Sur1KO mice have an impaired glucagon response to insulin-induced hypoglycemia. A, Changes in blood glucose after ip injection of insulin 0. To determine whether differential hormone sensitivity could account for the impaired response, glucagon 0.

WT mice exhibited a transient, less than 2-fold, increase in blood glucose that returned to the control value within 60 min, whereas the Sur1KO animals displayed a greater, sustained hyperglycemia Fig.

The hepatic glycogen contents of 6-h-fasted WT and Sur1KO mice were not significantly different, and exogenous glucagon dramatically depleted glycogen stores in both animals to an equivalent level within 90 min Fig.

The plasma insulin levels were significantly lower in Sur1KO vs. WT mice Fig. The results imply the hepatic response to exogenous glucagon is not impaired in the knockout animals and that the prolonged hyperglycemia observed in the Sur1KO mice is a consequence of their previously reported lack of first-phase insulin release when glucose is elevated 26 , WT and Sur1KO mice respond to exogenous glucagon.

A, Blood glucose changes after injection of 0. A previous study reported that glucagon release from K IR 6. This report focused on the central nervous system CNS component, concluding it is impaired. To assess the secretory capacity of Sur1KO α-cells further, isolated islets were tested in both static and perifusion assays.

When tested under hypoglycemic conditions 2 h in 1. control islets Fig. Isolated Sur1KO islets have an attenuated response to low glucose. Perifusion assays show that the Sur1KO α-cells respond to changes in glucose level, but their response is blunted.

Figure 3B illustrates the normal biphasic insulin response of WT islets to a stepwise change in glucose concentration. Figure 3D shows that switching WT islets from low to high glucose 2. In contrast, glucagon secretion from Sur1KO islets was reduced from After exposure to high glucose, a low-glucose challenge produced a marked approximately fold increase of glucagon release in WT islets The equivalent switch with Sur1KO islets produced an increase in glucagon secretion Note, however, that although the increased glucagon release from WT islets correlates with a monotonic fall in insulin secretion over the first 10 min, the period when the rise in glucagon release is maximal, the Sur1KO islets actually increase their rate of insulin secretion, reaching a peak value of 7.

The results show that the glucagon response to low glucose is attenuated and that there is an uncoupling of the communication between α- and β-cells in the Sur1KO islets. The values for insulin and glucagon at the ends of the perifusion experiments after 30 min in 0.

The values are means ± se. P values comparing WT vs. Glibenclamide strongly stimulates insulin secretion from WT islets in 0.

Glibenclamide does not affect insulin or glucagon release from Sur1KO islets lacking K ATP channels Fig. Note that the levels of glucagon secretion from WT islets treated with glibenclamide mimic the impaired release observed for Sur1KO islets compare Fig. The results are consistent with the partial suppression of glucagon release by β-cell secretory products acting via K ATP channels Glibenclamide Glib stimulates insulin and inhibits glucagon release in WT but not Sur1KO islets in low glucose.

A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig. In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig. These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 , Table 1 summarizes the insulin and glucagon secretion values at 30 min after switching the glucose concentration from The Sur1KO islets have an increased output of insulin and a decreased output of glucagon in response to hypoglycemic challenge compared with WT islets.

Glibenclamide does not affect hormone secretion from Sur1KO islets after 30 min of incubation, whereas blocking L-type calcium channels with nifedipine effectively inhibits insulin secretion in both WT and Sur1KO islets.

Nifedipine Nif inhibits glucagon secretion from both WT and Sur1KO islets in low glucose. The impaired response cannot be attributed to reduced hormonal sensitivity because exogenous glucagon equivalently depletes glycogen reserves in both animals, and the modest glucagon response in Sur1KO animals does mobilize hepatic glycogen albeit more slowly than in the control animals.

Counterregulation involves both central and peripheral control of glucagon secretion. The results extend the analysis reported for K IR 6. The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo.

However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion. In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels.

This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0.

Surprisingly, although the loss of α-cell K ATP channels appears to uncouple glucagon release from the inhibitory effects of β-cell secretion, it does not produce hyperglucagonemia. It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets.

This can be seen clearly, for example, in Fig. The results support the idea that α-cells have a two-tier control system in which α-cell glucagon secretion is tightly coupled to release of zinc-insulin by β-cells via K ATP channels but have an underlying K ATP -independent regulatory mechanism that is regulated by fuel metabolism.

