Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose.
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.
Claus
Thomas H
TH
Department of Metabolic Disorders Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA.
Lowe
Derek B
DB
Liang
Yin
Y
Salhanick
Arthur I
AI
Lubeski
Christine Keiper
CK
Yang
Ling
L
Lemoine
Lynn
L
Zhu
Jian
J
Clairmont
Kevin B
KB
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D004285:Dogs; D005215:Fasting; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism; D005990:Glycerol / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008066:Lipolysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000235:genetics; D013997:Time Factors
D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D008055:Lipids; D002787:Sterol Esterase; D005990:Glycerol