Impaired cathepsin L gene expression in skeletal muscle is associated with type 2 diabetes.
To identify abnormally expressed genes associated with muscle insulin resistance or type 2 diabetes, we screened the mRNA populations using cDNA differential display combined with relative RT-PCR analysis from muscle biopsies of diabetes-prone C57BL/6J and diabetes-resistant NMRI mice fed with a high-fat or normal diet for 3 or 15 months. Six abnormally expressed genes were isolated from the mice after a 3-month fat feeding; one of them was cathepsin L. No significant difference in mRNA levels of these genes was observed between fat- and normal-diet conditions in either strains. However, cathepsin L mRNA levels in muscle were higher in normal diet-fed C57BL/6J mice compared with normal diet-fed NMRI mice at 3 months (0.72 +/- 0.04 vs. 0.51 +/- 0.04 relative units, P < 0.01, n = 8-10) and at 15 months (0.41 +/- 0.05 vs. 0.27 +/- 0.04 relative units, P = 0.01, n = 9-10). Further, cathepsin L mRNA levels in muscle correlated inversely with plasma glucose in both strains regardless of diets at 3 (r = -0.49, P < 0.01, n = 31) and 15 (r = -0.42, P = 0.007, n = 39) months. To study whether cathepsin L plays a role in human diabetes, we measured cathepsin L mRNA levels in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and from 12 control subjects. Basal cathepsin L mRNA levels were not significantly different between the study groups. Insulin infusion increased cathepsin L mRNA levels in control subjects from 1.03 +/- 0.30 to 1.90 +/- 0.32 relative units (P = 0.03). Postclamp cathepsin L mRNA levels were lower in diabetic twins but similar in nondiabetic twins compared with control subjects (0.66 +/- 0.22, 1.16 +/- 0.18 vs. 1.38 +/- 0.21 relative units, P < 0.02, NS, respectively). Further, postclamp cathepsin L mRNA levels were correlated with insulin-mediated glucose uptake (r = 0.37, P = 0.03), particularly, with glucose oxidation (r = 0.37, P = 0.03), and fasting glucose concentrations (r = -0.45, P < 0.01) across all three study groups. In conclusion, muscle cathepsin L gene expression is increased in diabetes-prone mice and related to glucose tolerance. In humans, insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism.
Huang
Xudong
X
Department of Endocrinology, Wallenberg Laboratory, Malmo, Sweden. xudong@sickkids.ca
Vaag
Allan
A
Carlsson
Emma
E
Hansson
Mona
M
Ahrén
Bo
B
Groop
Leif
L
D000818:Animals; D001786:Blood Glucose; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics*; D003546:Cysteine Endopeptidases; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D004041:Dietary Fats / Q000494:pharmacology; D005215:Fasting; D005260:Female; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D014430:Twins, Monozygotic
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D012333:RNA, Messenger; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse