RARE DISEASE
Glycogen storage disease due to glycogen synthase deficiency
Glycogen storage disease due to glycogen synthase deficiency
Glycogen storage disease due to glycogen synthase deficiency
Synonyms: GSD due to glycogen synthase deficiency, Glycogenosis due to glycogen synthase deficiency
Synonyms: GSD due to glycogen synthase deficiency, Glycogenosis due to glycogen synthase deficiency
Synonyms: GSD due to glycogen synthase deficiency, Glycogenosis due to glycogen synthase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Glycogen storage disease due to glycogen synthase deficiency (GSD0) is a rare autosomal recessive disorder caused by GYS2 mutations, impairing hepatic glycogen synthesis [1][2][4]. Patients exhibit fasting ketotic hypoglycemia without hepatomegaly, accompanied by low alanine/lactate levels, and postprandial hyperglycemia/hyperlactatemia [1][6][8]. Diagnosis hinges on genetic testing or liver biopsy showing reduced glycogen and enzyme deficiency [2][5].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
42 drug discovery papers about Glycogen storage disease due to glycogen synthase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
42 drug discovery papers about Glycogen storage disease due to glycogen synthase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-08-09 | Isolated short stature as the only presenting symptom of glycogen storage disease type 0a in a Chinese child: A case report.
Glycogen storage disease type 0a (GSD0a) is a rare autosomal recessive disorder caused by glycogen synthase deficiency. Short stature is a characteristic feature in 29% of GSD0a patients, but isolated short stature as the only presenting symptom is exceedingly rare, with only 2 cases reported worldwide. A 4-year-old girl presented with persistent growth retardation despite previous treatment for renal tubular acidosis. Based on clinical presentation and whole exome sequencing results, the patient was diagnosed with GSD0a. Uncooked cornstarch therapy was initiated at 2 g/kg every 6 hours. After 3 years of treatment, the patient's height SDS improved from -2.24 to -1.06, with enhanced glycemic control and no complications. This case emphasizes considering GSD0a in unexplained short stature and the value of continuous glucose monitoring. Early diagnosis and treatment can optimize growth in GSD0a patients.
2024-02-29 | Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases
Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides. As a simple metabolite, uridine plays a pivotal role in various biological processes. In addition to nucleic acid synthesis, uridine is critical to glycogen synthesis through the formation of uridine diphosphate glucose in which promotes the production of UDP-GlcNAc in the hexosamine biosynthetic pathway and supplies UDP-GlcNAc for O-GlcNAcylation. This process can regulate protein modification and affect its function. Moreover, Uridine has an effect on body temperature and circadian rhythms, which can regulate the metabolic rate and the expression of metabolic genes. Abnormal levels of blood uridine have been found in people with diabetes and obesity, suggesting a link of uridine dysregulation and metabolic disorders. At present, the role of uridine in glucose metabolism and lipid metabolism is controversial, and the mechanism is not clear, but it shows the trend of long-term damage and short-term benefit. Therefore, maintaining uridine homeostasis is essential for maintaining basic functions and normal metabolism. This article summarizes the latest findings about the metabolic effects of uridine and the potential of uridine metabolism as therapeutic target in treatment of metabolic disorders.
2023-09-18 | From common to rare: repurposing of bempedoic acid for the treatment of glycogen storage disease type 1
Hypoketotic hypoglycaemia is a biochemical hallmark of glycogen storage disease type 1 (GSD1). This is due to inhibition of carnitine-palmitoyl transferase 1 by malonyl-CoA. This inhibits the influx of long-chain fatty acids into the mitochondrial matrix for fatty acid oxidation. This leads to reduced hepatic ketogenesis and impaired energy production in the liver and kidney. Hypoketotic hypoglycaemia may result in CNS symptoms due to energy depletion.Recently, it was reported that enzymes involved in mitochondrial long-chain fatty acid oxidation are upregulated in PBMC from patients suffering from GSD1.I suggest that administration of the prodrug bempedoic acid results in reduced production of malonyl-CoA by inhibiting the ATP-citrate lyase, thus releasing the block of mitochondrial long-chain fatty acid influx. These fatty acids could make use of the increased capacity of fatty acid oxidation as observed in PBMC recently. In the liver, ketogenesis is activated, and energy production is increased in both the liver and kidney. This could result in improved metabolic control and avoidance of cerebral energy depletion.Bempedoic acid is approved as medication in adult patients with hypercholesterolaemia and mixed dyslipidaemia. Repurposing bempedoic acid for the use in GSD1 may improve metabolic control in GSD1.
