scholarly journals FAILURE OF PANCREATIC ALPHA CELLS TO RESPOND TO HYPOGLYCEMIA IS LINKED TO IMPAIRED GLUTAMATE RECEPTOR SIGNALING IN DIABETES

2021 ◽  
Author(s):  
Julia Katharina Panzer ◽  
Alejandro Tamayo ◽  
Alejandro Caicedo
Keyword(s):  
Type 1 Diabetes ◽  
Glucagon Secretion ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Allosteric Modulators ◽  
Alpha Cells ◽  
Receptor Signaling ◽  
Pancreatic Alpha Cells ◽  
Positive Allosteric Modulators

Glucagon secretion from the pancreatic alpha cells is crucial to prevent hypoglycemia. People with type 1 diabetes, however, lose this glucoregulatory mechanism and are susceptible to dangerous insulin treatment-induced hypoglycemia. We established that activating glutamate receptors of the AMPA/kainate type in alpha cells is needed for decreases in glucose levels to elicit full glucagon responses from mouse and human islets. We performed functional studies using living pancreas slices from donors with type 1 diabetes and found that alpha cells had normal glucagon content and responded typically to KCl depolarization, but failed to respond to decreases in glucose concentration and had severely impaired AMPA/kainate receptor signaling. Reactivating residual AMPA/kainate receptor function with the positive allosteric modulators cyclothiazide and aniracetam partially rescued glucagon secretion in response to hypoglycemia. Positive allosteric modulators of AMPA/kainate receptors already approved to treat other conditions could thus be repurposed to prevent hypoglycemia and improve management of diabetes.

scholarly journals Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Angela Kim ◽  
Jakob G Knudsen ◽  
Joseph C Madara ◽  
Anna Benrick ◽  
Thomas Hill ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Arginine Vasopressin ◽  
Glucagon Secretion ◽  
Glucagon Release ◽  
Alpha Cells ◽  
Major Barrier ◽  
Circulating Levels

Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon - the body's principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

scholarly journals AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes

2020 ◽  
Author(s):  
Angela Kim ◽  
Jakob G. Knudsen ◽  
Joseph C. Madara ◽  
Anna Benrick ◽  
Thomas Hill ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Alpha Cells ◽  
Glucagon Receptor ◽  
Major Barrier ◽  
Neuron Activation ◽  
Circulating Levels

AbstractHypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon – the body’s principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia. Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

scholarly journals Specific Reprogramming of Alpha Cells to Insulin-Producing Cells by Short Glucagon Promoter-Driven Pdx1 and MafA

2021 ◽  
Author(s):  
Ping Guo ◽  
Ting Zhang ◽  
Aiping Lu ◽  
Chiyo Shiota ◽  
Matthieu Huard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Alpha Cells ◽  
Diabetic Mice ◽  
Novel Therapy ◽  
Mouse Pancreas ◽  
Pancreatic Alpha Cells ◽  
Insulin Producing Cells ◽  
Chemically Induced ◽  
Initial Basis

Abstract Endogenous reprogramming of pancreas-derived non-beta cells into insulin-producing cells is a promising approach to treat type 1 diabetes (T1D). One strategy that has yet to be explored is the specific delivery of insulin-producing essential genes, Pdx1 and MafA, to pancreatic alpha cells to reprogram the cells into insulin-producing cells in an adult pancreas. In this study, we utilized an alpha cell-specific glucagon (GCG) promoter to drive Pdx1 and MafA transcription factors to reprogram alpha cells to insulin-producing cells in chemically induced and autoimmune diabetic mice. Our results showed that a combination of a short glucagon-specific promoter with AAV serotype 8 can be used to successfully deliver Pdx1 and MafA into alpha cells in the mouse pancreas. Pdx1 and MafA expression specifically in alpha cells was also able to correct hyperglycemia in both induced and autoimmune diabetic mice. With this technology, targeted gene specificity and reprogramming were accomplished with an alpha-specific promotor combined with an AAV-specific serotype and provide an initial basis to develop a novel therapy for the treatment of T1D.

scholarly journals Specific Reprogramming of Alpha Cells to Insulin-Producing Cells by Short Glucagon Promoter-Driven Pdx1 and MafA

2021 ◽  
Author(s):  
Ping Guo ◽  
Ting Zhang ◽  
Aiping Lu ◽  
Chiyo Shiota ◽  
Matthieu Huard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Alpha Cells ◽  
Diabetic Mice ◽  
Novel Therapy ◽  
Mouse Pancreas ◽  
Pancreatic Alpha Cells ◽  
Insulin Producing Cells ◽  
Chemically Induced ◽  
Initial Basis

