A novel stop-loss mutation in NKX2-2 gene as a cause of neonatal diabetes mellitus: molecular characterization and structural analysis.

AIM: To identify the genetic etiology of neonatal diabetes in an infant and to elucidate the molecular mechanism of the identified mutation underlying the pathogenesis. METHODS: Genetic analysis was carried out by sequencing of known etiological genes associated with NDM. Molecular characterization was performed by constructing a identified mutation in NKX2-2 gene and  functional aspects was tested using transactivation, protein expression, DNA binding, nuclear localization assays. Structural analysis was performed by modeling the NKX2-2 protein structure. RESULTS: A novel homozygous frameshift mutation  c.772delC, p.Q258SFs*59 in the NKX2-2 gene was identified in a patient with neonatal diabetes. Functional studies revealed that this mutation resulted in an elongated protein sequence, affecting DNA binding activity and transcriptional function. Structural analysis suggested alterations in the protein's tertiary structure, likely contributing to its dysfunction. CONCLUSION: This study presents the first report of a stop-loss mutation in the NKX2-2 gene associated with NDM. Our findings emphasize the importance of functional and structural characterization to understand the biological consequences of such mutations. This comprehensive analysis provides insights into the molecular mechanisms underlying NDM and its clinical phenotype, which may aid in better diagnosis and management of patients with similar variants in the future.

Molecular characterization and re-interpretation of HNF1A variants identified in Indian MODY subjects towards precision medicine.

Background: HNF1A is an essential component of the transcription factor network that controls pancreatic ß-cell differentiation, maintenance, and glucose stimulated insulin secretion (GSIS). A continuum of protein malfunction is caused by variations in the HNF1A gene, from severe loss-of-function (LOF) variants that cause the highly penetrant Maturity Onset Diabetes of the Young (MODY) to milder LOF variants that are far less penetrant but impart a population-wide risk of type 2 diabetes that is up to five times higher. Before classifying and reporting the discovered variations as relevant in clinical diagnosis, a critical review is required. Functional investigations offer substantial support for classifying a variant as pathogenic, or otherwise as advised by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ACMG/AMP criteria for variant interpretation. Objective: To determine the molecular basis for the variations in the HNF1A gene found in patients with monogenic diabetes in India. Methods: We performed functional protein analyses such as transactivation, protein expression, DNA binding, nuclear localization, and glucose stimulated insulin secretion (GSIS) assay, along with structural prediction analysis for 14 HNF1A variants found in 20 patients with monogenic diabetes. Results: Of the 14 variants, 4 (28.6%) were interpreted as pathogenic, 6 (42.8%) as likely pathogenic, 3 (21.4%) as variants of uncertain significance, and 1 (7.14%) as benign. Patients harboring the pathogenic/likely pathogenic variants were able to successfully switch from insulin to sulfonylureas (SU) making these variants clinically actionable. Conclusion: Our findings are the first to show the need of using additive scores during molecular characterization for accurate pathogenicity evaluations of HNF1A variants in precision medicine.

Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins.

Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding HNF1A variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding HNF1A variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of HNF1A promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including ANGPTL3 and PCSK9. In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins.

Identification of appropriate biochemical parameters and cut points to detect Maturity Onset Diabetes of Young (MODY) in Asian Indians in a clinic setting.

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes which is detected by genetic testing. We looked at clinical and biochemcial variables that could help detect possible MODY among Asian Indians with youth-onset diabetes. From the diabetes electronic medical records of a diabetes care centre in Chennai in southern India, demographic, anthropometric, and biochemical details of 34 genetically confirmed MODY participants were extracted. They were compared with patients with type 1 diabetes (T1D) (n = 1011) and type 2 diabetes (T2D) (n = 1605), diagnosed below 30 years of age. Clinical and biochemical variables including body mass index (BMI), glycated hemoglobin, HDL cholesterol, and C-peptide (fasting and stimulated) were analyzed to determine whether cut points could be derived to identify individuals who could be sent for genetic testing to diagnose or rule out MODY in this ethnic group. The age at diagnosis was higher for T2D (26.5 ± 4.0 years) compared to T1D (18.2 ± 6.1 years) and MODY (17.8 ± 6.0 years). Individuals with MODY had BMI, glycated hemoglobin, total cholesterol, triglycerides, HDL cholesterol, and C-peptide levels which were intermediate between T1D and T2D. The identified probable parameters and their cut points to identify cases for MODY genetic screening were BMI 21.2-22.7 kg/m2, glycated hemoglobin 7.2-10%, HDL cholesterol 43-45 mg/dl, fasting C -peptide, 1.2-2.1 ng/ml and stimulated C-peptide, 2.1-4.5 ng/ml. Asian Indians with MODY have clinical features that are intermediate between T1D and T2D and selected biochemical parameters, especially stimulated C peptide cut points were the most useful to diagnose MODY.

A novel mutation in the KCNJ11 gene (p.Val36Glu), predisposes to congenital hyperinsulinemia.

The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.

Common and Distinct Genetic Architecture of Age at Diagnosis of Diabetes in South Indian and European Populations.

OBJECTIVE: South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent. RESEARCH DESIGN AND METHODS: We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. RESULTS: We identified two signals near the TCF7L2 and CDKAL1 genes associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (rs7903146; P = 2.4 × 10-12, ß = -0.436; SE 0.02) and chromosome 6p22.3 in CDKAL1 (rs9368219; P = 2.29 × 10-8; ß = -0.053; SE 0.01) were directionally consistent across ethnic groups and present at similar frequencies; however, both loci harbored additional independent signals that were only present in the South Indian cohorts. A genome-wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; P = 3.255 × 10-8; ß = 1.44; SE 0.25), specifically in the South Indian cohorts. Heritability estimates for the age at diagnosis were much stronger in South Indians than Europeans, and a polygenic risk score constructed based on South Indian GWAS explained ∼2% trait variance. CONCLUSIONS: Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.

Prevalence, clinical features and complications of common forms of Maturity Onset Diabetes of the Young (MODY) seen at a tertiary diabetes centre in south India.

BACKGROUND: Maturity Onset Diabetes of the Young (MODY) is a form of monogenic diabetes caused by mutations in single genes, affecting adolescents or young adults. MODY is frequently misdiagnosed as type 1 diabetes (T1). Though several studies from India have reported on the genetic aspects of MODY, the clinical profile, complications and treatments given have not been reported so far, nor compared with T1D and type 2 diabetes (T2D). AIM: To determine the prevalence, clinical features, and complications of common forms of genetically proven MODY seen at a tertiary diabetes centre in South India and compare them with matched individuals with T1D and T2D. METHODS: Five hundred and thirty individuals identified as 'possible MODY' based on clinical criteria, underwent genetic testing for MODY. Diagnosis of MODY was confirmed based on pathogenic or likely pathogenic variants found using Genome Aggregation Database (gnomAD) and American College of Medical Genetics (ACMG) criteria. The clinical profile of MODY was compared with individuals with type 1 (T1D) and type 2 (T2D) diabetes, matched for duration of diabetes. Retinopathy was diagnosed by retinal photography; nephropathy by urinary albumin excretion > 30 µg/mg of creatinine and neuropathy by vibration perception threshold > 20 v on biothesiometry. RESULTS: Fifty-eight patients were confirmed to have MODY (10.9%). HNF1A-MODY (n = 25) was the most common subtype followed by HNF4A-MODY (n = 11), ABCC8-MODY (n = 11), GCK-MODY (n = 6) and HNF1B-MODY (n = 5). For comparison of clinical profile, only the three 'actionable' subtypes - defined as those who may respond to sulphonylureas, namely, HNF1A, HNF4A and ABCC8-MODY, were included. Age at onset of diabetes was lower among HNF4A-MODY and HNF1A-MODY than ABCC8-MODY, T1D and T2D. Prevalence of retinopathy and nephropathy was higher among the three MODY subtypes taken together (n = 47) as compared to T1D (n = 86) and T2D (n = 86). CONCLUSION: This is one of the first reports of MODY subtypes from India based on ACMG and gnomAD criteria. The high prevalence of retinopathy and nephropathy in MODY points to the need for earlier diagnosis and better control of diabetes in individuals with MODY.

Impact of Lipid Genetic Risk Score and Saturated Fatty Acid Intake on Central Obesity in an Asian Indian Population.

