Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

Torekov, Signe S.; Ma, Lina; Grarup, Niels; Hartmann, Bolette; Hainerová, Irena Aldhoon; Kielgast, Urd; Kissow, Hannelouise; Lebl, Jan; Witte, Daniel R.; Jørgensen, Torben; Sandbaek, Anelli; Lauritzen, Torsten; Madsen, Ole; Wang, J.; Linneberg, Allan; Madsbad, Sten; Holst, Jens J.; Hansen, Torben; Pedersen, Oluf

doi:10.1007/s00125-011-2265-7

Cited by 16 publications

(11 citation statements)

References 26 publications

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“…Some of the mechanisms behind the lower GLP-1 response in both prediabetes and overweight may include genetic variation in the regulation of GLP-1 synthesis (3,31,32,39), since twin studies have shown that GLP-1 response has a heritability of up to 67% (31). Lower GLP-1 response has also been observed in the twin with diabetes of twin pairs discordant for type 2 diabetes (3).…”

Section: Potential Mechanismsmentioning

confidence: 99%

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

et al. 2015

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The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear.We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and b-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

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Section: Potential Mechanismsmentioning

confidence: 99%

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

et al. 2015

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“…Each patient was matched with respect to BMI, age, and sex with two randomly chosen control subjects from the Inter99 (11,12) or the Health (13) studies. A computer algorithm was applied to randomly select matching control subjects to be invited to participate in the study solely based on their best match with sex, BMI, and age.…”

Section: Study Participantsmentioning

confidence: 99%

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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“…In contrast, rs4664447 C/C (fwd strnd) of the GCG gene, which was -to our knowledge -the only previously reported risk genotype to be associated with a reduced GLP-1 response, occurs only in approximately 4 out of 10 000 individuals with European origin (Ensemble genomic database -Human -GRCh38.p13) [22,23]. Fig.…”

Section: Discussionmentioning

confidence: 89%

Reduced GLP-1 response to a meal is associated with the CTLA4 rs3087243 G/G genotype

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Nyírő

et al. 2019

cejoi

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Although insulitis is the characteristic main feature of type 1 diabetes mellitus (T1DM), many aspects of β cell loss still remain elusive. Immune dysregulation and alterations in the dipeptidyl-peptidase-4-incretin system might have a role in disease development, but their connection is poorly understood. We assessed the associations of a few selected, immunologically relevant single nucleotide gene variants with the DPP-4-incretin system in individuals with T1DM and in healthy controls. Prandial plasma (total, active) GLP-1 levels, serum DPP-4 activity, CD25 and CTLA-4 expression of T cells and DPP4 rs6741949, CTLA4 rs3087243, CD25 rs61839660 and PTPN2 rs2476601 SNPs were assessed in 33 T1DM patients and 34 age-, gender-, BMI-matched non-diabetic controls without a family history of T1DM. CTLA-4 expression was lower in the Foxp3 + CD25 + regulatory T cells from individuals homozygous for the CTLA4 rs3087243-G variant compared to those who carry an A allele. Prandial plasma total GLP-1 levels 45 min after a standardized meal were reduced in individuals homozygous for the CTLA4 rs3087243 G major allele compared to A allele carriers both in the entire study population (with statistical power over 90%) and within the T1DM group. Here we report for the first time a reduced total prandial GLP-1 plasma concentration in individuals with the CTLA4 rs3087243 G/G genotype. One may speculate that immune response-related L cell damage might possibly explain this novel association.

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Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

Cited by 16 publications

References 26 publications

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

KCNQ1 Long QT Syndrome Patients Have Hyperinsulinemia and Symptomatic Hypoglycemia

Reduced GLP-1 response to a meal is associated with the CTLA4 rs3087243 G/G genotype

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