Severe Defect in Proglucagon Processing in Islet A-cells of Prohormone Convertase 2 Null Mice

Furuta, Machi; Zhou, An; Webb, Gene C.; Carroll, Raymond J.; Ravazzola, Mariella; Orci, Lelio; Steiner, Donald F.

doi:10.1074/jbc.m103362200

Cited by 153 publications

(129 citation statements)

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“…This ability to increase and decrease both activity and cell populations allows for a highly dynamic structure that is finely attuned to normal metabolic demands, but which may be disturbed in diabetes and other disorders. PC2 Ϫ/Ϫ mice exhibit marked hyperplasia and hypertrophy of the pancreatic ␣-cells, as well as chronic hypoglycemia and elevated levels of circulating glucagon precursors, but they have little or no active glucagon (2,7). These observations are consistent with the action of a feedback mechanism that regulates ␣-cell activity and the production of mature glucagon.…”

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confidence: 73%

Glucagon Replacement via Micro-Osmotic Pump Corrects Hypoglycemia and α-Cell Hyperplasia in Prohormone Convertase 2 Knockout Mice

et al. 2002

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Prohormone convertase 2 (PC2) plays an essential role in the processing of proglucagon to mature active glucagon in pancreatic ␣-cells (J Biol Chem 276:27197-27202, 2001). Mice lacking PC2 demonstrate multiple defects, including chronic mild hypoglycemia and dramatic hyperplasia of the pancreatic ␣-cells. To define the contribution of mature glucagon deficiency to the hypoglycemia and ␣-cell hyperplasia, we have attempted to correct the defects by delivery of exogenous glucagon by micro-osmotic pumps. Intraperitoneal delivery of 0.5 g glucagon/h in PC2 ؊/؊ mice resulted in the normalization of blood glucose concentrations. Islet remodeling through the loss of hyperplastic ␣-cells was evident by day 11 after pump implantation; by 25 days postimplantation, PC2؊/؊ islets were indistinguishable from wildtype islets. These rapid changes were brought about by induction of apoptosis in the ␣-cell population. Morphological normalization of islets was also accompanied by marked downregulation of endogenous preproglucagon gene expression, but with little or no change in the level of preproinsulin gene expression. Exogenous glucagon delivery also normalized hepatic expression of the gluconeogenic enzyme PEPCK. These results demonstrate that the lack of mature glucagon in PC2 ؊/؊ mice is responsible for the aberrant blood glucose levels, islet morphology, and gene expression, and they confirm the role of glucagon as a tonic insulin antagonist in regulating glycemia. Diabetes 51:398 -405, 2002 S ubtilisin-like prohormone convertases (PCs) proteolytically process many precursor proteins in the secretory pathway, including the maturation of active hormones from inactive prohormones in the regulated secretory pathway (1). PC1/3 and PC2 are thought to be the major convertases, acting on prohormones in multiple neuroendocrine tissues throughout the body. PC2 Ϫ/Ϫ mice have both islet and central nervous system (CNS) processing defects (1,2), including a block in the conversion of preproglucagon to mature glucagon in the pancreatic ␣-cells. This observation is consistent with earlier findings that PC2 is the predominant convertase in the ␣-cells and that PC2 is capable of independently processing proglucagon to mature glucagon (3,4).The pancreatic islet is a dynamic structure that acts to control energy homeostasis. Changes in demand for islet hormones lead to alterations in the size and activity of islet cell populations. This is most generally noted for the ␤-cell population, where increased demand for insulin because of obesity, peripheral insulin resistance, or gestation leads to an enlarged ␤-cell population and increased activity of the ␤-cells (rev. in 5,6). When the increased demand is relieved, the ␤-cell population returns to normal levels. This ability to increase and decrease both activity and cell populations allows for a highly dynamic structure that is finely attuned to normal metabolic demands, but which may be disturbed in diabetes and other disorders. PC2 Ϫ/Ϫ mice exhibit marked hyperplasia and hypertrophy of the ...

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Glucagon Replacement via Micro-Osmotic Pump Corrects Hypoglycemia and α-Cell Hyperplasia in Prohormone Convertase 2 Knockout Mice

et al. 2002

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“…Although hIAPP ϩ/ϩ /PC2 Ϫ/Ϫ mouse islets form amyloid rapidly during culture with high glucose, these animals in our hands do not develop significant levels of islet amyloid in vivo (L.M., C.B.V., unpublished observations), likely because of their lower blood glucose levels and resulting decreased IAPP synthesis associated with their impaired glucagon production in the absence of PC2 (41). Islets from hIAPP ϩ/ϩ /PC2 Ϫ/Ϫ mice have a much higher rate of cell death in culture compared with hIAPP ϩ/ϩ / PC2 ϩ/ϩ mouse islets, which are able to completely process proIAPP to mature IAPP.…”

Section: Discussionmentioning

confidence: 93%

Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death

et al. 2006

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“…PC2 is responsible in a-cells for the production of glucagon in addition to other products such as glicentin, glicentin-related pancreatic polypeptide, intervening peptide 1 and the major proglucagon fragment (84 -86) . The importance of PC2 for the correct processing of glucagon has been proven in experiments using PC2 knockout (KO) mice (87) . In contrast to the results in some clonal a-cell lines (88,89) , studies in isolated rat islets indicate that the effect of glucose on glucagon gene expression is not direct but occurs via paracrine mechanisms that stimulate the inhibitory insulin signal (44) .…”

Section: Glucagon Synthesismentioning

confidence: 99%

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

et al. 2014

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Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic a-and b-cells, respectively. While b-cells have been the focus of intense research, less is known about a-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of a-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and a-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in a-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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Severe Defect in Proglucagon Processing in Islet A-cells of Prohormone Convertase 2 Null Mice

Cited by 153 publications

References 32 publications

Glucagon Replacement via Micro-Osmotic Pump Corrects Hypoglycemia and α-Cell Hyperplasia in Prohormone Convertase 2 Knockout Mice

Glucagon Replacement via Micro-Osmotic Pump Corrects Hypoglycemia and α-Cell Hyperplasia in Prohormone Convertase 2 Knockout Mice

Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

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