Heterogeneity in the aetiology of diabetes mellitus in young adults: A prospective study from north India

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools. Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing. Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients. Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

Prevalence & risk factors of pre-hypertension & hypertension in an affluent north Indian population.

BACKGROUND & OBJECTIVES: Urban Indians have a high prevalence of insulin resistance, hypertension and cardiovascular disease. We studied the prevalence of pre-hypertension and hypertension, as well their association with cardiovascular risk factors, in a north Indian upper socio-economic population. METHODS: A total of 1746 adults (age >or=30 yr) residing in an urban colony of high-income group residents in the city of Lucknow, north India, were invited to be enrolled for the study. The response rate was 64 per cent (n=1112). Blood pressure, anthropometry, plasma glucose in response to oral glucose tolerance test and lipids were measured. The variables contributing significantly to pre-hypertension and hypertension were analyzed by multiple logistic regression analysis. RESULTS: The age and sex adjusted prevalence of hypertension was 32.2 per cent and pre-hypertension was 32.3 per cent. In contrast to hypertension, which was highest in the age group 60-69 yr (64%), prehypertension was highest (36%) in the group 30-39 yr. There was a high prevalence of cardiovascular risk factors in the general population [central obesity (86.7%), elevated LDL cholesterol (22.8%), abnormal glucose tolerance (41.6%) and smoking (20.3% of males)]. Two or more of the cardiovascular risk factors were present in a higher proportion of hypertensive [66%, odds ratio (OR) 3.0, P<0.0001] and pre-hypertensive, (56%, OR 2.0, P<0.0001) compared to normotensive subjects (39%). Subjects with pre-hypertension had body mass index, waist-hip ratio and frequency of glucose intolerance, which was intermediate between normotensive and hypertensive subjects. In multiple logistic regression analysis, increasing age, body mass index, waist hip ratio and impaired glucose tolerance/diabetes were independent risk factors for both hypertension and pre-hypertension. INTERPRETATION & CONCLUSION: A high prevalence of pre-hypertension and hypertension were noted in affluent urban north Indians. Increasing age, body mass index, central obesity and impaired glucose tolerance/diabetes were significantly associated with both hypertension and pre-hypertension. Pre-hypertension was associated with an increased prevalence of cardiovascular risk factors.

Validation and reproducibility of a food frequency questionnaire to assess energy and fat intake in affluent north Indians.

BACKGROUND: India is currently witnessing a sharp rise in noncommunicable disorders such as obesity, diabetes, hypertension and cardiovascular diseases. This rise can be related in part to dietary changes such as increased intake of calories, fat (especially saturated fat) and cholesterol. A simple, accurate and reproducible method to measure these nutrients is essential to study the role of diet in these diseases in epidemiological studies. We aimed to develop and validate a food frequency questionnaire that could be used for this purpose. METHODS: Thirty urban north Indian subjects (age 23-64 years, 16 men) belonging to a high socioeconomic group were studied. The subjects were selected consecutively over a period of 3 weeks from among those participating in an epidemiological survey on cardiovascular risk factors in an affluent population. A 102-item food frequency questionnaire was developed to capture the intake of calories, fat, saturated fat and cholesterol. The results obtained by the food frequency questionnaire were compared with a 5-day diet record. To assess the reproducibility of the food frequency questionnaire, it was re-administered after 3 months to the 23 subjects available. RESULTS: It took the dietician 20 minutes or less to administer the questionnaire. There was good correlation between the nutrient values as calculated by the food frequency questionnaire and 5-day diet record. The correlation for energy intake was 0.80, and varied between 0.55 and 0.69 for unadjusted intake of other nutrients. After adjusting for calories, the correlation varied between 0.45 and 0.68. In general, the food frequency questionnaire overestimated the energy-adjusted nutrient intake by 6%-17%. When intake was classified into quartiles, there was good agreement between the two methods: 43%-100% for calories; 29%-86% for other nutrients for unadjusted intake; 29%-71% for nutrients after energy adjustment. On calculation of intake after re-administration of the food frequency questionnaire, there was a moderate to strong correlation (energy adjusted r=0.49-0.90) between the two evaluations for various nutrients. CONCLUSION: The food frequency questionnaire developed for the assessment of nutrient intake in a north Indian population was easy to administer, showed moderate to good correlation with the 5-day diet record and was reproducible.

The clinical spectrum of fibrocalculous pancreatic diabetes in north India.

BACKGROUND: Fibrocalculous pancreatic diabetes (FCPD) is a secondary form of diabetes, unique to tropical countries. In earlier reports, patients with FCPD had severe insulin-requiring diabetes, malnutrition and a dismal prognosis. With Improvements in nutrition and medical care, the presentation and prognosis of FCPD may have changed. We report on the clinical profile and prognosis of a cohort of FCPD patients from north India and compare our findings with earlier reports. METHODS: Eighty consecutive FCPD patients who presented to the Diabetes, Gastroenterology and Surgical Gastroenterology services were evaluated for their nutritional status, clinical presentation, beta-cell function (fasting C-peptide) and exocrine function (faecal chymotrypsin). All patients diagnosed between 1994 and 2000 (n = 32) were followed prospectively for weight gain and glycaemic control. RESULTS: Only 55% of FCPD patients had a low body mass index (< 18 kg/m2). At the time of diagnosis of diabetes, only 26 (33%) patients presented with severe insulin-requiring diabetes; these patients were younger [23.7 (8.3) years v. 28.7 (10.6) years, p = 0.04], and had higher haemoglobin A1c [9.7 (3.8)% v. 7.3 (2.6)%, p = 0.005] than those requiring diet control or oral hypoglycaemic agents. FCPD patients had a wide range of fasting serum C-peptide (0.03-0.76 nmol/L). C-peptide was negatively associated with increasing duration of diabetes (r = -0.48, p = 0.001), but there was no correlation with faecal chymotrypsin. On prospective follow up (mean 2.3 years), there was significant improvement in body mass index [19.4 (2.9) kg/m2 v. 17.0 (3.7) kg/m2, p < 0.01] and haemoglobin A,c [6.4 (1.6)% v. 8.0 (3.0)%, p < 0.001]. CONCLUSION: FCPD patients differed from those described in earlier reports in many respects, Including improved nutritional status, a wide range of 3cell function and a more favourable prognosis.

