Performance of European prediction models for classification of type 1 and type 2 diabetes in Indians.

AIM: We aimed to determine the performance of European prediction models in an Indian population to classify type 1 diabetes(T1D) and type 2 diabetes(T2D). METHODS: We assessed discrimination and calibration of published models of diabetes classification, using retrospective data from electronic medical records of 83309 participants aged 18-50 years living in India. Diabetes type was defined based on C-peptide measurement and early insulin requirement. Models assessed combinations of clinical measurements: age at diagnosis, body mass index(mean = 26.6 kg/m2), sex(male = 64.9 %), Glutamic acid decarboxylase(GAD) antibody, serum cholesterol, serum triglycerides, and high-density lipoprotein(HDL) cholesterol. RESULTS: 67955 participants met inclusion criteria, of whom 0.8 % had T1D, which was markedly lower than model development cohorts. Model discrimination for clinical features was broadly similar in our Indian cohort compared to the European cohort: area under the receiver operating characteristic curve(AUC ROC) was 0.90 vs. 0.90 respectively, but was lower in the subset of young participants with measured GAD antibodies(n = 2404): and an AUC ROC of 0.87 when clinical features, sex, lipids and GAD antibodies were combined. All models substantially overestimated the likelihood of T1D, reflecting the lower prevalence of T1D in the Indian population. However, good model performance was achieved after recalibration by updating the model intercept and slope. CONCLUSION: Models for diabetes classification maintain the discrimination of T1D and T2D in this Indian population, where T2D is far more common, but require recalibration to obtain appropriate model probabilities. External validation and recalibration are needed before these tools can be used in non-European populations.

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.

Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).

BACKGROUND: Non-communicable disease (NCD) rates are rapidly increasing in India with wide regional variations. We aimed to quantify the prevalence of metabolic NCDs in India and analyse interstate and inter-regional variations. METHODS: The Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, a cross-sectional population-based survey, assessed a representative sample of individuals aged 20 years and older drawn from urban and rural areas of 31 states, union territories, and the National Capital Territory of India. We conducted the survey in multiple phases with a stratified multistage sampling design, using three-level stratification based on geography, population size, and socioeconomic status of each state. Diabetes and prediabetes were diagnosed using the WHO criteria, hypertension using the Eighth Joint National Committee guidelines, obesity (generalised and abdominal) using the WHO Asia Pacific guidelines, and dyslipidaemia using the National Cholesterol Education Program-Adult Treatment Panel III guidelines. FINDINGS: A total of 113 043 individuals (79 506 from rural areas and 33 537 from urban areas) participated in the ICMR-INDIAB study between Oct 18, 2008 and Dec 17, 2020. The overall weighted prevalence of diabetes was 11·4% (95% CI 10·2-12·5; 10 151 of 107 119 individuals), prediabetes 15·3% (13·9-16·6; 15 496 of 107 119 individuals), hypertension 35·5% (33·8-37·3; 35 172 of 111 439 individuals), generalised obesity 28·6% (26·9-30·3; 29 861 of 110 368 individuals), abdominal obesity 39·5% (37·7-41·4; 40 121 of 108 665 individuals), and dyslipidaemia 81·2% (77·9-84·5; 14 895 of 18 492 of 25 647). All metabolic NCDs except prediabetes were more frequent in urban than rural areas. In many states with a lower human development index, the ratio of diabetes to prediabetes was less than 1. INTERPRETATION: The prevalence of diabetes and other metabolic NCDs in India is considerably higher than previously estimated. While the diabetes epidemic is stabilising in the more developed states of the country, it is still increasing in most other states. Thus, there are serious implications for the nation, warranting urgent state-specific policies and interventions to arrest the rapidly rising epidemic of metabolic NCDs in India. FUNDING: Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Intermittent Use of Continuous Glucose Monitoring: A New Paradigm in Treatment of Type 2 Diabetes.

OBJECTIVES: To suggest how continuous glucose monitoring (CGM) may be used intermittently in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The use of CGM is largely in those with type 1 diabetes (T1D), in whom it makes sense to use CGM continuously as CGM provides a valuable tool to not only adjust their insulin doses but also to match it with their diet, physical activity, and other lifestyle modifications. In the case of T2D, however, especially for those not on insulin, the use of CGM may not be needed on a continuous basis. The use of CGM on an intermittent basis is rarely discussed in the literature. This article tries to provide clinical situations where CGM can be used intermittently. RESULTS: Intermittent use of CGM defined as the "use of CGM once in 2 or 3 months or a fixed frequency," and may be useful in several situations in those with T2D. We suggest the following indications for the intermittent use of CGM in T2D-newly diagnosed patients where treatment is being started, uncontrolled diabetes where treatment is being altered, starting intensive lifestyle modification, during infections, during preoperative control, in children and adolescents with T2D, as a motivational tool to improve behavioral modification, after metabolic surgery, and in patients on steroids, apart from other indications. CONCLUSION: Intermittent use of CGM in T2D can be useful in special situations and can also be cost saving particularly in resource-constrained regions of the world.

Role of cystatin C in the detection of sight-threatening diabetic retinopathy in Asian Indians with type 2 diabetes.

AIM: To study the association between cystatin C and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2DM). METHODS: In a cross-sectional study carried out at two tertiary centres in India in 2022, individuals with T2DM underwent clinical and ophthalmic assessments and estimation of serum cystatin C. Grading of DR was done by retina specialists. STDR was defined by the presence of severe non-proliferative DR (NPDR), proliferative DR (PDR) and/or diabetic macular edema. Receiver operating characteristic (ROC) curves were used to identify cystatin C cut-off value for detecting STDR. RESULTS: Among 420 individuals with T2DM (mean age 56 ± 9 years; mean duration of diabetes 14.5 ± 7.9 years), 121 (24.1 %) had No-DR, 119 (28.3 %) had No-STDR and 200 (49.6 %) had STDR. Mean cystatin C level was significantly higher in individuals with STDR compared to those with no-STDR and No-DR (1.34 vs 1.06 vs 0.93 mg/L, p < 0.001). Cystatin C cut-off value ≥1.11 mg/L had a C statistic of 0.944 (95 % CI: 0.909-0.968, p < 0.001), 96.8 % sensitivity and 78.2 % specificity for detection of STDR. CONCLUSION: Elevated serum cystatin C was strongly associated with STDR and could possibly be used as a biomarker for screening for sight-threatening diabetic retinopathy.

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.

Strategies for participant retention in long term clinical trials: A participant -centric approaches.

A clinical trial is the most foolproof method to evaluate the efficacy of a new intervention. Successful completion of clinical trials depends on the retention of the participants enrolled. Poor participant retention can lead to significant time and cost burden and have potentially adverse biases on the results. A high retention rate of participants is an important criterion for the validity and credibility of randomized controlled clinical trials. Many long-term trials fail due to low retention of study participants. Efforts at participant retention should start even before the first participant is recruited into the study. Retention is not only the responsibility of the investigators but also all other stakeholders in a clinical trial. In recent years, retention materials, participant camps, and introduction of national study coordinators have helped in improving retention. Quality of the relationship developed between the research staff and the study participant is a key factor for success of any trial. In our experience, in the context of resource-challenged low- and middle-income countries, we have found that it is possible to achieve high retention rates, 95%-100%. The rapport built between the investigating team and the participant plays a vital role in retention. In addition, personalized care, including listening to the participant's problems and enabling to contact investigators or study team at any time of the day, has shown benefits in retention.

Monogenic diabetes.

Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients' quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.

Clinical and biochemical profile of childhood-adolescent-onset type 1 diabetes and adult-onset type 1 diabetes among Asian Indians.

AIM: To compare the clinical and biochemical profile and prevalence of complications among childhood/adolescent-onset (CAO; onset of diabetes< 20 years of age) and adult-onset (AO; onset of diabetes- ≥ 20 years of age) type 1 diabetes (T1D), seen at a tertiary care diabetes center in south India. METHOD: Data of 5578 individuals with T1D, diagnosed based on a history of diabetic ketoacidosis or ketonuria, fasting C-peptide < 0.3 pmol/mL and stimulated C-peptide values < 0.6 pmol/mL, and requirement of insulin right from the time of diagnosis, presenting to our center between 1991 and 2021, were retrieved from our electronic medical records. Retinopathy was assessed by retinal photography, chronic kidney disease (CKD) by urinary albumin excretion ≥ 30 µg/mg of creatinine and/or eGFR < 60 mL/min, and neuropathy by vibration perception threshold >= 20v on biothesiometry. RESULTS: Overall, 3559 (63.8%) of individuals with T1D, belonged to CAO group and 2019 (36.2%) to AO category. AO had higher prevalence of all microvascular complications compared to CAO at every diabetes duration interval, even after adjusting for A1c. Among the AO group, prevalence of retinopathy, CKD, and neuropathy was higher in the GAD negative group. Among CAO there were no differences between the GAD negative and GAD positive groups with respect to prevalence of complications of diabetes. CONCLUSION: AO with T1D had higher prevalence of microvascular complications compared to CAO. Among AO, GAD negative individuals had higher percentage of retinopathy and CKD compared to GAD positive group.

Macronutrient Recommendations for Remission and Prevention of Diabetes in Asian Indians Based on a Data-Driven Optimization Model: The ICMR-INDIAB National Study.

OBJECTIVE: To derive macronutrient recommendations for remission and prevention of type 2 diabetes (T2D) in Asian Indians using a data-driven optimization approach. RESEARCH DESIGN AND METHODS: Dietary, behavioral, and demographic assessments were performed on 18,090 adults participating in the nationally representative, population-based Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study. Fasting and 2-h postglucose challenge capillary blood glucose and glycosylated hemoglobin (HbA1c) were estimated. With HbA1c as the outcome, a linear regression model was first obtained for various glycemic categories: newly diagnosed diabetes (NDD), prediabetes (PD), and normal glucose tolerance (NGT). Macronutrient recommendations were formulated as a constrained quadratic programming problem (QPP) to compute optimal macronutrient compositions that would reduce the sum of the difference between the estimated HbA1c from the linear regression model and the targets for remission (6.4% for NDD and 5.6% for PD) and prevention of progression in T2D in PD and NGT groups. RESULTS: Four macronutrient recommendations (%E- Energy) emerged for 1) diabetes remission in NDD: carbohydrate, 49-54%; protein, 19-20%; and fat, 21-26%; 2) PD remission to NGT: carbohydrate, 50-56%; protein,18-20%; fat, 21-27%; 3 and 4) prevention of progression to T2D in PD and NGT: carbohydrate, 54-57% and 56-60%; protein, 16-20% and 14-17%, respectively; and fat 20-24% for PD and NGT. CONCLUSIONS: We recommend reduction in carbohydrates (%E) and an increase in protein (%E) for both T2D remission and for prevention of progression to T2D in PD and NGT groups. Our results underline the need for new dietary guidelines that recommend appropriate changes in macronutrient composition for reducing the burden due to diabetes in South Asia.

Remission of Type 2 Diabetes: How, When, and for Whom?

Type 2 diabetes (T2DM) is conventionally considered a progressive disorder, with most patients requiring increasingly intensive therapy to control hyperglycemia over time. Recently, there has been a major paradigm shift towards trying to reverse T2DM. Emerging evidence suggests that remission of T2DM is feasible in a subset of patients. Identification and careful selection of candidates for remission are crucial for the success of these programs. Among various dietary strategies, low-calorie diets (LCDs) and low-carbohydrate diets (LCBDs) have been demonstrated as being effective in facilitating remission of T2DM in a targeted population within a clinical setting. Remission with LCBDs may be maintained in the absence of weight loss, however, long-term evidence is limited and remission may not be maintained without long-term carbohydrate restriction, which poses major challenges. In very low-calorie diets (VLCDs), weight loss of 15 kg or greater and maintenance of weight loss is the main driver and predictor of remission. However, most individuals with T2DM were unable to maintain remission beyond 2 years, despite being on VLCDs. More data are required on the long-term sustainability of remission in an ethnically diverse population like Asian Indians with T2DM who have less obesity and hence less weight to lose. Moreover, "re-reversal" or "relapse" of diabetes can occur in a large percentage of individuals who discontinue the dietary restrictions. Hence, regular follow-up by a multi-disciplinary team to ensure sustainability of the lifestyle modification is crucial to the maintenance of remission of T2DM.

Higher Intake of Dairy Is Associated with Lower Cardiometabolic Risks and Metabolic Syndrome in Asian Indians.

There is conflicting evidence about the association between dairy products and cardiometabolic risk (CMR). We aimed to assess the association of total dairy intake with CMR factors and to investigate the association of unfermented and fermented dairy intake with CMR in Asian Indians who are known to have greater susceptibility to type 2 diabetes and cardiovascular diseases compared to white Europeans. The study comprised 1033 Asian Indian adults with normal glucose tolerance chosen from the Chennai Urban Rural Epidemiological Study (CURES). Dietary intake was assessed using a validated open-ended semi-quantitative food frequency questionnaire. Metabolic syndrome (MS) was diagnosed based on the new harmonising criteria using central obesity, dyslipidaemia [low high-density lipoprotein cholesterol (HDL) and increased serum triglycerides (TG)], hypertension and glucose intolerance. Increased consumption of dairy (≥5 cups per day of total, ≥4 cups per day of unfermented or ≥2 cups per day of fermented dairy) was associated with a lower risk of high fasting plasma glucose (FPG) [hazards ratio (HR), 95% confidence interval (CI): 0.68, 0.48−0.96 for total dairy; 0.57, 0.34−0.94 for unfermented dairy; and 0.64, 0.46−0.90 for fermented dairy; p < 0.05 for all] compared to a low dairy intake (≤1.4 cups per day of total dairy; ≤1 cup per day of unfermented dairy; and ≤0.1 cup per day of fermented dairy). A total dairy intake of ≥5 cups per day was also protective against high blood pressure (BP) (HR: 0.65, 95% CI: 0.43−0.99, p < 0.05), low HDL (HR: 0.63, 95% CI: 0.43−0.92, p < 0.05) and MS (HR: 0.71, 95% CI: 0.51−0.98, p < 0.05) compared to an intake of ≤1.4 cups per day. A high unfermented dairy intake (≥4 cups per day) was also associated with a lower risk of high body mass index (BMI) (HR: 0.52, 95% CI: 0.31−0.88, p < 0.05) compared to a low intake (≤1 cup per day), while a reduced risk of MS was observed with a fermented dairy intake of ≥2 cups per day (HR: 0.71, 95% CI: 0.51−0.98, p < 0.05) compared to an intake of ≤0.1 cup per day. In summary, increased consumption of dairy was associated with a lower risk of MS and components of CMR.

Carbohydrate profiling & glycaemic indices of selected traditional Indian foods.

Background & objectives: Consumption of high glycaemic index (GI) food is associated with a high risk for diabetes. There is a felt need to understand the GI of common Indian traditional foods using standard GI protocols. The present study was aimed to analyse the carbohydrate profile of common traditional Indian food preparation and to determine their GI using standardized protocols. Methods: Twelve food preparations made of millets, wheat, maize and pulses were evaluated for nutrient composition including detailed carbohydrate profiling and tested for GI in healthy volunteers using standard methodology. Capillary blood glucose responses for the test foods containing 50 g available carbohydrates were recorded and compared to the reference food (50 g glucose). GI was calculated from the incremental area under the curve (IUAC) for the test and reference foods. Results: Available carbohydrate content of the food preparations ranged between 13.6 and 49.4 g per cent. Maize roti showed the highest total dietary fibre (7.5 g%). White chick pea 'sundal' showed highest resistant starch content (3.95 g%). Amongst the 12 test foods, five fell in the high GI category (finger millet balls, sorghum, pearl millet and maize roti), four in the medium GI category (sorghum idli, wheat dosa, methi roti and adai) and three in the low GI category (broken wheat upma, white peas sundal and white chick peas sundal). Interpretation & conclusions: Merely being a whole grain-based food does not qualify for a lower GI. The method of processing, food structural integrity and preparation could influence the GI. The type and quality of fibre are important than the quantity of fibre alone. Judicious planning of accompaniments using low GI legumes may favourably modify the glycaemic response to high GI foods in a meal.