title: Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact.
abstract: Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic beta-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 beta-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.
authors.affiliation: Department of Cell and Molecular Biology, Physiological Sciences, and Medicine, Lund University, SE-221 84 Lund, Sweden. hendrik.mulder@medkem.lu.se
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Maria
authors.initials: M
authors.lastname: Sörhede-Winzell
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Contreras
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Ström
authors.forename: Thorkil
authors.initials: T
authors.lastname: Ploug
authors.forename: Henrik
authors.initials: H
authors.lastname: Galbo
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundberg
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Cecilia
authors.initials: C
authors.lastname: Holm
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000737:chemistry; D015153:Blotting, Western; D001835:Body Weight; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D007545:Isoproterenol / Q000494:pharmacology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics*; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D007328:Insulin; D001120:Arginine; D002787:Sterol Esterase; D005947:Glucose; D007545:Isoproterenol