Top

Published in:

01-02-2009 | Article

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

Authors: M. Fex, G. Haemmerle, N. Wierup, M. Dekker-Nitert, M. Rehn, M. Ristow, R. Zechner, F. Sundler, C. Holm, L. Eliasson, H. Mulder

Published in: Diabetologia | Issue 2/2009

Abstract

Aims/hypothesis

The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results.

Methods

To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods.

Results

We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia.

Conclusions/interpretation

Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipid-derived signal essential for normal insulin secretion.

Available only for authorised users

Prentki M, Corkey BE (1996) Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45:273–283PubMedCrossRef

Vaughan M, Berger JE, Steinberg D (1964) Hormone-sensitive lipase and monoglyceride lipase activities in adipose tissue. J Biol Chem 239:401–409PubMed

Yeaman SJ (2004) Hormone-sensitive lipase—new roles for an old enzyme. Biochem J 379:11–22PubMedCrossRef

Holm C, Osterlund T, Laurell H, Contreras JA (2000) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu Rev Nutr 20:365–393PubMedCrossRef

Mulder H, Holst LS, Svensson H et al (1999) Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells. Diabetes 48:228–232PubMedCrossRef

Corkey BE, Glennon MC, Chen KS, Deeney JT, Matschinsky FM, Prentki M (1989) A role for malonyl-CoA in glucose-stimulated insulin secretion from clonal pancreatic beta-cells. J Biol Chem 264:21608–21612PubMed

Deeney JT, Gromada J, Hoy M et al (2000) Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT T-15 and NMRI beta-cells). J Biol Chem 275:9363–9368PubMedCrossRef

Hu L, Deeney JT, Nolan CJ et al (2005) Regulation of lipolytic activity by long-chain acyl-coenzyme A in islets and adipocytes. Am J Physiol Endocrinol Metab 289:E1085–E1092PubMedCrossRef

Kanehara H, Suzuki J, Zenimaru Y et al (2004) Function of hormone-sensitive lipase in diacylglycerol-protein kinase C pathway. Diabetes Res Clin Pract 65:209–215PubMedCrossRef

10.

Yaney GC, Korchak HM, Corkey BE (2000) Long-chain acyl CoA regulation of protein kinase C and fatty acid potentiation of glucose-stimulated insulin secretion in clonal beta-cells. Endocrinology 141:1989–1998PubMedCrossRef

11.

Olofsson CS, Salehi A, Holm C, Rorsman P (2004) Palmitate increases L-type Ca²⁺ currents and the size of the readily releasable granule pool in mouse pancreatic beta-cells. J Physiol 557:935–948PubMedCrossRef

12.

Branstrom R, Leibiger IB, Leibiger B et al (2007) Single residue (K332A) substitution in Kir6.2 abolishes the stimulatory effect of long-chain acyl-CoA esters: indications for a long-chain acyl-CoA ester binding motif. Diabetologia 50:1670–1677PubMedCrossRef

13.

Mulder H, Yang S, Winzell MS, Holm C, Ahren B (2004) Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. Diabetes 53:122–128PubMedCrossRef

14.

Claus TH, Lowe DB, Liang Y et al (2005) Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose. J Pharmacol Exp Ther 315:1396–1402PubMedCrossRef

15.

Sorhede Winzell M, Ahren B (2004) Glucagon-like peptide-1 and islet lipolysis. Horm Metab Res 36:795–803PubMedCrossRef

16.

Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG (2001) Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50:1771–1777PubMedCrossRef

17.

Unger RH, Orci L (2000) Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Relat Metab Disord 24(Suppl 4):S28–S32PubMed

18.

Osuga J, Ishibashi S, Oka T et al (2000) Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci U S A 97:787–792PubMedCrossRef

19.

Wang SP, Laurin N, Himms-Hagen J et al (2001) The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes Res 9:119–128PubMedCrossRef

20.

Haemmerle G, Zimmermann R, Hayn M et al (2002) Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem 277:4806–4815PubMedCrossRef

21.

Mulder H, Sorhede-Winzell M, Contreras JA et al (2003) Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact. J Biol Chem 278:36380–36388PubMedCrossRef

22.

Chung S, Wang SP, Pan L, Mitchell G, Trasler J, Hermo L (2001) Infertility and testicular defects in hormone-sensitive lipase-deficient mice. Endocrinology 142:4272–4281PubMedCrossRef

23.

Wang SP, Chung S, Soni K et al (2004) Expression of human hormone-sensitive lipase (HSL) in postmeiotic germ cells confers normal fertility to HSL-deficient mice. Endocrinology 145:5688–5693PubMedCrossRef

24.

Harada K, Shen WJ, Patel S et al (2003) Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. Am J Physiol Endocrinol Metab 285:E1182–1195PubMed

25.

