Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity...Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of nonspecific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. Octreo Scan was negative. Serum glucagon was elevated to 66 pmol/L(normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene(GCGR) sequencing revealed a heterozygous deletion,K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.展开更多
Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signa...Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signal remains missing.Existing hypotheses include inflammation,mitochondrial dysfunction,hyperinsulinemia,hyperglucagonemia,glucotoxicity,and lipotoxicity.Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines.In this review,multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance.The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand,which we have named“mitochondrial overheating.”Overheating occurs because of substrate oversupply to mitochondria,leading to extra ATP production.The ATP overproduction contributes to the systemic insulin resistance through several mechanisms,such as inhibition of AMPK,induction of mTOR,hyperinsulinemia,hyperglucagonemia,and mitochondrial dysfunction.Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates.Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading.The downregulation of the mitochondrial overloading by medicines,bypass surgeries,calorie restriction,and physical exercise leads to insulin sensitization in patients.Therefore,ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply.The prevention of ATP overproduction represents a key strategy for insulin sensitization.展开更多
文摘Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of nonspecific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. Octreo Scan was negative. Serum glucagon was elevated to 66 pmol/L(normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene(GCGR) sequencing revealed a heterozygous deletion,K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.
基金This work is supported by the National Key R&D Program of China(No.2018YFA0800603).
文摘Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signal remains missing.Existing hypotheses include inflammation,mitochondrial dysfunction,hyperinsulinemia,hyperglucagonemia,glucotoxicity,and lipotoxicity.Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines.In this review,multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance.The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand,which we have named“mitochondrial overheating.”Overheating occurs because of substrate oversupply to mitochondria,leading to extra ATP production.The ATP overproduction contributes to the systemic insulin resistance through several mechanisms,such as inhibition of AMPK,induction of mTOR,hyperinsulinemia,hyperglucagonemia,and mitochondrial dysfunction.Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates.Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading.The downregulation of the mitochondrial overloading by medicines,bypass surgeries,calorie restriction,and physical exercise leads to insulin sensitization in patients.Therefore,ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply.The prevention of ATP overproduction represents a key strategy for insulin sensitization.
