Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

Abstract

Aims/hypothesis. The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 (CAPN10). Methods. We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-3 H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l).Results. There was a linear increase in NEFA levels (p<0.0005) and WHR (p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance (r=−0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity (r= −0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations (r=−0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3±0.4 vs 7.2±0.4 mg·ffm kg −1 min −1 ·mU·l −1 ; p<0.005). Conclusions/interpretation. We conclude that the prediabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

Common variants in HNF-1 α and risk of type 2 diabetes

“…A total of 200 Swedish men (66±2 years) underwent a stepwise assessment of acute insulin response to arginine at three different glucose concentrations (fasting, 14 and 28 mmol/l) [24]. The insulin response to arginine at a glucose concentration of 28 mmol/l was used as a surrogate measure of total insulin secretory capacity or beta cell mass.…”

A common variant upstream of the PAX6 gene influences islet function in man

“…Effect of PAX6 rs685428 on glucose and argininestimulated insulin secretion in vivo and in vitro We also studied the effect of rs685428 on arginine-stimulated insulin secretion in 167 Malmö men (Table 1) [21,32]. The AIR to arginine was lower in AG/GG than in AA genotype carriers at all glucose concentrations (p=0.04; Fig.…”

“…In the Malmö men (MM) study, acute insulin response (AIR) during a glucose-dependent arginine stimulation test was analysed in a subgroup of 168 men from the Malmö Preventive Project study who had impaired glucose tolerance at the screening visit 20 years earlier [19][20][21]. At the time of the test 70 men had developed type 2 diabetes and were either treated with diet alone (42%) or with oral hypoglycaemic agents that were discontinued the day before the test.…”

“…Arginine-stimulated insulin secretion Insulin secretion in response to an acute bolus of arginine was measured at three glucose concentrations (fasting, 14 and 28 mmol/l) as previously described [21]. The AIR was calculated from the +2 to 5 min values using the trapezoidal rule.…”

“…The AIR was calculated from the +2 to 5 min values using the trapezoidal rule. Potentiation of insulin secretion by glucose was calculated as the slope between AIR at fasting and 14 mmol/l glucose [21].…”