Increasing hepatic glycogen moderates the diabetic phenotype in insulin-deficient Akita mice

Abstract

Hepatic glycogen metabolism is impaired in diabetes. We previously demonstrated that strategies to increase liver glycogen content in a high-fat-diet mouse model of obesity and insulin resistance led to a reduction in food intake and ameliorated obesity and glucose tolerance. These effects were accompanied by a decrease in insulin levels, but whether this decrease contributed to the phenotype observed in this animal was unclear. Here we sought to evaluate this aspect directly, by examining the long-term effects of increasing liver glycogen in an animal model of insulin-deficient and monogenic diabetes, namely the Akita mouse, which is characterized by reduced insulin production. We crossed Akita mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate Akita mice with increased liver glycogen content (Akita-PTGOE). Akita-PTGOE animals showed lower glycemia, lower food intake, and decreased water consumption and urine output compared with Akita mice. Furthermore, Akita-PTGOE mice showed a restoration of the hepatic energy state and a normalization of gluconeogenesis and glycolysis back to nondiabetic levels. Moreover, hepatic lipogenesis, which is reduced in Akita mice, was reverted in Akita-PTGOE animals. These results demonstrate that strategies to increase liver glycogen content lead to the long-term reduction of the diabetic phenotype, independently of circulating insulin. Hepatic glycogen metabolism is impaired in diabetes. We previously demonstrated that strategies to increase liver glycogen content in a high-fat-diet mouse model of obesity and insulin resistance led to a reduction in food intake and ameliorated obesity and glucose tolerance. These effects were accompanied by a decrease in insulin levels, but whether this decrease contributed to the phenotype observed in this animal was unclear. Here we sought to evaluate this aspect directly, by examining the long-term effects of increasing liver glycogen in an animal model of insulin-deficient and monogenic diabetes, namely the Akita mouse, which is characterized by reduced insulin production. We crossed Akita mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate Akita mice with increased liver glycogen content (Akita-PTGOE). Akita-PTGOE animals showed lower glycemia, lower food intake, and decreased water consumption and urine output compared with Akita mice. Furthermore, Akita-PTGOE mice showed a restoration of the hepatic energy state and a normalization of gluconeogenesis and glycolysis back to nondiabetic levels. Moreover, hepatic lipogenesis, which is reduced in Akita mice, was reverted in Akita-PTGOE animals. These results demonstrate that strategies to increase liver glycogen content lead to the long-term reduction of the diabetic phenotype, independently of circulating insulin. Glycogen is synthesized by glycogen synthase (GS) (1Roach P.J. Depaoli-Roach A.A. Hurley T.D. Tagliabracci V.S. Glycogen and its metabolism: Some new developments and old themes.Biochem. J. 2012; 441: 763-787Crossref PubMed Scopus (366) Google Scholar), an enzyme regulated allosterically and by phosphorylation at multiple sites. Protein phosphatase 1 (PP1) catalyzes the dephosphorylation of GS and thus its activation. PP1 is composed of a catalytic subunit (PP1C) and a glycogen-targeting subunit (G subunit). G subunits are molecular scaffolds that localize the catalytic subunit to the glycogen particle (2Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Organizing glucose disposal: Emerging roles of the glycogen targeting subunits of protein phosphatase-1.Diabetes. 2000; 49: 1967-1977Crossref PubMed Scopus (144) Google Scholar), where it can interact with enzymes of glycogen metabolism. In mammals, seven G subunits have been identified (PPP1R3A–G), each with a distinct tissue expression pattern (1Roach P.J. Depaoli-Roach A.A. Hurley T.D. Tagliabracci V.S. Glycogen and its metabolism: Some new developments and old themes.Biochem. J. 2012; 441: 763-787Crossref PubMed Scopus (366) Google Scholar, 2Newgard C.B. Brady M.J. O'Doherty R.M. Saltiel A.R. Organizing glucose disposal: Emerging roles of the glycogen targeting subunits of protein phosphatase-1.Diabetes. 2000; 49: 1967-1977Crossref PubMed Scopus (144) Google Scholar, 3Ceulemans H. Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button.Physiol. Rev. 2004; 84: 1-39Crossref PubMed Scopus (517) Google Scholar). Protein targeting to glycogen (PTG) (PPP1R3C or PPP1R5) and GL (PPP1R3B) are expressed in the liver (4O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. Activation of direct and indirect pathways of glycogen synthesis by hepatic overexpression of protein targeting to glycogen.J. Clin. Invest. 2000; 105: 479-488Crossref PubMed Scopus (67) Google Scholar), where they promote the storage of glycogen. Accordingly, overexpression of PTG and GL in the liver has been shown to increase glycogen levels (4O'Doherty R.M. Jensen P.B. Anderson P. Jones J.G. Berman H.K. Kearney D. Newgard C.B. Activation of direct and indirect pathways of glycogen synthesis by hepatic overexpression of protein targeting to glycogen.J. Clin. Invest. 2000; 105: 479-488Crossref PubMed Scopus (67) Google Scholar, 5Mehta M.B. Shewale S.V. Sequeira R.N. Millar J.S. Hand N.J. Rader D.J. Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis.J. Biol. Chem. 2017; 292: 10444-10454Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 6Lopez-Soldado I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar). Hepatic glycogen synthesis plays a critical role in maintaining normal glucose homeostasis. After a mixed meal, glucose is taken up by the liver from the portal vein and the systemic circulation and is temporarily stored as glycogen (7Taylor R. Magnusson I. Rothman D.L. Cline G.W. Caumo A. Cobelli C. Shulman G.I. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects.J. Clin. 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After short-term (24 h) insulin treatment, glycogen synthesis is improved but not normalized (10Bischof M.G. Krssak M. Krebs M. Bernroider E. Stingl H. Waldhausl W. Roden M. Effects of short-term improvement of insulin treatment and glycemia on hepatic glycogen metabolism in type 1 diabetes.Diabetes. 2001; 50: 392-398Crossref PubMed Scopus (72) Google Scholar). Long-term near normoglycemia, resulting from tight metabolic control, is required to normalize hepatic glycogen metabolism in type 1 diabetic patients. However, the contribution of the indirect (gluconeogenic) pathway of glycogen synthesis remains increased, indicating augmented gluconeogenesis in these patients (11Bischof M.G. Bernroider E. Krssak M. Krebs M. Stingl H. Nowotny P. Yu C. Shulman G.I. Waldhausl W. Roden M. Hepatic glycogen metabolism in type 1 diabetes after long-term near normoglycemia.Diabetes. 2002; 51: 49-54Crossref PubMed Scopus (72) Google Scholar). Impaired GK activity (12Mason T.M. Gupta N. Goh T. El-Bahrani B. Zannis J. van de Werve G. Giacca A. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats.Metabolism. 2000; 49: 1411-1416Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 13Velho G. Petersen K.F. Perseghin G. Hwang J.H. Rothman D.L. Pueyo M.E. Cline G.W. Froguel P. Shulman G.I. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.J. Clin. Invest. 1996; 98: 1755-1761Crossref PubMed Scopus (191) Google Scholar) or increased phosphoenolpyruvate carboxykinase (PEPCK) activity (14Kramer K.L. Giffin B.F. Fox J.W. Drake R.L. Insulin replacement therapy in diabetic rats using an osmotic pump normalizes expression of enzymes key to hepatic carbohydrate metabolism.Arch. Biochem. Biophys. 1999; 368: 291-297Crossref PubMed Scopus (6) Google Scholar, 15Brichard S.M. Henquin J.C. Girard J. Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism.Diabetologia. 1993; 36: 292-298Crossref PubMed Scopus (57) Google Scholar) could explain this alteration. In rodent models of type 1 diabetes, glycogen stores are depleted, thereby contributing to the development of hyperglycemia (16Ros S. Garcia-Rocha M. Calbo J. Guinovart J.J. Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats.Diabetologia. 2011; 54: 2639-2648Crossref PubMed Scopus Google Scholar, R. Newgard C.B. Hepatic expression of a targeting subunit of protein in rats reverses hyperglycemia and hyperphagia Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. B. C. Glycogen in type 1 diabetic the of diabetic glycogen molecular J. Biol. PubMed Scopus Google Scholar, T. J.C. I. G. R. therapy improves insulin-deficient type 1 diabetes by in S. A. PubMed Scopus (144) Google Scholar, A. J. E. S. therapy with and reverses metabolic in insulin-deficient diabetic PubMed Scopus Google Scholar), and hepatic glycogen is to normal levels after insulin treatment (12Mason T.M. Gupta N. Goh T. El-Bahrani B. Zannis J. van de Werve G. Giacca A. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats.Metabolism. 2000; 49: 1411-1416Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, K.L. Giffin B.F. Fox J.W. Drake R.L. Insulin replacement therapy in diabetic rats using an osmotic pump normalizes expression of enzymes key to hepatic carbohydrate metabolism.Arch. Biochem. Biophys. 1999; 368: 291-297Crossref PubMed Scopus (6) Google Scholar). In to of metabolism to the and with patients with diabetes B. in type 1 PubMed Scopus Google Scholar). In of control, patients with type 1 diabetes with increased levels in type 1 diabetes J. 1995; PubMed Scopus Google Scholar) and B. in type 1 PubMed Scopus Google Scholar). and are the increase in tissue promotes the of to the Hepatic synthesis is reduced in type 1 diabetic patients P. P. P. A. S. H. resonance of hepatic in with type 1 diabetes compared to 2015; 64: Full Text Full Text PDF PubMed Scopus Google Scholar) and in insulin-dependent diabetic mice S. C. Hepatic and of type 1 diabetic mice in and PubMed Scopus Google Scholar), and insulin therapy was to promote P. P. P. A. S. H. resonance of hepatic in with type 1 diabetes compared to 2015; 64: Full Text Full Text PDF PubMed Scopus Google Scholar). Akita is a mouse model of insulin-deficient and monogenic diabetes. A in the insulin to of the insulin which to in reduced and decreased insulin Akita mice insulin-deficient diabetes and and by to of We previously showed that strategies to increase liver glycogen stores food intake and obesity in a high-fat-diet mouse model of obesity and insulin resistance I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar). effect was accompanied by a of has been that obesity and its A. S.M. obesity independently of insulin 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). to whether these effects were on the of we a model with reduced insulin the Akita mouse, to the long-term effects of increasing liver glycogen on glucose food intake, and diabetes We crossed Akita mice with animals overexpressing PTG in the liver I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar). resulting mice showed increased liver glycogen and long-term reduction of the diabetic that strategies to increase liver glycogen can an to insulin-deficient diabetes. the Akita hyperglycemia at of and this with diabetic phenotype is in in M. T. T. A. A to on in PubMed Scopus Google Scholar). Akita mice were crossed with that PTG in the liver I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar) to generate the Akita-PTGOE mice. PTG overexpression in the of and is the of the were on Liver glycogen is decreased in streptozotocin diabetic models (16Ros S. Garcia-Rocha M. Calbo J. Guinovart J.J. Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats.Diabetologia. 2011; 54: 2639-2648Crossref PubMed Scopus Google Scholar, R. Newgard C.B. Hepatic expression of a targeting subunit of protein in rats reverses hyperglycemia and hyperphagia Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T. J.C. I. G. R. therapy improves insulin-deficient type 1 diabetes by in S. A. PubMed Scopus (144) Google Scholar, A. J. E. S. therapy with and reverses metabolic in insulin-deficient diabetic PubMed Scopus Google Scholar) and in diabetic mice M.J. Newgard C.B. therapy in insulin-deficient type S. A. PubMed Scopus Google Scholar). Akita mice showed a reduction in liver glycogen compared with and Akita-PTGOE mice showed a to increase in hepatic glycogen content compared with and Akita mice, glucose levels were in and mice Akita mice showed hyperglycemia with glucose levels at of and this hyperglycemia with Akita-PTGOE mice showed a reduction in glucose levels compared with Akita mice at the indicating that hyperglycemia at the and during the of the reduced in to increased liver glycogen. of the diabetic mice showed hyperglycemia decreased and we to the at of this Akita mice showed a decrease in compared with mice which to a decrease in and and Akita-PTGOE mice were Akita mice in was with a in Akita-PTGOE mice in Akita mice was with hyperphagia and