2022-01-18 | The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling
Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.
2021-11-10 | p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1
During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.
proteins
2022-01-05 | Catestatin induces glycogenesis by stimulating the phosphoinositide 3‐kinase‐AKT pathway
Defects in hepatic glycogen synthesis contribute to post-prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372 ) improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis.We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild-type (WT) as well as in CST knockout (CST-KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting.CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline-induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS-1 by enhancing phospho-AKT signals through the stimulation of PDK-1 and mTORC2 (mTOR Complex 2, rapamycin-insensitive complex) activities.CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling.
2020-11-01 | Catestatin induces glycogenesis by stimulating phosphoinositide 3-kinase-AKT pathway
Abstract Aim Defects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA 352-372 ) has been shown to improve glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis. Methods We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG), and glycogen synthase (GYS2) activities; plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels in fed and fasted liver of lean and obese mice as well as in CST knockout (CST-KO) mice after treatments with saline, CST, or insulin. We also determined glycogen synthesis and glycogenolysis in primary hepatocytes. In addition, we analyzed phosphorylation signals of Insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (an enzyme in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mTOR (mammalian/mechanistic target of rapamycin) by immunoblotting. Results CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of UDPG and increased GYS2 activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST can improve insulin signals downstream of insulin receptor IR and IRS-1 by enhancing phospho-AKT signals through stimulation of PDK-1 and mTORC2 (mTOR complex 2) activities. Conclusions We conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production, (ii) increasing glycogen synthesis from UDPG, and (iii) reducing glycogenolysis. This is achieved by enhancing downstream insulin signaling.
2018-03-07 | NRG1-Fc improves metabolic health via dual hepatic and central action
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat–enriched secreted factor NRG4 protects mice from high-fat diet–induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.
2017-05-05 | Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis
Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3bΔhep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12–36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.
2001-09-01 | Effect of Growth Hormone Treatment on Hypoglycemia in a Patient with both Hepatic Glycogen Synthase and Isolated Growth Hormone Deficiencies
Abstract A 7 year-old boy presenting with growth retardation, fasting hypoglycemia and ketoacidosis was diagnosed as having both idiopathic growth hormone (GH) deficiency and hepatic glycogen synthase (GS) deficiency caused by a homozygous mutation in exon 5 of the liver glycogen synthase gene (GYS-2). After four years of treatment with recombinant human GH, height increased from -4.9 SDS to -2.05 SDS which is near his target height of -1.6 SDS. The GH treatment, however, did not prevent the fasting hypoglycemia. Blood glucose levels were only normalized after avoiding fasting intervals of more than five hours and the frequent feeding of protein-rich meals according to the guidelines for treatment of hepatic GS deficiency.
small molecules
2024-08-09 | Isolated short stature as the only presenting symptom of glycogen storage disease type 0a in a Chinese child: A case report.
Glycogen storage disease type 0a (GSD0a) is a rare autosomal recessive disorder caused by glycogen synthase deficiency. Short stature is a characteristic feature in 29% of GSD0a patients, but isolated short stature as the only presenting symptom is exceedingly rare, with only 2 cases reported worldwide. A 4-year-old girl presented with persistent growth retardation despite previous treatment for renal tubular acidosis. Based on clinical presentation and whole exome sequencing results, the patient was diagnosed with GSD0a. Uncooked cornstarch therapy was initiated at 2 g/kg every 6 hours. After 3 years of treatment, the patient's height SDS improved from -2.24 to -1.06, with enhanced glycemic control and no complications. This case emphasizes considering GSD0a in unexplained short stature and the value of continuous glucose monitoring. Early diagnosis and treatment can optimize growth in GSD0a patients.
2024-02-29 | Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases
Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides. As a simple metabolite, uridine plays a pivotal role in various biological processes. In addition to nucleic acid synthesis, uridine is critical to glycogen synthesis through the formation of uridine diphosphate glucose in which promotes the production of UDP-GlcNAc in the hexosamine biosynthetic pathway and supplies UDP-GlcNAc for O-GlcNAcylation. This process can regulate protein modification and affect its function. Moreover, Uridine has an effect on body temperature and circadian rhythms, which can regulate the metabolic rate and the expression of metabolic genes. Abnormal levels of blood uridine have been found in people with diabetes and obesity, suggesting a link of uridine dysregulation and metabolic disorders. At present, the role of uridine in glucose metabolism and lipid metabolism is controversial, and the mechanism is not clear, but it shows the trend of long-term damage and short-term benefit. Therefore, maintaining uridine homeostasis is essential for maintaining basic functions and normal metabolism. This article summarizes the latest findings about the metabolic effects of uridine and the potential of uridine metabolism as therapeutic target in treatment of metabolic disorders.
2023-09-18 | From common to rare: repurposing of bempedoic acid for the treatment of glycogen storage disease type 1
Hypoketotic hypoglycaemia is a biochemical hallmark of glycogen storage disease type 1 (GSD1). This is due to inhibition of carnitine-palmitoyl transferase 1 by malonyl-CoA. This inhibits the influx of long-chain fatty acids into the mitochondrial matrix for fatty acid oxidation. This leads to reduced hepatic ketogenesis and impaired energy production in the liver and kidney. Hypoketotic hypoglycaemia may result in CNS symptoms due to energy depletion.Recently, it was reported that enzymes involved in mitochondrial long-chain fatty acid oxidation are upregulated in PBMC from patients suffering from GSD1.I suggest that administration of the prodrug bempedoic acid results in reduced production of malonyl-CoA by inhibiting the ATP-citrate lyase, thus releasing the block of mitochondrial long-chain fatty acid influx. These fatty acids could make use of the increased capacity of fatty acid oxidation as observed in PBMC recently. In the liver, ketogenesis is activated, and energy production is increased in both the liver and kidney. This could result in improved metabolic control and avoidance of cerebral energy depletion.Bempedoic acid is approved as medication in adult patients with hypercholesterolaemia and mixed dyslipidaemia. Repurposing bempedoic acid for the use in GSD1 may improve metabolic control in GSD1.
2022-01-18 | The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling
Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.
2021-11-10 | p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1
During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.
proteins
2022-01-05 | Catestatin induces glycogenesis by stimulating the phosphoinositide 3‐kinase‐AKT pathway
Defects in hepatic glycogen synthesis contribute to post-prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372 ) improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis.We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild-type (WT) as well as in CST knockout (CST-KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting.CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline-induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS-1 by enhancing phospho-AKT signals through the stimulation of PDK-1 and mTORC2 (mTOR Complex 2, rapamycin-insensitive complex) activities.CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling.
2020-11-01 | Catestatin induces glycogenesis by stimulating phosphoinositide 3-kinase-AKT pathway
Abstract Aim Defects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA 352-372 ) has been shown to improve glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis. Methods We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG), and glycogen synthase (GYS2) activities; plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels in fed and fasted liver of lean and obese mice as well as in CST knockout (CST-KO) mice after treatments with saline, CST, or insulin. We also determined glycogen synthesis and glycogenolysis in primary hepatocytes. In addition, we analyzed phosphorylation signals of Insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (an enzyme in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mTOR (mammalian/mechanistic target of rapamycin) by immunoblotting. Results CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of UDPG and increased GYS2 activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST can improve insulin signals downstream of insulin receptor IR and IRS-1 by enhancing phospho-AKT signals through stimulation of PDK-1 and mTORC2 (mTOR complex 2) activities. Conclusions We conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production, (ii) increasing glycogen synthesis from UDPG, and (iii) reducing glycogenolysis. This is achieved by enhancing downstream insulin signaling.
2018-03-07 | NRG1-Fc improves metabolic health via dual hepatic and central action
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat–enriched secreted factor NRG4 protects mice from high-fat diet–induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.
2017-05-05 | Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis
Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3bΔhep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12–36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.
2001-09-01 | Effect of Growth Hormone Treatment on Hypoglycemia in a Patient with both Hepatic Glycogen Synthase and Isolated Growth Hormone Deficiencies
Abstract A 7 year-old boy presenting with growth retardation, fasting hypoglycemia and ketoacidosis was diagnosed as having both idiopathic growth hormone (GH) deficiency and hepatic glycogen synthase (GS) deficiency caused by a homozygous mutation in exon 5 of the liver glycogen synthase gene (GYS-2). After four years of treatment with recombinant human GH, height increased from -4.9 SDS to -2.05 SDS which is near his target height of -1.6 SDS. The GH treatment, however, did not prevent the fasting hypoglycemia. Blood glucose levels were only normalized after avoiding fasting intervals of more than five hours and the frequent feeding of protein-rich meals according to the guidelines for treatment of hepatic GS deficiency.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.