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Zhongxiuzi Gao Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Li Zhang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Wenting Xie Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Siqi Wang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Xiaorui Bao Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Yuli Guo Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Houjian Zhang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Qingzhong Hu Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Yi Chen Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Zeen Wang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Maoqiang Xue Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Guanghui Jin Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome characterized by multiple tumors in the parathyroid glands, endocrine pancreas and anterior pituitary. Recent clinical studies have revealed a strong association between MEN1 syndrome and the risk of developing diabetes mellitus; however, the underlying mechanisms remain unknown. In this study, heterozygous Men1 knockout (Men1 +/−) mice were used as MEN1 models to investigate MEN1-associated glucose metabolic phenotypes and mechanisms. Heterozygous deficiency of Men1 in 12-month-old male mice induced fasting hyperglycemia, along with increased serum insulin levels. However, male Men1 +/− mice did not show insulin resistance, as evidenced by Akt activation in hepatic tissues and an insulin tolerance test. Increased glucose levels following pyruvate challenge and expression of key gluconeogenic genes suggested increased hepatic glucose output in the male Men1 +/− mice. This effect could be partly due to higher basal serum glucagon levels, which resulted from pancreatic islet cell proliferation induced by heterozygous loss of Men1. Taken together, our results indicate that fasted male Men1 +/− mice, in the early stage of development of MEN1, display glucose metabolic disorders. These disorders are caused not by direct induction of insulin resistance, but via increased glucagon secretion and the consequent stimulation of hepatic glucose production.

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Anthony Raffo Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Kolbe Hancock Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Teresa Polito Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Yuli Xie Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Gordon Andan Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Piotr Witkowski Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA
Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Mark Hardy Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Pasquale Barba Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Caterina Ferrara Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Antonella Maffei Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA
Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Matthew Freeby Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Robin Goland Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Rudolph L Leibel Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Ian R Sweet Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Paul E Harris Department of Medicine, Barnard College, Department of Surgery of Columbia University Medical Center, Department of Surgery, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naomi Berrie Diabetes Center, Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA

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Abstract

Despite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous l-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.

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