Maturity-onset Diabetes Research Articles

Implications of endoplasmic reticulum stress and beta-cell loss in immunodeficient diabetic NRG-Akita mice for understanding monogenic diabetes.

Immunodeficient mice models have become increasingly important as in vivo models engrafted with human cells or tissues for research. The NOD-Rag1null Ins2Akita Il2rnull (NRG Akita) mice is a model combined with immunodeficient NRG and monogenic diabetes Akita mice that develop spontaneous hyperglycemia with progressive loss of pancreatic insulin-producing beta-cells with age. This model is one of the monogenic diabetic models, which has been providing a powerful platform for transplantation experiments of stem cells-generated human β-cells. This research aimed to provide insights into the mechanisms underlying this monogenic diabetes, which remains incompletely understood. Histological and immunofluorescence analyses were conducted on endocrine pancreatic islets to compare NRG wild-type (Wt) controls with NRG-Akita mice. Our investigation focused on assessing the expression of endocrine hormones, transcription factors, proliferation, ER stress, and apoptosis. Histological analyses on NRG-Akita mice revealed smaller islets at 6-weeks-old, due to fewer β-cells in the islets, compared to NRG-Wt controls, which further progressed with age. The proliferation rate decreased, and apoptosis was abundant in β-cells in NRG Akita mice. Interestingly, our mechanistic analyses revealed that β-cells in NRG-Akita mice progressively accumulated the endoplasmic reticulum (ER) stresses, leading to a decreased expression of pivotal β-cell transcriptional factor PDX1. Altogether, our mechanistic insight into β-cell loss in this model could shed light on essential links between ER stress, proliferation, and cell identity, which might open the door to new therapeutic strategies for various diseases since ER stress is one of the most common features not only in diabetes but also in other degenerative diseases.

Investigation of Monogenic Diabetes Genes in Thai Children with Autoantibody Negative Diabetes Requiring Insulin.

The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin. Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES). All participants were ten men and twenty women. The median age to onset of diabetes was 8 years and 3 months. A total of 20 people with monogenic diabetes carried genes related to monogenic diabetes. The PAX4 (rs2233580) in ten patients with monogenic diabetes was found. Seven variants of WFS1 (Val412Ala, Glu737Lys, Gly576Ser, Cys673Tyr, Arg456His, Lys424Glu, and Gly736fs) were investigated in patients in this study. Furthermore, the pathogenic variant, rs115099192 (Pro407Gln) in the GATA4 gene was found. Most patients who carried PAX4 (c.575G>A, rs2233580) did not have a history of DKA. The pathogenic variant GATA4 variant (c.1220C>A, rs115099192) was found in a patient with a history of DKA. This study demonstrated significant genetic overlap between autoantibody-negative diabetes and monogenic diabetes using WES. All candidate variants were considered disease risk with clinically significant variants. WES screening was the first implemented to diagnose monogenic diabetes in Thai children, and fourteen novel variants were identified in this study and need to be investigated in the future.

Genetic architecture and biology of youth-onset type 2 diabetes

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10−6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies—and rare variants in particular—are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.

Multifaceted nature of young-onset diabetes - can genomic medicine improve the precision of diagnosis and management?

Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.

Causal linkage between type 2 diabetes mellitus and inflammatory bowel disease: an integrated Mendelian randomization study and bioinformatics analysis.

