Identification of a subgroup of black South Africans with type 1 diabetes who are older at diagnosis but have lower levels of glutamic acid decarboxylase and islet antigen 2 autoantibodies.

AIMS: To compare the age at diagnosis and prevalence of islet autoantibody [glutamic acid decarboxylase (65 kDa) 65 and islet antigen 2] positivity in black and white participants with type 1 diabetes in South Africa, and to analyse the relationship between age at diagnosis and the presence of autoantibodies. METHODS: Participants were recruited from diabetes outpatient departments and autoantibodies to glutamic acid decarboxylase (65 kDa) and islet antigen 2 were measured by enzyme-linked immunosorbent assay. RESULTS: We recruited 472 (353 black and 119 white) participants with type 1 diabetes. Age at diagnosis of diabetes was later in black (19.7 ± 10.5) than in white participants (12.7 ± 10.8 years; P < 0.001) with a median (interquartile range) disease duration of 5.0 (2.0-10.0) and 8.5 (4.0-20.0) years (P < 0.001), respectively. An older age at diagnosis (≥ 21 years) was more frequent in black (152 of 340, 45%) than in white participants (24 of 116, 21%; P < 0.001). The prevalence of islet antigen 2 autoantibodies was 19% (66/352) in black and 41% in white participants (48/118; P < 0.001). There was no significant difference in glutamic acid decarboxylase (65 kDa) autoantibody positivity between black (212/353, 60%) and white participants (77/117, 66%; P = 0.269). In black, but not white, participants the prevalence of both glutamic acid decarboxylase (65 kDa) and islet antigen 2 autoantibody positivity was significantly lower in participants diagnosed at age ≥ 21 years (P < 0.001 for both comparisons). CONCLUSIONS: The older age at diagnosis, lower prevalence of islet antigen 2 autoantibodies and a distinct subgroup of participants with type 1 diabetes with age at diagnosis of > 20 years in the black compared to white population suggest a difference in the immunological aetiology of type 1 diabetes in these two population groups.

Prevalence of low serum testosterone levels among men with type 2 diabetes mellitus attending two outpatient diabetes clinics in KwaZulu-Natal Province, South Africa.

BACKGROUND: The reported prevalence of low testosterone among men with type 2 diabetes mellitus (T2DM) is high. However, there is a dearth of information on the prevalence of androgen deficiency symptoms and low serum testosterone levels in men with T2DM from sub-Saharan Africa. Scanty data are available from Nigeria, Ghana and South Africa (SA). OBJECTIVES: To determine the prevalence of low serum testosterone and associated risk factors and the prevalence of androgen deficiency symptoms in men with T2DM. METHODS: In a cross-sectional observational study, androgen deficiency symptoms in men with T2DM attending two outpatient diabetes clinics in Durban, KwaZulu-Natal Province, SA, were assessed using the Ageing Males' Symptoms Scale (AMS) questionnaire and direct enquiry. Serum total testosterone (TT), sex hormone-binding globulin (SHBG), luteinising hormone (LH), fructosamine, serum lipids and glycated haemoglobin (HbA1c) were measured and free testosterone (FT) was calculated. TT, SHBG and FT levels were measured in control subjects with no history of diabetes. RESULTS: There were 148 men with T2DM in the study group and 50 control subjects in the control group. In the study group, the majority were black Africans (58.8%); Indians (39.2%) and whites (2.0%) constituted the remainder. The mean (standard deviation (SD)) age was 57.5 (11.2) years, the mean duration of diabetes 11.4 (8.9) years and the mean HbA1c 8.6% (1.9%). Of the study group, 85.8% had metabolic syndrome. Mean TT, SHBG and FT and median LH (interquartile range) in the study group were within normal ranges. However, mean (SD) serum TT and FT were lower in the study group than in the control subjects (14.5 (5.8) v. 18.8 (7.2) nmol/L; p<0.001 and 265.9 (90.4) v. 351.7 (127.3) pmol/L; p<0.001, respectively). The prevalence of low serum total testosterone (LSTT) and low serum free testosterone (LSFT) in the study group was 35.8% and 16.2%, respectively. The prevalence of androgen deficiency symptoms using the AMS questionnaire was 74.5% and correlated poorly with LSTT or LSFT. In multivariate analysis, LSFT was significantly associated with age (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.02 - 1.218; p=0.043) and waist circumference (WC) (OR 1.033, 95% CI 0.999 - 1.068; p=0.059). LSTT was associated with body mass index (BMI) only (OR 1.138, 95% CI 1.063 - 1.218; p<0.0001). TT correlated inversely with BMI, WC and the number of metabolic syndrome criteria. FT correlated inversely with BMI, WC and WHR. CONCLUSIONS: There was a high prevalence of LSTT, LSFT and androgen deficiency symptoms in this study. Serum TT and FT were lower in men with T2DM than in control subjects. Risk factors associated with LSFT or LSTT included higher BMI and WC and older age. The AMS score was a poor predictor of low testosterone. More research is required locally before any screening policy can be recommended.

Cardiovascular disease management in people with diabetes outside North America and Western Europe in 2006 and 2015.

