The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal ...diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6 months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.
To describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting.
This was a nationwide retrospective ...cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease).
A total of 19,256 COVID-19-related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio aHR 1.23 95% CI 1.14, 1.32), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18-49 years aHR 1.50 95% CI 1.05, 2.15, age 50-64 years 1.29 1.10, 1.51, and age ≥65 years 1.18 1.09, 1.29;
value for age-type 2 diabetes interaction = 0.002).
Type 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.
Summary Background Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous ...analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. Methods In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. Findings Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001). Interpretation Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. Funding Wellcome Trust and Diabetes UK.
People with type 1 diabetes are at elevated risk of mortality and cardiovascular disease, yet current guidelines do not consider age of onset as an important risk stratifier. We aimed to examine how ...age at diagnosis of type 1 diabetes relates to excess mortality and cardiovascular risk.
We did a nationwide, register-based cohort study of individuals with type 1 diabetes in the Swedish National Diabetes Register and matched controls from the general population. We included patients with at least one registration between Jan 1, 1998, and Dec 31, 2012. Using Cox regression, and with adjustment for diabetes duration, we estimated the excess risk of all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, acute myocardial infarction, stroke, cardiovascular disease (a composite of acute myocardial infarction and stroke), coronary heart disease, heart failure, and atrial fibrillation. Individuals with type 1 diabetes were categorised into five groups, according to age at diagnosis: 0–10 years, 11–15 years, 16–20 years, 21–25 years, and 26–30 years.
27 195 individuals with type 1 diabetes and 135 178 matched controls were selected for this study. 959 individuals with type 1 diabetes and 1501 controls died during follow-up (median follow-up was 10 years). Patients who developed type 1 diabetes at 0–10 years of age had hazard ratios of 4·11 (95% CI 3·24–5·22) for all-cause mortality, 7·38 (3·65–14·94) for cardiovascular mortality, 3·96 (3·06–5·11) for non-cardiovascular mortality, 11·44 (7·95–16·44) for cardiovascular disease, 30·50 (19·98–46·57) for coronary heart disease, 30·95 (17·59–54·45) for acute myocardial infarction, 6·45 (4·04–10·31) for stroke, 12·90 (7·39–22·51) for heart failure, and 1·17 (0·62–2·20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26–30 years were 2·83 (95% CI 2·38–3·37) for all-cause mortality, 3·64 (2·34–5·66) for cardiovascular mortality, 2·78 (2·29–3·38) for non-cardiovascular mortality, 3·85 (3·05–4·87) for cardiovascular disease, 6·08 (4·71–7·84) for coronary heart disease, 5·77 (4·08–8·16) for acute myocardial infarction, 3·22 (2·35–4·42) for stroke, 5·07 (3·55–7·22) for heart failure, and 1·18 (0·79–1·77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1·9 (95% CI 1·71–2·11) per 100 000 person-years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17·7 life-years (95% CI 14·5–20·4) for women and 14·2 life-years (12·1–18·2) for men.
Age at onset of type 1 diabetes is an important determinant of survival, as well as all cardiovascular outcomes, with highest excess risk in women. Greater focus on cardioprotection might be warranted in people with early-onset type 1 diabetes.
Swedish Heart and Lung Foundation.
Type 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is ...not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.
In this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes.
13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 95% CI 26·7–28·0 vs 32·4 kg/m2 32·2–32·5; p<0·0001), were more likely to use insulin in the first year after diagnosis (89% 476/537 vs 6% 648/11 696; p<0·0001), and were more likely to have diabetic ketoacidosis (11% 61/537 vs 0·3% 30/11 696; p<0·0001).
Genetic susceptibility to type 1 diabetes results in non-obesity-related, insulin-dependent diabetes, which presents throughout the first six decades of life. Our results highlight the difficulty of identifying type 1 diabetes after age 30 years because of the increasing background prevalence of type 2 diabetes. Failure to diagnose late-onset type 1 diabetes can have serious consequences because these patients rapidly develop insulin dependency.
Wellcome Trust and Diabetes UK.
With rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in ...identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes.
We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency <3 years from diagnosis.
In the WTCCC, the T1D GRS, based on 30 T1D-associated risk variants, was highly discriminative of T1D and T2D (area under the curve AUC 0.88 95% CI 0.87-0.89; P < 0.0001), and the T2D GRS added little discrimination (AUC 0.89). A T1D GRS >0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (<0.234, <5th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just nine single nucleotide polymorphisms (AUC 0.87). In young adults with diabetes, T1D GRS alone predicted progression to insulin deficiency (AUC 0.87 95% CI 0.82-0.92; P < 0.0001). T1D GRS, autoantibody status, and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC 0.96 95% CI 0.94-0.99; P < 0.0001).
A T1D GRS can accurately identify young adults with diabetes who will require insulin treatment. This will be an important addition to correctly classifying individuals with diabetes when clinical features and autoimmune markers are equivocal.
The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as "diabetes." Increased knowledge of ...this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by ...clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal ...cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.
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