scholarly journals AFF3 and BACH2 are master regulators of metabolic inflexibility, β/α-cell transition, and dedifferentiation in type 2 diabetes

2019 ◽  
Author(s):  
Jinsook Son ◽  
Hongxu Ding ◽  
Domenico Accii ◽  
Andrea Califano
Keyword(s):  
Type 2 Diabetes ◽  
Single Cell ◽  
Cell Mass ◽  
Lineage Tracing ◽  
Calcium Flux ◽  
Pharmacological Intervention ◽  
Β Cell ◽  
Master Regulators ◽  
Metabolic Inflexibility

ABSTRACTType 2 Diabetes is associated with defective insulin secretion, reduced β-cell mass, and increased glucagon production. Cell lineage-tracing in rodents and human autopsy surveys support the notion of β-cell dedifferentiation as a unifying mechanism for these abnormalities. Yet, mechanistic determinants of human β-cell failure remain elusive. Using regulatory-network-based single-cell analysis of human islets, we identify aberrant, diabetes-enriched transitional states characterized by metabolic inflexibility, α/β-transition, and endocrine progenitor/stem cell features. A coordinated transcription factor hierarchy mediating cell state transition emerged and was validated using barcoded guide-based, single-cell gene transfer and calcium flux measures in primary human islet cells. Specifically, two master regulators and associated epigenetic drivers emerged, one (AFF3) controlling β- to α-like-cell reprogramming, the other (BACH2) transition to a dedifferentiated endocrine progenitor-like cell. The findings provide mechanistic insight into diabetic islet cell dysfunction and suggest actionable pathways for pharmacological intervention.

scholarly journals Systemic Metabolic Alterations Correlate with Islet-Level Prostaglandin E2 Production and Signaling Mechanisms That Predict β-Cell Dysfunction in a Mouse Model of Type 2 Diabetes

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 58 ◽  
Author(s):  
Michael D. Schaid ◽  
Yanlong Zhu ◽  
Nicole E. Richardson ◽  
Chinmai Patibandla ◽  
Irene M. Ong ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Prostaglandin E2 ◽  
Genetic Model ◽  
Cell Mass ◽  
Arachidonic Acid Metabolite ◽  
Β Cell ◽  
Human Organ ◽  
Cell Dysfunction ◽  
Primary Mouse

The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

scholarly journals Development of a Nongenetic Mouse Model of Type 2 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Elizabeth R. Gilbert ◽  
Zhuo Fu ◽  
Dongmin Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Serum Insulin ◽  
Cell Mass ◽  
Low Fat ◽  
Β Cell ◽  
Islet Mass ◽  
Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

scholarly journals Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

2015 ◽  
Vol 228 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Xinrong Zhou ◽  
Bangguo Qian ◽  
Ning Ji ◽  
Conghui Lui ◽  
Zhiyuan Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Bypass ◽  
Rat Model ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Cell Mass ◽  
Cell Area ◽  
Obese Patients ◽  
Β Cell

Gastric bypass surgery produces clear antidiabetic effects in a substantial proportion of morbidly obese patients. In view of the recent trend away from ‘bariatric’ surgery and toward ‘metabolic’ surgery, it is important to elucidate the enhancing effect of bypass surgery on pancreatic β-cell mass, which is related to diabetes remission in non-obese patients. We investigated the effects of gastric bypass surgery on glycemic control and other pancreatic changes in a spontaneous non-obese type 2 diabetes Goto-Kakizaki rat model. Significant improvements in postprandial hyperglycemia and plasma c-peptide level were observed when glucose was administered orally post-surgery. Other important events observed after surgery were enhanced first phase insulin secretion in a in site pancreatic perfusion experiment, pancreatic hyperplasia, improved islet structure (revealed by immunohistochemical analysis), striking increase in β-cell mass, slight increase in ratio of β-cell area to total pancreas area, and increased number of small islets closely related to exocrine ducts. No notable changes were observed in ratio of β-cell to non-β endocrine cell area, β-cell apoptosis, or β-cell proliferation. These findings demonstrate that gastric bypass surgery in this rat model increases endocrine cells and pancreatic hyperplasia, and reflect the important role of the gastrointestinal system in regulation of metabolism.