The nature of the underlying mechanism is not understood but may be similar to the control s regulating insulin release in K ATP -null β-cells 39 , Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels.

The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia.

The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation. Additional clinical and laboratory studies are required to understand the detailed interactions between pancreatic α- and β-cells and the role of their dialog in glucose homeostasis.

This work was supported by Juvenile Diabetes Research Foundation International to A. and to J. Jiang G , Zhang BB Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab : E — E Google Scholar. Shah P , Basu A , Basu R , Rizza R Impact of lack of suppression of glucagon on glucose tolerance in humans.

Am J Physiol : E — E Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45 : — Cryer PE Diverse causes of hypoglycemia-associated autonomic failure in diabetes.

N Engl J Med : — Malouf R , Brust JC Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 17 : — The Diabetes Control and Complications Trial Research Group. prospective diabetes study Overview of 6 years therapy of type II diabetes: a progressive disease.

Prospective Diabetes Study Group. Diabetes 44 : — Bolli GB , Fanelli CG Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am 28 : — Rorsman P , Berggren PO , Bokvist K , Ericson H , Mohler H , Ostenson CG , Smith PA Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels.

Nature : — Wendt A , Birnir B , Buschard K , Gromada J , Salehi A , Sewing S , Rorsman P , Braun M Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells.

Diabetes 53 : — Gerich JE , Charles MA , Grodsky GM Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. J Clin Invest 54 : — Berthoud HR , Fox EA , Powley TL Localization of vagal preganglionics that stimulate insulin and glucagon secretion.

Am J Physiol : R — R Maruyama H , Hisatomi A , Orci L , Grodsky GM , Unger RH Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74 : — Samols E , Stagner JI , Ewart RB , Marks V The order of islet microvascular cellular perfusion is B-A-D in the perfused rat pancreas.

J Clin Invest 82 : — Samols E , Stagner JI Intra-islet regulation. Ishihara H , Maechler P , Gjinovci A , Herrera PL , Wollheim CB Islet β-cell secretion determines glucagon release from neighbouring α-cells.

Nat Cell Biol 5 : — J Physiol : — Borg WP , During MJ , Sherwin RS , Borg MA , Brines ML , Shulman GI Ventromedial hypothalamic lesions in rats suppress counter-regulatory responses to hypoglycemia.

J Clin Invest 93 : — Borg MA , Sherwin RS , Borg WP , Tamborlane WV , Shulman GI Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.

J Clin Invest 99 : — Taborsky Jr GJ , Ahren B , Mundinger TO , Mei Q , Havel PJ Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia. Diabetes Nutr Metab 15 : — Raju B , Cryer PE Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans.

Diabetes 54 : — Aguilar-Bryan L , Bryan J Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 20 : — Seghers V , Nakazaki M , DeMayo F , Aguilar-Bryan L , Bryan J Sur1 knockout mice.

A model for K ATP channel-independent regulation of insulin secretion. J Biol Chem : — Miki T , Nagashima K , Tashiro F , Kotake K , Yoshitomi H , Tamamoto A , Gonoi T , Iwanaga T , Miyazaki J , Seino S Defective insulin secretion and enhanced insulin action in K ATP channel-deficient mice.

Proc Natl Acad Sci USA 95 : — Shiota C , Larsson O , Shelton KD , Shiota M , Efanov AM , Hoy M , Lindner J , Kooptiwut S , Juntti-Berggren L , Gromada J , Berggren PO , Magnuson MA Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.

Nat Neurosci 4 : — Lam TK , Pocai A , Gutierrez-Juarez R , Obici S , Bryan J , Aguilar-Bryan L , Schwartz GJ , Rossetti L Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11 : — Pocai A , Lam TK , Gutierrez-Juarez R , Obici S , Schwartz GJ , Bryan J , Aguilar-Bryan L , Rossetti L Hypothalamic K ATP channels control hepatic glucose production.

Shiota C , Rocheleau JV , Shiota M , Piston DW , Magnuson MA Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Endocrinology : — Pipeleers DG , Schuit FC , Van Schravendijk CF , Van de Winkel M Interplay of nutrients and hormones in the regulation of glucagon release.

Roe JH , Dailey RE Determination of glycogen with the anthrone reagent. Anal Biochem 15 : — Hussain K , Bryan J , Christesen HT , Brusgaard K , Aguilar-Bryan L , Serum glucagon counter-regulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.