Observational studies have indicated associations between type 2 diabetes mellitus (T2DM) and both colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, the underlying causality and biological mechanisms between these associations remains unclear. We conducted a bidirectional Mendelian randomization (MR) analysis employing summary statistics from genome-wide association studies involving European individuals. The inverse variance weighting (IVW) method was the primary method used to assess causality. Additionally, we applied MR Egger, Weighted median, Simple mode, and Weighted mode to evaluate the robustness of the results. Outliers were identified and eliminated using the MR-PRESSO, while the MR-Egger intercept was used to assess the horizontal pleiotropic effects of single nucleotide polymorphisms (SNPs). The heterogeneity was evaluated using the Cochrane Q test, and sensitivity analysis was performed using leave-one-out method. The F statistic was calculated to evaluate weak instrumental variable bias. Finally, a pilot bioinformatics analysis was conducted to explore the underlying biological mechanisms between T2DM and IBD/UC. The IVW results demonstrated that T2DM significantly reduced risks of IBD (OR=0.885, 95% CI: 0.818-0.958, P=0.002) and ulcerative colitis (UC) (OR=0.887, 95% CI: 0.812-0.968, P=0.007). Although the 95% CIs of MR Egger, Weighted median, Simple mode, and Weighted mode were broad, the majority of their estimates were consistent with the direction of IVW. Despite significant heterogeneity among SNPs, no horizontal pleiotropy was observed. The leave-one-out analysis showed that the causality remained consistent after each SNP was removed, underscoring the reliability of the results. Reverse MR analysis indicated that genetic susceptibility to both CRC and IBD had no significant effect on the relative risk of T2DM. Ten hub genes were identified, which mainly enriched in pathways including maturity onset diabetes of the young, thyroid cancer, gastric acid secretion, longevity regulating pathway, melanogenesis, and pancreatic secretion. The presence of T2DM does not increase the risk of CRC or IBD. Moreover, T2DM might reduce risk of IBD, including UC. Conversely, the occurrence of CRC or IBD does not influence the risk of T2DM. The association between T2DM and IBD/UC may be related to the changes in multiple metabolic pathways and CTLA-4-mediated immune response.

Management of monogenic diabetes in pregnancy: A narrative review.

Pregnancy in women with monogenic diabetes is potentially complex, with significant implications for both maternal and fetal health. Among these, maturity-onset diabetes of the young (MODY) stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice. Each subtype of MODY requires a distinct approach tailored to the pregnancy, diverging from management strategies in non-pregnant individuals. Glucokinase MODY (GCK-MODY) typically does not require treatment outside of pregnancy, but special considerations arise when a woman with GCK-MODY becomes pregnant. The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus. During pregnancy, the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha (HNF1A)-MODY and HNF4A-MODY depends on the mother's specific circumstances and the available expertise. Management of other rarer MODY subtypes is individualized, with decisions made on a case-by-case basis. Therefore, a collaborative approach involving expert diabetes and obstetric teams is crucial for the comprehensive management of MODY pregnancies.

P-21 Maturity onset diabetes of the young 7: Case report

Abstract Introduction Maturity Onset Diabetes of the Young (MODY) is a rare form of diabetes which is different from both type 1 and type 2 diabetes, and runs strongly in families. MODY is autosomal dominant inherited type of diabetes, caused by a mutation (or change) in a single gene. If a parent has this gene mutation, any child they have, has a 50% chance of inheriting it from them. Recently, 14 gene mutations have been found to be associated with MODY. The Krüppel-like factor 11 (KLF11) gene mutation is the pathogenic gene of MODY7. Clinical Case A 17-year-old female patient with a previous history of obesity was admitted at outpatient office for regular control of weight and body mass index (BMI). Two years ago the patient was diagnosed with obesity, hyperinsulinemia and insulin resistance, with body weight (BW) 90 kg, body height (BH) 167 cm and BMI 32,3. The patient is on therapy with Metformin 2×500 mg. Results of the moment of examination: BW 100 kg, BH 168 cm, BMI 35,4; HbA1c 5,96%; Fasting plasma glucose (FPG) 6.8 mmol/l; Insulinemia 13,17; C-peptide 1,00; oral glucose tolerant test (OGTT): 0’ 6,5 mmol/l 120’ 11,0 mmol/l; insulinemia during OGTT (μU/mL): 0’ 14,05; 120’ 98,75; C-peptide during OGTT (ng/mL): 0’ 1,00; 120’ 6.95; Fundus examination and Doppler ultrasonography of both lower limbs showed no abnormalities. Family history was positive for Diabetes mellitus type 2 (mother, grandmother). The Immunological tests for Diabetes mellitus type 1 were negative for antibodies: GAD65, IAA, ICA and IA-2; Because there was doubt for MODY, genetic tests were performed with targeted resequencing of 4800 clinically relevant genes. The presence in the KLF11 gene associated with MODY7 was determined, c.911&amp;gt;G, p.(Lys304Arg). Тhe change is found in heterozygous form and is inherited from the mother. The patient continued treatment with metformin and lifestyle changes and this resulted in weight loss and good glycoregulation. Control one year later showed weight loss and good glycoregulation, FPG 5.1 mmol/l; HbA1c 5.5%; BW 89 kg, BH 168 cm, BMI 31.5; The level of blood glucose was controlled and stable. The patient's mother and grandmother were also treated with metformin. Conclusion Young patients with signs of DM2 should be tested for genetic types of diabetes. The number of patients with MODY is small, especially regarding MODY7, which rarely occurs. MODY is the most common type of monogenic β-cell function defect. It accounts for 2% to 15% of young diabetic patients. Studies have found that oral hypoglycemic drugs and dietary interventions are beneficial for MODY7 patients, and the control of the intake of staple food carbohydrates helps to control blood glucose which was also shown in our patient (1). 1. Chen L, Hou X. Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young. J Diabetes Res. 2021;2021:7136869

CCL7 and olfactory transduction pathway activation play an important role in the formation of CaOx and CaP kidney stones.

Background: The deposition of calcium oxalate (CaOx) and calcium phosphate (CaP) is the most common cause of kidney stone disease (KSD). Whether KSDs caused by CaOx and CaP have common genetic targets or signaling pathways remained unclear. Methods: The present study utilized public data GSE73680 to analyze differentially expressed genes between CaOx or CaP tissues and normal tissues, respectively. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of co-DEGs were performed. The protein-protein interaction (PPI) network was constructed to identify hub genes, and the top hub gene was selected for gene set enrichment analysis (GSEA). Finally, real-time PCR of patients' urine was performed to validate the bioinformatic results. Results: In total, 155 significantly co-upregulated DEGs and 64 co-downregulated DEGs were obtained from the datasets. The Gene Ontology analysis showed that DEGs were significantly enriched in chemical stimulus in sensory perception, detection of chemical stimulus in sensory perception of smell, and olfactory receptor activity. The KEGG analysis showed that the olfactory transduction pathway was significantly enriched. According to protein-protein interaction, 10 genes were identified as the hub genes, and CCL7 was the top hub gene. The olfactory transduction, maturity-onset diabetes of the young, linoleic acid metabolism, and fat digestion and absorption were significantly enriched in the high-CCL7 subgroup by GSEA. In total, 9 patients who had primarily CaOx mixed with some CaP stones and 9 healthy subjects were enrolled. The RT-PCR results showed that CCL7 level in the stone group was significantly higher than that in the control group (p < 0.05). For the olfactory transduction pathway, the expression of OR10A5, OR9A2, and OR1L3 was significantly upregulated in the stone group compared with the control group (p < 0.05). Conclusion: CCL7 may play a key role in the development of both CaOx and CaP, and this process may depend on olfactory transduction pathway activation.

Double whammy: Coexistence of Mature onset diabetes of the young and autoimmune diabetes: A case report

Maturity-Onset Diabetes of the Young (MODY)encompasses genetic disorders caused by mutations in single genes associated with beta cell dysfunction, constituting 1-6% of all diabetes cases. Mutations in ATP binding cassette transporter subfamily C member 8 (ABCC8) causes MODY 12 which accounts for 1% among MODY cases. It can present in childhood, adolescence or adulthood. Despite growing awareness, accurate MODY diagnosis remains challenging, often leading to misclassification as type 1 or type 2 diabetes. Correct identification is crucial for tailored treatment and implications for family members. The coexistence of MODY and autoimmune related diabetes is a very rare phenomenon with only a handful of cases reported. We describe a unique case where the index patient was initially diagnosed with type 1 diabetes at age 8 due to antibody positivity, leading to insulin treatment. After 15 years, he presented with evidence of all microvascular complications. Interestingly, his brother also developed diabetes at age of 14 years but with out antibody positivity. Due to a strong family history, both siblings underwent genetic testing, revealing a heterozygous mutation in the ABCC8 gene (C.4799630 G&gt;A; P-Arg 1600His).

Clinical screening for GCK-MODY in 2,989 patients from the Brazilian Monogenic Diabetes Study Group (BRASMOD) and the Brazilian Type 1 Diabetes Study Group (BrazDiab1SG).

