Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Smushkin, Galina; Sathananthan, Matheni; Sathananthan, Airani; Man, Chiara Dalla; Micheletto, Francesco; Zinsmeister, Alan R.; Cobelli, Claudio; Vella, Adrian

doi:10.2337/db11-1732

Cited by 36 publications

(34 citation statements)

References 29 publications

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“…In our study of carriers of functional KCNQ1 mutations, we do not find any difference in circulating incretin levels between patients and control individuals. This is in agreement with recent studies of L cells (45) and recent human genetic studies (46), indicating that KCNQ1 does not have a major influence on incretin secretion.…”

supporting

confidence: 93%

KCNQ1 Long QT Syndrome Patients Have Hyperinsulinemia and Symptomatic Hypoglycemia

et al. 2014

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Patients with loss-of-function mutations in KCNQ1 have KCNQ1 long QT syndrome (LQTS). KCNQ1 encodes a voltage-gated K + channel located in both cardiomyocytes and pancreatic b-cells. Inhibition of KCNQ1 in b-cells increases insulin secretion. Therefore KCNQ1 LQTS patients may exhibit increased insulin secretion. Fourteen patients, from six families, diagnosed with KCNQ1 LQTS were individually matched to two randomly chosen BMI-, age-, and sex-matched control participants and underwent an oral glucose tolerance test (OGTT), a hypoglycemia questionnaire, and continuous glucose monitoring. KCNQ1 mutation carriers showed increased insulin release (area under the curve 45.6 6 6.3 vs. 26.0 6 2.8 min $ nmol/L insulin) and b-cell glucose sensitivity and had lower levels of plasma glucose and serum potassium upon oral glucose stimulation and increased hypoglycemic symptoms. Prolonged OGTT in four available patients and matched control subjects revealed hypoglycemia in carriers after 210 min (range 1.4-3.6 vs. 4.1-5.3 mmol/L glucose), and 24-h glucose profiles showed that the patients spent 77 6 18 min per 24 h in hypoglycemic states (<3.9 mmol/L glucose) with 36 6 10 min (<2.8 mmol/L glucose) vs. 0 min (<3.9 mmol/L glucose) for the control participants. The phenotype of patients with KCNQ1 LQTS, caused by mutations in KCNQ1, includes, besides long QT, hyperinsulinemia, clinically relevant symptomatic reactive hypoglycemia, and low potassium after an oral glucose challenge, suggesting that KCNQ1 mutations may explain some cases of "essential" reactive hypoglycemia.

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confidence: 93%

KCNQ1 Long QT Syndrome Patients Have Hyperinsulinemia and Symptomatic Hypoglycemia

et al. 2014

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“…Pilgaard et al (10) also reported lower plasma glucagon levels over a 24-hour profile, though another recent study performed in healthy subjects carrying the T allele confirms those findings (15). TCF7L2, however, is a transcription factor of the proglucagon gene that is processed to glucagon in ␣-and L-cells (6,23).…”

Section: Discussionmentioning

confidence: 77%

“…The meal was consumed by all participants in less than 10 minutes. Blood samples were then obtained at regular intervals (5,15,30,60,90,120,150,180, 240 minutes) till study end. Blood was sampled into fluoride tubes for plasma glucose analysis and into tubes containing heparin or EDTA plus aprotinin (250 KIU, BD-Plymouth, United Kingdom) for tracers and hormone analyses.…”

Section: Study Protocolmentioning

confidence: 99%

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

Daniele

Gaggini

Comassi

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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“…This pattern is consistent with our previous observation that suppression of glucagon is lower in subjects with the TT genotype during a hyperglycemic clamp. Of particular interest, suppression of glucagon during that experiment did not differ in subjects with the CT and CC genotypes (32). As in the current series of experiments, Lyssenko et al (33) reported no effect of TCF7L2 on fasting glucagon concentrations.…”

Section: Discussionmentioning

confidence: 86%

TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes

et al. 2015

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The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)–induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. β-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that β-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and β-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.

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Diabetes-Associated Common Genetic Variation and Its Association With GLP-1 Concentrations and Response to Exogenous GLP-1

Cited by 36 publications

References 29 publications

KCNQ1 Long QT Syndrome Patients Have Hyperinsulinemia and Symptomatic Hypoglycemia

KCNQ1 Long QT Syndrome Patients Have Hyperinsulinemia and Symptomatic Hypoglycemia

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

TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes

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