Features of carbohydrate metabolism and incretin secretion in patients with Cushing disease and acromegaly

Introduction. The relevance of carbohydrate metabolism studying in patients with Cushing disease can be explained by frequent occurrence of glucose metabolism disturbances on the one hand, and difficulties in glucose-lowering therapy in these patients on the other. The effectiveness of hyperglycaemia treatment may be reduced due to difficulties in remission / cure of the underlying disease, as well as to the use of specific drug-therapy, leading to the hyperglycaemia. There is a growing interest in research aimed at studying the role of incretin system in the pathogenesis of secondary hyperglycemia associated with neuroendocrine diseases recently.Methods. A total of 20 patients with Cushing disease were included, (19 female and 1 male), the mean age was 37.5 years (18-69). All of the patients were diagnosed with Cushing disease for the first time (using urinary free cortisol levels and MRI-data); none of them had a history of previous drug therapy, radiotherapy or pituitary surgery. The mean HbA1c level was 5,8% (5,3-6,2). All patients underwent OGTT, during which glucose, glucagon, GLP1, GLP2, GIP, ghrelin were measured at 0, 30 and 120 min respectively. The control group included 21 patients without previous history of carbohydrate metabolism disturbances. After OGTT 57% were presented without any carbohydrate metabolism disturbances, 28,57% presented with prediabetes and 14,43% were diagnosed with diabetes.Results. After glucose levels analyzing 40% of patients were diagnosed with early carbohydrate metabolism disturbances ,15% were diagnosed with diabetes. After glucose intake a slight inrease in glucagon levels with a peak by 30’ (p=0,001) compared to gradually decreasing levels in controls was observed . The levels of GIP during OGTT were not significantly different compared to control group. GLP-1 and GLP-2 levels were significantly higher compared to controls (p=0,017 and p<0,001 respectively) with peak levels at 30’. Ghrelin levels were also significantly higher compared to controls (p=0,013)Conclusion. Incretins levels can be possible markers of specific carbohydrate metabolism disturbances in patients with Cushing disease and presumably will help to differentiate steroid diabetes from T2DM. Further investigations needed to prove these speculations.

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An AlphaScreen Assay for the Discovery of Synthetic Chemical Inhibitors of Glucagon Production

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057115622201 ◽

2015 ◽

Vol 21 (4) ◽

pp. 325-332 ◽

Cited By ~ 6

Author(s):

Matthew R. Evans ◽

Shuguang Wei ◽

Bruce A. Posner ◽

Roger H. Unger ◽

Michael G. Roth

Keyword(s):

Cell Culture ◽

Small Molecules ◽

Culture Media ◽

Glucagon Secretion ◽

Cell Culture Media ◽

Glucagon Receptor ◽

Synthetic Compounds ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Chemical Inhibitors

Glucose homeostasis is primarily controlled by two opposing hormones, insulin and glucagon, and diabetes results when insulin fails to inhibit glucagon action. Recent efforts to control glucagon in diabetes have focused on antagonizing the glucagon receptor, which is effective in lowering blood glucose levels but leads to hyperglucogonemia in rodents. An alternative strategy would be to control glucagon production with small molecules. In pursuit of this goal, we developed a homogeneous AlphaScreen assay for measuring glucagon in cell culture media and used this in a high-throughput screen to discover synthetic compounds that inhibited glucagon secretion from an alpha cell–like cell line. Some of these compounds inhibited transcription of the glucagon gene.

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Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

10.2337/figshare.13256231.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Nadejda Bozadjieva Kramer ◽

Camila Lubaczeuski ◽

Manuel Blandino-Rosano ◽

Grant Barker ◽

...

Keyword(s):

Glucose Homeostasis ◽

Phosphoenolpyruvate Carboxykinase ◽

Cell Mass ◽

Glucagon Secretion ◽

Glucagon Receptor ◽

Glucose Levels ◽

Conditional Deletion ◽

Mtorc1 Signaling ◽

Nutrient Signaling ◽

A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2KO mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2KO mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

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Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

10.2337/figshare.13256231 ◽

2020 ◽

Author(s):

Nadejda Bozadjieva Kramer ◽

Camila Lubaczeuski ◽

Manuel Blandino-Rosano ◽

Grant Barker ◽

George K. Gittes ◽

...

Keyword(s):

Glucose Homeostasis ◽

Phosphoenolpyruvate Carboxykinase ◽

Cell Mass ◽

Glucagon Secretion ◽

Glucagon Receptor ◽

Glucose Levels ◽

Conditional Deletion ◽

Mtorc1 Signaling ◽

Nutrient Signaling ◽

A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2KO mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2KO mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

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Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

10.2337/figshare.13256231.v2 ◽

2020 ◽

Author(s):

Nadejda Bozadjieva Kramer ◽

Camila Lubaczeuski ◽

Manuel Blandino-Rosano ◽

Grant Barker ◽

George K. Gittes ◽

...

Keyword(s):

Glucose Homeostasis ◽

Phosphoenolpyruvate Carboxykinase ◽

Cell Mass ◽

Glucagon Secretion ◽

Glucagon Receptor ◽

Glucose Levels ◽

Conditional Deletion ◽

Mtorc1 Signaling ◽

Nutrient Signaling ◽

A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2KO). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2KO was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2KO mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2KO mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

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Glucagon-like peptide-2 and glucagon in patients with acromegaly and Cushing’s disease: secretion features and influence on glucose metabolism

Problems of Endocrinology ◽

10.14341/probl2017635299-306 ◽

2017 ◽

Vol 63 (5) ◽

pp. 299-306

Author(s):

Lubov V. Machekhina ◽

Ekaterina А. Shestakova ◽

Zhanna Е. Belaya ◽

Larisa V. Nikankina ◽

Lyudmila I. Astafieva ◽

...