scholarly journals Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽  
2009 ◽  
Vol 24 (6) ◽  
pp. 325-331 ◽  
Author(s):  
Marc Y. Donath ◽  
Marianne Böni-Schnetzler ◽  
Helga Ellingsgaard ◽  
Jan A. Ehses
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Metabolic Stress ◽  
Innate Immune ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Amyloid Deposits ◽  
Impaired Insulin ◽  
Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

scholarly journals Differential Effects of Prenatal and Postnatal Nutritional Environment on β-Cell Mass Development and Turnover in Male and Female Rats

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5647-5656 ◽  
Author(s):  
Aleksey V. Matveyenko ◽  
Inderroop Singh ◽  
Bo-Chul Shin ◽  
Senta Georgia ◽  
Sherin U. Devaskar
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Growth Restriction ◽  
Female Rats ◽  
Cell Replication ◽  
Β Cell ◽  
Male And Female ◽  
Fractional Area ◽  
Mass Development

Fetal nutrient and growth restriction is associated with development of type 2 diabetes. Although the exact mechanisms responsible for this association remain debated, intrauterine and/or postnatal maldevelopment of β-cell mass has been proposed as a potential mechanism. To address this hypothesis, β-cell mass development and turnover was assessed in rats exposed to either intrauterine and/or postnatal caloric/growth restriction. In total, four groups of male and female Sprague Dawley rats (n = 69) were developed and studied: 1) control rats, i.e. control mothers rearing control pups; 2) intrauterine calorically and growth-restricted rats, i.e. 50% prenatal calorically restricted pups cross-fostered to control mothers; 3) postnatal calorically and growth-restricted rats, i.e. 50% calorically restricted mothers rearing pups born to control mothers; and 4) prenatal and postnatal calorically and growth restricted rats, i.e. 50% calorically restricted mothers rearing intrauterine 50% calorically restricted pups. Intrauterine growth restriction resulted in approximately 45% reduction of postnatal β-cell fractional area and mass characterized by reduced rate of β-cell replication and decreased evidence of neogenesis. In contrast, β-cell fractional area and weight-adjusted β-cell mass in postnatal growth restriction was approximately 30% higher than in control rats. Rats exposed to both intrauterine and postnatal caloric and growth restriction demonstrated approximately 80% decrease in β-cell mass, reduction in β-cell replication, and decreased evidence of neogenesis compared with control. Neither intrauterine nor postnatal caloric restriction significantly affected the rate of β-cell apoptosis. These data support the hypothesis that intrauterine maldevelopment of β-cell mass may predict the increased risk of type 2 diabetes in adult life.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

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.

Managing the β-cell with GLP-1 in type 2 diabetes

2008 ◽  
Vol 8 (2_suppl) ◽  
pp. S19-S25 ◽  
Author(s):  
Baptist Gallwitz
Keyword(s):  
Type 2 Diabetes ◽  
Phase Ii ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Neonatal Rat ◽  
Β Cell ◽  
Β Cell Function

The clinical course of type 2 diabetes mellitus is characterised by a progressive decline in β -cell mass. The changing β-cell mass reflects a shifting balance between β-cell neogenesis, islet neogenesis and β-cell apoptosis. In persons with diabetes, administration of exogenous glucagon-like peptide-1 (GLP-1) improves glucose sensitivity and insulin synthesis and may help increase β cell mass. As the effects of GLP-1 on the β cell are becoming better understood at both the molecular and cellular levels, it has become possible to develop therapies with the potential to harness and sustain the positive effects of endogenous GLP-1 in patients with type 2 diabetes. Data from in vitro, preclinical and phase II studies show promising results with GLP-1 analogues in improving β-cell function in patients with type 2 diabetes. For example, in vitro models have shown the GLP-1 analogue liraglutide inhibits β-cell apoptosis in isolated neonatal rat islets. In vitro, animal models demonstrate increasing β-cell mass with liraglutide administration. Results from a recently completed phase II clinical trial with liraglutide in patients with type 2 diabetes demonstrate that daily treatment markedly improves β -cell function as shown by an increased first-phase insulin response and secretory capacity and a decreased proinsulin:insulin ratio. Now, phase III trials continue to bear out the potential for liraglutide for treatment of patients with type 2 diabetes.Br J Diabetes Vasc Dis 2008;8 (Suppl 2): S19-S25

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

Sign in / Sign up

Export Citation Format

Share Document