Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,771) and generalized our findings in 9 additional studies (HISLA Stage 2, n=10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification

Soultz-sous-Forêts Geothermal Reservoir: Structural Model Update and Thermo-Hydraulic Numerical Simulations Based on Three Years of Operation Data

The geothermal powerplant of Soultz-sous-Forêts (France) is investigating the possibility of producing more energy with the same infrastructure by reinjecting the geothermal fluid at lower temperatures. Indeed, during the operation of the powerplant, the geothermal fluid is currently reinjected at 60–70 °C in a deep fractured granite reservoir, and the MEET project aims to test its reinjection at 40 °C. A 3D hydrothermal study was performed in order to evaluate the spreading of the thermal front during colder reinjection and its impact on the production temperature. In the first step, a 3D structural model at fault scale was created, integrating pre-existing models from 2D vintage seismic profiles, vertical seismic profiles, seismic cloud structure and borehole image logs calibrated with well data. This geometrical model was then adapted to be able to run hydrothermal simulation. In the third step, a 3D hydrothermal model was built based on the structural model. After calibration, the effect of colder reinjection on the production temperature was calculated. The results show that a decrease of 10 °C in the injection temperature leads to a drop in the production temperature of 2 °C after 2 years, reaching 3 °C after 25 years of operation. Lastly, the accuracy of the structural model on which the simulations are based is discussed and an update of the structural model is proposed in order to better reproduce the observations

Divergent Perceptions of Barriers to Diabetic Retinopathy Screening Among Patients and Care Providers, Los Angeles, California, 2014-2015.

IntroductionDespite availability of screening for diabetic retinopathy, testing is underused by many low-income and racial/ethnic minority patients with diabetes. We examined perceived barriers to diabetic retinopathy screening among low-income patients and their health care providers and provider staffers.MethodsWe collected survey data from 101 patients with diabetes and 44 providers and staffers at a safety-net clinic where annual diabetic retinopathy screening rates were low. Barriers specified in the survey were derived from the literature.ResultsPatients surveyed (mean [standard deviation] age, 54.0 [7.7] y; 41% were male) were primarily Hispanics (70%) and African Americans (27%) of low socioeconomic status. Overall, 55% of patients received diabetic retinopathy screening in the previous year. Patients who could not explain why this screening is needed reported more barriers than patients who could (2.5 vs 1.4 barriers, P = .02). Fewer patients reported that they experienced barriers such as transportation (15%), language issues (15%), cultural beliefs or myths (4%), denial (8%), and fear (5%), which providers and staffers considered very or extremely important (all P &lt; .001). Financial burdens (26%) and depression (22%) were most commonly reported by patients as barriers, yet providers and staffers did not rate these barriers as important, P &lt; .001.ConclusionPatients and health care providers had markedly divergent perceptions of barriers to diabetic retinopathy screening. Patients with poor understanding of the need for screening were more likely to report such barriers. These results suggest a need for active community engagement to find key elements for education programs and other interventions to increase rates of diabetic retinopathy screening, particularly among low-income, minority populations

The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism

AimsGlucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults.MethodsHispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8).ResultsGlucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035).ConclusionsGLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency

Heat flow density estimates in the Upper Rhine Graben using laboratory measurements of thermal conductivity on sedimentary rocks

International audienceThe Upper Rhine Graben (URG) has been extensively studied for geothermal exploitation over the past decades. Yet, the thermal conductivity of the sedimentary cover is still poorly constrained, limiting our ability to provide robust heat flow density estimates. To improve our understanding of heat flow density in the URG, we present a new large thermal conductivity database for sedimentary rocks collected at outcrops in the area including measurements on (1) dry rocks at ambient temperature (dry); (2) dry rocks at high temperature (hot) and (3) water-saturated rocks at ambient temperature (wet). These measurements, covering the various lithologies composing the sedimentary sequence, are associated with equilibrium-temperature profiles measured in the Soultz-sous-Forêts wells and in the GRT-1 borehole (Rittershoffen) (all in France). Heat flow density values considering the various experimental thermal conductivity conditions were obtained for different depth intervals in the wells along with average values for the whole boreholes. The results agree with the previous heat flow density estimates based on dry rocks but more importantly highlight that accounting for the effect of temperature and water saturation of the formations is crucial to providing accurate heat flow density estimates in a sedimentary basin. For Soultz-sous-Forêts, we calculate average conductive heat flow density to be 127 mW/m 2 when considering hot rocks and 184 mW/m 2 for wet rocks. Heat flow density in the GRT-1 well is estimated at 109 and 164 mW/m 2 for hot and wet rocks, respectively. Results from the Rit-tershoffen well suggest that heat flow density is nearly constant with depth, contrary to the observations for the Soultz-sous-Forêts site. Our results show a positive heat flow density anomaly in the Jurassic formations, which could be explained by a combined effect of a higher radiogenic heat production in the Jurassic sediments and thermal disturbance caused by the presence of the major faults close to the Soultz-sous-Forêts geothermal site. Although additional data are required to improve these estimates and our understanding of the thermal processes, we consider the heat flow densities estimated herein as the most reliable currently available for the URG

Adiponectin, Insulin Sensitivity and Diabetic Retinopathy in Latinos With Type 2 Diabetes.

Context and objectiveInsulin resistance and chronic inflammation are key elements in the pathogenesis of type 2 diabetes. We hypothesized that similar mechanisms could have a role in the development of diabetic retinopathy (DR), an important microvascular complication in Latinos with type 2 diabetes.Design and settingA cross-sectional, family-based, observational cohort study.PatientsLatino subjects with type 2 diabetes (n = 507), ascertained in families via a proband with known diabetes duration of 10 years or more and/or with DR, were included.Main outcome measuresSerum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). DR was assessed by seven-field digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale (range of severity levels, 10-85).ResultsFasting adiponectin concentrations were elevated in patients with DR compared to those without (12.9 ± 0.5 vs 10.5 ± 0.5 μg/mL; P = .0004) and remained significant after adjusting for multiple covariates (age, gender, body mass index, glycosylated hemoglobin, diabetes duration, statin use, blood pressure, and renal function; P = .013 to .018). Adiponectin was also positively correlated with severity of DR in patients with nonproliferative DR (P &lt; .0003), significant also after all covariate adjustments (P = .018). When the proliferative DR group was included, this relationship was attenuated by adjustments, possibly an influence of estimated glomerular filtration rate reduction in the proliferative DR group. HOMA-IR was not different in the DR and non-DR groups. Although elevated, adiponectin retained a typical inverse relationship with HOMA-IR in DR, similar to that seen in the non-DR group.ConclusionsSerum adiponectin is elevated in DR, is positively correlated with DR severity in Latinos with type 2 diabetes, and maintains a relationship to insulin sensitivity. Adiponectin, whether as a marker or biological mediator, may play an important role in DR, which appears to be independent of its relationship to insulin sensitivity

Adiponectin, Insulin Sensitivity and Diabetic Retinopathy in Latinos With Type 2 Diabetes.

Context and objectiveInsulin resistance and chronic inflammation are key elements in the pathogenesis of type 2 diabetes. We hypothesized that similar mechanisms could have a role in the development of diabetic retinopathy (DR), an important microvascular complication in Latinos with type 2 diabetes.Design and settingA cross-sectional, family-based, observational cohort study.PatientsLatino subjects with type 2 diabetes (n = 507), ascertained in families via a proband with known diabetes duration of 10 years or more and/or with DR, were included.Main outcome measuresSerum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). DR was assessed by seven-field digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale (range of severity levels, 10-85).ResultsFasting adiponectin concentrations were elevated in patients with DR compared to those without (12.9 ± 0.5 vs 10.5 ± 0.5 μg/mL; P = .0004) and remained significant after adjusting for multiple covariates (age, gender, body mass index, glycosylated hemoglobin, diabetes duration, statin use, blood pressure, and renal function; P = .013 to .018). Adiponectin was also positively correlated with severity of DR in patients with nonproliferative DR (P &lt; .0003), significant also after all covariate adjustments (P = .018). When the proliferative DR group was included, this relationship was attenuated by adjustments, possibly an influence of estimated glomerular filtration rate reduction in the proliferative DR group. HOMA-IR was not different in the DR and non-DR groups. Although elevated, adiponectin retained a typical inverse relationship with HOMA-IR in DR, similar to that seen in the non-DR group.ConclusionsSerum adiponectin is elevated in DR, is positively correlated with DR severity in Latinos with type 2 diabetes, and maintains a relationship to insulin sensitivity. Adiponectin, whether as a marker or biological mediator, may play an important role in DR, which appears to be independent of its relationship to insulin sensitivity

Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes.

ObjectiveResidual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes.DesignProspective, cross-sectional, family-based study.Participants585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10 years and/or with diabetic retinopathy.Outcome measuresCIRCULATING LEVELS OF FASTING INSULIN AND C PEPTIDE MEASURED AND CORRELATED TO DEGREE OF DIABETIC RETINOPATHY, ASSESSED BY DIGITAL FUNDUS PHOTOGRAPHY AND GRADED USING THE MODIFIED AIRLIE HOUSE CLASSIFICATION AND THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SCALE (RANGE: levels 10-85).ResultsFasting plasma insulin (β=-0.29; 95% CI -0.38 to -0.20; p&lt;0.0001) and C peptide (β=-0.21; 95% CI -0.30 to -0.13; p&lt;0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function.ConclusionsThese data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease