No more hypoglycaemia on days with physical activity and unrestricted diet when using a closed-loop system for 12 weeks: A post hoc secondary analysis of the multicentre, randomized controlled Diabeloop WP7 trial.

A post hoc analysis of the Diabeloop WP7 multicentre, randomized controlled trial was performed to investigate the efficacy of the Diabeloop Generation-1 (DBLG1) closed-loop system in controlling the hypoglycaemia induced by physical activity (PA) in real-life conditions. Glycaemic outcomes were compared between days with and without PA in 56 patients with type 1 diabetes (T1D) using DBLG1 for 12 weeks. After the patient announces a PA, DBLG1 reduces insulin delivery and, if necessary, calculates the amount of preventive carbohydrates (CHO). Daily time spent in the interstitial glucose range less than 70 mg/dL was not significantly different between days with and without PA (2.0% ± 1.5% vs. 2.2% ± 1.1%), regardless of the intensity or duration of the PA. Preventive CHO intake recommended by the system was significantly higher in days with PA (41.1 ± 35.5 vs. 21.8 ± 28.5 g/day; P < .0001), and insulin delivery was significantly lower (31.5 ± 10.5 vs. 34.0 ± 10.5 U/day; P < .0001). The time spent in hyperglycaemia and the glycaemic variation coefficient increased significantly on days with PA. In real-life conditions, the use of DBLG1 avoids PA-induced hypoglycaemia. Insulin adjustments and preventive CHO recommendation may explain this therapeutic benefit.

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials.

AIMS: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. MATERIALS AND METHODS: Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. RESULTS: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). CONCLUSIONS: In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial.

OBJECTIVE: To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this phase 3a, open-label, parallel-group, randomized controlled trial, 813 subjects with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point was change from baseline in HbA1c at week 56. RESULTS: Mean HbA1c (8.3% [67.7 mmol/mol] at baseline) was reduced by 1.5% (16.8 mmol/mol) with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER [ETD] -0.62% [95% CI -0.80, -0.44] [-6.78 mmol/mol (95% CI -8.70, -4.86)]; P < 0.0001 for noninferiority and superiority). Mean body weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER (ETD -3.78 kg [95% CI -4.58, -2.98]; P < 0.0001). Significantly more subjects treated with semaglutide (67%) achieved HbA1c <7.0% (<53 mmol/mol) versus those taking exenatide ER (40%). Both treatments had similar safety profiles, but gastrointestinal adverse events were more common in semaglutide-treated subjects (41.8%) than in exenatide ER-treated subjects (33.3%); injection-site reactions were more frequent with exenatide ER (22.0%) than with semaglutide (1.2%). CONCLUSIONS: Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment; the drugs had comparable safety profiles. These results indicate that semaglutide treatment is highly effective for subjects with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs.

Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications.

Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging and to predict cancer. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease and is associated with higher prevalence of cancers. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10(-5)) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10(-5)). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10(-4)). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10(-3)). In conclusion, given the increased risk of cancer in CME carriers, our results may have profound clinical implications in patients with severe T2D.

What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications?

Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits.SNPs were genotyped in several case-control studies: French and Danish T2D studies (N(cases) = 6,920-N(controls) = 3,875 and N(cases) = 3,561-N(controls) = 2,623; respectively), two French studies one for diabetic nephropathy (N(cases) = 1,242-N(controls) = 860) and the other for diabetic retinopathy (N(cases) = 1,336-N(controls) = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions.In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10(-5)). Furthermore, the same allele was associated with higher glycated hemoglobin levels (ß = 0.02%; P = 9.2×10(-3)). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients.In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia.

Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.

Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose.

OBJECTIVE: Estrogen receptor 1 (ESR1) mediates effects of estrogens on glucose homeostasis. Polymorphisms in intron 1, 2, and 4 of the ESR1 gene have been found to be associated with type 2 diabetes (T2D) in Hungarian, Chinese, and African-American and European-American cohorts. The aim of this study was to investigate the association between ESR1 polymorphisms and T2D as well as quantitative phenotypes related to glucose homeostasis in French and Swedish Caucasians. METHODS: The French cohort included 941 normoglycemic controls and 988 T2D patients. The Swedish cohort consisted of 1045 controls with normal glucose tolerance, 324 participants with impaired glucose tolerance, and 276 T2D patients. A total of 20 single nucleotide polymorphisms (SNPs) distributed across the ESR1 gene were genotyped. RESULTS: SNPs in introns 3 and 4 of the ESR1 gene associated significantly with T2D in the French cohort (rs3020314, rs985694, P = 0.0009-0.001) and with fasting plasma glucose in Swedish men (rs9397456, rs3020314 rs3020317, P = 0.0002-0.0022) after Bonferroni correction for the analysis of 20 SNPs. In addition, nominal association of ESR1 rs1884051 (P=0.011) with T2D in the French cohort replicates a previously observed association in Finns (empirical P=0.024) (http://www.broad.mit.edu/diabetes/). CONCLUSION: This study provides further evidence that ESR1 genetic polymorphisms are associated with T2D and with fasting plasma glucose. No current evidence that the investigated SNPs are functional is present, thus, we suggest that the association between T2D and ESR1 variants may be because of other unidentified ESR1 polymorphisms that regulate glucose homeostasis.

Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value.

BACKGROUND: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. METHODOLOGY/PRINCIPAL FINDINGS: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (OR(rs7756992) = 1.30[1.19-1.42], P = 2.3x10(-9)), CDKN2A/2B (OR(rs10811661) = 0.74[0.66-0.82], P = 3.5x10(-8)) and more modestly for IGFBP2 (OR(rs1470579) = 1.17[1.07-1.27], P = 0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D-associated TCF7L2 rs7903146 SNP, were combined (8.68-fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. CONCLUSIONS/SIGNIFICANCE: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/2B strongly associate with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

Evaluating the association of common PBX1 variants with type 2 diabetes.

BACKGROUND: PBX1 is a biological candidate gene for type 2 diabetes at the 1q21-q24 susceptibility locus. The aim of this study was to evaluate the association of common PBX1 variants with type 2 diabetes in French Caucasian subjects. METHODS: Employing a case-control design, we genotyped 39 SNPs spanning the PBX1 locus in 3,093 subjects to test for association with type 2 diabetes. RESULTS: Several PBX1 SNPs, including the G21S coding SNP rs2275558, were nominally associated with type 2 diabetes but the strongest result was obtained with the intron 2 SNP rs2792248 (P = 0.004, OR 1.20 [95% CI 1.06-1.37]). The SNPSpD multiple testing correction method gave a significance threshold of P = 0.002 for the 39 SNPs genotyped, indicating that the rs2792248 association did not survive multiple testing adjustment. SNP rs2792248 did not show evidence of association with the French 1q linkage signal (P = 0.31; weighted NPL score 2.16). None of the PBX1 SNPs nominally associated with type 2 diabetes were associated with a range of quantitative metabolic traits in the normoglycemic control subjects CONCLUSION: The available data does not support a major influence of common PBX1 variants on type 2 diabetes susceptibility or quantitative metabolic traits. In order to make progress in identifying the elusive susceptibility variants in the 1q region it will be necessary to carry out further large association studies, meta-analyses of existing data from individual studies, and deep resequencing of the 1q region.

EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families.

One of the most replicated loci influencing type 2 diabetes-related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes-and metabolic syndrome-associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic beta-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat beta-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation.