Biomedical subjects
Publications and source records attributed to V Mohan.
Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes secondary to tropical calcific pancreatitis (TCP). The usual age of onset of FCPD is between 15 and 50 years. This paper reports on two unusual cases of FCPD with age of onset below 5 years. This is the first report of FCPD in infancy and raises intriguing questions about the rapidity with which calcification occurs in this entity.
To assess the risk of pancreatic cancer in subjects with tropical calcifying pancreatitis (TCP), we have followed 185 patients with TCP from the Diabetes Research Center in Madras, India for an average of 4.5 years. The diagnosis of TCP was based upon long-standing epigastric pain, laboratory tests, presence of pancreatic calculi, endoscopic retrograde cholangiopancreatography (ERCP) findings, and ultrasonography. During the follow-up period, 24 patients died from all causes, with 6 deaths (25%) from cancer of the pancreas. Three pancreatic cancers were biopsy positive. Average age at onset of pancreatic cancer was 45.6 +/- 7.3 years--considerably younger than for Western populations. When compared with the background pancreatic cancer rate, subjects with TCP appear to have a significantly increased risk of pancreatic cancer: relative risk = 100, 95% CI = 37-218. Even under the most stringent assumptions (restricting the analysis to biopsy-proven cases, assuming that the true background rate of pancreatic cancer in Madras resembles high-risk Western populations, assuming that tropical pancreatitis begins at birth) the risk is still elevated: relative risk = 5, 95% CI = 1.03-3-14.6. The exact mechanism linking various forms of pancreatitis to pancreatic cancer remains to be elucidated.
Type 2 diabetes is characterized by abnormalities in both glucose and lipoprotein metabolism and genes involved in lipid metabolism are legitimate candidates for involvement in Type 2 diabetes. We have previously reported an association in Nauruans between a Taq 1 polymorphism of the apolipoprotein D gene (apo D) and Type 2 diabetes. In this study these findings were investigated further in the Nauruan population as well as two other ethnic groups. In South Indian subjects, there was a significant difference in genotype distribution of apo D genotypes between diabetic subjects (n = 110) and controls (n = 88; p = 0.004) which was similar to that previously found in the Nauruan subjects. No such association was seen in elderly Finnish subjects (diabetic n = 69; impaired glucose tolerance n = 26 and normal glucose tolerance n = 31). Linkage between the apo D polymorphism and diabetes in 12 Nauruan families was only excluded under a highly penetrant dominant model and was unlikely under other single gene models. Since the beta cell glucose transporter gene (Glut 2) is found in a similar chromosomal location to apo D, South Indian subjects (diabetic n = 95 and controls n = 56) were typed at this locus. No association between diabetes and the Glut 2 Taq I polymorphism was found in the South Indian subjects. Furthermore, there was no evidence of linkage disequilibrium between the apo D and Glut 2 genes. In conclusion, apo D might act as a modifying gene for Type 2 diabetes in some ethnic groups.
The aim of the study was to look for any time-realted fluctuation in the pancreatic beta cell function in normal offspring of diabetic parents, over a period of three years. Serum insulin (IRI) and C-peptide (CP) responses to oral glucose were reevaluated three years after the initial study in 25 normoglycaemic offspring of conjugal Type 2 diabetic parents. The mean area under the curve of IRI (AUC IRI) response was higher than normal control value in the offspring at both time points (P < 0.01) and the two values did not differ much. The 2 hr IRI was also significantly higher (P < 0.05) than the control value. CP responses at both time points in the offspring did not differ from the mean control value. Wide fluctuations in the individual IRI were noted on follow-up despite similar plasma glucose response. Follow-up IRI was higher in 6, lower in 5 (+/- 25% of the initial) and remained unaltered in the other 4 offspring. The corresponding CP showed increased values in 3, decreased values in 5 and no change in 7 offspring. The fluctuations were nonuniform in nature among the individuals studied. Disparity between the IRI and CP responses were present in 5 offspring during the follow-up. This study thus shows that wide fluctuations in insulin responses occur even in the normoglycaemic offspring of diabetic parents.
We report the calculated characteristics of nonnatural triplex-forming oligonucleotide (TFO) bases recognizing base-pair reversals (TA-->AT) in a double-helical DNA sequence. Ab initio and molecular mechanics calculations have been carried out to characterize the geometric and energetic consequences at the base-pair reversal sites. We have estimated the free energies of solvation of the natural and proposed bases by solving the linearized Poisson-Boltzmann equation. The calculations indicate that the proposed TFO bases should bind with some specificity to the duplex. Implications of the strategy used in the context of molecular biology is discussed.
Mutations of the glucokinase gene have been implicated in the development of glucose intolerance in pedigrees with maturity-onset diabetes of the young. However, the contribution of the glucokinase gene to the aetiology of common Type 2 (non-insulin-dependent) diabetes mellitus is uncertain. We have studied the role of the glucokinase gene in the pathogenesis of Type 2 diabetes in South Indians, using both population-association and linkage methodology. A pair of CA-repeat sequences (GCK(3') and GCK(5')) straddling the glucokinase gene were employed as markers, each subject being typed using the polymerase chain reaction and polyacrylamide gel electrophoresis. Comparisons of allele frequencies at these markers were made between 168 Type 2 diabetic subjects and 70 racially-matched control subjects. No differences in allele frequencies were apparent at the GCK(5') marker; however, there were significant differences in allele frequencies at the GCK(3') marker between the Type 2 diabetic subjects and control subjects (chi 2 = 11.6, df = 3, p = 0.009) with an increase of the z allele (78.0% vs 66.4%) and a decrease of the z + 2 allele (13.7% vs 25.0%) amongst the diabetic subjects. Linkage between glucose intolerance and the glucokinase gene was studied in 53 nuclear pedigrees under a variety of genetic models. Linkage was excluded (lod score < -2) at a recombination fraction of zero under five of the ten models used and highly unlikely (-2 < lod score < -1) under the others. The combination of positive association and negative linkage suggests that glucokinase acts as a minor gene influencing the development of Type 2 diabetes within this population.
Micronutrient antioxidants interact with glutathione in tissues to facilitate the disposal of reactive oxygen species and xenobiotic metabolites derived via cytochromes P450. Published evidence linking cytochrome P450I induction with chronic pancreatitis therefore led us to compare antioxidant status in patients at Manchester in the northwest of England and at Madras in the southeast of India. Serum studies in healthy volunteers showed that the biologic availabilities of selenium and alpha-tocopherol were equally high in the two zones but that the availabilities of beta-carotene and ascorbic acid were lower in the tropical area (p < 0.001), where the ratio of ascorbic acid to total vitamin C concentration in serum was substantially reduced (p < 0.001). The serum antioxidant profiles of the chronic pancreatitis groups reflected these indigenous differences: a decrement in selenium and alpha-tocopherol was evident in both zones, whereas beta-carotene and ascorbic acid values were subnormal only in the Manchester group. The concentration of inorganic sulphate in urine--an index of long-term intake of sulphur amino acids for synthesis of glutathione and other detoxifiers--was similar in controls and patients from Manchester, but levels were lower than in their Madras counterparts (p < 0.02, p < 0.01, respectively). The results suggest that culinary practices that erode the biologic availabilities of ascorbic acid and beta-carotene may predispose to pancreatic oxidative stress and thereby to the changes leading to chronic pancreatitis at an early age in south India. These findings have implications for treatment and prophylaxis.
Two patients with cystic fibrosis from the same family are reported. Both patients had features of chronic respiratory disease with evidence of pancreatic and other systemic manifestations. To our knowledge this is the first report from our country of cystic fibrosis multiplex cases occurring in the same family.
A 'screening' test is needed to identify patients with chronic pancreatitis among diabetics in tropical field surveys. We have examined the potential diagnostic yield of the BT-PABA/PAS test of exocrine pancreatic function in this setting. The recoveries of both PABA and PAS in eight healthy controls from Madras, south India, were lower than in controls from Manchester, north west England (mean +/- S.D., 51 +/- 11 vs. 79 +/- 7%, P < 0.001 for PABA; 52 +/- 11% vs. 81 +/- 7%, P < 0.001 for PAS) but the % PABA/PAS excretion index (PEI) was similar (0.96 +/- 0.14 vs. 0.96 +/- 0.06). Using a cut-off value of 0.75 for the PEI in a study group including eight patients with chronic pancreatitis and 26 with primary forms of diabetes, test sensitivity was 75%, specificity 92%, positive predictive value 75%, negative predictive value 92% and efficiency 88%.
Dense sclerosis of most of the vertebral body has been termed as "ivory vertebra". While this condition occurs rather frequently in adults it is not found very often in children.
Islet amyloid polypeptide (IAPP), otherwise called amylin, is the monomeric component of islet amyloid. Deposition of this amyloid is a characteristic feature of non-insulin-dependent diabetes mellitus in humans and may play a role in the pathogenesis of the disease. As such, abnormalities in the structure or expression of the IAPP gene might contribute to the inheritance of this condition. The IAPP gene was studied in a well-characterised population of 62 unrelated Dravidian subjects with non-insulin-dependent diabetes mellitus and 56 normal Dravidian controls, using a restriction fragment length polymorphism generated by PvuII digestion. Genotype and allele frequencies did not differ between diabetic subjects and controls. Taken together with recent findings in Europid and other racial groups, an abnormality of the IAPP gene is highly unlikely to represent a major gene for the development of non-insulin-dependent diabetes mellitus.
In a comparative study of tropical chronic pancreatitis (TCP) and alcoholic chronic pancreatitis (ACP) occurring in the same population, we analyzed the clinical profile of 50 patients of ACP seen over the past 3 years at our centers and compared this with the profile of our TCP patients. A majority (75%) of patients in both groups belonged to Tamil Nadu and 90% had never consumed cassava. Whereas TCP occurred in young subjects of both sexes, ACP patients were all males and presented at an older age. The frequency of pain, diabetes, and pancreatic calcification was similar in the two groups. Patients in both groups were lean, but signs of severe malnutrition were rare. Prediabetic patients had normal body mass index. There were striking differences in radiological appearance of pancreatic calculi in TCP and ACP. Malignancy of the pancreas was present in three patients with TCP. Benign bile duct stenosis was seen in three patients with ACP but not in TCP. Compared to ACP seen in the West, our ACP patients had a shorter duration of symptoms in spite of having advanced disease. TCP and ACP have distinct clinical profiles and it is possible that some environmental factors may hasten the progress of ACP in the tropics.
The frequency of diabetes is much higher in tropical calcific pancreatitis (TCP) as compared with alcoholic chronic pancreatitis. We report 97 patients with tropical calcific pancreatitis and compare the profile of 21 patients without diabetes (called TCP for the purpose of this report) with that of 76 patients with diabetes, called fibrocalculous pancreatic diabetes (FCPD) according to the World Health Organization (WHO) study group classification of diabetes. TCP patients were a decade younger and had marginally higher body mass indices (BMIs) as compared with the FCPD group. Of the TCP patients, 13 had abnormal glucose tolerance tests (GTT) and the others had normal GTT. Immunoreactive insulin (IRI) responses to glucose load in the TCP group did not differ significantly from that of the control group. This study shows the existence of early stages of glucose intolerance in TCP.
Non-insulin-dependent diabetes mellitus affects approximately 10% of urban Indian and Indian migrant populations and as such carries major health implications for these groups. Whilst a strong genetic component to the aetiology of non-insulin-dependent diabetes mellitus is incontestable, progress in identifying the specific genetic determinants involved in its pathogenesis has been slow. In studies of South Indian pedigrees, preliminary segregation analysis indicates that non-insulin-dependent diabetes mellitus is likely to be a polygenic disease. A number of candidate genes have been studied with the aim of demonstrating either association or linkage with the disease; in South Indians the only positive results thus far have been associations between non-insulin-dependent diabetes mellitus and the genes for insulin, apolipoprotein D and complement component C4B. However, it seems likely that these genes contribute only a small proportion of the genetic susceptibility to non-insulin-dependent diabetes mellitus in this ethnic group and that the major genes underlying glucose intolerance remain to be determined.
Immunoreactive glucagon responses were measured in 21 normoglycaemic adult offspring of non-insulin dependent (Type 2) diabetic parents, in the fasting state and during an oral glucose tolerance test. In 7 of the 21 offspring, the mean fasting immunoreactive glucagon value was significantly lower than the control value (p < 0.001). In this group, glucose stimulation did not produce inhibition of immunoreactive glucagon secretion. The insulin response in this group was not significantly different from the values in the other study groups. In the other 14 offspring, the pattern of glucagon response to glucose stimulation was similar to controls. It is likely that this non-suppressive effect of glucose on immunoreactive glucagon in some of the "prediabetic" individuals is an early change in the alpha cell function during the natural history of non-insulin dependent diabetes in Asian Indian subjects.
The effect of varying degrees of hyperglycaemia on insulin secretion was studied in newly diagnosed non-insulin dependent diabetic patients, stratified according to the fasting plasma glucose values. Of the 116 patients studied, 62 were non-obese and 54 obese. Insulin response patterns during 2h oral glucose tolerance test were analysed in comparison with the values in weight matched control subjects and also with respect to the degree of hyperglycaemia. The effect of hyperglycaemia on beta cell secretion differed in obese and non-obese patients. In the non-obese, fasting insulin levels were within normal range even in those with severe hyperglycaemia while the corresponding values in response to glucose stimulation showed a decreasing pattern. In obese patients, even fasting immunoreactive insulin (IRI) value was decreased and with increasing hyperglycaemia the reduction in IRI response to glucose stimulation was of greater magnitude compared to non-obese patients. Thus the modulating effect of obesity on insulin secretion appears to disappear with development of hyperglycaemia. The insulinogenic index was low in all the diabetic patients.
The effect of AZT on serum HIV p24 antigen and endogenous serum alpha interferon levels was studied in AIDS and ARC patients. Following administration of AZT there was a rapid decline in the serum levels of both HIV p24 antigen and alpha interferon. When AZT treatment was interrupted, the levels of both HIV p24 antigen and of interferon rapidly increased. These findings suggest that HIV or some other AZT sensitive microorganism is the inducer of interferon which is characteristically found in the serum of AIDS and symptomatic HIV infected patients. They also suggest that the rapid decline in interferon levels may underlie some of the symptomatic benefit that follows administration of AZT.