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

Tajima, Kazuki; Shirakawa, Jun; Okuyama, Tomoko; Kyohara, Mayu; Yamazaki, Shunsuke; Togashi, Yuichi; Terauchi, Yasuo

doi:10.1152/ajpendo.00447.2016

Cited by 26 publications

(24 citation statements)

References 54 publications

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“…It was important to investigate whether metformin‐induced improvement of hippocampal deterioration in middle‐aged DIO mice is involved in recovery from type 2 diabetes. Previous studies have shown that long‐term metformin treatment has no effect on body weight or blood glucose levels in HFD‐fed mice . Consistent with these results, prolonged treatment with metformin failed to improve weight gain, elevated levels of fasting blood glucose, and feeding behavior in middle‐aged DIO mice (Fig.…”

Section: Resultssupporting

confidence: 80%

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase ( AMPK ), atypical protein kinase C ζ ( aPKC ζ), and insulin receptor substrate 1 ( IRS 1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK , aPKC ζ/λ, and IRS 1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

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Section: Resultssupporting

confidence: 80%

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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“…In addition, long-term exposure to FFA results in suppressed glucose-stimulated insulin secretion (GSIS) and reduced insulin biosynthesis [ 72 ], eventually leading to adaptive decline of β-cell mass and/or function as a compensatory response to insulin resistance. Chronic glucose and fatty acid exposure eventually result in β-cell failure and the development of diabetes [ 72 , 73 ].…”

Section: Metformin Improves Pancreatic β-Cell Functionmentioning

confidence: 99%

“…The effect of metformin on high-glucose-induced pancreatic β-cell hyperplasia remains controversial. HFD-triggered adaptive pancreatic β-cell replication was suppressed by eight weeks of metformin treatment [ 73 ]. However, after sixty weeks of HFD feeding, increased β-cell mass was not suppressed [ 73 ].…”

Section: Metformin Improves Pancreatic β-Cell Functionmentioning

confidence: 99%

“…HFD-triggered adaptive pancreatic β-cell replication was suppressed by eight weeks of metformin treatment [ 73 ]. However, after sixty weeks of HFD feeding, increased β-cell mass was not suppressed [ 73 ]. High-glucose-induced β-cell proliferation was also inhibited by metformin in both islets and INS-1 cells [ 73 ].…”

Section: Metformin Improves Pancreatic β-Cell Functionmentioning

confidence: 99%

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Metformin: An Old Drug with New Applications

Zhou

Massey

Story

et al. 2018

IJMS

182

124

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Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action.

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“…Studies on rats proved that metformin, by decreasing oxidative stress in pancreatic islets, might have a direct beneficial effect on insulin secretion [89]. It improves insulin resistance and suppresses the compensatory β-cell hyperplasia induced by high-fat diet [90], therefore it might reduce visceral fatty tissue.…”

Section: Promising Results For Drug-based Therapiesmentioning

confidence: 99%

Non-alcoholic fatty pancreas disease – practices for clinicians

Pinte

Balaban

Băicuș

et al. 2019

Romanian Journal of Internal Medicine

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Obesity is a growing health burden worldwide, increasing the risk for several diseases featuring the metabolic syndrome – type 2 diabetes mellitus, dyslipidemia, non-alcoholic fatty liver disease and cardiovascular diseases. With the increasing epidemic of obesity, a new pathologic condition has emerged as a component of the metabolic syndrome – that of non-alcoholic fatty pancreas disease (NAFPD). Similar to non-alcoholic fatty liver disease (NAFLD), NAFPD comprises a wide spectrum of disease – from deposition of fat in the pancreas – fatty pancreas, to pancreatic inflammation and possibly pancreatic fibrosis. In contrast with NAFLD, diagnostic evaluation of NAFPD is less standardized, consisting mostly in imaging methods. Also the natural evolution of NAFPD and its association with pancreatic cancer is much less studied. Not least, the clinical consequences of NAFPD remain largely presumptions and knowledge about its metabolic impact is limited. This review will cover epidemiology, pathogenesis, diagnostic evaluation tools and treatment options for NAFPD, with focus on practices for clinicians.

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

Cited by 26 publications

References 54 publications

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Metformin: An Old Drug with New Applications

Non-alcoholic fatty pancreas disease – practices for clinicians

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