass ◽

Pancreatic Beta Cell Function

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Defective exocytosis and processing of insulin in a cystic fibrosis mouse model

Journal of Endocrinology ◽

10.1530/joe-18-0570 ◽

2019 ◽

Vol 241 (1) ◽

pp. 45-57 ◽

Cited By ~ 2

Author(s):

A Edlund ◽

M Barghouth ◽

M Hühn ◽

M Abels ◽

J S E Esguerra ◽

...

Keyword(s):

Cystic Fibrosis ◽

Mouse Model ◽

Beta Cell ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Hormone Secretion ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Number

Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine alpha and beta cell function in the Cftr tm1 EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild type (WT) mice aged 7–10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in (1) reduced number of docked insulin granules and reduced exocytosis and (2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.

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

10.2337/figshare.13626674.v1 ◽

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 db/db mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with db/db mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db 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.

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

10.21203/rs.3.rs-132280/v1 ◽

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.

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Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

Journal of Diabetes Research ◽

10.1155/2014/618652 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 23

Author(s):

Valérie Plaisance ◽

Gérard Waeber ◽

Romano Regazzi ◽

Amar Abderrahmani

Keyword(s):

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Oxidized Ldl ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Proliferation ◽

Beta Cell Compensation ◽

And Function

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

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