Sphingosine‑1‑phosphate induces islet β‑cell proliferation and decreases cell apoptosis in high‑fat diet/streptozotocin diabetic mice

Abstract Background High-fat-diet induces pancreatic β-cell compensatory proliferation, and impairments in pancreatic β-cell proliferation and function can lead to defects in insulin secretion and diabetes. NFATc3 is important for HFD-induced adipose tissue inflammation. But it is unknown whether NFATc3 is required for β cell compensatory growth in mice fed with HFD. Methods NFATc3 mRNA and protein expression levels were quantified by RT-qPCR and Western blotting, respectively, in pancreatic islets of WT mice fed on HFD for 12–20 weeks. Adenoviral-mediated overexpression of NFATc3 were conducted in Min6 cells and cultured primary mouse islets. NFATc3-/- mice and WT control mice were fed with HFD and metabolic and functional parameters were measured. Results We observed that the NFATc3 expression level was reduced in the islets of high-fat-diet (HFD)-fed mice. Adenovirus-mediated overexpression of NFATc3 enhanced glucose-stimulated insulin secretion and β-cell gene expression in cultured primary mouse islets. Nfatc3-/- mice initially developed similar glucose tolerance at 2–4 weeks after HFD feeding than HFD-fed WT mice, but Nfatc3-/- mice developed improved glucose tolerance and insulin sensitivity after 8 weeks of HFD feeding compared to Nfatc3+/+fed with HFD. Furthermore, Nfatc3-/- mice on HFD exhibited decreased β-cell mass and reduced expression of genes important for β-cell proliferation and function compared to Nfatc3+/+mice on HFD. Conclusions The findings suggested that NFATc3 played a role in maintaining the pancreatic β-cell compensatory growth and gene expression in response to obesity.

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Increased β-cell Proliferation and β-cell Mass Induced Through High Fat Diet in Mice*

Journal of Clinical Lipidology ◽

10.1016/j.jacl.2013.03.026 ◽

2013 ◽

Vol 7 (3) ◽

pp. 244

Author(s):

Kavin Arasi ◽

Rockann Mosser ◽

Maureen Gannon

Keyword(s):

Cell Proliferation ◽

High Fat Diet ◽

Cell Mass ◽

High Fat ◽

Β Cell

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TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation

Development ◽

10.1242/dev.194928 ◽

2021 ◽

Author(s):

Molly K. Altman ◽

Charles M. Schaub ◽

Matthew T. Dickerson ◽

Karolina E. Zaborska ◽

Prasanna K. Dadi ◽

...

Keyword(s):

Cell Proliferation ◽

Glucose Tolerance ◽

High Fat Diet ◽

Transient Receptor Potential ◽

Cell Function ◽

Cell Mass ◽

Transient Receptor Potential Channels ◽

High Fat ◽

Β Cell ◽

Β Cell Function

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic β-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in β-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, α-cell and β-cell mass. This resulted in modestly impaired glucose tolerance. However, TRPM7 ablation following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences β-cell hyperplasia under insulin resistant conditions. β-cell proliferation induced by high-fat diet was significantly decreased in TRPM7-deficient β-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters β-cell Mg2+ and reduces the magnitude of elevation in β-cell Mg2+ during proliferation. Together, these findings reveal that TRPM7 controls pancreatic development and β-cell proliferation, which is likely due to regulation of Mg2+ homeostasis.

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γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endocrinology ◽

10.1210/en.2014-1748 ◽

2015 ◽

Vol 156 (4) ◽

pp. 1242-1250 ◽

Cited By ~ 21

Author(s):

Chisayo Kozuka ◽

Sumito Sunagawa ◽

Rei Ueda ◽

Moritake Higa ◽

Hideaki Tanaka ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Er Stress ◽

High Fat Diet ◽

Diabetic Mice ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Glucose Stimulated Insulin Secretion

Abstract Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

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Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic β-cell function and mass through IRS2 in diabetic rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00434.2007 ◽

2007 ◽

Vol 103 (5) ◽

pp. 1764-1771 ◽

Cited By ~ 36

Author(s):

Sunmin Park ◽

Sang Mee Hong ◽

Ji Eun Lee ◽

So Ra Sung

Keyword(s):

Cell Proliferation ◽

High Fat Diet ◽

Cell Function ◽

Cell Mass ◽

Diabetic Rats ◽

Pancreatic Β Cell ◽

High Fat ◽

Β Cell ◽

Igf I ◽

Β Cell Function

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic β-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic β-cell mass. This resulted from stimulated β-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, β-cell mass was maintained in HF rats just as much as in control rats via increased individual β-cell size and neogenesis from precursor cells. Consistent with the results of β-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize β-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate β-cell function and mass to overcome insulin resistance in two different pathways.

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