OBJECTIVE-We evaluated insulin sensitivity and insulin secretion across the entire range of fasting (FPG) and 2-h plasma glucose (PG), and we investigated the differences in insulin sensitivity and insulin release in different glucose tolerance categories.RESEARCH DESIGN AND METHODS-A total of 6,414 Finnish men (aged 57 Ϯ 7 years, BMI 27.0 Ϯ 3.9 kg/m 2 ) from our ongoing population-based METSIM (Metabolic Syndrome in Men) study were included. Of these subjects, 2,168 had normal glucose tolerance, 2,859 isolated impaired fasting glucose (IFG), 217 isolated impaired glucose tolerance (IGT), 701 a combination of IFG and IGT, and 469 newly diagnosed type 2 diabetes. RESULTS-TheMatsuda index of insulin sensitivity decreased substantially within the normal range of FPG (Ϫ17%) and 2-h PG (Ϫ37%) and was approximately Ϫ65 and Ϫ53% in the diabetic range of FPG and 2-h PG, respectively, compared with the reference range (FPG and 2-h PG Ͻ5.0 mmol/l). Early-phase insulin release declined by only approximately Ϫ5% within the normal range of FPG and 2-h PG but decreased significantly in the diabetic range of FPG (by 32-70%) and 2-h PG (by 33-51%). Changes in insulin sensitivity and insulin secretion in relation to hyperglycemia were independent of obesity. The predominant feature of isolated IGT was impaired peripheral insulin sensitivity. Isolated IFG was characterized by impaired early and total insulin release.CONCLUSIONS-Peripheral insulin sensitivity was already decreased substantially at low PG levels within the normoglycemic range, whereas impairment in insulin secretion was observed mainly in the diabetic range of FPG and 2-h PG. Obesity did not affect changes in insulin sensitivity or insulin secretion in relation to hyperglycemia. Diabetes 58:1212-1221, 2009 T ype 2 diabetes is preceded by a long pre-diabetic state, characterized by mild elevation of fasting and/or postprandial glucose levels. This asymptomatic phase may last for years, and about one-third of these individuals finally develop type 2 diabetes (1). The pre-diabetic state, defined by an oral glucose tolerance test (OGTT), includes impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or their combination (2). Epidemiological studies have shown that IFG and IGT represent two distinct subgroups of abnormal glucose tolerance (1,3-5) that differ in their age and sex distribution (6,7) and associated cardiovascular risk (8). Therefore, IFG and IGT are likely to have different pathophysiologies.Impaired insulin secretion and impaired insulin action are the two main pathophysiological disturbances leading to abnormal glucose tolerance. Previous studies on the role of impaired insulin secretion and insulin resistance in the development of IFG and IGT have yielded contradictory results (4 -23). Inconsistencies across the studies are explained by differences in study populations, study designs and methods to assess insulin resistance and insulin secretion, and most importantly by a small sample size. Categorization of glucose tolerance is based on arb...

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6×10−14) greater metformin-induced in haemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 is the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Systemic hypertension is associated with obstructive sleep apnoea syndrome (OSAS) but the pathophysiological mechanisms are incompletely understood. A collaborative European network of 24 sleep centres established a European Sleep Apnoea Database to evaluate cardiovascular morbidity associated with OSAS.11 911 adults referred with suspected OSAS between March 2007 and September 2013 underwent overnight sleep studies, either cardiorespiratory polygraphy or polysomnography. We compared the predictive value of the apnoea-hypopnoea index (AHI) and 4% oxygen desaturation index (ODI) for prevalent hypertension, adjusting for relevant covariates including age, smoking, obesity, dyslipidaemia and diabetes.Among patients (70% male, mean¡SD age 52¡12 years), 78% had AHI .5 events?h -1 and 41% systemic hypertension. Both AHI and ODI independently related to prevalent hypertension after adjustment for relevant covariates (p,0.0001 for linear trend across quartiles (Q) of severity for both variables). However, in multiple regression analysis with both ODI and AHI in the model, ODI was, whereas AHI was not, independently associated with prevalent hypertension: odds ratios (95% CI) for Q4 versus Q1 regarding ODI were 2.01 (1.61-2.51) and regarding AHI were 0.92 (0.74-1.15) (p,0.0001 and p50.3054, respectively).This cross sectional study suggests that chronic intermittent hypoxia plays an important role in OSASrelated hypertension. @ERSpublications These findings indicate that ODI is superior to AHI in the prediction of hypertension in patients with OSAS http://ow.ly/xFn6RSupport statement: The authors also acknowledge the financial support of Philips Respironics PLC and ResMed PLC, which each provided unrestricted grants to support overall maintenance of the European Sleep Apnoea Database (ESADA) Project. These companies had no input into the design or implementation of the ESADA Project and played no role in the design or completion of the present study. Nonfinancial support was provided by the European Sleep Research Society and the European Respiratory Society (ERS) in terms of logistics for communication, meetings and data presentations for the ESADA collaborators. The ERS also funded a Task Force to support the evaluation of associations between obstructive sleep apnoea syndrome and hypertension.

Therapeutic response to metformin, a first‐line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large‐scale meta‐analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2‐K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

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Pharmacogenetic studies revealed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to investigate possible associations of the variants in genes encoding organic cationic transporters-solute carrier family 22, members A1, A2 (SLC22A1, SLC22A2) and solute carrier family 47, member A1 (SLC47A1) with response to metformin in type 2 diabetes. One hundred forty-eight drug-naive patients with type 2 diabetes were included in the study. Genotyping for SLC22A1 rs622342, SLC22A2 rs316019 and SLC47A1 rs2289669 variants was performed using real-time PCR with subsequent melting-curve analysis. SLC47A1 rs2289669 genotype was significantly associated with the reduction in haemoglobin A1c (HbA1c) after 6 months. Twenty percentage of patients with diabetes that are homozygous for A-allele of SLC47A1 had twofold reduction in HbA1c in comparison with the patients carrying G-allele (GG + GA: 0.55 ± 0.09% vs. AA: 1.10 ± 0.18%, p = 0.018). In conclusion, the results of this study might have in future practical implication in personalised treatment of patients with type 2 diabetes.

The aim of the present study was to analyse effects of sulphonylurea treatment on parameters of glycaemic control in relation to transcription factor 7-like 2 (TCF7L2) genotypes. In 87 patients with type 2 diabetes who failed to achieve glycaemic control on metformin monotherapy, effects of 6-month sulphonylurea in addition to metformin on reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels were evaluated. Reduction in HbA1c and FPG in response to 6-month sulphonylurea treatment was significantly higher in patients with CC genotype compared to those with the CT+TT genotype (1.16 ± 0.07 vs. 0.86 ± 0.07%, p = 0.003; 1.57 ± 0.12 vs. 1.14 ± 0.14 mmol/l, p = 0.031, respectively). In the multivariate analysis, baseline HbA1c and the TCF7L2 genotype were the only significant predictors of HbA1c reduction. In conclusion, the magnitude of HbA1c and FPG reductions after 6-month sulphonylurea treatment in addition to metformin is related to the TCF7L2 gene polymorphism.

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (β = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.