To evaluate the accuracy of routinely available parameters in screening for GCK maturity-onset diabetes of the young (MODY), leveraging data from two large cohorts - one of patients with GCK-MODY and the other of patients with type 1 diabetes (T1D). The study included 2,687 patients with T1D, 202 patients with clinical features of MODY but without associated genetic variants (NoVar), and 100 patients with GCK-MODY (GCK). Area under the receiver-operating characteristic curve (ROC-AUC) analyses were used to assess the performance of each parameter - both alone and incorporated into regression models - in discriminating between groups. The best parameter discriminating between GCK-MODY and T1D was a multivariable model comprising glycated hemoglobin (HbA1c), fasting plasma glucose, age at diagnosis, hypertension, microvascular complications, previous diabetic ketoacidosis, and family history of diabetes. This model had a ROC-AUC value of 0.980 (95% confidence interval [CI] 0.974-0.985) and positive (PPV) and negative (NPV) predictive values of 43.74% and 100%, respectively. The best model discriminating between GCK and NoVar included HbA1c, age at diagnosis, hypertension, and triglycerides and had a ROC-AUC value of 0.850 (95% CI 0.783-0.916), PPV of 88.36%, and NPV of 97.7%; however, this model was not significantly different from the others. A novel GCK variant was also described in one individual with MODY (7-44192948-T-C, p.Ser54Gly), which showed evidence of pathogenicity on in silico prediction tools. This study identified a highly accurate (98%) composite model for differentiating GCK-MODY and T1D. This model may help clinicians select patients for genetic evaluation of monogenic diabetes, enabling them to implement correct treatment without overusing limited resources.

Clinical characteristics in children with maturity-onset diabetes of the young detected by urine glucose screening at schools in the Tokyo Metropolitan Area.

This study aimed to examine the clinical characteristics of young children diagnosed with maturity-onset diabetes (MODY) using urine glucose screening at schools. The study participants were 70 non-obese children who were clinically diagnosed with type 2 diabetes through urine glucose screening at schools in Tokyo between 1974 and 2020. Of these children, 55 underwent genetic testing, and 21 were finally diagnosed with MODY: MODY2 in eight, MODY3 in eight, MODY1 in four and MODY5 in one. A family history of diabetes was found in 76.2% of the patients. Fasting plasma glucose levels did not differ between the different MODY subtypes, while patients with MODY 3, 1, and 5 had significantly higher levels of glycosylated hemoglobin and 2-hour glucose in an oral glucose tolerance test than those with MODY2. In contrast, most patients exhibit mild insulin resistance and sustained β-cell function. In the initial treatment, all patients with MODY2 were well controlled with diet and exercise, whereas the majority of those with MODY3, 1, and 5 required pharmacological treatment within one month of diagnosis. In conclusion, urine glucose screening in schools appears to be one of the best opportunities for early detection of the disease and providing appropriate treatment to patients.

Research Progress on the Diagnosis and Treatment of Maturity Onset Diabetes of the Young 9

Research Progress on the Diagnosis and Treatment of Maturity Onset Diabetes of the Young 9

Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques.

As an essential transcriptional activator, PDX1 plays a crucial role in pancreatic development and β-cell function. Mutations in the PDX1 gene may lead to type 4 maturity-onset diabetes of the young (MODY4) and neonatal diabetes mellitus. However, the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models. In this study, three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology, all of which succumbed shortly postpartum, exhibiting pancreatic agenesis. Notably, one tri-allelic PDX1-mutant cynomolgus macaque (designated as M4) developed a pancreas, whereas the two mono-allelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation. RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions, indicating developmental delay and PDX1 haploinsufficiency. A marked change in m6A methylation was identified in the M4 pancreas, confirmed through cultured PDX1-mutant islet organoids. Notably, overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids. This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

Nutritional management of sepsis secondary to infective acute gastroenteritis with diabetes

ABSTRACT A 36-year-old Chinese male was presented at the emergency department and admitted to the Geriatric Intensive Care Unit for severe diabetic ketoacidosis (DKA) secondary to acute gastroenteritis (AGE) with symptoms of severe vomiting and diarrhoea. He had underlying maturity-onset diabetes of the young, hypertension, dihydrolipoamide dehydrogenase dihydrolipoamide dehydrogenase (DLD) and chronic kidney disease Stage 3 and had a history of hospital admission for the episodes of hypoglycaemia. The current diagnosis was sepsis secondary to infective AGE, resolved DKA, non-oliguric acute kidney injury, neck haematoma and left-hand cellulitis. He was referred to dietitian for diabetic counselling. His calculated body mass index was 19.4 kg/m2 (normal) with no history of fat and muscle loss. The biochemical data showed abnormalities for glycated haemoglobin, renal profile, liver function test and full blood count.