Reversal of catecholamine induced cardiomyopathy in a patient with bilateral malignant pheochromocytoma.

A patient of catecholamine induced cardiomyopathy (CMP) due to bilateral malignant adrenal pheochromocytoma (PCC), successfully reversed on treatment is described here. To the best of our knowledge, this is first report of catecholamine induced CMP due to bilateral malignant adrenal PCC, which could be reversed after surgery.

Clinical profile and prognosis of Addison's disease in India.

BACKGROUND: The clinical presentation of primary adrenocortical insufficiency (Addison's disease) in India may differ from that in developed countries. We therefore studied the clinical profile and prognosis of Addison's disease, with special reference to patients with tuberculous infection. We also evaluated the utility of various clinical parameters in differentiating tuberculous from idiopathic Addison's disease. METHODS: In a retrospective and prospective study, 45 consecutive patients of Addison's disease (20 patients with tuberculous aetiology) were studied for their clinical features, autoantibody profile (adrenal cytoplasmic, thyroid microsomal and gastric parietal cell antibodies) and prognosis. RESULTS: A tuberculous aetiology was present in 47% of the patients and of these, 85% had enlargement of one or both adrenal glands. While patients with tuberculous Addison's disease had a higher prevalence of extra-adrenal tuberculosis (55% v. 9%, p = 0.001), a lower frequency of adrenal cytoplasmic antibodies (17% v. 50%, p = 0.03) and parietal cell or thyroid microsomal antibodies (11% v. 55%, p = 0.004), a considerable overlap was observed. Despite adverse circumstances, during a mean follow up of 3.3 years, only 2 (5%) patients died, neither of whom had tuberculous involvement. Five (13%) patients suffered from one or more episodes of Addisonian crises, though none of these resulted in mortality. CONCLUSION: Tuberculosis remains an important cause of Addison's disease in India. The presence of extra-adrenal tuberculosis, or lack of adrenal cytoplasmic antibodies, does not, with certainty, differentiate between a tuberculous and idiopathic aetiology. The prognosis of Addison's disease was good despite unfavourable circumstances.

Carcinoma in Graves' disease.

Association of thyroid carcinoma in thyrotoxicosis is uncommon. Preoperative diagnosis of such association is difficult. In a retrospective study of 49 operated cases of Graves' disease (GD) such an association was found in four patients. Findings of a palpable nodule, calcification and a cold nodule on scanning in Graves' disease should increase suspicion for such an association and a frozen section study should be underken in all these cases during surgery to exclude possible co-existing malignancy.

Extraovarian endocrine abnormalities in north Indian women with premature ovarian failure.

BACKGROUND. Premature ovarian failure is a rare syndrome characterized by cessation of menstruation before 35 years of age associated with an elevated gonadotropin level (serum follicle stimulating hormone > 40 IU/L) and oestrogen deficiency. Premature ovarian failure is often the result of an autoimmune process and involvement of other endocrine glands has been reported but available studies are hampered by a lack of uniformity in diagnostic criteria. METHODS. The endocrine profile of 37 north Indian women with premature ovarian failure was studied. The investigations included measurement of serum follicle stimulating hormone, luteinizing hormone, oestradiol, prolactin, total thyroxine, total triiodothyronine and thyroid stimulating hormone. To assess adrenocortical reserve, adrenocorticotropic hormone stimulated plasma cortisol levels were estimated. RESULTS. Eighteen (49%) patients had extraovarian endocrine abnormalities. Eight (22%) had abnormal thyroid function tests and 12 of 29 (41%) patients tested for adrenocortical reserve showed impaired response of plasma cortisol to adrenocorticotropic hormone stimulation. CONCLUSION. Extraovarian endocrine (especially adrenocortical) involvement is frequent in patients with premature ovarian failure. Because none of the patients had overt clinical evidence of thyroid or adrenocortical disease, we suggest that tests for thyroid and adrenal function be performed routinely in females presenting with premature ovarian failure.

T-cell antigen receptor gamma chain polymorphisms in type 1 diabetes.

The T-cell antigen receptor gamma chain, in conjunction with the delta chain, forms a functional receptor on a small percentage of circulating T-cells. Using restriction enzymes Msp 1 and Stu 1, and a human gamma chain cDNA probe, pT gamma 1, frequent restriction fragment length polymorphisms (RFLPs; 8 kb Msp 1 band; 7.6, 5.0, and 4.3/4.0 kb Stu 1 bands) were detected using DNA from healthy controls. These RFLPs allowed determination of parental alleles at the gamma chain locus, and follow up of their inheritance within families. Since Type 1 diabetes is an organ-specific autoimmune disease thought to be mediated by T-cells, the association of gamma chain polymorphisms with Type 1 diabetes was studied in a population study. No significant association was found with any of the polymorphic bands. The segregation of the gamma chain alleles among diabetic sibs in 6 multiplex families with Type 1 diabetes was also studied but linkage with diabetes could not be demonstrated.