Early-onset Type 2 Diabetes Research Articles

Ethnic differences in the manifestation of early-onset type 2 diabetes

IntroductionWe undertook phenotypic characterization of early-onset and late-onset type 2 diabetes (T2D) in adult black African and white European populations with recently diagnosed T2D to explore ethnic differences in the...

Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

Testosterone in prevention and treatment of type 2 diabetes in men: Focus on recent randomized controlled trials.

In epidemiological studies, lowered serum testosterone concentrations are common in men with obesity, prediabetes, and established type 2 diabetes (T2D). In men with prediabetes, lowered serum testosterone also predicts a future risk of T2D in men. Administration of testosterone consistently reduces fat mass and increases skeletal muscle mass-body compositional changes expected to be metabolically favorable. In men with established T2D, the effects of testosterone treatment on glycemic measures are inconsistent. Irrespective of baseline serum testosterone concentration in men with prediabetes or newly diagnosed early-onset T2D, testosterone treatment prescribed in conjunction with a lifestyle program has been reported to reduce the risk of T2D by 40% after 2 years, suggesting that either a lifestyle program is required to facilitate the glycemic benefit of testosterone treatment and/or that testosterone treatment has more favorable effects on glycemia in men early in the evolution or onset of the disease. The durability of the benefit and longer-term safety of testosterone treatment have not been established. Therefore, more studies are required before testosterone treatment can be recommended for the prevention and/or treatment of men with or at elevated risk of T2D who do not have hypogonadism due to an established disease of the hypothalamic-pituitary-testicular axis.

A GENETIC RISK SCORE OF EARLY-ONSET TYPE 2 DIABETES PREDICTS EARLY DEATH AND BENEFITS OF INTENSIVE GLYCEMIC CONTROL IN ADVANCE TRIAL

Objective: Context: Early-onset type 2 diabetes (T2D) increases rapidly worldwide, alongside obesity, and carries an excess risk of microvascular complications and early death compared to when it started later in life. We have developed a multi-polygenic risk score (multiPRS) that predicts the risk of major micro- and macrovascular complications of T2D. We showed that individuals with high multiPRS scores for macrovascular events benefited more from tight blood pressure control while those with high multiPRS scores for microvascular events benefited from glycemic control. Early-onset T2D is genetically determined. Objective: To develop a genetic risk score that identifies individuals who are more susceptible to early-onset T2D and assess whether they could benefit from tight glycemic control. Design and method: We developed a genetic risk score (GRS) composed of 22 SNPs associated with early-onset T2D. We analysed 545 participants of European descent of ADVANCE with the highest GRS values and 526 subjects with the lowest GRS for early-onset T2D. Results: The median age at diagnosis of T2D was 54.9 in the high GRS and 64.6 in the low GRS group. Compared to participants with low GRS, those with high GRS were slightly heavier with a BMI of 30.8 (5.1 SD) vs 29.6 (4.9 SD), p = 7.2 x 10-5, they received more antidiabetic drugs (n= 1.5 (0.8) vs 1.2 (0.8), p = 1.2 x 10-7) and they died 5.7 years earlier (70.8 vs 76.5 years old p = 9 x 10-7). Contrary to the low GRS group, intensive glycemic control reduced mortality significantly in the high GRS group. Combination of intensive blood pressure and glycemia control led to a relative risk reduction of 52% (p = 0.028) and a number needed to treat of only 10 in the high GRS group while no significant effects were observed in the low GRS group. Conclusions: This novel GRS can identify individuals at risk of early-onset T2D who can benefit from tight glycemic control while its combination with blood pressure control is the most effective in reducing cardiorenal outcomes and death rate.

Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program.

We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide. Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

Abstract P437: Cumulative Effect of Early-Onset Type 2 Diabetes on Left Ventricular Geometry - The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: Type 2 diabetes (T2D) is increasingly common in young adults. Increases in left ventricular (LV) mass and wall thickness are early manifestations of myocardial involvement in T2D. The association between the cumulative burden of risk factors (RFs) and LV structural abnormalities in patients with early-onset T2D has not been well characterized. Objective: Investigate how metabolic RFs accumulated in a 25-year period among patients with early-onset T2D relate to LV mass index (LVMI) and relative wall thickness (RWT). Methods: We used data from the Coronary Artery Risk Development in Young Adults study (CARDIA, baseline to year 25). We defined early-onset T2D by self-reported T2D or anti-diabetic medication use, fasting glucose (FG) ≥126 mg/dL, or oral glucose ≥200 mg/dL at or before follow-up year 10 (age&lt;40). LV outcomes were measured by Doppler echocardiography (LVMI by Devereux formula indexed to body surface area; RWT = LV posterior wall thickness at end diastole x 2/LV internal dimension at end-diastole). Hypertrophy was defined by LVMI ≥115 g/m 2 in men or ≥95 g/m 2 in women. We used the area under the growth curve (AUC) that was derived from quadratic random-effects models of ≥4 repeated measures of RFs (BMI, SBP, DBP, LDL-c, HDL-c, triglycerides, fasting glucose, and fasting insulin) to estimate the cumulative burden of T2D through adulthood. We performed linear regressions to examine the associations of the total AUC of each RF with LVMI or RWT, accounting for sex, race, mid-life age, education, smoking, and control for hypertension, lipids, and diabetes. We assessed the associations by sex and race. Results: Among 227 patients with early-onset T2D, 39% had hypertrophy, and 13% had RWT&gt;0.42 at midlife. Each standard deviation (SD) increase in total AUCs of BMI, SBP, DBP, triglycerides, FG, and fasting insulin was significantly associated with increased LVMI (β coefficients =5.9, 11.5, 10, 7, 4.1, and 6.7, respectively), while high total AUC of HDL-c was inversely associated with LVMI (β = -5.1). Increased total AUC of triglycerides was associated with increased RWT (β = 0.2). Significant sex and race differences were shown in the cumulative effect of RFs on outcomes. The positive associations between AUC of RFs and LVMI were significant in both sexes, but the associations were stronger in male patients than in women. The inverse association between AUC of HDL-c and LVMI was only significant in male patients (P-interaction &lt;0.05). Women with early-onset T2D but not men exhibited significantly increased RWT related to the increase in AUCs of SBP, DBP, triglycerides, FG, and insulin (P-interaction &lt;0.05). The positive association between AUC of BMI and LVMI was significant in Whites but not Blacks (P-interaction &lt;0.05). Conclusion: Cumulative RFs alter mid-adulthood LV geometry in patients with early-onset T2D. This cumulative impact of early-onset T2D on LV geometry varies by sex and race.

Clinical features of early-onset type 2 diabetes and its association with triglyceride glucose-body mass index: a cross-sectional study.

The incidence of early-onset type 2 diabetes (T2D) has increased significantly, with insulin resistance (IR) and obesity being the main drivers of its onset. This study aims to investigate the clinical characteristics of early-onset T2D and its association with triglyceride glucose body mass index (TyG-BMI), an emerging surrogate of IR. A total of 1000 adults newly diagnosed with T2D were enrolled and divided into early-onset T2D (18~40 years, N=500) and late-onset T2D groups (≥40 years, N=500). Independent t and chi-squared tests were used to compare the characteristics of the two groups, and logistic regression analysis, trend tests, restricted cubic spline curves (RCSs), and receiver operating characteristic (ROC) curves were used to identify the relationship between TyG-BMI and early-onset T2D. Patients with early-onset T2D were more likely to have a higher body mass index (BMI), hemoglobin A1C (HbA1c), fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), serum uric acid (SUA), triglyceride glucose index (TyG), and TyG-BMI (P < 0.05). A higher TyG-BMI was associated with an increased risk of early-onset T2D (P < 0.001). The RCSs showed a nonlinear relationship between TyG-BMI and early-onset T2D, and the slope of the curve increased with an increase in TyG-BMI (P for nonlinearity < 0.001). In the subgroup analysis, additive interactions between TyG-BMI and the risk of early-onset T2D were observed for sex, family history of diabetes, BMI, fatty liver, and hypertension (P < 0.001). ROC curve showed that the area under the curve of TyG-BMI was 0.6781, which was larger than its main components (TyG, BMI, FPG, TG). The best cutoff value was 254.865, the sensitivity was 74.6%, and the specificity was 53.6%. Patients with early-onset T2D are characterized by severe IR, metabolic disorders, and being overweight/obese and an increase in TyG-BMI is independently associated with an increased risk of early-onset T2D.

Early onset age increases the risk of musculoskeletal damage in patients with type 2 diabetes.

It's not clear whether there are differences in musculoskeletal damage and body composition among different age groups of type 2 diabetes. Therefore, the purpose of this study is to analyze the difference between early-onset type 2 diabetes (EOT2D) and non-early-onset type 2 diabetes (NOT2D) in musculoskeletal damage. A total of 964 patients with type 2 diabetes mellitus were selected by 1:1 propensity score matching, including 534 males and 430 females, with an average age of 52 ± 7 years and an average course of 10 ± 8.5 years. Bone mineral density and body composition were measured, and combined with biochemical tests, linear regression and binary logic regression were used to analyze the relationship between EOT2D, NOT2D and musculoskeletal damage. In addition, 414 patients with T2DM were selected according to whether they were hospitalized twice or not, and the median follow-up period was 44 months. COX survival analysis further elucidates the relationship between EOT2D, NOT2D and musculoskeletal damage. Compared with patients with non-early-onset type 2 diabetes, A/G was negatively correlated with the age of onset, and had statistical significance. EOT2D has a higher risk of sarcopenia, osteoporosis and even musculoskeletal damage. With the prolongation of the course of the disease, the risk of muscle mass and/or bone mineral density decrease in EOT2D increases. EOT2D brings a greater risk of sarcopenia and/or osteoporosis, as well as a higher risk of reduced ASM and BMD. In addition, fat distribution may be more central.

Comparison of clinical characteristics and disease burden between early- and late-onset type 2 diabetes patients: a population-based cohort study

BackgroundThe clinical characteristics of early-onset type 2 diabetes (T2D) patients are not fully understood. To address this gap, we conducted a cohort study to evaluate clinical characteristics and disease burden in the new-onset T2D population, especially regarding the progression of diseases.MethodsThis cohort study was conducted using a population-based database. Patients who were diagnosed with T2D were identified from the database and were classified into early- (age < 40) and late-onset (age ≥ 40) groups. A descriptive analysis was performed to compare clinical characteristics and disease burden between early- and late-onset T2D patients. The progression of disease was compared using Kaplan‒Meier analysis.ResultsA total of 652,290 type 2 diabetic patients were included. Of those, 21,347 were early-onset patients, and 300,676 were late-onset patients. Early-onset T2D patients had poorer glycemic control than late-onset T2D patients, especially at the onset of T2D (HbA1c: 9.3 [7.5, 10.9] for early-onset vs. 7.7 [6.8, 9.2] for late-onset, P < 0.001; random blood glucose: 10.9 [8.0, 14.3] for early-onset vs. 8.8 [6.9, 11.8] for late-onset, P < 0.001). Insulin was more often prescribed for early-onset patients (15.2%) than for late-onset patients (14.8%). Hypertension (163.0 [28.0, 611.0] days) and hyperlipidemia (114.0 [19.0, 537.0] days) progressed more rapidly among early-onset patients, while more late-onset patients developed hypertension (72.7% vs. 60.1%, P < 0.001), hyperlipidemia (65.4% vs. 51.0%, P < 0.001), cardiovascular diseases (66.0% vs. 26.7%, P < 0.001) and chronic kidney diseases (5.5% vs. 2.1%, P < 0.001) than early-onset patients.ConclusionsOur study results indicate that patients with newly diagnosed early-onset T2D had earlier comorbidities of hypertension and hyperlipidemia. Both clinical characteristics and treatment patterns suggest that the degree of metabolic disturbance is more severe in patients with early-onset type 2 diabetes. This highlights the importance of promoting healthy diets or lifestyles to prevent T2D onset in young adults.

Cardiovascular disease risk in early-onset vs late-onset type 2 diabetes in China: A population-based cross-sectional study.

This study investigated the effects of early-onset type 2 diabetes (EOD) vs late-onset type 2 diabetes (LOD) on nonfatal cardiovascular diseases (CVD) in China. We conducted a cross-sectional survey of 46 239 participants from 14 provinces in China from 2007 to 2008, selecting 4949 participants with type 2 diabetes for analysis. Participants were categorized as EOD (<40 years) or LOD (≥40 years) based on age at diabetes diagnosis. Sociodemographic and nonfatal CVD information was collected through an interviewer-assisted questionnaire and clinical examination. Logistic regression analysis was used to investigate the nonfatal CVD risk. Out of 4949 participants with type 2 diabetes, 390 (7.88%) had nonfatal CVD. Participants with EOD had a higher age-standardized prevalence of nonfatal CVD than those with LOD (11.4% vs 4.4%). Compared to LOD patients, EOD patients tended to be males and had a higher family history of diabetes, unhealthy lifestyle behaviors, and lower blood pressure levels. After adjustment for age and sex, EOD patients had a higher risk of nonfatal CVD than LOD patients (odds ratio [OR] 2.3, 95% CI 1.5-3.5). After further adjustment for diabetes duration, use of drugs, and other risk factors, the OR of nonfatal CVD was reduced but significant (OR 1.8, 95% CI 1.1-2.9). Sensitivity analysis revealed that EOD patients with metabolic syndrome had an increased nonfatal CVD risk compared to LOD patients (OR 2.0, 95% CI 1.2-3.5). EOD patients are at increased risk of nonfatal CVD. Individualized intervention and management measures for EOD patients are necessary.

Clinical characteristics of patients with early-onset diabetes mellitus: a single-center retrospective study

BackgroundThe prevalence of diabetes mellitus (DM) is dramatically increasing around the world, and patients are getting younger with changes in living standards and lifestyle. This study summarized and analyzed the clinical characteristics of different types of newly diagnosed diabetes mellitus patients with an onset age between 18 and 40 years to provide clinical evidence for the early diagnosis and treatment of diabetes, reduce short-term and long-term complications and offer scientific and personalized management strategies.MethodsA total of 655 patients newly diagnosed with early-onset diabetes mellitus in the Department of Endocrinology, the First Medical Center of PLA General Hospital from January 2012 to December 2022 were retrospectively enrolled in this study, with an onset age of 18–40 years. Their clinical data were collected and investigated. All patients were divided into two groups according to whether they presented with diabetic microangiopathy. Similarly, patients with early-onset type-2 diabetes were grouped in accordance with whether they had ketosis at the time of diagnosis. Binary logistic regression analysis was performed to analyze risk factors, and receiver-operating characteristic (ROC) analysis was used to explore the predictive value of significant risk factors.ResultsThe findings were as follows: (1) Of 655 enrolled patients, 477 (72.8%) were male and 178 (27.1%) were female, with a mean age of onset of was 29.73 years ± 0.24 SD. (2) The prevalence of early-onset diabetes was gradually increasing. Type-2 diabetes was the most common type of early-onset diabetes (491, 75.0%). The ages of onset of early-onset type-1 diabetes, type-2 diabetes and LADA were mainly 18–24 years, 25–40 years and 33–40 years, respectively. (3) Initial clinical manifestations of early-onset diabetes were classic diabetes symptoms (361, 55.1%), followed by elevated blood glucose detected through medical examination (207, 31.6%). (4) Binary logistic regression analysis suggested that high serum uric acid (UA), a high urinary albumin-to-creatinine ratio (UACR) and diabetic peripheral neuropathy (DPN) were risk factors for microangiopathy in early-onset diabetes patients (P < 0.05). The area under the curve (AUC) on ROC analysis of the combination of UA, UACR and DPN was 0.848, 95% CI was 0.818 ~ 0.875, sensitivity was 73.8% and specificity was 85.9%, which had higher predictive value than those of UA, UACR and DPN separately. (5) Weight loss, high glycosylated hemoglobin (HbA1c) and young onset age were risk factors for ketosis in patients with early-onset type-2 diabetes (P < 0.05).Conclusion(1) Men were more likely to have early-onset diabetes than women. (2) Early-onset diabetes patients with high serum uric acid levels, high UACRs and peripheral neuropathy were prone to microangiopathy. Comprehensive evaluation of these risk factors could have higher predictive value in the prediction, diagnosis and treatment of microvascular lesions. (3) Patients with weight loss at onset, high HbA1c and young onset age were more likely to develop ketosis. Attention should be given to the metabolic disorders of these patients.

Ten-year clinical characteristics of patients with early-onset type 2 diabetes: A single-center experience in China.

The incidence of type 2 diabetes in China has exhibited an increasing trend, including younger individuals, over the past years. Early-onset type 2 diabetes (EOT2D) refers to diabetes diagnosed before 40 years of age. These patients have poor metabolic control and are highly susceptible to diabetic complications, which poses challenges for treatment. However, few studies have reported on the treatment of EOT2D. We determined clinical features and trends in drug use in patients with type 2 diabetes mellitus (T2DM). This retrospective study was performed at the Endocrinology Ward, Peking Union Medical College Hospital (PUMCH). "Diabetes" was used when searching PUMCH's Electronic Medical Record Analytical Database to obtain clinical data of patients between January 2013 and May 2022. The analysis included 1590 patients with T2DM. Among them, 609 (38.3%) had EOT2D. Compared with late-onset type 2 diabetes (LOT2D) patients, EOT2D patients exhibited worse glycemic control and higher body weight and lipid levels despite significant age differences. EOT2D patients also had a higher risk of diabetic retinopathy and nephropathy. Under the general trend of increasing use of dipeptidylpeptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide-1 agonists, patients with EOT2D were more likely to use organ-protective drugs. Compared with LOT2D patients, EOT2D patients have a longer course of diabetes, worse metabolic control, and a higher rate of developingmicrovascular complications. The administration of combined therapy, including new agents, may require consideration when selecting hypoglycemic agents for treating EOT2D.

1355-P: Risk of Chronic Kidney Disease in Early-Onset Type 2 Diabetes in Mexico

Patients with early onset type 2 diabetes (EOD) seem to be at increased risk of developing complications. Screening and diagnosis for CKD is poorly executed in primary care (PC) of low-and-middle income countries. Thus, we aimed to analyze the presence of CKD in EOD in comparison with later-onset diabetes (LOD). Data were obtained from the largest cohort of patients with T2D evaluated for CKD within the PC in Mexico (DIABEMPIC). EOD and LOD were defined as the age of diagnosis &amp;lt;40 and ≥40 years, respectively. CKD assessment included albuminuria through urinary albumin-creatinine ratio (≥30mg/g for CKD) and estimated glomerular filtration rate (eGFR≤60 ml/min/1.73m2 for CKD). A total of 1,592 patients were included. The burden of CKD at different diabetes durations are shown in Table 1. The prevalence of overall CKD was significantly higher in the EOD group (p&amp;lt;0.008), associated to a greater presence of albuminuria; a higher prevalence of albuminuria was observed after 10 years of diagnosis in the EOD (p&amp;lt;0.0001). In the univariate analysis, EOD was associated with an increased risk of CKD (OR 1.33, 95%CI 1.08-1.65). In conclusion, EOD patients presented a higher risk of CKD, particularly on account for albuminuric-CKD phenotype, even though they are comparatively younger. Our results enhance the need for the management of risk factors and proper screening of CKD in T2D, especially in EOD, in PC settings, and through albuminuria measurement. Disclosure R.Silva-tinoco: Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Inc., Novo Nordisk. J.Mejia-vilet: None. J.Ochoa-moreno: None. J.Serna: None. O.Lopez-arellano: None. T.Cuatecontzi-xochitiotzi: None. E.B.Guzman-olvera: None. V.Delatorre-saldaña: None. A.Galindez-fuentes: None. L.Castillo-martinez: None. F.Bernal-ceballos: None. V.Rios-carbajal: None. N.Torres-sandoval: None.

Prevalence and Clinical Characteristics of PDX1 Variant Induced Diabetes in Chinese Early-Onset Type 2 Diabetes.

Maturity-onset diabetes of the young 4 (MODY4) is caused by mutations of PDX1; its prevalence and clinical features are not well known. This study aimed to investigate the prevalence and clinical characteristics of MODY4 in Chinese people clinically diagnosed with early-onset type 2 diabetes (EOD), and to evaluate the relationship between the PDX1 genotype and the clinical phenotype. The study cohort consisted of 679 patients with EOD. PDX1 mutations were screened by DNA sequencing, and their pathogenicity was evaluated by functional experiments and American College of Medical Genetics and Genomics guidelines. MODY4 was diagnosed in individuals with diabetes who carry a pathogenic or likely pathogenic PDX1 variant. All reported cases were reviewed for analyzing the genotype-phenotype relationship. 4 patients with MODY4 were identified, representing 0.59% of this Chinese EOD cohort. All the patients were diagnosed before 35 years old, either obese or not obese. Combined with previously reported cases, the analysis revealed that the carriers of homeodomain variants were diagnosed earlier than those with transactivation domain variants (26.10 ± 11.00 vs 41.85 ± 14.66 years old, P < .001), and the proportions of overweight and obese individuals with missense mutation were higher than those with nonsense or frameshift mutations (27/34 [79.4%] vs 3/8 [37.5%], P = .031). Our study suggested that MODY4 was prevalent in 0.59% of patients with EOD in a Chinese population. It was more difficult to identify clinically than other MODY subtypes owning to its clinical similarity to EOD. Also, this study revealed that there is some relationship between genotype and phenotype.

The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes

Diabetes is one of the most common phenotypes of Wolfram syndrome owing to the presence of the variants of the WFS1 gene and is often misdiagnosed as other types of diabetes. We aimed to explore the prevalence of WFS1-related diabetes (WFS1-DM) and its clinical characteristics in a Chinese population with early-onset type 2 diabetes (EOD). We sequenced all exons of the WFS1 gene in 690 patients with EOD (age at diagnosis ≤ 40 years) for rare variants. Pathogenicity was defined according to the standards and guidelines of the American College of Medical Genetics and Genomics. We identified 33 rare variants predicted to be deleterious in 39 patients. The fasting [1.57(1.06–2.22) ng/ml] and postprandial C-peptide levels [2.8(1.75–4.46) ng/ml] of the patients with such WFS1 variations were lower than those of the patients without WFS1 variation [2.09(1.43–3.05) and 4.29(2.76–6.07) respectively, ng/ml]. Six (0.9%) patients carried pathogenic or likely pathogenic variants; they met the diagnostic criteria for WFS1-DM according to the latest guidelines, but typical phenotypes of Wolfram syndrome were seldom observed. They were diagnosed at an earlier age and usually presented with an absence of obesity, impaired beta cell function, and the need for insulin treatment. WFS1-DM is usually mistakenly diagnosed as type 2 diabetes, and genetic testing is helpful for individualized treatment.

Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history in China

PurposeEarly-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort.MethodsOf 6470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case–control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 early-onset T2D patients without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP, and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families.ResultsCompared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m2, P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes (KLF11, GCK, ABCC8, PAX4, BLK and HNF1A) of MODY.ConclusionseDia3 patients had unique clinical features. Known MODY genes were not common causes in these patients.

1144-P: Risk of Diabetic Retinopathy in Early-Onset Type 2 Diabetes in Mexico

Early onset type 2 diabetes (EOD) seems to have an aggressive disease progression with a higher risk for diabetes complications at an early age. Screening for Diabetic Retinopathy (DR) is poorly executed in primary care of low-and-middle income countries. Thus, we aimed to analyze the characteristics of EOD in comparison with later-onset group. Data were obtained from the largest cohort of patients evaluated for DR within the primary care in Mexico (DIABEMPIC program) . Early and later-onset groups were defined as age of diagnosis &amp;lt;40 and ≥40 years, respectively. DR assessment by an ophthalmologist included fundoscopy with a mydriatic camera. Proliferative DR and severe non-proliferative DR were considered as severe DR. A total of 3063 patients with T2D were included of which 9had EOD. Prevalence of DR and severe DR was significantly higher in the EOD group than in the later-onset group (p&amp;lt;0.0001) ; however, an increase in the prevalence of DR and severe DR was observed after years of diagnosis (p&amp;lt;0.0001) . Burden of DR at different diabetes durations are shown in Table 1. EOD was associated with increased risk of DR compared with late onset T2D (OR 2.18, 95%CI 1.85-2.57) . In conclusion, EOD patients with regular primary care presented a higher risk of DR and of severe DR not only explained for longer disease duration. Our study enhances the need for the management of DR risk factors and proper screening of DR in patients with T2D, especially in EOD. Disclosure R.Silva-tinoco: n/a. E.León-garcía: None. J.Ochoa-moreno: n/a. O.Lopez-arellano: None. T.Cuatecontzi-xochitiotzi: None. D.Cabrera-gerardo: n/a. V.Delatorre-saldaña: None. L.Castillo-martinez: None. F.Bernal-ceballos: None. E.B.Guzman: None. S.Bouchan-delino: None. A.Ramirez: None.

138-OR: Earlier Onset of Type 2 Diabetes Increases Genetic Risk of Cardiovascular Complication

Earlier age at diagnosis of type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD) . However, genetic risk factors associated with accelerated CVD in people with early onset T2D remain elusive. We aimed to investigate if the impact of polygenic risk for developing CVD differs according to age at diagnosis of T2D. Using prospective cohorts of UK Biobank (T2D, N=15,915) and Seoul National University Hospital (SNUH) T2D cohort (N=1,228) , we compared the incidence of newly developed CVD among four groups based on age at diagnosis of T2D (30-39, 40-49, 50-59, and 60-69 years of age) using time to event analysis. Polygenic risk scores (PRSs) for T2D and coronary artery disease (CAD) were calculated by PRS-CS, Bayesian regression using continuous shrinkage priors, using 1.1 million SNPs each from summary statistics of DIAGRAM and CARDIoGRAMplusC4D Consortium. In UK Biobank, people diagnosed as T2D between age 30-39 had 5.8 (95% CI 4.04-8.42) fold increased risk of CVD compared to those who developed T2D between 60-69. Higher T2D PRS was associated with earlier onset of T2D but not with risk of myocardial infarction (MI) . On the other hand, higher CAD PRS was associated with increased risk of MI but not with earlier age at diagnosis of T2D. The effect of CAD PRS on MI was largest in people diagnosed between age 30-39 and its effect size decreased as the age at diagnosis increased: HR 2.34 (1.47-3.71) for age 30-39, 1.42 (1.20-1.68) for 40-49, 1.39 (1.25-1.54) for 50-59, and 1.28 (1.11-1.48) for 60-69. Interaction analysis between age at diagnosis and CAD PRS showed additional 10% increase in risk of MI for year earlier onset of T2D (P=0.0056) . These findings were replicated in the SNUH T2D cohort, which is a hospital based cohort of East Asians. In summary, people with earlier onset T2D had higher risks for CVD, and the impact of CAD PRS for incident MI increased as age at diagnosis decreased. Genetic information in people with early onset T2D could be used to identify those with increased risk of CVD. Disclosure H.Lee: None. J.Choi: None. N.Kim: None. S.Lee: None. K.Park: None. S.Kwak: None.

Contribution of rare variants in monogenic diabetes-genes to early-onset type 2 diabetes

AimThis study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D). MethodsA nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested. ResultsWhen all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08–2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87–22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01–1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02). ConclusionRare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.

Epidemiology of Type 2 Diabetes in Indigenous Communities in the United States

The present review focuses on the epidemiology of type 2 diabetes (T2D) in Indigenous communities in the continental United States (U.S.)-including disease prevention and management-and discusses special considerations in conducting research with Indigenous communities. Previous studies have reported the disparately high prevalence of diabetes, especially T2D, among Indigenous peoples in the U.S. The high prevalence and incidence of early-onset T2D in Indigenous youth relative to that of all youth in the U.S. population pose challenges to the prevention of complications of diabetes. Behavioral, dietary, lifestyle, and genetic factors associated with T2D in Indigenous communities are often investigated. More limited is the discussion of the historical and ongoing consequences of colonization and displacement that impact the aforementioned risk factors. Future research is necessary to assess community-specific needs with respect to diabetes prevention and management across the diversity of Indigenous communities in the U.S.