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J. Biol. Chem., Vol. 278, Issue 38, 36380-36388, September 19, 2003

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Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact^*

Hindrik Mulder  , Maria Sörhede-Winzell , Juan Antonio Contreras , Malin Fex , Kristoffer Ström , Thorkil Ploug ¶, Henrik Galbo ¶, Peter Arner ||, Cecilia Lundberg **, Frank Sundler **, Bo Ahrén  and Cecilia Holm 

From the Departments of Cell and Molecular Biology, ^**Physiological Sciences, and Medicine, Lund University, SE-221 84 Lund, Sweden, ^||Department of Medicine, Huddinge University Hospital, SE-141 86 Stockholm, Sweden, and ^¶Copenhagen Muscle Research Center, Panum Institute, Copenhagen DK-2200, Denmark

Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic -cells, lipids are mobilized from acylglycerides by the hormone-sensitive lipase (HSL). Here, the consequences of a targeted disruption of the HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release of increased amounts of insulin. Impaired insulin sensitivity was further indicated by retarded glucose disposal during an insulin tolerance test. A euglycemic hyperinsulinemic clamp revealed that hepatic glucose production was insufficiently blocked by insulin in HSL null mice. In vitro, insulin-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of -cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance. Insulin secretion in vitro, examined by perifusion of isolated islets, was not impacted by HSL deficiency. Thus, HSL deficiency results in a moderate impairment of insulin sensitivity in multiple target tissues of the hormone but is compensated by hyperinsulinemia.

Received for publication, December 20, 2002 , and in revised form, June 2, 2003.

^* This work was supported in part by the Swedish Research Council Grants 14196 (to H. M.), 11284 (to C. H.), and 6834 (to B. A.), by A Center of Excellence Grant from the Juvenile Diabetes Foundation, United States of America, by the Knut and Alice Wallenberg Foundation, Sweden (to C. H. and P. A.), by Juvenile Diabetes Research Foundation International Grant 10-2000-676 (to H. M.), and by the Swedish Diabetes Association, Novo Nordisk Fond, the Crafoord, Thelma Zoega, Ingrid and Fredrik Thuring, Åke Wiberg and Albert Påhlsson Foundations, and the Medical Faculty at Lund University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Section for Molecular Signaling, Dept. of Cell and Molecular Biology, Lund University, BMC C11, SE-221 84 Lund, Sweden. Tel.: 46-46-222-0473; Fax: 46-46-222-4022; E-mail: hindrik.mulder{at}medkem.lu.se.

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