and food intake was that of mice and consumption was that of nondiabetic mice. Akita-PTGOE animals and showed in water consumption and urine output compared with Akita mice G and We previously demonstrated that strategies to increase liver glycogen content lead to a reduction in food intake and obesity and glucose in a mouse These effects were accompanied by a decrease in insulin levels. was to in the circulating levels of insulin and key in the Akita Akita mice lower levels of insulin and nondiabetic but these levels were not in the is an involved in the regulation of food intake and energy and the regulation of in PubMed Scopus Google Scholar). In insulin-deficient diabetic and levels are decreased S. D. P. W. R.L. in diabetic and diabetic and normal rats.Metabolism. Full Text PDF PubMed Scopus Google Scholar, M. J. H. T. C. M. of on diabetes, diabetic and in insulin-deficient diabetic 2011; PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar), and this could explain levels are not by PTG overexpression in Akita mice In the of glucose in Akita-PTGOE mice was of in the levels of circulating and were in Akita and Akita-PTGOE mice. and in and nondiabetic in whether of hyperglycemia in Akita-PTGOE mice was with in hepatic glucose we the expression of the key enzymes and Akita mice showed an increase in and a decrease in GK and thereby indicating an increase in gluconeogenesis and a decrease in Akita-PTGOE mice showed a of these effects is a of that the of gluconeogenic enzymes as expression was in the of Akita mice but normalized in of Akita-PTGOE animals These were with an increase in the hepatic content of in the model We the of PTG overexpression on hepatic metabolism. is in insulin-deficient diabetes. Accordingly, hepatic were decreased in Akita compared with nondiabetic mice. However, Akita-PTGOE mice showed levels of hepatic as nondiabetic animals expression of of the synthase and was lower in the of Akita mice compared with and but was in Akita-PTGOE compared with Akita mice 1 expression was the at levels in the liver G. R. Hepatic overexpression of and promotes direct of and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and to hepatic activity and a direct role in liver G. R. Hepatic overexpression of and promotes direct of and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). are in the of insulin-deficient mice A. J. E. S. therapy with and reverses metabolic in insulin-deficient diabetic PubMed Scopus Google Scholar), and we the pattern in the of Akita mice and However, Akita-PTGOE animals showed levels of and compared with of nondiabetic and as diabetes lead to decreased C. S. S. J. J. 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We demonstrate that long-term of liver glycogen reduces Akita-PTGOE mice showed a decrease in glucose that was as the reduction in hyperglycemia was accompanied by an of the diabetic and effect was of in circulating or these an the observed phenotype sought in the in the liver by PTG Akita-PTGOE mice have increased the of glucose the synthesis of glycogen explain the reduced However, that the reduction in glucose is the lower gluconeogenic and observed in the liver of Akita-PTGOE mice. has been identified as a key of hepatic gluconeogenesis and its expression is increased in diabetes J.C. P. G. J. J. G. J. Newgard C.B. of hepatic gluconeogenesis the 2001; PubMed Scopus Google Scholar, D.J. G. and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In Akita-PTGOE mice, we that and expression was to normal levels. these animals showed normalized GK protein which to glucose levels. GK plays a role in the of glucose and it has been that strategies to increase the hepatic expression or activity of GK in diabetic patients In this GK overexpression has been demonstrated to glucose levels R.M. D.L. S. Newgard C.B. of overexpression in of glucose in rats is accompanied by 1999; PubMed Scopus Google Scholar). Akita-PTGOE mice showed an of expression and an increase in hepatic which could a of increased GK in the of these as previously shown in of type diabetes rats overexpressing GK J. A. S. Newgard C.B. Guinovart J.J. overexpression glucose and storage in from diabetic Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is that hepatic metabolism was in Akita-PTGOE mice. In this hepatic increased and the expression of and was increase in could to the increase in hepatic it has been that in the liver as a of GK overexpression to increased of and the a the R.M. D.L. S. 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J.S. of glucose metabolism from a PubMed Scopus Google Scholar). increase in the hepatic content in Akita-PTGOE mice could to an increase in the expression of GK and in the liver the of reduction in an to the increase in was that Akita-PTGOE mice a lower food intake compared with Akita mice. results that or insulin not to the effect were reduced in Akita and decrease in food intake could by the of the hepatic energy state observed in Akita-PTGOE mice, we have demonstrated that the regulation of food intake by liver glycogen I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar) is on hepatic to the the hepatic of the G. Duran J. Garcia-Rocha M. D. I. M. P. Guinovart J.J. of glycogen accumulation and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). In we demonstrate that the long-term of liver glycogen reduces the diabetic phenotype by partially the in hepatic glucose and metabolism by insulin-deficient diabetes. These on by (16Ros S. Garcia-Rocha M. Calbo J. Guinovart J.J. Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats.Diabetologia. 2011; 54: 2639-2648Crossref PubMed Scopus Google Scholar) and R. Newgard C.B. Hepatic expression of a targeting subunit of protein in rats reverses hyperglycemia and hyperphagia Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that a short-term increase in hepatic glycogen content by overexpression of an of liver GS (16Ros S. Garcia-Rocha M. Calbo J. Guinovart J.J. Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats.Diabetologia. 2011; 54: 2639-2648Crossref PubMed Scopus Google Scholar) or of a targeting subunit of PP1 R. Newgard C.B. Hepatic expression of a targeting subunit of protein in rats reverses hyperglycemia and hyperphagia Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) reduces diabetes in diabetic However, were using short-term hepatic overexpression of the it a in the levels of the and the of the was to 1 In the we that the treatment is in the liver glycogen of the metabolic with insulin-deficient diabetes, and it independently of the levels of circulating insulin. the of these the of glycogen deposition as a the treatment of insulin-deficient diabetes. were by the and in with the and the of the and of animals. Akita mice were from were crossed with that PTG in the that PTG were as previously I. Zafra D. Duran J. Adrover A. Calbo J. Guinovart J.J. Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model.Diabetes. 2015; 64: 796-807Crossref PubMed Scopus (30) Google Scholar). the PTG the of the was an by A was the and the PTG to the expression to the of a resulting mouse was with an animal which the expression of PTG to the were in they a diabetic the mice were animals were at of and by and were and in was from the in and and was stored at food intake, mice were and 1 intake was Liver glycogen was as previously I. A. Adrover A. Duran J. Guinovart J.J. of liver glycogen during long-term fasting energy state in PubMed Scopus Google Scholar). Hepatic and were by in as previously G. Duran J. Garcia-Rocha M. D. I. M. P. Guinovart J.J. of glycogen accumulation and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). Liver was in using a Hepatic was in and the by and of content on the of obesity J. Google Scholar) and using a and were by and were using a glucose and were using a were using a Liver were in 1 1 1 and a Protein was using the protein of was using the from E. and GK by were by the of the was using the protein Liver and were as previously S. Zafra D. J. Garcia-Rocha M. S. J. Calbo J. Guinovart J.J. Hepatic overexpression of a of liver glycogen synthase improves glucose homeostasis.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were and was as a and were by magnetic resonance are in on each the the and the and of the the and to the were using with as are on from the of We to and I. We the of the to I. and J. J. G. the the the and the I. and the and the J. D. the animal model and contributed to the the of the to I. is of the of the as a is the of a of from of was by a from to J. G. and J. the de de and de

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