Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 10/2011

01-10-2011 | Article

Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats

Authors: S. Ros, M. García-Rocha, J. Calbó, J. J. Guinovart

Published in: Diabetologia | Issue 10/2011

Login to get access

Abstract

Aims/hypothesis

Glycogen deposition is impaired in diabetes, thus contributing to the development of hyperglycaemia. Several glucose-lowering strategies have attempted to increase liver glycogen deposition by modulating targets, which eventually trigger the activation of liver glycogen synthase (LGS). However, these targets also alter several other biological processes, and therefore their therapeutic use may be limited. Here we tested the approach of directly activating LGS and evaluated the potential of this strategy as a possible treatment for diabetes.

Methods

In this study, we examined the efficacy of directly overproducing a constitutively active form of LGS in the liver to ameliorate streptozotocin-induced diabetes in rats.

Results

Activated mutant LGS overproduction in the liver of streptozotocin-induced diabetic rats normalised liver glycogen content, despite low levels of glucokinase and circulating insulin. Moreover, this overproduction led to a decrease in food intake and in the production of the main gluconeogenic enzymes, glucose-6-phosphatase, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase. The resulting combined effect was a reduction in hyperglycaemia.

Conclusions/interpretation

The restoration of liver glycogen ameliorated diabetes and therefore is considered a potential strategy for the treatment of this disease.
Literature
1.
Roach PJ, Cheng C, Huang D et al (1998) Novel aspects of the regulation of glycogen storage. J Basic Clin Physiol Pharmacol 9:139–151PubMedCrossRef
2.
Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI (1992) Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest 90:1323–1327PubMedCrossRef
3.
Cline GW, Rothman DL, Magnusson I, Katz LD, Shulman GI (1994) 13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. J Clin Invest 94:2369–2376PubMedCrossRef
4.
Velho G, Petersen KF, Perseghin G et al (1996) Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest 98:1755–1761PubMedCrossRef
5.
O’Doherty RM, Lehman DL, Telemaque-Potts S, Newgard CB (1999) Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes 48:2022–2027PubMedCrossRef
6.
Baker DJ, Greenhaff PL, MacInnes A, Timmons JA (2006) The experimental type 2 diabetes therapy glycogen phosphorylase inhibition can impair aerobic muscle function during prolonged contraction. Diabetes 55:1855–1861PubMedCrossRef
7.
Gasa R, Clark C, Yang R, DePaoli-Roach AA, Newgard CB (2002) Reversal of diet-induced glucose intolerance by hepatic expression of a variant glycogen-targeting subunit of protein phosphatase-1. J Biol Chem 277:1524–1530PubMedCrossRef
8.
Yang R, Newgard CB (2003) Hepatic expression of a targeting subunit of protein phosphatase-1 in streptozotocin-diabetic rats reverses hyperglycemia and hyperphagia despite depressed glucokinase expression. J Biol Chem 278:23418–23425PubMedCrossRef
9.
Ros S, Garcia-Rocha M, Dominguez J, Ferrer JC, Guinovart JJ (2009) Control of liver glycogen synthase activity and intracellular distribution by phosphorylation. J Biol Chem 284:6370–6378PubMedCrossRef
10.
Ros S, Zafra D, Valles-Ortega J et al (2010) Hepatic overexpression of a constitutively active form of liver glycogen synthase improves glucose homeostasis. J Biol Chem 285:37170–37177PubMedCrossRef
11.
Gomis RR, Ferrer JC, Guinovart JJ (2000) Shared control of hepatic glycogen synthesis by glycogen synthase and glucokinase. Biochem J 351:811–816PubMedCrossRef
12.
Becker TC, Noel RJ, Coats WS et al (1994) Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell Biol 43:161–189PubMedCrossRef
13.
Cid E, Gomis RR, Geremia RA, Guinovart JJ, Ferrer JC (2000) Identification of two essential glutamic acid residues in glycogen synthase. J Biol Chem 275:33614–33621PubMedCrossRef
14.
Massague J, Guinovart JJ (1977) Insulin control of rat hepatocyte glycogen synthase and phosphorylase in the absence of glucose. FEBS Lett 82:317–320PubMedCrossRef
15.
Thomas JA, Schlender KK, Larner J (1968) A rapid filter paper assay for UDPglucose–glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem 25:486–499PubMedCrossRef
16.
Chan TM, Exton JH (1976) A rapid method for the determination of glycogen content and radioactivity in small quantities of tissue or isolated hepatocytes. Anal Biochem 71:96–105PubMedCrossRef
17.
Garcia-Rocha M, Roca A, de la Iglesia N et al (2001) Intracellular distribution of glycogen synthase and glycogen in primary cultured rat hepatocytes. Biochem J 357:17–24PubMedCrossRef