Keyword(s):

Cushing’S Disease ◽

Glucagon Secretion ◽

Pituitary Surgery ◽

Tolerance Test ◽

Cushing's Disease ◽

Oral Glucose ◽

Glucagon Level ◽

Metabolism Regulation ◽

History Of

Aim. To analyze secretion of GLP-2 and glucagon in patients with Cushing’s disease (CD) and acromegaly in response to glucose load. Material and methods. The study included 42 patients with Cushing’s disease and acromegaly; the mean patient age was 37.5 years. All patients were newly diagnosed with Cushing’s disease and acromegaly: none of them had a history of previous drug therapy, radiotherapy, or pituitary surgery. All patients underwent the oral glucose tolerance test with measurements of glucose, glucagon, and GLP-2 levels at 0, 30, and 120 min, respectively. Results. A significantly higher glucagon level was observed in CD patients at all cut-off points (р=0.001); in acromegaly patients, the glucagon level did not significantly differ from that in controls (р=0.12). The GLP-2 concentration in CD patients was also significantly higher compared to that in controls (р<0.001). There were no significant differences between acromegaly patients and controls. We also found a strong correlation between GLP-2 and glucagon levels at 0 and 30 min in CD patients. In acromegaly patients, a correlation between GLP-2 and glucagon levels was observed only at 0 min. Different GLP-2 and glucagon secretion patterns in patients with CD and acromegaly suggest a direct influence of glucocorticoids on glucagon secretion and no influence in the case of IGF-1. Conclusion. The found correlation between GLP-2 and glucagon levels might help specify the role of GLP-2 in carbohydrate metabolism regulation. Interactions of cortisol, IGF-1, and GLP-2 look promising for a better understanding of secondary hyperglycemia pathogenesis.

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The history of pituitary surgery for Cushing disease

Journal of Neurosurgery ◽

10.3171/2011.8.jns102005 ◽

2012 ◽

Vol 116 (2) ◽

pp. 261-268 ◽

Cited By ~ 15

Author(s):

Gautam U. Mehta ◽

Russell R. Lonser ◽

Edward H. Oldfield

Keyword(s):

Cushing Syndrome ◽

Pituitary Surgery ◽

Selective Removal ◽

Cushing Disease ◽

Historical Texts ◽

Harvey Cushing ◽

Transient Improvement ◽

History Of ◽

Unclear Etiology ◽

Acth Secreting

Although he never performed a pituitary operation for the disease, Harvey Cushing was the first to describe and treat patients with Cushing disease (CD). Other surgeons at the time were reluctant to operate on the pituitary due to the normal sella on skull radiographs in CD and the unclear etiology of the disorder. To better define and understand factors influencing the history of pituitary surgery for CD, the authors analyzed historical texts related to CD biology, diagnosis, and treatment. Cushing's monograph on basophilic pituitary adenomas and cortisol excess appeared in 1932. One year later in 1933, Alfred Pattison performed the first successful pituitary operation for CD by implanting radon seeds in the sella. Resection of a pituitary adenoma for CD was attempted 1 month later in 1933 by Howard Naffziger, resulting in only transient improvement that corresponded to the lack of tumor in the resected tissue. Soon thereafter, Susman in 1935 and Costello in 1936 described pituitary basophilic adenomas at autopsy in patients without premorbid endocrinopathy. They concluded that the adrenal gland was the cause of CD, which resulted in a 3-decade abandonment of pituitary surgery for CD. Jules Hardy in 1963 used the operating microscope to perform the first selective removal of an adrenocorticotropic hormone (ACTH)–secreting microadenoma, which established a pituitary cause and defined the modern treatment of CD. Subsequent reports by Hardy, Laws, and Wilson resulted in widespread acceptance of pituitary surgery for CD. Initial reluctance to operate on the pituitary for CD was multifaceted and included general uncertainty surrounding the etiology of Cushing syndrome as well as a lack of early surgical success, both due to the small size of ACTH-secreting adenomas. Selective removal of ACTH-secreting adenomas identified the source of CD and ended the delay in acceptance of pituitary surgery for CD.

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Dapagliflozin suppresses glucagon signaling in rodent models of diabetes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705845114 ◽

2017 ◽

Vol 114 (25) ◽

pp. 6611-6616 ◽

Cited By ~ 12

Author(s):

May-yun Wang ◽

Xinxin Yu ◽

Young Lee ◽

Sara Kay McCorkle ◽

Shiuhwei Chen ◽

...

Keyword(s):

Blood Glucose ◽

Glucagon Secretion ◽

Zucker Rats ◽

Hepatic Glycogen ◽

Alpha Cells ◽

Lower Blood Glucose ◽

Glucagon Receptor ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Lower Blood

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose. In these type 1 diabetic rats, glucose stimulated glucagon secretion by alpha cells; this was prevented by dapagliflozin. Two models of type 2 diabetes, severely diabetic Zucker rats and db/db mice fed dapagliflozin, showed significant improvement of blood glucose levels and glucose disposal, with reduced evidence of glucagon signaling in the liver, as exemplified by reduced phosphorylation of hepatic cAMP-responsive element binding protein, reduced expression of phosphoenolpyruvate carboxykinase 2, increased hepatic glycogen, and reduced hepatic glucose production. Plasma glucagon levels did not change significantly. However, dapagliflozin treatment reduced the expression of the liver glucagon receptor. Dapagliflozin in rodents appears to lower blood glucose levels in part by suppressing hepatic glucagon signaling through down-regulation of the hepatic glucagon receptor.

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