Nihal Thomas

Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial

BACKGROUND Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs. METHODS In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18–75 years with type 2 diabetes and glycosylated haemoglobin (HbA(1C)) of 7·0–11·0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer-generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA(1C) after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884. FINDINGS Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA(1C) levels were much the same across treatment groups, at 7·3% (SD 1·1), 7·4% (1·0), 7·5% (1·1), and 7·2% (0·9), respectively. Estimated mean HbA(1C) treatment differences from insulin degludec by comparison with insulin glargine were 0·08% (95% CI –0·23 to 0·40) for the three dose per week schedule, 0·17% (–0·15 to 0·48) for group A, and 0·28% (–0·04 to 0·59) for group B. Few participants had hypoglycaemia and the number of adverse events was much the same across groups, with no apparent treatment-specific pattern. INTERPRETATION Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile. FUNDING Novo Nordisk.

Associations of variants in FTO and Near MC4R with obesity traits in South Asian Indians

Recent genome‐wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity‐related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity‐ and type 2 diabetes (T2DM)‐related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity‐related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist—hip ratio. Consistent associations were observed for adipose tissue‐specific measurements such as skinfold thickness reinforcing the association with obesity‐related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity‐related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity‐related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian “thin‐fat” phenotype.

DOES HYPERPARATHYROIDISM CAUSE PANCREATITIS? A SOUTH INDIAN EXPERIENCE AND A REVIEW OF PUBLISHED WORK

Background:  The association between pancreatic disease and primary hyperparathyroidism (PHPT) is controversial. We attempt to suggest a causal correlation and characterize the nature of pancreatic disease in PHPT.

Attitude of medical students towards Early Clinical Exposure in learning endocrine physiology

BackgroundDifferent teaching-learning methods have been used in teaching endocrine physiology for the medical students, so as to increase their interest and enhance their learning. This paper describes the pros and cons of the various approaches used to reinforce didactic instruction in endocrine physiology and goes on to describe the value of adding an Early Clinical Exposure program (ECE) to didactic instruction in endocrine physiology, as well as student reactions to it as an alternative approach.DiscussionVarious methods have been used to reinforce didactic instruction in endocrine physiology such as case-stimulated learning, problem-based learning, patient-centred learning and multiple-format sessions. We devised a teaching-learning intervention in endocrine physiology, which comprised of traditional didactic lectures, supplemented with an ECE program consisting of case based lectures and a hospital visit to see patients. A focus group discussion was conducted with the medical students and, based on the themes that emerged from it, a questionnaire was developed and administered to further enquire into the attitude of all the students towards ECE in learning endocrine physiology.The students in their feedback commented that ECE increased their interest for the subject and motivated them to read more. They also felt that ECE enhanced their understanding of endocrine physiology, enabled them to remember the subject better, contributed to their knowledge of the subject and also helped them to integrate their knowledge. Many students said that ECE increased their sensitivity toward patient problems and needs. They expressed a desire and a need for ECE to be continued in teaching endocrine physiology for future groups of students and also be extended for teaching other systems as well. The majority of the students (96.4%) in their feedback gave an overall rating of the program as good to excellent on a 5 point Likert scale.SummaryThe ECE program was introduced as an alternative approach to reinforce didactic instruction in endocrine physiology for the first year medical students. The study demonstrated that students clearly enjoyed the experience and perceived that it was valuable. This method could potentially be used for other basic science topics as well.

PREVALENCE OF OSTEOPOROSIS IN AMBULATORY POSTMENOPAUSAL WOMEN FROM A SEMIURBAN REGION IN SOUTHERN INDIA: RELATIONSHIP TO CALCIUM NUTRITION AND VITAMIN D STATUS

OBJECTIVE To assess the prevalence of osteoporosis in healthy ambulatory postmenopausal Indian women as measured by dual-energy x-ray absorptiometry and to study the dietary calcium intake and vitamin D status and their influence on bone mineral density (BMD). METHODS We conducted a community-based cross-sectional study in a semiurban region. A randomized cluster sampling technique was used. The study cohort consisted of 150 ambulatory postmenopausal women (> or = 50 years old). Dual-energy x-ray absorptiometry for BMD was performed at the lumbar spine and femoral neck. Dietary calcium intake and biochemical variables were assessed. RESULTS The prevalence of osteoporosis was 48% at the lumbar spine, 16.7% at the femoral neck, and 50% at any site. The mean dietary calcium intake was much lower than the recommended intake for this age-group. There was a significant positive correlation between body mass index and BMD at the lumbar spine and the femoral neck (r = 0.4; P = .0001). BMD at the femoral neck was significantly less (mean, 0.657 versus 0.694 g/cm(2)) in the vitamin D-insufficient study subjects in comparison with the vitamin D-sufficient women (P = .03). CONCLUSION The high prevalence of osteoporosis and vitamin D insufficiency in this semiurban group of postmenopausal women in India is a major health concern. Measures such as adequate calcium intake and vitamin D supplementation in women of this age-group may be beneficial.

Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone.