Abnormalities in lipid metabolism have been linked to the development of obesity. We used a nutrigenetic approach to establish a link between lipids and obesity in Asian Indians, who are known to have a high prevalence of central obesity and dyslipidaemia. A sample of 497 Asian Indian individuals (260 with type 2 diabetes and 237 with normal glucose tolerance) (mean age: 44 ± 10 years) were randomly chosen from the Chennai Urban Rural Epidemiological Study (CURES). Dietary intake was assessed using a previously validated questionnaire. A genetic risk score (GRS) was constructed based on cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genetic variants. There was a significant interaction between GRS and saturated fatty acid (SFA) intake on waist circumference (WC) (Pinteraction = 0.006). Individuals with a low SFA intake (≤23.2 g/day), despite carrying ≥2 risk alleles, had a smaller WC compared to individuals carrying <2 risk alleles (Beta = −0.01 cm; p = 0.03). For those individuals carrying ≥2 risk alleles, a high SFA intake (>23.2 g/day) was significantly associated with a larger WC than a low SFA intake (≤23.2 g/day) (Beta = 0.02 cm, p = 0.02). There were no significant interactions between GRS and other dietary factors on any of the measured outcomes. We conclude that a diet low in SFA might help reduce the genetic risk of central obesity confirmed by CETP and LPL genetic variants. Conversely, a high SFA diet increases the genetic risk of central obesity in Asian Indians.

Molecular Characterization and Management of Congenital Hyperinsulinism: A Tertiary Centre Experience.

BACKGROUND: There is limited data from India regarding medical management of congenital hyperinsulinism (CHI). OBJECTIVE: To study the molecular diagnosis, medical management and outcomes of children with CHI. STUDY DESIGN: Ambispective. PARTICIPANTS: Children with CHI admitted in from December, 2011 till March, 2020 at a tertiary care referral hospital. OUTCOMES: Clinical and genetic profile, treatment, and response. RESULTS: 42 children with a median age of 3 days (range 1 day to 6 years) were enrolled, of which 23 (54.7%) were diazoxide-responsive. Mutations were identified in 28 out of 41 (68.2%) patients. The commonest gene affected was ABCC8 in 22 patients. The pathogenic variant c.331G>A in ABCC8 gene was identified in 6 unrelated cases from one community. Good response to daily octreotide was seen in 13 of the 19 (68.4%) diazoxide-unresponsive patients. Monthly long-acting octreotide was initiated and daily octreotide could be stopped or tapered in 9 patients. Sirolimus was tried with variable response in 6 patients but was discontinued in 5 due to adverse effects. Four patients had focal CHI, of which one underwent partial pancreatic resection. The disease severity reduced with age and neurodevelopment was good in the patients with identifiable genetic defects who were optimally managed. CONCLUSIONS: Medical management of CHI is effective, if compliance can be ensured, with good quality of life and neurological outcomes.

Prediction of Major Adverse Cardiovascular Events From Retinal, Clinical, and Genomic Data in Individuals With Type 2 Diabetes: A Population Cohort Study.

OBJECTIVE: Improved identification of individuals with type 2 diabetes at high cardiovascular (CV) risk could help in selection of newer CV risk-reducing therapies. The aim of this study was to determine whether retinal vascular parameters, derived from retinal screening photographs, alone and in combination with a genome-wide polygenic risk score for coronary heart disease (CHD PRS) would have independent prognostic value over traditional CV risk assessment in patients without prior CV disease. RESEARCH DESIGN AND METHODS: Patients in the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study were linked to retinal photographs, prescriptions, and outcomes. Retinal photographs were analyzed using VAMPIRE (Vascular Assessment and Measurement Platform for Images of the Retina) software, a semiautomated artificial intelligence platform, to compute arterial and venous fractal dimension, tortuosity, and diameter. CHD PRS was derived from previously published data. Multivariable Cox regression was used to evaluate the association between retinal vascular parameters and major adverse CV events (MACE) at 10 years compared with the pooled cohort equations (PCE) risk score. RESULTS: Among 5,152 individuals included in the study, a MACE occurred in 1,017 individuals. Reduced arterial fractal dimension and diameter and increased venous tortuosity each independently predicted MACE. A risk score combining these parameters significantly predicted MACE after adjustment for age, sex, PCE, and the CHD PRS (hazard ratio 1.11 per SD increase, 95% CI 1.04-1.18, P = 0.002) with similar accuracy to PCE (area under the curve [AUC] 0.663 vs. 0.658, P = 0.33). A model incorporating retinal parameters and PRS improved MACE prediction compared with PCE (AUC 0.686 vs. 0.658, P < 0.001). CONCLUSIONS: Retinal parameters alone and in combination with genome-wide CHD PRS have independent and incremental prognostic value compared with traditional CV risk assessment in type 2 diabetes.

Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders.

Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations.

Insulin gene mutations linked to permanent neonatal diabetes mellitus in Indian population.

BACKGROUND AND AIM: Neonatal diabetes mellitus (NDM) is a rare monogenic disorder of pancreatic beta cell mass and/or function. In the present study we aimed to evaluate the INS gene mutations in a cohort of children with Permanent Neonatal Diabetes Mellitus (PNDM) and to explore the clinical and genetic characteristics of PNDM caused by INS mutations. METHODS: Direct sequencing of all exons of INS genes was carried out in 189 children with PNDM. Clinical and biochemical data were collected and correlated. The pathogenicity of mutations was determined based on the American College of Medical Genetics and Genomics and Association of Medical Pathology guidelines. RESULTS: Two novel mutations (His34Pro, Leu35Met) in a compound heterozygous state and seven known mutations (Gly32Ser, Phe48Cys, Arg89Cys, Cys96Tyr, Ser98Ile, Try108Asp and Cys109Phe) in the INS gene were identified in 8 patients out of the total of 189 PNDM children studied. Four mutations were involved in defects with disulphide bond formation and hence were in crucial regions of the gene. All the mutations were de novo in origin. CONCLUSIONS: This is the first comprehensive study from India to investigate the insulin gene mutations in PNDM and to show that INS gene mutations also contribute to the causation of PNDM.

Lower Dietary Intake of Plant Protein Is Associated with Genetic Risk of Diabetes-Related Traits in Urban Asian Indian Adults.

The increasing prevalence of type 2 diabetes among South Asians is caused by a complex interplay between environmental and genetic factors. We aimed to examine the impact of dietary and genetic factors on metabolic traits in 1062 Asian Indians. Dietary assessment was performed using a validated semi-quantitative food frequency questionnaire. Seven single nucleotide polymorphisms (SNPs) from the Transcription factor 7-like 2 and fat mass and obesity-associated genes were used to construct two metabolic genetic risk scores (GRS): 7-SNP and 3-SNP GRSs. Both 7-SNP GRS and 3-SNP GRS were associated with a higher risk of T2D (p = 0.0000134 and 0.008, respectively). The 3-SNP GRS was associated with higher waist circumference (p = 0.010), fasting plasma glucose (FPG) (p = 0.002) and glycated haemoglobin (HbA1c) (p = 0.000066). There were significant interactions between 3-SNP GRS and protein intake (% of total energy intake) on FPG (Pinteraction = 0.011) and HbA1c (Pinteraction = 0.007), where among individuals with lower plant protein intake (<39 g/day) and those with >1 risk allele had higher FPG (p = 0.001) and HbA1c (p = 0.00006) than individuals with ≤1 risk allele. Our findings suggest that lower plant protein intake may be a contributor to the increased ethnic susceptibility to diabetes described in Asian Indians. Randomised clinical trials with increased plant protein in the diets of this population are needed to see whether the reduction of diabetes risk occurs in individuals with prediabetes.

Circulating adiponectin mediates the association between omentin gene polymorphism and cardiometabolic health in Asian Indians.

BACKGROUND: Plasma omentin levels have been shown to be associated with circulating adiponectin concentrations and cardiometabolic disease-related outcomes. In this study, we aim to examine the association of omentin gene polymorphism with serum adiponectin levels and cardiometabolic health status using a genetic approach, and investigate whether these associations are modified by lifestyle factors. METHODS: The study included 945 normal glucose tolerant and 941 unrelated individuals with type 2 diabetes randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Study participants were classified into cardiometabolically healthy and unhealthy, where cardiometabolically healthy were those without hypertension, diabetes, and dyslipidemia. Fasting serum adiponectin levels were measured by radioimmunoassay. The omentin A326T (rs2274907) single nucleotide polymorphism (SNP) was screened by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. RESULTS: The 'A' allele of the omentin SNP was significantly associated with lower adiponectin concentrations after adjusting for age, sex, body mass index (BMI), waist circumference (WC) and cardiometabolic health status (p = 1.90 x 10-47). There was also a significant association between circulating adiponectin concentrations and cardiometabolic health status after adjusting for age, sex, BMI, WC and Omentin SNP (p = 7.47x10-10). However, after adjusting for age, sex, BMI, WC and adiponectin levels, the association of 'A' allele with cardiometabolic health status disappeared (p = 0.79) suggesting that adiponectin serves as a mediator of the association between omentin SNP and cardiometabolic health status. There were no significant interactions between the SNP and dietary factors on adiponectin levels and cardiometabolic health status (p>0.25, for all comparisons). CONCLUSIONS: Our findings show that adiponectin might function as a mechanistic link between omentin SNP and increased risk of cardiometabolic diseases independent of common and central obesity in Asian Indians. Before strategies to promote adiponectin modulation could be implemented, further studies are required to confirm the molecular mechanisms involved in this triangular relationship between omentin gene, adiponectin and cardiometabolic diseases.

Challenges Involved in Incorporating Personalised Treatment Plan as Routine Care of Patients with Diabetes.

Diabetes is a heterogenous disorder, and patients with this disorder vary considerably in their clinical presentation, response to therapy and risk of complications. Expanding knowledge about the pathophysiology of various forms of diabetes has raised the possibility that diagnostic and therapeutic modalities can be tailored to the individual patient in a personalized manner. The recent publication of a Consensus Statement on precision diabetes care underlines the major strides made in this field in the recent past. However, while personalized diabetes care has the potential to significantly improve outcomes in patients with diabetes in a safe and cost-effective manner, its wider application presents several challenges, especially in resource-strained settings. These challenges pertain equally to precision diagnostics, precision therapeutics and precision monitoring. This article discusses some of the important challenges that care providers are likely to face in applying the personalized approach in caring for their patients with diabetes, in the context of diagnosis and management of type 1 diabetes, type 2 diabetes and monogenic forms of diabetes. Suggestions are also presented for overcoming some of these challenges.

Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India.

BACKGROUND: Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. METHODS: 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. RESULTS: Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. CONCLUSIONS: We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.

Trans-ethnic gut microbial signatures of prediabetic subjects from India and Denmark.

BACKGROUND: Recent studies have indicated an association of gut microbiota and microbial metabolites with type 2 diabetes mellitus (T2D). However, large-scale investigation of the gut microbiota of "prediabetic" (PD) subjects has not been reported. Identifying robust gut microbiome signatures of prediabetes and characterizing early prediabetic stages is important for the understanding of disease development and could be crucial in early diagnosis and prevention. METHODS: The current study performed amplification and sequencing on the variable regions (V1-V5) of the 16S rRNA genes to profile and compare gut microbiota of prediabetic individuals (N = 262) with normoglycemic individuals (N = 275) from two cohorts in India and Denmark. Similarly, fasting serum inflammatory biomarkers were profiled from the study participants. RESULTS: After correcting for strong country-specific cohort effect, 16 operational taxonomic units (OTUs) including members from the genera Prevotella9, Phascolarctobacterium, Barnesiella, Flavonifractor, Tyzzerella_4, Bacteroides, Faecalibacterium, and Agathobacter were identified as enriched in normoglycaemic subjects with respect to the subjects with prediabetes using a negative binomial Wald test. We also identified 144 OTUs enriched in the prediabetic subjects, which included members from the genera Megasphaera, Streptococcus, Prevotella9, Alistipes, Mitsuokella, Escherichia/Shigella, Prevotella2, Vibrio, Lactobacillus, Alloprevotella, Rhodococcus, and Klebsiella. Comparative analyses of relative abundance of bacterial taxa revealed that the Streptococcus, Escherichia/Shigella, Prevotella2, Vibrio, and Alloprevotella OTUs exhibited more than fourfold enrichment in the gut microbiota of prediabetic subjects. When considering subjects from the two geographies separately, we were able to identify additional gut microbiome signatures of prediabetes. The study reports a probable association of Megasphaera OTU(s) with impaired glucose tolerance, which is significantly pronounced in Indian subjects. While the overall results confirm a state of proinflammation as early as in prediabetes, the Indian cohort exhibited a characteristic pattern of abundance of inflammatory markers indicating low-grade intestinal inflammation at an overall population level, irrespective of glycemic status. CONCLUSIONS: The results present trans-ethnic gut microbiome and inflammation signatures associated with prediabetes, in Indian and Danish populations. The identified associations may be explored further as potential early indicators for individuals at risk of dysglycemia.

Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review.

Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.

Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

BACKGROUND: There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). OBJECTIVES: To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. METHODS: Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. RESULTS: We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. CONCLUSIONS: This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.