Gastric bypass prevents diabetes in genetically modified mice and chemically induced diabetic mice

Obese subjects have increase probabilities of developing type 2 diabetes (T2D). In this study, we sought to determine whether gastric bypass prevents the progression of prediabetes to overt diabetes in genetically modified mice and chemically induced diabetic mice. Roux-en-Y gastric bypass (RYGB) was performed in C57BL/KsJ-db/db null (BKS-db/db,) mice, high-fat diet (HFD)-fed NONcNZO10/LtJ (NZO) mice, C57BL/6 db/db null (B6-db/db) mice and streptozotocin (STZ)-induced diabetic mice. Food consumption, body weight, fat mass, fast blood glucose level, circulating insulin and adiponectin and glucose tolerance test were analyzed. The liver and pancreatic tissues were subjected to H&E and immunohistochemistry staining and islet cells to flow cytometry for apoptotic analysis. RYGB resulted in sustained normoglycemia and improved glucose tolerance in young prediabetic BKS-db/db mice (at the age of 6 weeks with hyperglycemia and normal insulinemia) and HFD-fed NZO and B6-db/db mice. Remarkably, RYGB improved liver steatosis, preserved the pancreatic β-cells and reduced β-cell apoptosis with increases in circulating insulin and adiponectin in young prediabetic BKS-db/db mice. However, RYGB neither reversed hyperglycemia in adult diabetic BKS-db/db mice (12 weeks old) nor attenuated hyperglycemia in STZ-induced diabetic mice. These results demonstrate that gastric bypass improves hyperglycemia in genetically modified prediabetic mice; however, it should be performed prior to β-cells exhaustion.

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Compound K protects pancreatic islet cells against apoptosis through inhibition of the AMPK/JNK pathway in type 2 diabetic mice and in MIN6 β-cells

Life Sciences ◽

10.1016/j.lfs.2014.04.034 ◽

2014 ◽

Vol 107 (1-2) ◽

pp. 42-49 ◽

Cited By ~ 22

Author(s):

Feng Ying Guan ◽

Jian Gu ◽

Wei Li ◽

Ming Zhang ◽

Yingshi Ji ◽

...

Keyword(s):

Pancreatic Islet ◽

Islet Cells ◽

Pancreatic Islet Cells ◽

Diabetic Mice ◽

Compound K ◽

Β Cells ◽

Jnk Pathway ◽

Type 2 Diabetic

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Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

Molecules ◽

10.3390/molecules25194381 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4381

Author(s):

Zakiyatul Faizah ◽

Bella Amanda ◽

Faisal Yusuf Ashari ◽

Efta Triastuti ◽

Rebecca Oxtoby ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

In Vivo Models ◽

Type 2 Dm ◽

Type 1 Dm

Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus.

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Could TDX-1 explain the changes observed in endocrine pancreas due to chronic cola drink consumption in rats? A global point of view

10.1101/2020.11.20.391060 ◽

2020 ◽

Author(s):

Gabriel Cao ◽

Julián González ◽

Juan P. Ortiz Fragola ◽

Angélica Muller ◽

Mariano Tumarkin ◽

...

Keyword(s):