Abstract Objective: To compare efficacy and safety of hydroxychloroquine with pioglitazone in type 2 diabetes mellitus (T2DM). Research design and methods: This double-blind study randomized 267 uncontrolled type 2 diabetes patients (HbA1c ≥7.5% and ≤11.5%), post 3 months’ treatment with glimepiride/gliclazide and metformin, to additionally receive hydroxychloroquine 400 mg/day (n = 135) or pioglitazone 15 mg/day (n = 132) for 24 weeks. Efficacy was assessed by changes in HbA1c, fasting (FBG) and post-prandial (PPG) blood glucose at Week 12 and Week 24. Results: At Week 12 and Week 24, HbA1c, FBG and PPG significantly reduced from baseline in both groups. Mean reduction in glycemic parameters at Week 12 (HbA1c: −0.56% vs −0.72%, p = 0.394; FBG: −0.99 mmol/L vs −1.05 mmol/L, p = 0.878; PPG: −1.93 mmol/L vs −1.52 mmol/L, p = 0.423) and Week 24 (HbA1c: −0.87% vs −0.90%, p = 0.909; FBG: −0.79 mmol/L vs −1.02 mmol/L, p = 0.648; PPG: −1.77 mmol/L vs −1.36 mmol/L, p = 0.415) was not significantly different between the hydroxychloroquine and pioglitazone groups. Change in total cholesterol (TC) and LDL-C was significant in favor of hydroxychloroquine (TC: −0.37 mmol/L vs 0.03 mmol/L, p = 0.002; LDL-C: −0.23 mmol/L vs 0.09 mmol/L, p = 0.003). Triglycerides significantly reduced in both groups at Week 24. Mean HDL-C remained unchanged. Study treatments were well tolerated. Conclusion: With favorable effects on glycemic parameters and lipids, hydroxychloroquine may emerge as well tolerated therapeutic option for T2DM. Limitations: The sample size for this study was small. However, based on the encouraging results of this proof-of-concept study, longer duration studies in larger population can be conducted to further confirm these findings. Trial registration details: Clinical Trial Registry–India URL: http://ctri.nic.in, Registration Number: CTRI/2009/091/001036.

HyPOVITAmINOsIs D AND BONE mINERAl DENsITy IN HumAN ImmuNODEfICIENCy VIRus-INfECTED mEN fROm INDIA, WITH OR WITHOuT ANTIRETROVIRAl THERAPy

OBJECTIVE To study the vitamin D status and bone mineral density (BMD) in men infected with human immunodeficiency virus (HIV) in a tertiary care center from southern India. METHODS We conducted a cross-sectional study of 35 HIV-infected men (between 20 and 50 years old) receiving highly active antiretroviral therapy (HAART) (group 1) in comparison with 35 age- and body mass index-matched HIV-positive antiretroviral therapy-naïve men (group 2) and 35 HIV-negative healthy control subjects (group 3). RESULTS A significantly greater proportion (P = .002) of patients (74%) in the HAART group had vitamin D deficiency (<20 ng/mL) in comparison with the other 2 groups (37% in each group). The mean intact parathyroid hormone level was higher (P<.001) and the mean duration of exposure to sunlight was lower (P = .001) in the HAART group than in the other 2 groups. By logistic regression analysis, HAART was found to be significantly associated with vitamin D deficiency. The BMD in the femoral neck was significantly lower in men with HIV infection who were receiving HAART in comparison with the other 2 groups (P = .006). On multivariate logistic regression, older age, low body mass index, and high parathyroid hormone levels emerged as factors significantly associated with decreased BMD at the femoral neck. CONCLUSION A significant proportion of patients receiving HAART had vitamin D deficiency. The secondary hyperparathyroidism probably due to vitamin D deficiency is an important contributing factor for the observed changes in BMD. Vitamin D deficiency noted in this group is probably multifactorial, and further research is needed to determine whether the effect of HAART on vitamin D metabolism is an additional causative factor and what benefit vitamin D supplementation might confer in these patients.

Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms.

Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing

To establish and utilize a Next‐Generation Sequencing (NGS)‐based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early‐onset diabetes.

Type 1 diabetes versus type 2 diabetes with onset in persons younger than 20 years of age.

Type 1 diabetes (T1D) is the most common form of diabetes in children in Western countries. There have been no large studies of childhood diabetes from India. We undertook the MEDI study (Multicenter Survey of Early Onset Diabetes in India) to assess the proportion of various subtypes of diabetes among the young subjects presenting to the endocrinology divisions of seven large teaching hospitals in different regions of India. In addition, we compared the clinical features of T1D and type 2 diabetes (T2D) in Indian subjects. Patients with onset of disease at younger than 20 years of age were included in this study. Six hundred and three subjects (603) were studied of whom 535 subjects (89%) had T1D, 36 (6%) had T2D, 18 (3%) had diabetes related to tropical pancreatitis or other forms of chronic pancreatitis, while other subtypes accounted for the rest. Compared to those with T2D, subjects with T1D were younger, had a lower C‐peptide level, higher prevalence of ketosis, lower prevalence of acanthosis nigricans, and lower LDL and triglyceride levels. When compared with that of T2D, a higher proportion of patients with T1D were positive for GAD‐65 and IA‐2 antibodies, and this difference was statistically significant for GAD‐65 antibodies. Overall, this large multicenter study showed that T1D is the commonest form of diabetes in childhood. T2D is the next most common kind, while chronic pancreatitis‐related diabetes is uncommon.