Park SY, Kim HJ, Wang S et al (2005) Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. Am J Physiol Endocrinol Metab 289:E30–E39PubMedCrossRef

26.

Fex M, Olofsson CS, Fransson U et al (2004) Hormone-sensitive lipase deficiency in mouse islets abolishes neutral cholesterol ester hydrolase activity but leaves lipolysis, acylglycerides, fat oxidation, and insulin secretion intact. Endocrinology 145:3746–3753PubMedCrossRef

27.

Roduit R, Masiello P, Wang SP, Li H, Mitchell GA, Prentki M (2001) A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. Diabetes 50:1970–1975PubMedCrossRef

28.

Peyot ML, Nolan CJ, Soni K et al (2004) Hormone-sensitive lipase has a role in lipid signaling for insulin secretion but is nonessential for the incretin action of glucagon-like peptide 1. Diabetes 53:1733–1742PubMedCrossRef

29.

Zimmermann R, Strauss JG, Haemmerle G et al (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–1386PubMedCrossRef

30.

Fex M, Lucas S, Sörhede Winzell M, Ahrén B, Holm C, Mulder H (2006) Beta-cell lipases and insulin secretion. Diabetes 55:S24–S31CrossRef

31.

Gannon M, Shiota C, Postic C, Wright CV, Magnuson M (2000) Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 26:139–142PubMedCrossRef

32.

Ristow M, Mulder H, Pomplun D et al (2003) Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J Clin Invest 112:527–534PubMed

33.

Fex M, Wierup N, Nitert MD, Ristow M, Mulder H (2007) Rat insulin promoter 2-Cre recombinase mice bred onto a pure C57BL/6J background exhibit unaltered glucose tolerance. J Endocrinol 194:551–555PubMedCrossRef

34.

Barg S, Galvanovskis J, Gopel SO, Rorsman P, Eliasson L (2000) Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49:1500–1510PubMedCrossRef

35.

Fex M, Nitert MD, Wierup N, Sundler F, Ling C, Mulder H (2007) Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet. Diabetologia 50:74–83PubMedCrossRef

36.

Brommage R (2003) Validation and calibration of DEXA body composition in mice. Am J Physiol Endocrinol Metab 285:E454–E459PubMed

37.

Elks ML (1993) Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology 133:208–214PubMedCrossRef

38.

Kashima Y, Miki T, Shibasaki T et al (2001) Critical role of cAMP-GEFII–Rim2 complex in incretin-potentiated insulin secretion. J Biol Chem 276:46046–46053PubMedCrossRef

39.

Ammala C, Eliasson L, Bokvist K, Larsson O, Ashcroft FM, Rorsman P (1993) Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells. J Physiol 472:665–688PubMed

40.

Ceddia RB, William WN Jr, Curi R (1999) Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. Int J Obes Relat Metab Disord 23:75–82PubMedCrossRef

41.

Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946PubMedCrossRef

42.

Masiello P, Novelli M, Bombara M et al (2002) The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets. Metabolism 51:110–114PubMedCrossRef

43.

Okazaki H, Osuga J, Tamura Y et al (2002) Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases. Diabetes 51:3368–3375PubMedCrossRef

44.

Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS (2004) Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 279:47066–47075PubMedCrossRef

45.

Lindvall H, Nevsten P, Strom K et al (2004) A novel hormone-sensitive lipase isoform expressed in pancreatic beta-cells. J Biol Chem 279:3828–3836PubMedCrossRef

46.

Masiello P (2006) Animal models of type 2 diabetes with reduced pancreatic beta-cell mass. Int J Biochem Cell Biol 38:873–893PubMedCrossRef

47.

Cnop M, Landchild MJ, Vidal J et al (2002) The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments. Diabetes 51:1005–1015PubMedCrossRef

48.

Lee JY, Ristow M, Lin X, White MF, Magnuson MA, Hennighausen L (2006) RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function. J Biol Chem 281:2649–2653PubMedCrossRef

49.

Sekiya M, Osuga J, Okazaki H et al (2004) Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J Biol Chem 279:15084–15090PubMedCrossRef

Title: A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis
Authors: M. Fex
G. Haemmerle
N. Wierup
M. Dekker-Nitert
M. Rehn
M. Ristow
R. Zechner
F. Sundler
C. Holm
L. Eliasson
H. Mulder
Publication date: 01-02-2009
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 2/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-1191-9

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

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

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 2/2009

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

Improvements in the lifestyle of patients who have had type 1 diabetes for 50 years: an optimistic message

Ramadan-focused education and awareness in type 2 diabetes

Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat

Congenital rubella and diabetes mellitus

Metabolic consequences of a 50% partial pancreatectomy in humans

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

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

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page