The direct relationship of proinsulin-insulin hypersecretion to basal serum levels of cholesterol and triglyceride in myotonic dystrophy.

Excessive pancreatic insulin secretory responses to a variety of beta-cytotropic agents have been observed in 40 to 60 per cent of subjects with myotonic dystrophy; in addition, 25 to 30 per cent of affected persons manifest mild glucose intolerance, suggesting that circulating insulin may be biologically ineffective. To test this hypothesis, 8 men with myotonic dystrophy were challenged with a 100 gm. oral glucose load; responses were compared to an age, sex, weight-matched control group. Fasting serum immunoreactive insulin (IRI), cholesterol, and triglyceride levels in the myotonic group did not differ significantly from the controls. In contrast, fasting blood glucose and serum free fatty acid (FFA) levels in the myotonic group were significantly elevated above control, although still within the accepted normal range. Following oral glucose challenge, myotonic subjects exhibited mild glucose intolerance and excessive IRI response, but the FFA and serum alpha-amino nitrogen responses were comparable to control responses. Serum proinsulin was separated from insulin by gel filtration and quantitated by immunoassay. Overall, the proinsulin level in myotonic serum was not greater than the accepted normal level. The mean proinsulin level at the peak serum IRI response during the test was 18.6 +/- 4.1 per cent of the total IRI; 3 myotonic subjects responded with greater than 20 per cent proinsulin. The proinsulin secretory response correlated significantly with basal triglyceride (r = 0.972) and cholesterol (r = 0.794) levels but not with fasting glucose or FFA levels. Peak insulin response was also significantly correlated with triglyceride but not with cholesterol levels. Serum insulin-like activity (ILA) from myotonic dystrophic patients was assessed in vitro employing rat adipose tissue and skeletal muscle in the presence and absence of excess guinea pig anti-insulin serum. Comparison of suppressible insulin-like activity to immunoreactive insulin revealed that the mean biological recovery of serum insulin in these assay systems was 85 to 90 per cent, indicating that endogenous insulin was biologically active on both adipose tissue and skeletal muscle in vitro. We conclude that a biologically ineffective form of circulating insulin does not exist in myotonic dystrophy and that the pancreatic insulin response mechanism may be excessively sensitive, resulting in balanced hypersecretion of proinsulin and insulin. The highly significant correlation between proinsulin and serum triglyceride or cholesterol levels suggests that, in addition to insulin, proinsulin may also exert an important influence on lipid metabolism.