High Fat Diet Regulation of β-Cell Proliferation and β-Cell Mass

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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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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Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00447.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. E367-E380 ◽

Cited By ~ 8

Author(s):

Kazuki Tajima ◽

Jun Shirakawa ◽

Tomoko Okuyama ◽

Mayu Kyohara ◽

Shunsuke Yamazaki ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Proliferation ◽

High Fat Diet ◽

Cell Mass ◽

Mammalian Target Of Rapamycin ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Cell Hyperplasia

Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced β-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced β-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

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High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00460.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. E573-E582 ◽

Cited By ~ 58

Author(s):

Rockann E. Mosser ◽

Matthew F. Maulis ◽

Valentine S. Moullé ◽

Jennifer C. Dunn ◽

Bethany A. Carboneau ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Proliferation ◽

High Fat Diet ◽

Cell Mass ◽

Chow Diet ◽

High Fat ◽

Β Cell ◽

Peripheral Insulin Resistance ◽

Insulin Tolerance

Both short- (1 wk) and long-term (2–12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.

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Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

10.1101/2021.03.05.434145 ◽

2021 ◽

Author(s):

Sharon Baumel-Alterzon ◽

Liora S. Katz ◽

Gabriel Brill ◽

Clairete Jean-Pierre ◽

Yansui Li ◽

...

Keyword(s):

Cell Proliferation ◽

High Fat Diet ◽

Ex Vivo ◽

Cell Mass ◽

Conditional Knockout ◽

Diabetes Research ◽

Loss Of Function ◽

High Fat ◽

Β Cells ◽

Β Cell

SUMMARYFinding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation and mass. Depletion of Nrf2 in β-cells resulted in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and β-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding β-cell mass in diabetes.

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Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00040.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. E149-E159 ◽

Cited By ~ 76

Author(s):

Rachel E. Stamateris ◽

Rohit B. Sharma ◽

Douglas A. Hollern ◽

Laura C. Alonso

Keyword(s):

Cell Proliferation ◽

Cell Mass ◽

Extended Period ◽

Time Frame ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Cyclin D2 ◽

Mass Expansion

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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Reduced Compensatory β-Cell Proliferation in Nfatc3-Deficient Mice Fed on High-Fat Diet

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1008-9110 ◽

2019 ◽

Cited By ~ 2

Author(s):

Li Hu ◽

Fengli He ◽

Yan Luo ◽

Hairong Luo ◽

Luo Hai ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

High Fat Diet ◽

Compensatory Growth ◽

Pancreatic Β Cell ◽

High Fat ◽

Β Cell ◽

Primary Mouse ◽

Mouse Islets ◽

And Function

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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