Glucose Metabolism in High-Risk Subjects for Type 2 Diabetes Carrying the rs7903146TCF7L2Gene Variant

Abstract

In subjects at risk for T2DM, the TCF7L2 polymorphisms were associated with reduced Raex into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in β-cell function. The reduced Raex is likely due to greater glucose retention in the splanchnic area.

Performance of individually measured vs population‐based C‐peptide kinetics to assess β‐cell function in the presence and absence of acute insulin resistance

“…This is because DI is relatively insensitive to errors in the estimation of k 12 and k 21 , but sensitive to errors in the Measurement of β-cell function using the oral C-peptide minimal model depends on C-peptide kinetics. In previous studies, we 6,22,23 and others 24,25 intravenous glucose challenge (where the approach had been validated independently) 13 differs significantly from that in response to an oral challenge. 26,27 To ensure an ability to accurately detect insulin pulses in the hepatic venous circulation and in the systemic circulation (as part of a series of studies examining the pathogenesis of prediabetes), we estimated C-peptide kinetics in 56 people (whose body weight varied from 50 to 110 kg) during a pancreatic clamp to ensure that C-peptide measurement was not confounded by endogenous β-cell secretion.…”

“…Measurement of β‐cell function using the oral C‐peptide minimal model depends on C‐peptide kinetics. In previous studies, we and others have used C‐peptide kinetics data derived by Van Cauter et al whereby C‐peptide kinetic variables were estimated from direct measurement in a group of 200 people of varying age, gender, obesity and glucose tolerance. Although measures of β‐cell function using alternative methodology (independent of C‐peptide concentrations) can correlate well with those dependent on these measures of C‐peptide kinetics, direct comparison of functional indices obtained with or without individually determined C‐peptide kinetics has not been undertaken in the presence of acute change in insulin action during an oral glucose tolerance test.…”

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

“…It remains possible that, under conditions of daily living, portal concentrations of glucagon differ between groups (19). Intriguingly, Daniele et al (20) recently reported that the T allele at rs7903146 was associated with lower glucagon concentrations and decreased systemic meal appearance. This contrasts with our recent findings (14) and suggests the need for further study of hepatic extraction of ingested glucose using techniques designed to minimize measurement error of meal appearance (21).…”

Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia

“…Healthy carriers of the T allele of the TCF7L2 gene have been reported to have lower fasting glucagon concentrations compared with carriers of the C allele (26, 27, 28). Therefore, we hypothesised that carriers of the T allele could have a lower glucagon secretory capacity than carriers of the C allele, leading to diminished plasma glucagon responses during hypoglycaemia and thereby an increased risk of SH.…”

“…During the efforts to elucidate the underlying mechanism, a functional impact of the gene variant on glucagon concentrations has emerged. Thus, fasting glucagon concentrations were reported to be lower in healthy carriers of the T allele (approximately 30% of the population (25)) compared with those with the C allele (26, 27, 28), whereas incremental glucagon secretion after a meal test does not differ between the alleles in normal, glucose-tolerant subjects (29). The extent to which the TCF7L2 gene polymorphism influences glucagon secretion and/or risk of hypoglycaemia in people with type 1 diabetes is unknown.…”