scholarly journals Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD–scid IL-2rgnull RIP-DTR mice engrafted with human islets

2015 ◽  
pp. 387 ◽  
Author(s):  
Rita Bortell ◽  
Chaoxing Yang ◽  
Matthias Loehn ◽  
Agata Jurczyk ◽  
Natalia Przewozniak ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Islets ◽  
Human Beta Cell

scholarly journals OR14-01 FSTL3 Neutralizing Antibodies Restore Function to Diabetic Mouse and Human Islets: A New Approach for Treating Diabetes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alan Schneyer ◽  
Melissa L Brown ◽  
Nolan Meyer ◽  
Alexa Lopez ◽  
Alden Richter
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
High Glucose ◽  
Beta Cell Function ◽  
Neutralizing Antibodies ◽  
Cell Function ◽  
Human Islets ◽  
Extracellular Proteins ◽  
Chow Diet ◽  
Human Diabetes

Abstract Activin, GDF11 and myostatin are structurally related members of the TGFbeta superfamily of growth factors with many biological roles in animal models and humans. Their actions are neutralized by extracellular proteins such as follistatin and follistatin like-3 (FSTL3). We have previously demonstrated that genetic inactivation of Fstl3 results in enlarged pancreatic islets containing increased numbers of beta cells that produce more insulin in response to glucose compared to wild type litter mates. We further discovered that at least some of these new beta cells arise via transdifferentiation from alpha cells. We also demonstrated that functional human islets from normal donors produce very high levels of activin. In contrast, activin biosynthesis is vastly reduced and FSTL3 synthesis is significantly increased in human islets from diabetic donors suggesting that activin is critical for normal insulin production. This was substantiated by direct treatment of human diabetic islets with activin which restored their response to glucose. These observations support the hypothesis that an FSTL3 neutralizing antibody would constitute a novel therapeutic approach to curing diabetes through restoring beta cell function as well as accelerating generation of new beta cells through transdifferentiation. To test this hypothesis, we produced a mouse monoclonal antibody that neutralized hFSTL3 (FP-101), thereby releasing bioactive activin, GDF11, and myostatin. We have now tested this antibody for biological activity in vitro on mouse and human islets. We used islets from high fat diet (HFD) treated mice to model diabetes-inducing effects of obesity as well as 24-hour incubation in hyperglycemic (33 mM glucose) medium to create human islets that lose responsiveness to high glucose as a model for human diabetes. In mouse islets we found that stimulation of normal (chow diet) islets by high glucose produced a stimulation index (SI) of 3.5 that was reduced to 2 in HFD islets. Treatment with activin, FP-101, or a commercial polyclonal antibody to mFSTL3 all increased response of HFD islets to elevated glucose and partially restored SI to normal levels. In human islets, hyperglycemia eliminated the normal (2.5 SI) response to high glucose while activin or FP-101 treatments dose-responsively restored this response. These results demonstrate that anti-FSTL3 therapy can restore function to compromised beta cells from mouse and human diabetes models. The observation that activin has the same action as anti-FSTL3 antibody indicates that FP-101 works through enhancing the activin signaling pathway. Finally, these results demonstrate that the FSTL3-activin pathway is an important regulator of beta cell function in humans as well as mice, supporting further development of this therapy as a diabetes treatment.

scholarly journals Loss of MANF Causes Childhood Onset Syndromic Diabetes due to Increased Endoplasmic Reticulum Stress

2021 ◽  
Author(s):  
Hossam Montaser ◽  
Kashyap A Patel ◽  
Diego Balboa ◽  
Hazem Ibrahim ◽  
Väinö Lithovius ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Beta Cell Development ◽  
Human Beta Cell ◽  
And Function

MANF is an endoplasmic reticulum resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse beta cells, its precise role in human beta cell development and function is unknown. Herein, we show that lack of MANF in humans results in diabetes due to increased ER stress leading to impaired beta cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the <i>MANF</i> gene. To study the role of MANF in human beta cell development and function, we knocked out the <i>MANF </i>gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of <i>MANF</i> induced mild ER stress and impaired insulin processing capacity of beta cells <i>in vitro</i>. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in diabetic recipients. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human beta cell function and demonstrate the crucial role of MANF in this process.

scholarly journals The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro

2016 ◽  
Vol 19 (2) ◽  
pp. 257-265 ◽  
Author(s):  
Attilio Pingitore ◽  
Edward S. Chambers ◽  
Thomas Hill ◽  
Inmaculada Ruz Maldonado ◽  
Bo Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Short Chain Fatty Acid ◽  
Cell Function ◽  
Human Islets ◽  
Chain Fatty Acid ◽  
Short Chain

scholarly journals IL-1 produced and released endogenously within human islets inhibits beta cell function.

1998 ◽  
Vol 102 (3) ◽  
pp. 516-526 ◽  
Author(s):  
M Arnush ◽  
M R Heitmeier ◽  
A L Scarim ◽  
M H Marino ◽  
P T Manning ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Islets

scholarly journals Correction to: Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets

Diabetologia ◽  
2019 ◽  
Vol 62 (3) ◽  
pp. 553-554
Author(s):  
I. Goehring ◽  
N. S. Sauter ◽  
G. Catchpole ◽  
A. Assmann ◽  
L. Shu ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Line ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Islets ◽  
Metabolic Signature ◽  
Beta Cell Line
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