Background: Increases in PKC-theta (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary-induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC-theta mRNA expression has not been previously reported in patients with T2DM or in relation to in-vivo measurements of insulin sensitivity.
Methods: Diet-only treated patients with T2DM (n=7) and healthy nondiabetic controls (n=7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75-g oral glucose load and measurement of whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp.
Results: Type 2 DM patients were insulin resistant (M-value 3.0 +/- 0.4 vs. 8.6 +/- 0.8 mg glucose kg(-1) min(-1)) with fasting hyperinsulinaemia (306 +/- 116 vs. 34 +/- 9 pmol L(-1), P<0.001) and hypertriglyceridaemia (3.6 +/- 0.7 vs. 1.3 +/- 0.3 mmol L(-1), P<0.01) relative to controls. Semi-quantitative RT-PCR showed that expression of PKC-theta mRNA (relative to GAPDH mRNA) was 6-fold higher in T2DM subjects (0.63 + 0.25% vs. 0.09 + 0.07%, P<0.001), whereas there was no difference in expression of PKC-alpha mRNA between the two groups. Expression of PKC-theta mRNA was inversely correlated with insulin sensitivity (M) and positively correlated with fasting serum insulin concentration (P<0.02).
Conclusions: This is the first clinical study of PKC-theta mRNA expression in human diabetic skeletal muscle. The results indicate that transcriptional up-regulation of PKC-theta may at least partly contribute to the increased muscle PKC-theta signalling in T2DM, and that PKC-theta mRNA may be inversely related to in-vivo insulin sensitivity.