Polymorphism at the 5‘ end flanking region of the insulin gene is associated with reduced insulin secretion in healthy individuals

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Abstract
Sixty‐four unrelated healthy subjects were studied for the detection of a DNA polymorphism at the 5′ end of the insulin gene. No significant difference between the groups was found in blood glucose values at fasting and after an oral glucose load. A significant association was found between fasting (P < 0·05) and after load plasma C‐peptide levels (P < 0·01) and the presence of a 1·6 Kb insertion at the 5′ end of the insulin gene. A gene dose‐dependent effect was noted, class 3/3 individuals having the lowest after‐load C‐peptide concentration and class 1/3 an intermediate level (F for the linear trend: P=0·007). This might suggest that insulin gene polymorphism affects insulin secretion in healthy individuals. In order to confirm this, a subgroup of six class 3/3 and eight class 1/1 individuals subsequently underwent a hyperglycaemic clamp. The tissue sensitivity to insulin was similar in the two groups but glucose‐stimulated insulin secretion was markedly impaired in homozygotes for the class 3 allele. In this group, insulin secretion was, on average, only one‐third of that in class 1/1 individuals (P < 0·02). Similarly impaired in class 3/3 persons was the glucose+arginine‐stimulated insulin secretion (P < 0·05). We conclude that the polymorphism at the 5′ end of the insulin gene is associated with variations in insulin secretion in healthy humans.