Body Weight ◽

Glucose Tolerance ◽

Islet Cells ◽

Cross Sectional Area ◽

The Other ◽

Cell Area ◽

Sectional Area ◽

Β Cells ◽

Β Cell ◽

Cross Sectional

AbstractIn previous studies, we reported evidence showing that chronic cola consumption in rats impairs pancreatic metabolism of insulin and glucagon and produces some alterations typically observed in the metabolic syndrome (i.e, hyperglycemia, and hypertriglyceridemia) with an increase in oxidative stress. Of note, no apoptosis nor proliferation of islet cells could be demonstrated. In the present study, 36 male Wistar rats were divided in three groups to freely drink regular cola, light cola, or water (controls). We assessed the impact of the three different beverages in glucose tolerance, lipid levels, creatinine levels and immunohistochemical changes addressed for the expression of insulin, glucagon, PDX-1 and NGN3 in islet cells, to evaluate the possible participation of PDX-1 in the changes observed in α and β cells after 6 months of treatment. On the other hand, we assessed by stereological methods, the mean volume of islets (Vi) and three important variables, the fractional β-cell area, the cross-sectional area of alpha (A α-cell) and beta cells (A β-cell), and the number of β and α cell per body weight.Cola drinking caused impaired glucose tolerance as well as fasting hyperglycemia and increase of insulin immunolabeling. Immunohistochemical expression for PDX-1 was significantly high in regular cola consumption group compared to control. In this case, we observed cytoplasmatic and nuclear localization. Likewise, a mild but significant decrease of Vi was detected after 6 months of cola drink consumption compared with control group. Also, we observed a significant decrease of fractional β cell area compared with control rats. Accordingly, a reduced mean value of islet α and β cell number per body weight compared to control was detected. Interestingly, consumption of light cola increased the Vi compared to control. In line with this, a decreased cross-sectional area of β-cells was observed after chronic consumption of both, regular and light cola, compared to controls. On the other hand, NGN3 was negative in all three groups. Our results support for the first time, the idea that TDX-1 plays a key role in the dynamics of the pancreatic islets after chronic consumption of sweetened beverages. The loss of islets cells might be attributed to autophagy, favored by the local metabolic conditions.

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Islet cell engraftment and control of diabetes in rats after transplantation of pig pancreatic anlagen

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00445.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. E502-E509 ◽

Cited By ~ 17

Author(s):

Sharon A. Rogers ◽

Feng Chen ◽

Mike Talcott ◽

Marc R. Hammerman

Keyword(s):

Glucose Tolerance ◽

Islet Cells ◽

Diabetic Rats ◽

Tissue Loss ◽

Β Cells ◽

Porcine Pancreas ◽

Cell Engraftment ◽

Stromal Component ◽

Control Of Diabetes ◽

And Control

The insufficient supply of tissue, loss posttransplantation, and limited potential for expansion of β-cells restrict the use of islet allotransplantation for diabetes. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. We have shown that whole rat pancreatic anlagen isotransplanted into the omentum of rats, or xenotransplanted into costimulatory blocked mice, undergo growth and differentiate into islets surrounded by stoma without exocrine tissue. Isotransplants normalize glucose tolerance in diabetic hosts. Here, we show that embryonic day 29 porcine pancreas transplanted into the omentum of adult diabetic rats undergoes endocrine tissue differentiation over 20 wk and normalizes body weights and glucose tolerance. Unlike rat-to-rodent transplants, individual α- and β-cells engraft without a stromal component, and no immunosuppression is required for pig-to-rat transplants. Herein is described a novel means to effect the xenotransplantation of individual islet cells across a highly disparate barrier.

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Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Cells ◽

10.3390/cells10092237 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2237

Author(s):

Yuko Okano ◽

Atsuro Takeshita ◽

Taro Yasuma ◽

Masaaki Toda ◽

Kota Nishihama ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Mouse Model ◽

Pancreatic Islet ◽

Glucose Intolerance ◽

Cell Mass ◽

Diabetic Mice ◽

Β Cells ◽

Β Cell ◽

Diabetes Mouse

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

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Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery

10.2337/figshare.13166255 ◽

2020 ◽

Author(s):

Roman Vangoitsenhoven ◽

Rickesha Wilson ◽

Deepa V Cherla ◽

Chao Tu ◽

Sangeeta R Kashyap ◽

...

Keyword(s):

Gastric Bypass ◽

Metabolic Surgery ◽

Gastric Bypass Surgery ◽

Liver Steatosis ◽

Multivariable Analysis ◽

Diabetes Remission ◽

Independent Association ◽

Glycemic Outcomes ◽

Design And Methods

Objective: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and beta-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, <a>we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery.</a> Research design and methods: A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin < 6.5% off medications). Results: Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients, compared with 44/112 (39%) remission in patients without steatosis (P=0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96, [95% confidence interval 1.04 – 3.72], P=0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. Conclusion: This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are different variants of T2DM wherein metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

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