Study of Profile of Young Diabetics with Special Reference to Type 2 Diabetes Mellitus

Abstract Background: Data about the frequency of type 2 diabetes mellitus (T2DM) among young subjects below 25 years of age are sparse in the Indian subcontinent. Aims and Objectives: The objective of this study was to study the frequency and clinical profile of T2DM among young diabetics. Materials and Methods: The study was a prospective observational study conducted in the Department of General Medicine and Pediatrics in JSS Hospital, Mysuru, Karnataka, India. The subjects with age of onset of diabetes mellitus below 25 years were included in the study. They were categorized according to the C-peptide values as type 1 diabetes mellitus (T1DM) and T2DM. The statistical analyses were performed using Statistical Package for the Social Sciences (SPSS version 25) computer program. Results: Of the 250 patients included in the study, 208 (83.2%) subjects had T1DM, 38 (15.2%) T2DM, and 4 (1.6%) maturity-onset diabetes of the young. The mean age of onset of T1DM was 13.7 ± 6.201 years and T2DM was 23.28 ± 3.68 years. Body mass index and waist circumference of young T2DM patients were more compared to T1DM, which were statistically significant (P &lt; 0.0001), and family history showed strong positivity in patients with young T2DM compared to T1DM. Low-density lipoprotein-cholesterol, triglyceride, and total cholesterol were more in young T2DM patients compared to T1DM, which were statistically significant with P = 0.003, P = 0.0015, and P = 0.03, respectively. Conclusion: T2DM is now commonly occurring in young adults and children, probably due to a growing epidemic of childhood obesity and lifestyle. Obesity and dyslipidemia were more in T2DM compared to T1DM among young diabetics.

GCK-MODY у молодых мужчин: значение поведенческих и кардиометаболических факторов риска в развитии осложнений

Aim. Present two clinical cases of Maturity-Onset Diabetes of the Young, which is based on the presence of pathogenic variants in the glucokinase (GCK) gene — GCK-MODY; to characterize behavioral and cardiometabolic risk factors for diabetes complications. Key points. In the first clinical case, the pathogenic variant p.Trp257Ter (c.770G&gt;A, NM_000162.5) of the GCK gene, previously described in the literature, was identified in the proband and his father, in the second — the pathogenic variant p.Cys271Ter (c.1113C&gt;A, NM_000162. 5) GCK gene. Probands are young men, 22 and 21 years old, respectively. They were first diagnosed with diabetes in the ages of 10 and 6 years during routine examinations. There were no clinical symptoms of hyperglycemia; they did not take and do not currently take hypoglycemic drugs. When examined 11 and 15 years after the diagnosis of diabetes, in each patient the level of C-peptide was within the reference values, which indicates the preservation of the secretory function of pancreatic β-cells. Antibodies were negative, the level of glycated hemoglobin (HbA1c) was 5.7 and 6.1%, respectively. No complications of diabetes were identified in either patient. The fathers of probands from both families had HbA1c levels of 6.4 and 6.5%, respectively. The father of the proband from the first clinical case does not comply with recommendations for a healthy lifestyle and nutrition, and does not deny weekly alcohol consumption. Upon examination, he was found to be overweight, arterial hypertension, dyslipidemia, steatohepatitis, and atherosclerosis of the brachiocephalic vessels, which increase the risk of cardiovascular events. The father of the proband from the second clinical case follows recommendations for a healthy lifestyle. During the examination, body weight, blood pressure, blood lipids are within the target range. Conclusion. Presenting two clinical cases and family histories of patients with GCK-MODY, the authors note that the compliance with the principles of a healthy lifestyle, assessment and correction of the main risk factors will help avoid the emergence and progression of complications in patients with GCK-MODY. When monitoring and treating patients with diabetes of any type, it is important to follow the principles of preventive medicine. Keywords: Molecular genetic research, GCK gene, monogenic diabetes mellitus, Maturity-Onset Diabetes of the Young, hyperglycemia, diabetes mellitus in young people.