18.
de la Iglesia N, Veiga-da-Cunha M, van Schaftingen E, Guinovart JJ, Ferrer JC (1999) Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase. FEBS Lett 456:332–338PubMedCrossRef
19.
Gomis RR, Cid E, Garcia-Rocha M, Ferrer JC, Guinovart JJ (2002) Liver glycogen synthase but not the muscle isoform differentiates between glucose 6-phosphate produced by glucokinase or hexokinase. J Biol Chem 277:23246–23252PubMedCrossRef
20.
Gomis RR, Favre C, Garcia-Rocha M, Fernandez-Novell JM, Ferrer JC, Guinovart JJ (2003) Glucose 6-phosphate produced by gluconeogenesis and by glucokinase is equally effective in activating hepatic glycogen synthase. J Biol Chem 278:9740–9746PubMedCrossRef
21.
Trinh KY, O’Doherty RM, Anderson P, Lange AJ, Newgard CB (1998) Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem 273:31615–31620PubMedCrossRef
22.
Herz J, Gerard RD (1993) Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci USA 90:2812–2816PubMedCrossRef
23.
Burcelin R, Eddouks M, Kande J, Assan R, Girard J (1992) Evidence that GLUT-2 mRNA and protein concentrations are decreased by hyperinsulinaemia and increased by hyperglycaemia in liver of diabetic rats. Biochem J 288:675–679PubMed
24.
Doherty MJ, Cadefau J, Stalmans W, Bollen M, Cohen PT (1998) Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats. Biochem J 333:253–257PubMed
25.
Browne GJ, Delibegovic M, Keppens S, Stalmans W, Cohen PT (2001) The level of the glycogen targetting regulatory subunit R5 of protein phosphatase 1 is decreased in the livers of insulin-dependent diabetic rats and starved rats. Biochem J 360:449–459PubMedCrossRef
26.
Rao PV, Pugazhenthi S, Khandelwal RL (1995) The effects of streptozotocin-induced diabetes and insulin supplementation on expression of the glycogen phosphorylase gene in rat liver. J Biol Chem 270:24955–24960PubMedCrossRef
27.
Iynedjian PB (1993) Mammalian glucokinase and its gene. Biochem J 293:1–13PubMed
28.
Cherrington AD (1999) Banting Lecture, 1997. Control of glucose uptake and release by the liver in vivo. Diabetes 48:1198–1214PubMedCrossRef
29.
Sindelar DK, Havel PJ, Seeley RJ, Wilkinson CW, Woods SC, Schwartz MW (1999) Low plasma leptin levels contribute to diabetic hyperphagia in rats. Diabetes 48:1275–1280PubMedCrossRef
30.
31.
Russek M (1963) Participation of hepatic glucoreceptors in the control of intake of food. Nature 197:79–80PubMedCrossRef
32.
Tordoff MG, Friedman MI (1988) Hepatic control of feeding: effect of glucose, fructose, and mannitol infusion. Am J Physiol 254:R969–R976PubMed
33.
Tordoff MG, Tluczek JP, Friedman MI (1989) Effect of hepatic portal glucose concentration on food intake and metabolism. Am J Physiol 257:R1474–R1480PubMed
34.
Mayer J (1991) Bulletin of the New England Medical Center, Volume XIV, April–June 1952: the glucostatic theory of regulation of food intake and the problem of obesity (a review). Nutr Rev 49:46–48PubMedCrossRef
35.
36.
Winnick JJ, An Z, Ramnanan CJ et al (2011) Hepatic glycogen supercompensation activates AMP-activated protein kinase, impairs insulin signaling, and reduces glycogen deposition in the liver. Diabetes 60:398–407PubMedCrossRef
37.
Granner D, Pilkis S (1990) The genes of hepatic glucose metabolism. J Biol Chem 265:10173–10176PubMed
38.
Cline GW, Johnson K, Regittnig W et al (2002) Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes 51:2903–2910PubMedCrossRef
39.
Ring DB, Johnson KW, Henriksen EJ et al (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588–595PubMedCrossRef
40.
Lochhead PA, Coghlan M, Rice SQ, Sutherland C (2001) Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes 50:937–946PubMedCrossRef
41.
Coghlan MP, Culbert AA, Cross DA et al (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7:793–803PubMedCrossRef
42.
Irimia JM, Meyer CM, Peper CL et al (2010) Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice. J Biol Chem 285:12851–12861PubMedCrossRef
Metadata
Title
Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats
Authors
S. Ros
M. García-Rocha
J. Calbó
J. J. Guinovart
Publication date
01-10-2011
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 10/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2238-x

Other articles of this Issue 10/2011

Diabetologia 10/2011 Go to the issue

Article

No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach

Review

Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link

Article

Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat

Article

Individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy

Article

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Article

Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits