Effect of metformin adjunct therapy on cardiometabolic parameters in Indian adolescents with type 1 diabetes: a randomized controlled trial.

Introduction: Insulin resistance is being increasingly reported in type-1 Diabetes (T1D) and is known to accelerate microvascular complications. The Asian Indian population has a higher risk of double diabetes development compared to Caucasians. Hence, we studied the effect of adding Metformin to standard insulin therapy on glycemic control, insulin sensitivity (IS), cardiometabolic parameters and body composition in Indian adolescents with T1D. Methods: A Randomized controlled trial was conducted spanning 9 months (Registration number:CTRI/2019/11/022126). Inclusion: Age 10-19 years, T1D duration>1year, HbA1c>8% Exclusion: Uncontrolled vascular complications/comorbidities, Metformin intolerance, concomitant drugs affecting insulin sensitivity. Participants were randomized to Metformin/Placebo (n=41 each) groups and age, sex, duration-matched. Assessments were performed at baseline, 3 and 9 months. Results: 82 participants aged 14.7 ± 3years (40 females) were enrolled, with a mean diabetes duration of 5.2 ± 2.3 years. Over 9 months, HbA1c decreased significantly by 0.8 (95% confidence interval: -1.2 to -0.3) from 9.8 ± 1.8% to 9.1 ± 1.7% on Metformin but remained largely unchanged (difference of 0.2, 95% confidence interval: -0.7 to 0.2) i.e. 9.9 ± 1.6% and 9.7 ± 2.2% on placebo. HbA1c improvement correlated negatively with baseline IS (EGDR:r= -0.3;SEARCH:r = -0.24, p<0.05) implying better HbA1c-lowering in those with decreased initial IS. CGM-based glycemic variability (standard deviation) reduced by 6.3 mg/dL (95% confidence interval: -12.9 to 0.2) from 100.2 ± 19.1 mg/dL to 93.7 ± 19.9 mg/dL in those on Metformin (p=0.05) but not placebo (94.0 ± 20.5; 90.0 ± 22.6 mg/dL). Insulin sensitivity: CACTIexa & SEARCH scores demonstrated no change with Metformin but significant worsening on placebo. Significant increase in LDL-C(42%), total cholesterol(133.6 to 151.1 mg/dL), triglyceride (60.0 to 88.0 mg/dL) and carotid intima-media thickness was noted on placebo but not Metformin. Weight, BMI, fat Z-scores increased significantly on placebo but not Metformin. Adverse events (AE) were minor; AE, compliance and safety parameters were similar between the two groups. Conclusion: Metformin as an adjunct to insulin in Asian Indian adolescents with T1D demonstrated beneficial effect on glycemic control, glycemic variability, IS, lipid profile, vascular function, weight and body fat, with a good safety profile when administered for 9 months.

Effect of Calcium and Vitamin D Supplementation (Dairy vs. Pharmacological) on Bone Health of Underprivileged Indian Children and Youth with Type-1 Diabetes: A Randomized Controlled Trial.

BACKGROUND: Bone health is affected by chronic childhood disorders including type-1 diabetes mellitus (T1DM). We conducted this randomized controlled trial with the objective of investigating the effect of 1-year supplementation of vitamin-D with milk or with pharmacological calcium on bone mass accrual in underprivileged Indian children and youth with T1DM. METHODS: 5 to 23year old (n = 203) underprivileged children and youth with T1DM were allocated to one of three groups: Milk (group A-received 200 ml milk + 1000 international unit (IU) vitamin-D3/day), Calcium supplement (group B-received 500 mg of calcium carbonate + 1000 IU of vitamin-D3/day) or standard of care/control (group C). Anthropometry, clinical details, biochemistry, diet (3-day 24-h recall), physical activity (questionnaires adapted for Indian children) and bone health parameters (using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography- DXA and pQCT respectively) were evaluated at enrolment and end of 12 month intervention. RESULTS: Total body less head(TBLH) bone mineral content (BMC(g)) and bone mineral density (BMD(gm/cm2)) were significantly higher at end of study in girls in both supplemented groups (TBLHBMC-A-1011.8 ±â€¯307.8, B-983.2 ±â€¯352.9, C-792.8 ±â€¯346.8. TBLHBMD-A-± 0.2, B-0.8 ±â€¯0.2, C-0.6 ±â€¯0.2, p < 0.05). Z score of lumbar spine bone mineral apparent density of supplemented participants of both sexes was significantly higher than controls (Boys- A-0.7 ±â€¯1.1, B-0.6 ±â€¯1.4, C- -0.7 ±â€¯1.1; Girls- A-1.1 ±â€¯1.1, B-0.9 ±â€¯3.4, C- -1.7 ±â€¯1.3, p < 0.05). A significantly higher percentage increase was found in cortical thickness in girls in both supplemented groups (A-17.9 ±â€¯28.6, B-15.3 ±â€¯16.5, C-7.6 ±â€¯26.2); the differences remained after adjusting for confounders. CONCLUSION: Supplementation with milk or pharmacological calcium (+vitaminD3) improved bone outcomes-particularly geometry in children with T1DM with more pronounced effect in girls. Pharmacological calcium may be more cost effective in optimising bone health in T1DM in resource limited settings.

Adaptation and validation of an artificial intelligence based digital radiogrammetry tool for assessing bone health of indian children and youth with type-1 diabetes.

BACKGROUND AND OBJECTIVES: BoneXpert (BX) is an artificial intelligence software used primarily for bone age assessment. Besides, it can also be used to screen for bone health using the digital radiogrammetry tool called bone health index (BHI) for which normative reference values available are calculated from healthy European children. Due to ethnic difference in bone geometry, in a previous study, we generated reference curves based on healthy Indian children. The objectives of this study were: 1) To assess and compare bone health of Indian children with Type 1 diabetes (T1D) using both European and Indian BHI SDS reference data and 2) To identify determinants of poor bone health in Indian children and youth with T1D by using BHI tool (based on BHI-SDS Indian reference data) of BX. METHOD: The BHI was assessed retrospectively in 1159 subjects with T1D using digitalised left-hand x-rays and SDS were computed using European and Indian data. The demographic, anthropometric, clinical, biochemistry, dual x-ray absorptiometry (DXA) data and peripheral quantitative computed tomography (pQCT) data collection were performed using standard protocols and were extracted from hospital records. RESULTS: The BHI correlated well with DXA and pQCT parameters in subjects with T1D. BHI-SDS calculated using Indian reference data had better correlation with height and DXA parameters. 8.6% study participants had low (less than -2) BHI-SDS (Indian), with height SDS having significant effect. Subjects with low BHI-SDS were older, shorter and had higher duration of diabetes. They also had lower IGF1 and vitamin D concentrations, bone mineral density, and trabecular density. Female gender, increased duration of illness, poor glycaemic control, and vitamin D deficiency/insufficiency were significant predictors of poor BHI-SDS. CONCLUSION: Our study highlights the utility of digital radiogrammetry AI tool to screen for bone health of children with T1D and demonstrates and highlights the necessity of interpretation using ethnicity specific normative data.

Pilot Study on Gut Microbiota Profile in Indian Children with Type 1 Diabetes.

Background: Non-genetic factors like microbial dysbiosis may be contributing to the increasing incidence/progression of type 1 diabetes mellitus (T1DM). Objectives: To analyse the gut microbiota profile in Indian children with T1DM and its effect on glycaemic control. Methodology: Faecal samples of 29 children with T1DM were collected and faecal microbial DNA was extracted and subjected to 16S rRNA (ribosomal RNA) sequencing and further analysis. Results: The dominant phyla in children with T1DM were Firmicutes and Bacteroidetes. Butyrate-producing bacteria Blautia and Ruminococcus showed a significant negative correlation with the glycosylated haemoglobin (HbA1C) levels (p < 0.05). Coprococcus and Propionibacterium were important negative predictors of glycaemic control (p < 0.05). Conclusion: Our study suggests that Indian children with T1DM have a distinct gut microbiome taxonomic composition and that short-chain fatty acid-producing bacteria like Ruminococcus and Blautia (butyrate-producing) may play an important role in the glycaemic control of subjects with T1DM.

Adiponectin-leptin ratio as a marker of cardio-metabolic risk in Indian children and youth with type 1 diabetes.

OBJECTIVES: Adiponectin/leptin ratio (ALR) is a promising novel marker of cardio-metabolic risk in patients with metabolic syndrome. Our aim was to study the association of adiponectin-leptin ratio with markers of obesity and adiposity and also to assess its usefulness as a marker of increased cardiometabolic risk (CMR) in Indian children and youth with type 1 diabetes mellitus. METHODS: This observational study included 79 children and youth with type 1 diabetes (T1DM) (10-21 years) having disease duration>6 months. Demographic data and laboratory findings were obtained from patients' records. Patients with ALR<1 were categorised as having increased CMR and those with ALR>1 were categorised as having no CMR. RESULTS: ALR showed a significant negative correlation with body mass index (BMI), waist and hip circumference and body fat percentage (p<0.05). Body fat percentage was the single most important predictor of ALR. Children and youth with increased CMR had higher weight, BMI, waist and hip circumferences and body fat percentage as compared to those with no CMR (p<0.05). In T1DM children with dyslipidemia, ALR was significantly lower as compared to those without dyslipidemia (p<0.05). CONCLUSIONS: ALR may be a useful marker for adiposity and increased cardiometabolic risk in Indian children and youth with type 1 diabetes mellitus.

Impact of decreased physical activity due to COVID restrictions on cardio-metabolic risk parameters in Indian children and youth with type 1 diabetes.

BACKGROUND AND AIMS: Implementation of COVID restrictions following lockdown led to changes in routines of subjects with type 1 diabetes due to closure of schools and outdoor activities. The aim of this study was to assess the impact of decreased physical activity due to COVID restrictions on cardio-metabolic risk parameters (waist circumference, laboratory and body composition parameters) in Indian children and youth with T1D. METHODS: This observational study included 312 participants (2-21 years) with T1DM having disease duration of ≥6 months. Demographic, anthropometric, body composition data and investigations were recorded at two time points (during COVID restrictions when children came for follow up, pre COVID restriction data from medical and electronic records). RESULTS: Glycemic control improved during COVID restrictions (Hba1c: 9.8 ± 2.0%) as compared to pre COVID restrictions (Hba1C: 10.0 ± 1.9%) (p < 0.05). However, due to significant reduction in physical activity (p < 0.05) there was significant increase in waist circumference z-scores (-0.9 ± 1.1 vs -1.6 ± 1.1), body fat percentage z-scores (-0.2 ± 1.0 vs -0.3 ± 0.9) and lipid parameters like cholesterol, low density lipid cholesterol and triglyceride concentrations (p < 0.05) without any significant change in body mass index z-scores (p > 0.05). CONCLUSIONS: Prolonged COVID restrictions, although led to modest improvement in glycemic control, there was worsening of cardio-metabolic risk factors or indices of adiposity like waist circumference, body fat percentage and lipid parameters which could be attributed to decreased time spent in physical activity.

Impact of lockdown for COVID-19 pandemic in Indian children and youth with type 1 diabetes from different socio-economic classes.

OBJECTIVES: In March 2020, lockdown was imposed in India to combat spread of Coronavirus, which was extended till 31st May. Implementation of lockdown and limited outdoor activities resulted in changes in routines of children with diabetes. The aim of this study was to assess the impact of lockdown on glycemic control, weight and body mass index (BMI) patterns of children with type 1 diabetes (T1DM) from different socio-economic (SE) classes. METHODS: This observational study included 77 children and youth (5-20 years) with T1DM having disease duration of ≥6 months. Demographic data and investigations were recorded at two time points (post lockdown when the children came for follow up, pre lockdown data from medical records). RESULTS: Glycemic control improved (pre lockdown HbA1C 79.4±19.2 vs. post lockdown Hba1C 74.5±16.9 mmol/mol, p<0.05) and there was weight gain post lockdown (pre lockdown weight z-score -0.4±0.8 vs. post lockdown weight z-score -0.2±0.8, p<0.05) without any significant change in BMI and insulin requirements. Improved glycemic was seen in the lower SE group control post lockdown (p<0.05), whereas in higher SE group, it remained unchanged. Children whose parents were at home during lockdown showed an improved glycemic control (p<0.05) as compared to children whose parents continued to work during lockdown (p>0.01). CONCLUSIONS: During coronavirus lockdown, glycemic control was adequately maintained in children with T1DM, highlighting importance of stronger family support system leading to more steady daily routine.

Muscle and bone parameters in underprivileged Indian children and adolescents with T1DM.

BACKGROUND: The incidence of Type 1 diabetes mellitus (T1DM) is increasing and sarcopenia and osteoporosis have been reported to be associated with long standing diabetes. There is scarcity of data on bone health status of children with T1DM. Our aim was to assess bone health parameters [by Dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT)] and muscle strength (by hand grip) in underprivileged Indian children with T1DM. MATERIAL AND METHODS: A cross sectional, observational study was conducted in underprivileged children with diabetes attending the out patient clinic for T1DM at a tertiary care hospital. Children with T1DM with disease duration more than 1 year were included in the study. Age and gender matched controls were also enrolled. Data on age, gender, disease duration, anthropometric parameters and HbA1c were collected. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (Lunar iDXA) and peripheral quantitative computed tomography (pQCT, Stratec XCT 2000) and muscle strength by handgrip. Data were analysed using SPSS 25.0. RESULTS: 251 children with T1DM and 250 age gender matched controls were studied. Mean age of T1DM children was 10.8 ± 4.3yrs (controls 10.3 ± 3.6). Mean HbA1C was 9.7 ± 2.1%. The total body less head areal BMD (TBLH aBMD) and lumbar spine bone mineral apparent density (LSBMAD) Z-scores were significantly lower in children with T1DM (-1.5 ± 1.3, -1.3 ± 1.6 respectively) as compared to controls (-0.5 ± 1.3, -0.64 ± 1.5 respectively) (p < 0.05 for both). Z-scores for trabecular and total density (vBMD) were significantly lower in patients with T1DM (-0.7 ± 1.0, -0.7 ± 1.0 respectively) than controls (-0.15 ± 1.2, -0.31 ± 1.1), (p < 0.05) and trabecular density was lower at distal radius with increasing disease duration. Hand-grip strength Z-score was lower in children with T1DM (-3.0 ± 0.5) as compared to controls (-2.8 ± 0.5). Trabecular density and HbA1C concentrations were negatively correlated (R = -0.18, p < 0.05) as was muscle area and HbA1C concentrations (R = -0.17, p < 0.05,). CONCLUSION: Bone and muscle health were affected in children with poorly controlled T1DM. With increasing disease duration, attention is required for optimising musculoskeletal health.