Abstract Endogenous reprogramming of pancreas-derived non-beta cells into insulin-producing cells is a promising approach to treat type 1 diabetes (T1D). One strategy that has yet to be explored is the specific delivery of insulin-producing essential genes, Pdx1 and MafA, to pancreatic alpha cells to reprogram the cells into insulin-producing cells in an adult pancreas. In this study, we utilized an alpha cell-specific glucagon (GCG) promoter to drive Pdx1 and MafA transcription factors to reprogram alpha cells to insulin-producing cells in chemically induced and autoimmune diabetic mice. Our results showed that a combination of a short glucagon-specific promoter with AAV serotype 8 can be used to successfully deliver Pdx1 and MafA into alpha cells in the mouse pancreas. Pdx1 and MafA expression specifically in alpha cells was also able to correct hyperglycemia in both induced and autoimmune diabetic mice. With this technology, targeted gene specificity and reprogramming were accomplished with an alpha-specific promotor combined with an AAV-specific serotype and provide an initial basis to develop a novel therapy for the treatment of T1D.

scholarly journals Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes

2020 ◽  
Vol 11 ◽  
Author(s):  
Laura Nigi ◽  
Noemi Brusco ◽  
Giuseppina E. Grieco ◽  
Giada Licata ◽  
Lars Krogvold ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Alpha Cells ◽  
Pancreatic Alpha Cells

scholarly journals Specific Reprogramming of Alpha Cells to Insulin-Producing Cells by Short Glucagon Promoter-Driven Pdx1 and MafA

2021 ◽  
Author(s):  
Ping Guo ◽  
Ting Zhang ◽  
Aiping Lu ◽  
Chiyo Shiota ◽  
Matthieu Huard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Alpha Cells ◽  
Diabetic Mice ◽  
Novel Therapy ◽  
Mouse Pancreas ◽  
Pancreatic Alpha Cells ◽  
Insulin Producing Cells ◽  
Chemically Induced ◽  
Initial Basis

Abstract Endogenous reprogramming of pancreas-derived non-beta cells into insulin-producing cells is a promising approach to treat type 1 diabetes (T1D). One strategy that has yet to be explored is the specific delivery of insulin-producing essential genes, Pdx1 and MafA, to pancreatic alpha cells to reprogram the cells into insulin-producing cells in an adult pancreas. In this study, we utilized an alpha cell-specific glucagon (GCG) promoter to drive Pdx1 and MafA transcription factors to reprogram alpha cells to insulin-producing cells in chemically induced and autoimmune diabetic mice. Our results showed that a combination of a short glucagon-specific promoter with AAV serotype 8 can be used to successfully deliver Pdx1 and MafA into alpha cells in the mouse pancreas. Pdx1 and MafA expression specifically in alpha cells was also able to correct hyperglycemia in both induced and autoimmune diabetic mice. With this technology, targeted gene specificity and reprogramming were accomplished with an alpha-specific promotor combined with an AAV-specific serotype and provide an initial basis to develop a novel therapy for the treatment of T1D.

Impaired glucagon secretion in patients with fulminant type 1 diabetes mellitus

Endocrine ◽  
2018 ◽  
Vol 63 (3) ◽  
pp. 476-479 ◽  
Author(s):  
Hisako Komada ◽  
Yushi Hirota ◽  
Kazuhiko Sakaguchi ◽  
Yoko Okuno ◽  
Wataru Ogawa ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Glucagon Secretion ◽  
Fulminant Type 1 Diabetes ◽  
Fulminant Type

scholarly journals CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Julia Seyfarth ◽  
Heinz Ahlert ◽  
Joachim Rosenbauer ◽  
Christina Baechle ◽  
Michael Roden ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Promoter Polymorphism ◽  
Cytokine Receptor ◽  
Receptor Signaling ◽  
Diabetes Susceptibility

scholarly journals GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels

2018 ◽  
Vol 6 (17) ◽  
pp. e13852 ◽  
Author(s):  
Reshma Ramracheya ◽  
Caroline Chapman ◽  
Margarita Chibalina ◽  
Haiqiang Dou ◽  
Caroline Miranda ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
Alpha Cells ◽  
Pancreatic Alpha Cells ◽  
Ca2 Channels
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