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A Special Thanks to the Reviewers of Diabetes
doi : 10.2337/db21-en04
Diabetes 2021 Apr; 70 (4): 821-822
Pregnancies in Diabetes and Obesity: The Capacity-Load Model of Placental Adaptation
Gernot Desoye and Jonathan C.K. Wells
doi : 10.2337/db20-1111
Diabetes 2021 Apr; 70 (4): 823-830
Excess nutritional supply to the growing fetus, resulting from maternal diabetes and obesity, is associated with increased risks of fetal maldevelopment and adverse metabolic conditions in postnatal life. The placenta, interposed between mother and fetus, serves as the gateway between the two circulations and is usually considered to mediate maternal exposures to the fetus through a direct supply line. In this Perspective, however, we argue that the placenta is not an innocent bystander and mounts responses to fetal “signals of distress” to sustain its own adequate function and protect the fetus. We describe several types of protection that the placenta can offer the fetus against maternal metabolic perturbations and offer a theoretical model of how the placenta responds to the intrauterine environment in maternal diabetes and obesity to stabilize the fetal environment. Our approach supports growing calls for early screening and control of pregnancy metabolism to minimize harmful fetal outcomes.
Uncovering Pathways to Personalized Therapies in Type 1 Diabetes
Peter S. Linsley, Carla J. Greenbaum and Gerald T. Nepom
doi : 10.2337/db20-1185
Diabetes 2021 Apr; 70 (4): 831-841
The goal of personalized medicine is to match the right drugs to the right patients at the right time. Personalized medicine has been most successful in cases where there is a clear genetic linkage between a disease and a therapy. This is not the case with type 1 diabetes (T1D), a genetically complex immune-mediated disease of ?-cell destruction. Researchers over decades have traced the natural history of disease sufficiently to use autoantibodies as predictive biomarkers for disease risk and to conduct successful clinical trials of disease-modifying therapy. Recent studies, however, have highlighted heterogeneity associated with progression, with nonuniform rate of insulin loss and distinct features of the peri-diagnostic period. Likewise, there is heterogeneity in immune profiles and outcomes in response to therapy. Unexpectedly, from these studies demonstrating perplexing complexity in progression and response to therapy, new biomarker-based principles are emerging for how to achieve personalized therapies for T1D. These include therapy timed to periods of disease activity, use of patient stratification biomarkers to align therapeutic target with disease endotype, pharmacodynamic biomarkers to achieve personalized dosing and appropriate combination therapies, and efficacy biomarkers for “treat-to-target” strategies. These principles provide a template for application of personalized medicine to complex diseases.
Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
Olof Eriksson, Irina Velikyan, Torsten Haack, Martin Bossart, Andreas Evers, Katrin Lorenz, Iina Laitinen, Philip J. Larsen, Oliver Plettenburg, Lars Johansson, Stefan Pierrou and Michael Wagner
doi : 10.2337/db20-1096
Diabetes 2021 Apr; 70 (4): 842-853
Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with 68Ga. The resulting PET tracer [68Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68Ga]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68Ga]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation, Which Associates With Body Composition in the Offspring
Josefine Jönsson, Kristina M. Renault, Sonia García-Calzón, Alexander Perfilyev, Angela C. Estampador, Kirsten Nørgaard, Mads Vendelbo Lind, Allan Vaag, Line Hjort, Kim F. Michaelsen, Emma Malchau Carlsen, Paul W. Franks and Charlotte Ling
doi : 10.2337/db20-0487
Diabetes 2021 Apr; 70 (4): 854-866
Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring’s lean mass and early growth.
Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure
David M. Presby, Michael C. Rudolph, Vanessa D. Sherk, Matthew R. Jackman, Rebecca M. Foright, Kenneth L. Jones, Julie A. Houck, Ginger C. Johnson, Janine A. Higgins, P. Darrell Neufer, Robert H. Eckel and Paul S. MacLean
doi : 10.2337/db20-0763
Diabetes 2021 Apr; 70 (4): 867-877
Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.
Dynamic Uni- and Multicellular Patterns Encode Biphasic Activity in Pancreatic Islets
Manon Jaffredo, Eléonore Bertin, Antoine Pirog, Emilie Puginier, Julien Gaitan, Sandra Oucherif, Fanny Lebreton, Domenico Bosco, Bogdan Catargi, Daniel Cattaert, Sylvie Renaud, Jochen Lang and Matthieu Raoux
doi : 10.2337/db20-0214
Diabetes 2021 Apr; 70 (4): 878-888
Biphasic secretion is an autonomous feature of many endocrine micro-organs to fulfill physiological demands. The biphasic activity of islet ?-cells maintains glucose homeostasis and is altered in type 2 diabetes. Nevertheless, underlying cellular or multicellular functional organizations are only partially understood. High-resolution noninvasive multielectrode array recordings permit simultaneous analysis of recruitment, of single-cell, and of coupling activity within entire islets in long-time experiments. Using this unbiased approach, we addressed the organizational modes of both first and second phase in mouse and human islets under physiological and pathophysiological conditions. Our data provide a new uni- and multicellular model of islet ?-cell activation: during the first phase, small but highly active ?-cell clusters are dominant, whereas during the second phase, electrical coupling generates large functional clusters via multicellular slow potentials to favor an economic sustained activity. Postprandial levels of glucagon-like peptide 1 favor coupling only in the second phase, whereas aging and glucotoxicity alter coupled activity in both phases. In summary, biphasic activity is encoded upstream of vesicle pools at the micro-organ level by multicellular electrical signals and their dynamic synchronization between ?-cells. The profound alteration of the electrical organization of islets in pathophysiological conditions may contribute to functional deficits in type 2 diabetes.
Syntaxin 4 Mediates NF-?B Signaling and Chemokine Ligand Expression via Specific Interaction With I?B?
Rajakrishnan Veluthakal, Eunjin Oh, Miwon Ahn, Diti Chatterjee Bhowmick and Debbie C. Thurmond
doi : 10.2337/db20-0868
Diabetes 2021 Apr; 70 (4): 889-902
Enrichment of human islets with syntaxin 4 (STX4) improves functional ?-cell mass through a nuclear factor-?B (NF-?B)–dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. For determination of the signaling events linking STX4 enrichment and downregulation of NF-?B activity, STX4 was overexpressed in human islets, EndoC-?H1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1?, tumor necrosis factor-?, and interferon-? individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of I?B? but not I?B?. Inhibition of IKK? prevented I?B? degradation, suggesting that IKK? phosphorylates I?B?. Moreover, the IKK? inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKK? in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected I?B? from proteasomal degradation, and like wild-type STX4, stabilized STX4 coimmunoprecipitated with I?B? and the p50-NF-?B. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-?B signaling in ?-cells via associating with and preventing I?B? degradation, suppressing chemokine expression, and protecting islet ?-cells from cytokine-mediated dysfunction and demise.
Cell Cycle Regulation of the Pdx1 Transcription Factor in Developing Pancreas and Insulin-Producing ?-Cells
Xiaodong Zhu, Alexis Oguh, Morgan A. Gingerich, Scott A. Soleimanpour, Doris A. Stoffers and Maureen Gannon
doi : 10.2337/db20-0599
Diabetes 2021 Apr; 70 (4): 903-916
Current evidence indicates that proliferating ?-cells express lower levels of some functional cell identity genes, suggesting that proliferating cells are not optimally functional. Pdx1 is important for ?-cell specification, function, and proliferation and is mutated in monogenic forms of diabetes. However, its regulation during the cell cycle is unknown. Here we examined Pdx1 protein expression in immortalized ?-cells, maternal mouse islets during pregnancy, and mouse embryonic pancreas. We demonstrate that Pdx1 localization and protein levels are highly dynamic. In nonmitotic cells, Pdx1 is not observed in constitutive heterochromatin, nucleoli, or most areas containing repressive epigenetic marks. At prophase, Pdx1 is enriched around the chromosomes before Ki67 coating of the chromosome surface. Pdx1 uniformly localizes in the cytoplasm at prometaphase and becomes enriched around the chromosomes again at the end of cell division, before nuclear envelope formation. Cells in S phase have lower Pdx1 levels than cells at earlier cell cycle stages, and overexpression of Pdx1 in INS-1 cells prevents progression toward G2, suggesting that cell cycle–dependent regulation of Pdx1 is required for completion of mitosis. Together, we find that Pdx1 localization and protein levels are tightly regulated throughout the cell cycle. This dynamic regulation has implications for the dichotomous role of Pdx1 in ?-cell function and proliferation.
Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing ?-Cell Mass in db/db Mice
Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Yuki Yamauchi, Shinichiro Kawata, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi and Tatsuya Atsumi
doi : 10.2337/db20-0881
Diabetes 2021 Apr; 70 (4): 917-931
Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward ?-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as ?-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in ?-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of ?-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve ?-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in ?-cells by inhibiting glucokinase could prevent ?-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving ?-cell mass. Therefore, glucokinase inactivation in ?-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis
MacKenzie D. Williams, Rhonda Bacher, Daniel J. Perry, C. Ramsey Grace, Kieran M. McGrail, Amanda L. Posgai, Andrew Muir, Srikar Chamala, Michael J. Haller, Desmond A. Schatz, Todd M. Brusko, Mark A. Atkinson and Clive H. Wasserfall
doi : 10.2337/db20-0937
Diabetes 2021 Apr; 70 (4): 932-943
We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual ?-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA–2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0–60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA–2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous ?-cell function.
Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size
James J. Ross, Clive H. Wasserfall, Rhonda Bacher, Daniel J. Perry, Kieran McGrail, Amanda L. Posgai, Xiaoru Dong, Andrew Muir, Xia Li, Martha Campbell-Thompson, Todd M. Brusko, Desmond A. Schatz, Michael J. Haller and Mark A. Atkinson
doi : 10.2337/db20-0995
Diabetes 2021 Apr; 70 (4): 944-954
Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and before disease onset. We hypothesized that three pancreas enzymes (amylase, lipase, and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody–positive (1AAb+) and multiple-AAb+ (?2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb-negative (AAb?) first-degree relatives, and AAb? control subjects. Lipase and trypsinogen were significantly reduced in ?2AAb+, recent-onset, and established type 1 diabetes subjects versus control subjects and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (area under the receiver operating characteristic curve [AUROC] = 81.4%) performed equivalently to all three enzymes (AUROC = 81.4%) in categorizing ?2AAb+ versus 1AAb+ subjects. For cohort 2 (n = 246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPVBMI, P < 0.001), previously measured by MRI. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPVBMI and may improve disease staging in pretype 1 diabetes.
Natural Protection From Type 1 Diabetes in NOD Mice Is Characterized by a Unique Pancreatic Islet Phenotype
Joanne Boldison, Terri C. Thayer, Joanne Davies and F. Susan Wong
doi : 10.2337/db20-0945
Diabetes 2021 Apr; 70 (4): 955-965
The NOD mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally protected from developing diabetes, and currently, studies characterizing this cohort are very limited. Here, using both immunofluorescence and multiparameter flow cytometry, we focus on the pancreatic islet morphology and immune infiltrate observed in naturally protected NOD mice. We show that naturally protected NOD mice are characterized by an increased frequency of insulin-containing, smaller-sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed toward a regulatory phenotype in both T- and B-cell compartments. Pancreatic islets have an increased frequency of IL-10–producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift toward reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.
Longitudinal Assessment of 11C-5-Hydroxytryptophan Uptake in Pancreas After Debut of Type 1 Diabetes
Daniel Espes, Per-Ola Carlsson, Ram Kumar Selvaraju, Maria Rosestedt, Pierre Cheung, Håkan Ahlström, Olle Korsgren and Olof Eriksson
doi : 10.2337/db20-0776
Diabetes 2021 Apr; 70 (4): 966-975
The longitudinal alterations of the pancreatic ?-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by 11C-5-hydroxytryptophan (11C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of ?-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of 11C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of 11C-5-HTP correlated with the long-term metabolic control as estimated by HbA1c (P < 0.05). Our findings argue against a major destruction of ?-cell or islet mass in the 2-year period after diagnosis of T1D.
Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice
Vanessa Mhanna, Gwladys Fourcade, Pierre Barennes, Valentin Quiniou, Hang P. Pham, Paul-Gydeon Ritvo, Faustine Brimaud, Bruno Gouritin, Guillaume Churlaud, Adrien Six, Encarnita Mariotti-Ferrandiz and David Klatzmann
doi : 10.2337/db20-0896
Diabetes 2021 Apr; 70 (4): 976-985
Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic ?-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2–expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.
Novel Linkage Peaks Discovered for Diabetic Nephropathy in Individuals With Type 1 Diabetes
Jani Haukka, Niina Sandholm, Erkka Valo, Carol Forsblom, Valma Harjutsalo, Joanne B. Cole, Stuart J. McGurnaghan, Helen M. Colhoun and Per-Henrik Groop, on behalf of the FinnDiane Study Group
doi : 10.2337/db20-0158
Diabetes 2021 Apr; 70 (4): 986-995
Genome-wide association studies (GWAS) and linkage studies have had limited success in identifying genome-wide significantly linked regions or risk loci for diabetic nephropathy (DN) in individuals with type 1 diabetes (T1D). As GWAS cohorts have grown, they have also included more documented and undocumented familial relationships. Here we computationally inferred and manually curated pedigrees in a study cohort of >6,000 individuals with T1D and their relatives without diabetes. We performed a linkage study for 177 pedigrees consisting of 452 individuals with T1D and their relatives using a genome-wide genotyping array with >300,000 single nucleotide polymorphisms and PSEUDOMARKER software. Analysis resulted in genome-wide significant linkage peaks on eight chromosomal regions from five chromosomes (logarithm of odds score >3.3). The highest peak was localized at the HLA region on chromosome 6p, but whether the peak originated from T1D or DN remained ambiguous. Of other significant peaks, the chromosome 4p22 region was localized on top of ARHGAP24, a gene associated with focal segmental glomerulosclerosis, suggesting this gene may play a role in DN as well. Furthermore, rare variants have been associated with DN and chronic kidney disease near the 4q25 peak, localized on top of CCSER1.
The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium
Shylaja Srinivasan, Ling Chen, Jennifer Todd, Jasmin Divers, Samuel Gidding, Steven Chernausek, Rose A. Gubitosi-Klug, Megan M. Kelsey, Rachana Shah, Mary Helen Black, Lynne E. Wagenknecht, Alisa Manning, Jason Flannick, Giuseppina Imperatore, Josep M. Mercader, Dana Dabelea and Jose C. Florez, on behalf of the ProDiGY Consortium
doi : 10.2337/db20-0443
Diabetes 2021 Apr; 70 (4): 996-1005
The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ?10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10?8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10?20; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10?14; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10?12; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10?11; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10?9; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10?8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10?8; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.
Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress
Hossam Montaser, Kashyap A. Patel, Diego Balboa, Hazem Ibrahim, Väinö Lithovius, Anna Näätänen, Vikash Chandra, Korcan Demir, Sezer Acar, Tawfeg Ben-Omran, Kevin Colclough, Jonathan M. Locke, Matthew Wakeling, Maria Lindahl, Andrew T. Hattersley, Jonna Saarimäki-Vire and Timo Otonkoski
doi : 10.2337/db20-1174
Diabetes 2021 Apr; 70 (4): 1006-1018
Erratum. Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults. Diabetes 2020;69:181–192
Brittany Begaye, Karyne L. Vinales, Tim Hollstein, Takafumi Ando, Mary Walter, Clifton Bogardus, Jonathan Krakoff and Paolo Piaggi
doi : 10.2337/db21-er04a
Diabetes 2021 Apr; 70 (4): 1019