Diabetes , in press. Iozzo P , Geisler F , Oikonen V , Maki M , Takala T , Solin O , Ferrannini E , Knuuti J , Nuutila P Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET study.

J Nucl Med 44 : — Petersen KF , Laurent D , Rothman DL , Cline GW , Shulman GI Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest : — Nenquin M , Szollosi A , Aguilar-Bryan L , Bryan J , Henquin JC Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic β-cells.

Diabetes 50 : — Bancila V , Cens T , Monnier D , Chanson F , Faure C , Dunant Y , Bloc A Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat K ATP channel.

Prost AL , Bloc A , Hussy N , Derand R , Vivaudou M Zinc is both an intracellular and extracellular regulator of KATP channel function.

Franklin I , Gromada J , Gjinovci A , Theander S , Wollheim CB β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release. Stagner JI , Samols E The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41 : 93 — Diabetologia 47 : — Gopel S , Zhang Q , Eliasson L , Ma XS , Galvanovskis J , Kanno T , Salehi A , Rorsman P Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans.

J Physiol Lond : — Diabetes 53 : S — S Liu YJ , Vieira E , Gylfe E A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell.

Cell Calcium 35 : — Ma X , Zhang Y , Gromada J , Sewing S , Berggren PO , Buschard K , Salehi A , Vikman J , Rorsman P , Eliasson L Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. Mol Endocrinol 19 : — Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account.

Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Mobile Enter search term Search. Endocrine Society Journals. Advanced Search.

Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Materials and Methods. Journal Article. This can cause diabetes mellitus, weight loss, venous thrombosis and a characteristic skin rash. Unusual cases of deficiency of glucagon secretion have been reported in babies.

This results in severely low blood glucose which cannot be controlled without administering glucagon. Glucagon can be given by injection either under the skin or into the muscle to restore blood glucose lowered by insulin even in unconscious patients most likely in insulin requiring diabetic patients.

It can increase glucose release from glycogen stores. Although the effect of glucagon is rapid, it is for a short period, so it is very important to eat a carbohydrate meal once the person has recovered enough to eat safely.

About Contact Outreach Opportunities News. Search Search. Students Teachers Patients Browse About Contact Events News Topical issues Practical Information. You and Your Hormones. Students Teachers Patients Browse. Human body. Home Hormones Glucagon.

Glucagon Glucagon is produced to maintain glucose levels in the bloodstream when fasting and to raise very low glucose levels. Ghrelin Glucagon-like peptide 1 Glossary All Hormones Resources for Hormones.

What is glucagon? To do this, it acts on the liver in several ways: It stimulates the conversion of stored glycogen stored in the liver to glucose, which can be released into the bloodstream.

This process is called glycogenolysis. It promotes the production of glucose from amino acid molecules. This process is called gluconeogenesis. It reduces glucose consumption by the liver so that as much glucose as possible can be secreted into the bloodstream to maintain blood glucose levels.

Another rare effect of Glucagon, is its use as a therapy for beta blocker medication overdose. How is glucagon controlled? What happens if I have too much glucagon?

The results extend the analysis reported for K IR 6. The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo. However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion.

In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels. This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0.

Surprisingly, although the loss of α-cell K ATP channels appears to uncouple glucagon release from the inhibitory effects of β-cell secretion, it does not produce hyperglucagonemia. It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets.

This can be seen clearly, for example, in Fig. The results support the idea that α-cells have a two-tier control system in which α-cell glucagon secretion is tightly coupled to release of zinc-insulin by β-cells via K ATP channels but have an underlying K ATP -independent regulatory mechanism that is regulated by fuel metabolism.

The nature of the underlying mechanism is not understood but may be similar to the control s regulating insulin release in K ATP -null β-cells 39 , Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels.

The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia.

The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation.

Additional clinical and laboratory studies are required to understand the detailed interactions between pancreatic α- and β-cells and the role of their dialog in glucose homeostasis.

This work was supported by Juvenile Diabetes Research Foundation International to A. and to J. Jiang G , Zhang BB Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab : E — E Google Scholar. Shah P , Basu A , Basu R , Rizza R Impact of lack of suppression of glucagon on glucose tolerance in humans.

Am J Physiol : E — E Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45 : — Cryer PE Diverse causes of hypoglycemia-associated autonomic failure in diabetes.

N Engl J Med : — Malouf R , Brust JC Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 17 : — The Diabetes Control and Complications Trial Research Group. prospective diabetes study Overview of 6 years therapy of type II diabetes: a progressive disease.

Prospective Diabetes Study Group. Diabetes 44 : — Bolli GB , Fanelli CG Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am 28 : — Rorsman P , Berggren PO , Bokvist K , Ericson H , Mohler H , Ostenson CG , Smith PA Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels.

Nature : — Wendt A , Birnir B , Buschard K , Gromada J , Salehi A , Sewing S , Rorsman P , Braun M Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells.

Diabetes 53 : — Gerich JE , Charles MA , Grodsky GM Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas.

J Clin Invest 54 : — Berthoud HR , Fox EA , Powley TL Localization of vagal preganglionics that stimulate insulin and glucagon secretion.

Am J Physiol : R — R Maruyama H , Hisatomi A , Orci L , Grodsky GM , Unger RH Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74 : — Samols E , Stagner JI , Ewart RB , Marks V The order of islet microvascular cellular perfusion is B-A-D in the perfused rat pancreas.

J Clin Invest 82 : — Samols E , Stagner JI Intra-islet regulation. Ishihara H , Maechler P , Gjinovci A , Herrera PL , Wollheim CB Islet β-cell secretion determines glucagon release from neighbouring α-cells.

Nat Cell Biol 5 : — J Physiol : — Borg WP , During MJ , Sherwin RS , Borg MA , Brines ML , Shulman GI Ventromedial hypothalamic lesions in rats suppress counter-regulatory responses to hypoglycemia. J Clin Invest 93 : — Borg MA , Sherwin RS , Borg WP , Tamborlane WV , Shulman GI Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.

J Clin Invest 99 : — Taborsky Jr GJ , Ahren B , Mundinger TO , Mei Q , Havel PJ Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia. Diabetes Nutr Metab 15 : — Raju B , Cryer PE Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans.

Diabetes 54 : — Aguilar-Bryan L , Bryan J Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 20 : — Seghers V , Nakazaki M , DeMayo F , Aguilar-Bryan L , Bryan J Sur1 knockout mice.

A model for K ATP channel-independent regulation of insulin secretion. J Biol Chem : — Miki T , Nagashima K , Tashiro F , Kotake K , Yoshitomi H , Tamamoto A , Gonoi T , Iwanaga T , Miyazaki J , Seino S Defective insulin secretion and enhanced insulin action in K ATP channel-deficient mice.

Proc Natl Acad Sci USA 95 : — Shiota C , Larsson O , Shelton KD , Shiota M , Efanov AM , Hoy M , Lindner J , Kooptiwut S , Juntti-Berggren L , Gromada J , Berggren PO , Magnuson MA Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.

Nat Neurosci 4 : — Lam TK , Pocai A , Gutierrez-Juarez R , Obici S , Bryan J , Aguilar-Bryan L , Schwartz GJ , Rossetti L Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11 : — Pocai A , Lam TK , Gutierrez-Juarez R , Obici S , Schwartz GJ , Bryan J , Aguilar-Bryan L , Rossetti L Hypothalamic K ATP channels control hepatic glucose production.

Shiota C , Rocheleau JV , Shiota M , Piston DW , Magnuson MA Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Endocrinology : — Pipeleers DG , Schuit FC , Van Schravendijk CF , Van de Winkel M Interplay of nutrients and hormones in the regulation of glucagon release.

Roe JH , Dailey RE Determination of glycogen with the anthrone reagent. Anal Biochem 15 : — Hussain K , Bryan J , Christesen HT , Brusgaard K , Aguilar-Bryan L , Serum glucagon counter-regulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.

Diabetes , in press. Iozzo P , Geisler F , Oikonen V , Maki M , Takala T , Solin O , Ferrannini E , Knuuti J , Nuutila P Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET study.

J Nucl Med 44 : — Petersen KF , Laurent D , Rothman DL , Cline GW , Shulman GI Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest : — Nenquin M , Szollosi A , Aguilar-Bryan L , Bryan J , Henquin JC Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic β-cells.

Diabetes 50 : — Bancila V , Cens T , Monnier D , Chanson F , Faure C , Dunant Y , Bloc A Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat K ATP channel. Prost AL , Bloc A , Hussy N , Derand R , Vivaudou M Zinc is both an intracellular and extracellular regulator of KATP channel function.

Franklin I , Gromada J , Gjinovci A , Theander S , Wollheim CB β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release.

Stagner JI , Samols E The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41 : 93 — Diabetologia 47 : — Gopel S , Zhang Q , Eliasson L , Ma XS , Galvanovskis J , Kanno T , Salehi A , Rorsman P Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans.

J Physiol Lond : — Diabetes 53 : S — S Liu YJ , Vieira E , Gylfe E A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35 : — Ma X , Zhang Y , Gromada J , Sewing S , Berggren PO , Buschard K , Salehi A , Vikman J , Rorsman P , Eliasson L Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors.

Mol Endocrinol 19 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Mobile Enter search term Search.

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Volume Article Contents Materials and Methods. Journal Article. Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement. Alvaro Muñoz , Alvaro Muñoz. Oxford Academic. Min Hu. Khalid Hussain.

Joseph Bryan. Lydia Aguilar-Bryan. Arun S. Rajan, One Baylor Plaza, BCMA B, Houston, Texas PDF Split View Views. Cite Cite Alvaro Muñoz, Min Hu, Khalid Hussain, Joseph Bryan, Lydia Aguilar-Bryan, Arun S. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex.

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Open in new tab Download slide. TABLE 1. Insulin and glucagon secretion from WT and Sur1KO islets. Open in new tab. First Published Online August 25, and M. contributed equally to this work. Google Scholar Crossref. Search ADS. Google Scholar PubMed.

OpenURL Placeholder Text. Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.

N Engl J Med. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells.

Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. Localization of vagal preganglionics that stimulate insulin and glucagon secretion.

The order of islet microvascular cellular perfusion is B-A-D in the perfused rat pancreas. Islet β-cell secretion determines glucagon release from neighbouring α-cells. Ventromedial hypothalamic lesions in rats suppress counter-regulatory responses to hypoglycemia.

Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia.

Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans.

Molecular biology of adenosine triphosphate-sensitive potassium channels. Sur1 knockout mice. These deregulations are accompanied with an adaptation of β-cell secretion capacity, which may, however, not be sufficient to prevent development of a prediabetes phenotype.

Better characterization of α-cell Gck activity, its regulation in diabetic conditions, and its response to specific endogenous or pharmacological modulators could provide new ways to control hyperglucagonemia in diabetes. Studies were conducted in animals of 18—36 weeks of age, and included age-matched and sex-matched littermate control mice.

For all experiments, the mice were randomly assigned to experimental groups to ensure an unbiased distribution of animals. No blinding was used. All animal procedures were performed at the University of Lausanne and were reviewed and approved by the Veterinary Office of Canton de Vaud. The numbers of animals studied per genotype are indicated within each experiment.

To validate proper gene targeting, genomic DNA has been extracted from liver, hindbrain, ileum, and pancreatic islets using a Quick gDNA mini-prep kit Zymo Research, USA. RT-PCR analysis was performed using a Biometra T Thermocycler.

Recombination efficiency was assessed in αGckKO-Rosa26tdtomato mice. Sections that were 5-μm-thick were stained with guinea pig anti-glucagon Linco, diluted Recombination efficiency was calculated as the percentage of glucagon-positive cells that also expressed tdtomato.

α-cell mass and β-cell mass were then calculated based on individual pancreas weight. Insulin and glucagon content of the supernatant was then assessed by radioimmunoassay Merck Millipore , using insulin and glucagon standards, and expressed relative to initial pancreatic weight.

Before removal of the pancreas, a solution of Liberase TL 0. Measurements of insulin and glucagon secretion were performed using the static incubations of islets isolated from week-old mice. Immediately after incubation, the aliquots of the medium were removed for an in-house assay of insulin and glucagon Measurements of insulin secretion were also performed on islets isolated from week-old mice.

At the end of each static incubation, the islets were collected and lysed in acid ethanol to assess insulin and glucagon content. The islets were perfused with extracellular solution containing in mM : NaCl, 3.

Glucose, methyl-succinate, and FCCP have been added as indicated in Fig. Images were acquired at a frequency of 0. Electrical activity, transmembrane currents, and cell capacitance were recorded from randomly chosen cells on the peripheral of the islets. α-cells were identified by the expression of fluorescent protein tdtomato see Mouse Validation.

α-cells were identified by their electrical activity in response to glucose and lack of tdtomato fluorescence. Electrical activity and K ATP conductance were recorded using perforated patch-clamping technique. Perforating reagent gramicidin 0. Extracellular solution contains in mM : NaCl, 3.

After the experiments, the membrane potential recordings were exported as ASCII files and converted to ABF files axon binary file using ABF utility software version 2. The resultant ABF files were then imported into Clampfit software version 9. Depolarization-triggered cell exocytosis was monitored as increase in membrane capacitance.

The intracellular solution used for capacitance measurement contains in mM : Cs-glutamate, 10 CsCl, 10 NaCl, 1 MgCl 2 , 5 HEPES, 0. The extracellular solution contains in mM : NaCl, 5. Plasma glucagon levels were quantitated by radioimmunoassay Merck Millipore and by ELISA Mercodia.

Plasma insulin levels were assessed by ultra-sensitive ELISA Mercodia. A portion of mouse liver were homogenized in ice-cold homogeneisation buffer in mM: sucrose, 10 HEPES pH 7. Proteins from nuclear fractions were extracted, and the protein content was determined by bicinchoninic acid assay Pierce, Thermo Scientific.

Transfer to nitrocellulose membranes was performed using the Mini Trans-Blot apparatus from Bio-Rad. Bands corresponding to the specific proteins were visualized using enhanced chemiluminescence reagent Advansta. Digital images were acquired with Fusion FX7 system Vilber Lourmat and Bio-1D software Vilber Lourmat for quantification and normalization.

The same membranes were reprobed with anti-β-actin antibodies to confirm the equal loading of proteins for each sample. Real-time PCR was performed using Power SYBR Green Master Mix Applied Biosystems. All reactions were normalized to β-actin levels.

Specific mouse primers for each gene are listed in Supplementary Table 1. The animals were processed in the morning in the random-fed state.

The mice received a bolus of 14 Cdeoxy-D-glucose Perkin-Elmer; dil. The mice were then placed in cages without water or food.

After the last blood sampling, the mice were killed by cervical dislocation under isoflurane anesthesia. Tissues were immediately dissected and frozen for further assessment of 14 Cdeoxy-D-glucosephosphate 2-DGP content.

The Plasma radioactivity was determined at each time point by liquid scintillation counting, in order to calculate the area under the curve of the plasma tracer decay.

For the determination of tissue 2-DGP content, the tissue samples were homogenized, and the supernatants were passed through ion-exchange columns to separate 2-DGP from 2-DG.

Tissue 2DG uptake was calculated by normalizing the tissue 2DG-6P content as disintegrations per minute to the tissue weight and to the AUC of the plasma tracer decay. All collected data were included without data exclusion.

Statistical analysis was performed using GraphPad Prism 5. The data distribution was assumed to be normal. p -values less than 0. Other statistical methods were mentioned and indicated where they were used.

No statistical methods were used to pre-determine sample sizes, but sample sizes are similar to those used in our previous studies. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Diabetes Res. Download references. This work was supported by grants to B. from the Swiss National Science Foundation A0B and the European Research Council Advanced grants INSIGHT and INTEGRATE. was supported by a Diabetes UK RD Lawrence Fellowship. PR was supported by the Wellcome Trust and the Swedish Research Council.

PLH was funded by Fondation privée of the University Hospitals of Geneva and the NIDDK grant DK We thank the Mouse Metabolic Evaluation Facility MEF from the Center for Integrative Genomics for performing tissue glucose uptake measurements.

Center for Integrative Genomics, University of Lausanne, , Lausanne, Switzerland. Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK. Department of Clinical Science, UMAS, Division of Islet Cell Physiology, Lund, Sweden.

Department of Genetic Medicine and Development, , Geneva, Switzerland. You can also search for this author in PubMed Google Scholar. secured funding. performed the experiments. provided the the Gcg-Cre mice. provided expertise and assisted with the editing of the manuscripts.

Correspondence to Bernard Thorens. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.

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Toggle limited content width. GCG glucagoneglucagon recombinant. Interestingly, delivery of the SSTR2 antagonist did not further increase pancreatic glucagon and somatostatin, or plasma somatostatin. One of the key questions was whether the SSTR2 antagonist can actually prevent hypoglycemia.

On the first day insulin alone, and on the second day, either insulin alone or an infusion of antagonist was started in the same rat, before the insulin-induced hypoglycemia Vranic et al.

The reason for such designs is that even one episode of hypoglycemia sensitizes the endocrine and metabolic system so that you would expect that on the second day the rats would need a different amount of insulin. In order to avoid this problem, diabetic rats were injected for 3 days with insulin, in order to avoid further effect of antecedent hypoglycemia.

After the injection of insulin, rats became hypoglycemic, but with the SSTR2 antagonist, hypoglycemia was avoided. Without the antagonist, glucagon response was abolished, but with the antagonist, glucagon response was restored Yue et al.

These STZ-induced diabetic rats were not treated with insulin since they still have some residual insulin in the blood and in the pancreas. In contrast, BB rats are totally insulin-deprived, thus requiring insulin treatment, and therefore this model is more similar to human T1D; both caused by immune destruction of the β-cells.

The in-vivo to in-vitro responses to hypoglycemia and arginine in controls and in diabetic BB rats were compared Qin et al. In the in-vivo experiments, the glucose was clamped at 2. In contrast to the controls, the glucagon response was greatly diminished, but it was normalized during the infusion of the SSTR2 antagonist.

With glucagon response normalized, the BB rats did not need glucose infusion to maintain the clamp, while without the antagonist they needed a large amount of glucose infused because of the glucagon deficiency.

Interestingly, we used for the first time pancreatic slices to assess the effect of hypoglycemia and arginine. Surprisingly, hypoglycemia per se did not increase glucagon release. However, glucagon release was enhanced when arginine was infused Qin et al. The difference between in-situ and in-vitro experiments is that pancreatic slices are not controlled by the nervous system and are not exposed to hormones or metabolites such as, arginine that stimulate glucagon release.

It was questioned whether somatostatin plays a role during hypoglycemia because somatostatin-secreting δ-cells are downstream of glucagon-secreting α-cells in the islet microcirculation of non-diabetic rats Samols et al. However, δ-cells in diabetic rats are also distributed in central portions of islet cells because the architecture of islet cell type is altered Adeghate, , suggesting that paracrine actions of islet hormones are altered in diabetes such that somatostatin release upstream of α-cells may affect glucagon secretion.

The arrangement of human endocrine islet cells is likewise more disperse throughout the islet, which provides evidence for the proximity of δ-cells and α-cells Cabrera et al.

Furthermore, paracrine signaling may also occur via diffusion within the islet interstitium, independent of blood flow. The remaining question to be answered is to explore factors in blood that are necessary to sensitize the responses of α-cell to hypoglycemia and the mechanism of the potential sensitization of α-cells to insulin in diabetes.

These results indicate that SSTR2 blockade Rossowski et al. This strategy could lead to prevention of hypoglycemia in insulin-treated diabetics. Considerable work investigating glucagon secretion and α-cell signaling in healthy islets have been done as discussed above.

However, there has been relatively little progress in assessing the perturbation of α-cellular physiology and paracrine dysregulation during diabetes, which will require more innovative approaches.

One approach is the pancreatic slice preparation Huang et al. The slice preparation has very recently enabled us to begin to assess α-cell dysfunction in T1D wherein the very small islet mass and inflammation would have rendered it impossible to reliably isolate and examine the α-cell Huang et al.

This, along with the larger glucagon granules found on E. carrying larger amount of glucagon cargo, would trigger more glucagon release, thus explaining the basis of hyperglucagonemia in T1D Huang et al. Future studies employing the pancreas slice preparation will enable the elucidation of paracrine regulation within normal and diabetic islets.

Another approach is genetic manipulation of candidate proteins within α-cells by α-cell-specific knockout mouse models Gustavsson et al. Ideally, these clever approaches could be combined. From a clinical point of view, the mechanism whereby in T2D there is excessive response to glucagon during meals, and whether pharmacological intervention can prevent this problem.

A key question is also whether it is possible to prevent hypoglycemia in insulin-treated diabetics. So far, the evidence was obtained only in STZ-treated and BB rats.

Patrick E. MacDonald receives research funding for his work on α-cells from Merck. Herbert Y. Gaisano and Mladen Vranic have no financial or commercial relationships.

This work was supported by a grant to Herbert Y. Gaisano from the Canadian Diabetes Association OGHG. MacDonald holds an Alberta Innovates-Health Sciences Scholarship and the Canada Research Chair in Islet Biology.

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