Variantes genéticas associadas aos níveis de glicose em jejum na população brasileira: uma revisão de estudos de polimorfismos identificados em europeus

ABSTRACT Objective Impaired fasting glucose is a well-known risk factor for diabetes, and has been linked to other conditions, such as cardiovascular and Alzheimer’s disease. Whether these associations imply causation remains to be established. Observational studies are often afflicted by confounding and reverse causation, making them less than ideal for demonstrating causal relationships. Genetically-informed methods like Mendelian randomization, which are less susceptible to these biases, can be implemented. Mendelian randomization uses genetic variants as proxies (or instrumental variables) for modifiable exposures, testing their association with disease outcomes. However, since most genetic proxies have been described in European populations, applying Mendelian randomization in the Brazilian population necessitates the identification of locally relevant instruments. We investigated genetic variants associated with fasting glucose that were discovered in genome-wide association studies of Europeans and have also been examined in Brazil. The aim of our study was to define whether these variants served as proxies for fasting glucose in Brazil too. Methods We carried out an exhaustive literature search using databases of published research articles and a repository of Brazilian theses and dissertations. Results We examined a total of 38 papers and 27 dissertations/theses, published between 1997 and 2022, involving 21888 participants. We found few results for impaired fasting glucose, as opposed to many reports on the association of the selected genetic variants with diabetes. The genes GCK and TCF7L2 prevailed in the analyses, although studies on GCK were mainly related to Maturity-Onset Diabetes of the Young rather than to common diabetes conditions. Conclusion Additional studies with improved reporting of findings are imperative to elucidate the genetic predictors of fasting glucose (and possibly other risk factors) in Brazil.

Polygenic Risk Score and Precision Medicine in Diabetes

Precision medicine involves tailoring medical treatment to the individual characteristics, needs, and preferences of each patient. In the realm of diabetes, genetic, environmental, and lifestyle factors must all be considered when developing personalized management strategies. Polygenic risk refers to the cumulative risk of developing a disease based on the presence of multiple genetic variants across the genome. Understanding the polygenic nature of diabetes assists in identifying various genetic factors that contribute to its onset, progression, and the development of complications. Recent studies indicate that polygenic risk scores are instrumental in distinguishing between type 1 diabetes, monogenic diabetes, and type 2 diabetes. Moreover, these scores can predict incident type 2 diabetes in women with a history of gestational diabetes and can be used to forecast diabetic complications. When polygenic risk scores are combined with other risk factors such as age, body mass index, and family history, risk stratification is enhanced, pinpointing individuals who may benefit most from early intervention strategies. Challenges related to practical use of polygenic scores include ethnicity specificity, data privacy, and generating evidence in the clinical setting. We aim to explore opportunities as well as challenges related to utilizing polygenic risk in precision medicine.

A case of type A insulin resistance syndrome in a 14-year-old adolescent girl without common clinical features.

Type A insulin resistance syndrome is a rare congenital disorder caused by insulin receptor dysfunction arising from heterozygous mutations in the insulin receptor (INSR) gene. It is usually diagnosed in non-obese female adolescents with insulin resistance, acanthosis nigricans, or ovarian hyperandrogenism. We present the case of a 14-year-old adolescent girl with non-obesity diabetes and insulin resistance; however, she had no acanthosis nigricans, or menstrual abnormalities. The laboratory results were as follows: fasting plasma glucose 179 mg/dL; C-peptide 1.8 ng/mL; insulin 34.8 lU/mL; HbA1c 10.6%. Islet cell autoantibodies, insulin autoantibodies, and glutamic acid decarboxylase antibodies were negative. We performed a next-generation sequencing-based targeted gene panel for the known maturity-onset diabetes of the young and found a heterozygous mutation in the INSR gene c.3602G>A (p.Arg1201Gln). Her mother carried the same mutation as her and also did not present with acanthosis nigricans or menstruation abnormalities. Type A insulin resistance syndrome has diverse clinical phenotypes even with the same type of mutation at the same site in the INSR gene. Clinicians should consider genetic testing for early detection and adequate treatment approaches.

Maturity-onset diabetes of the young due to NR0B2 gene mutation.

Maturity-onset diabetes of the young due to NR0B2 gene mutation.