2142-P: Toll-Like Receptors 2 and 4 Act as Brakes to Regulate Adaptive ß-Cell Mass Expansion in Diet-Induced Obesity

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

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CTNNB1/β-catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes

Science Advances ◽

10.1126/sciadv.aax9605 ◽

2020 ◽

Vol 6 (2) ◽

pp. eaax9605 ◽

Cited By ~ 8

Author(s):

Maopei Chen ◽

Peng Lu ◽

Qinyun Ma ◽

Yanan Cao ◽

Na Chen ◽

...

Keyword(s):

Cross Talk ◽

High Fat Diet ◽

Genetic Factors ◽

Obesity Risk ◽

High Fat ◽

Diet Induced Obesity ◽

Whole Exome ◽

Obese Subjects ◽

Mass Expansion ◽

Transcription Factor Complex

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in CTNNB1/β-catenin associated with increased obesity risk. Specific ablation of β-catenin in mature adipocytes attenuated high-fat diet–induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα+ preadipocytes and less mature adipocytes. Mechanistically, β-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through β-catenin–TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that β-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of β-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/β-catenin pathway to combat obesity.

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Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice

Diabetologia ◽

10.1007/s00125-015-3670-0 ◽

2015 ◽

Vol 58 (9) ◽

pp. 2064-2073 ◽

Cited By ~ 16

Author(s):

Yili Xu ◽

Xiaojing Wang ◽

Li Gao ◽

Jiayu Zhu ◽

Hui Zhang ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Mass Expansion

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Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

Journal of Endocrinology ◽

10.1530/joe-14-0222 ◽

2014 ◽

Vol 223 (1) ◽

pp. 67-78 ◽

Cited By ~ 17

Author(s):

Noèlia Téllez ◽

Eduard Montanya

Keyword(s):

Cell Mass ◽

Β Cell ◽

Neurogenin 3 ◽

Glucose Levels ◽

Ductal Cells ◽

Blood Glucose Levels ◽

Morphometric Analyses ◽

Underlying Mechanisms ◽

Mass Expansion

Induction of β-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and β-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced β-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin- and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the Px+G and Px+V groups. However, in the Px+G group, the ductal structures showed lower levels of keratin 20 and β-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with Px+V rats. In Px+G rats, β-cell mass and the number of scattered β-cells were significantly increased compared with Px+V rats, whereas β-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased β-cell neogenesis and fostered β-cell mass expansion.

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XOMA 052, an Anti-IL-1β Monoclonal Antibody, Improves Glucose Control and β-Cell Function in the Diet-Induced Obesity Mouse Model

Endocrine Reviews ◽

10.1210/edrv.31.2.9992 ◽

2010 ◽

Vol 31 (2) ◽

pp. 261-261

Author(s):

Alexander M. Owyang ◽

Kathrin Maedler ◽

Lisa Gross ◽

Johnny Yin ◽

Lin Esposito ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Monoclonal Antibody ◽

Type 2 Diabetes Mellitus ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Diet Induced Obesity ◽

Β Cell Function

ABSTRACT Recent evidence suggests that IL-1β-mediated glucotoxicity plays a critical role in type 2 diabetes mellitus. Although previous work has shown that inhibiting IL-1β can lead to improvements in glucose control and β-cell function, we hypothesized that more efficient targeting of IL-1β with a novel monoclonal antibody, XOMA 052, would reveal an effect on additional parameters affecting metabolic disease. In the diet-induced obesity model, XOMA 052 was administered to mice fed either normal or high-fat diet (HFD) for up to 19 wk. XOMA 052 was administered as a prophylactic treatment or as a therapy. Mice were analyzed for glucose tolerance, insulin tolerance, insulin secretion, and lipid profile. In addition, the pancreata were analyzed for β-cell apoptosis, proliferation, and β-cell mass. Mice on HFD exhibited elevated glucose and glycated hemoglobin levels, impaired glucose tolerance and insulin secretion, and elevated lipid profile, which were prevented by XOMA 052. XOMA 052 also reduced β-cell apoptosis and increased β-cell proliferation. XOMA 052 maintained the HFDinduced compensatory increase in β-cell mass, while also preventing the loss in β-cell mass seen with extended HFD feeding. Analysis of fasting insulin and glucose levels suggests that XOMA 052 prevented HFD-induced insulin resistance. These studies provide new evidence that targeting IL-1β in vivo could improve insulin sensitivity and lead to β-cell sparing. This is in addition to previously reported benefits on glycemic control. Taken together, the data presented suggest that XOMA 052 could be effective for treating many aspects of type 2 diabetes mellitus.

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Spontaneous restoration of functional β-cell mass in obese SM/J mice

10.1101/2020.05.19.104588 ◽

2020 ◽

Author(s):

Mario A Miranda ◽

Caryn Carson ◽

Celine L St Pierre ◽

Juan F Macias-Velasco ◽

Jing W Hughes ◽

...

Keyword(s):

Insulin Secretion ◽

Mitotic Index ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Physiological Mechanisms ◽

Β Cell Function ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion ◽

Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

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JAK-2 Positive Polycythemia Vera with Paroxysmal Nocturnal Hemoglobinuria and Splanchic Thromboses: A Case Report and Review of the Literature.

10.21203/rs.3.rs-114657/v1 ◽

2020 ◽

Author(s):

Sevastianos Chatzidavid ◽

Nefeli Giannakopoulou ◽

Panagiotis Theodorou Diamantopoulos ◽

Eleni Gavriilaki ◽

Panagiota Katsiampoura ◽

...

Keyword(s):

Polycythemia Vera ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Myeloproliferative Neoplasms ◽

Left Kidney ◽

Cell Mass ◽

Interesting Case ◽

Haematopoietic Stem Cell ◽

Case Presentation ◽

Potential Association ◽

Mass Expansion

Abstract Background: Polycythemia vera (PV) is usually characterized by red cell mass expansion in the peripheral blood and can be complicated with thrombosis, bleeding, evolution to acute myeloid leukemia (AML) or a fibrotic phase. Paroxysmal nocturnal hemoglobinuria (PNH) in an acquired clonal haematopoietic stem cell disorder associated with chronic intravascular hemolysis, venous thrombosis, defective hematopoiesis, frequent episodes of infection and, rarely, leukemic transformation. Herein, we report an interesting case of a patient with co-existence of PNH clones and a JAK2V617F positive polycythemia vera, with unusual thromboses and not overt hemolysis.Case presentation: the case is a 51-year-old woman presented with increased levels of hematocrit and multiple liver, spleen, and left kidney infarctions with ascites; further investigation revealed a JAK2-positive polycythemia vera and a significant PNH population. Interestingly, our patient has experienced severe thrombotic events without reporting signs or symptoms of overt hemolysis.Conclusions: This case raises questions over uncharted aspects of the PNH etiopathogenesis, its potential association with myeloproliferative neoplasms (MPN) and highlights the difficulty of dealing with patients with more than one pro-thrombotic states, especially with established and severe thromboses.

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