AIM: Optimal treatment of cardiovascular disease is essential to decrease mortality among people with diabetes, but information is limited on how actual treatment relates to guidelines. We analysed changes in therapeutic approaches to anti-hypertensive and lipid-lowering medications in people with Type 2 diabetes from 2006 and 2015. METHODS: Summary data from clinical services in seven countries outside North America and Western Europe were collected for 39 684 people. Each site summarized individual-level data from outpatient medical records for 2006 and 2015. Data included: demographic information, blood pressure (BP), total cholesterol levels and percentage of people taking statins, anti-hypertensive medication (angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, thiazide diuretics) and antiplatelet drugs. RESULTS: From 2006 to 2015, mean cholesterol levels decreased in six of eight sites (range: -0.5 to -0.2), whereas the proportion with BP levels > 140/90 mmHg increased in seven of eight sites. Decreases in cholesterol paralleled increases in statin use (range: 3.1 to 47.0 percentage points). Overall, utilization of anti-hypertensive medication did not change. However, there was an increase in the use of angiotensin II receptor blockers and a decrease in angiotensin-converting enzyme inhibitors. The percentage of individuals receiving calcium channel blockers and aspirin remained unchanged. CONCLUSIONS: Our findings indicate that control of cholesterol levels improved and coincided with increased use of statins. The percentage of people with BP > 140/90 mmHg was higher in 2015 than in 2006. Hypertension treatment shifted from using angiotensin-converting enzyme inhibitors to angiotensin II receptor blockers. Despite the potentially greater tolerability of angiotensin II receptor blockers, there was no associated improvement in BP levels.

Study profile: the Durban Diabetes Study (DDS): a platform for chronic disease research.

The Durban Diabetes Study (DDS) is a population-based cross-sectional survey of an urban black population in the eThekwini Municipality (city of Durban) in South Africa. The survey combines health, lifestyle and socioeconomic questionnaire data with standardised biophysical measurements, biomarkers for non-communicable and infectious diseases, and genetic data. Data collection for the study is currently underway and the target sample size is 10 000 participants. The DDS has an established infrastructure for survey fieldwork, data collection and management, sample processing and storage, managed data sharing and consent for re-approaching participants, which can be utilised for further research studies. As such, the DDS represents a rich platform for investigating the distribution, interrelation and aetiology of chronic diseases and their risk factors, which is critical for developing health care policies for disease management and prevention. For data access enquiries please contact the African Partnership for Chronic Disease Research (APCDR) at data@apcdr.org or the corresponding author.

Retinopathy in subjects with type 2 diabetes at a tertiary diabetes clinic in Durban, South Africa: Clinical, biochemical and genetic factors.

AIM: To determine the prevalence of clinical and laboratory variables and genetic polymorphisms in association with diabetic retinopathy (DR) in subjects with type 2 diabetes attending a tertiary referral diabetes clinic in Durban, South Africa. METHODS: Cross-sectional study on 292 Indian and African patients with type 2 diabetes (71.5% women). The presence of DR was determined by direct ophthalmoscopy. Clinical and laboratory data were collected and polymorphisms in the NOS3 (rs61722009, rs2070744, rs1799983) and VEGF (rs35569394, rs2010963) genes were determined. RESULTS: DR was present in 113 (39%) subjects. Those with DR were older (60.6 ± 9.6 vs. 55.4 ± 12.9 years, p = 0.005), had longer duration diabetes (18.5 ± 8.8 vs. 11.9 ± 9.2 years, p < 0.0001), higher HbA1c (9.2 ± 1.8 vs. 8.8 ± 1.7%, p = 0.049), serum creatinine (106.3 ± 90.2 vs. 75.2 ± 33.4 µmol/l), triglycerides (2.1 ± 1.2 vs. 1.9 ± 1.6 mmol/l, p = 0.042), proteinuria (72% vs. 28%, p = 0.001), and used more insulin (78% vs. 39% p = 0.0001), anti-hypertensive (95% vs. 80%, p = 0.0003) and lipid-lowering therapy (70% vs. 56%, p = 0.023). There was no association between DR and any of the NOS3 or VEGF gene polymorphisms studied, although there were ethnic differences. After adjustment, diabetes duration (OR 1.05, 95% CI 1.01-1.08), presence of proteinuria (OR 4.15, 95% CI 1.70-10.11) and use of insulin therapy (OR 3.38, 95% CI 1.60-7.12) were associated with DR. CONCLUSION: Hyperglycemia, duration of diabetes and proteinuria are associated with DR in Indian and African patients in South Africa, whereas NOS3 and VEGF gene polymorphisms were not associated with DR.

Variants in PPARG, KCNJ11, TCF7L2, FTO, and HHEX genes in South African subjects of Zulu descent with type 2 diabetes

Polymorphisms in a number of genes have consistently been associated with type 2 diabetes in various Caucasian populations. Little, however, is known of the association between these genetic risk markers and type 2 diabetes in sub-Saharan African subjects. The aim of the current study was to determine the association between common variants in the PPARG, KCNJ11, TCF7L2, FTO and HHEX genes in African (black) subjects of Zulu descent in KwaZulu-Natal, South Africa. The association between type 2 diabetes and rs1801282 (PPARG), rs5215 (KCNJ11), rs12255372 (TCF7L2), rs7903146 (TCF7L2) rs9939609 (FTO) and rs1111875 (HHEX) was determined in 178 South African Zulu subjects and 200 healthy ethnically matched control subjects. rs1801282 (PPARG) and rs5215 (KCNJ11) were not found to be present in either the subjects with type 2 diabetes or the control subjects. No association between rs12255372 (TCF7L2), rs9939609 (FTO) and type 2 diabetes was found. Heterozygosity at rs7903146 (TCF7L2) was associated with type 2 diabetes (odds ratio 1.84, 95% confidence interval: 1.19­2.83, p=0.0035). Decreased frequency of homozygosity for the common allele at rs7903146 (TCF7L2) was observed in subjects with type 2 diabetes (odds ratio 0.54, 95% confidence interval: 0.34­0.84; p=0.0043). There was an increased frequency of C allele homozygosity in subjects with type 2 diabetes at rs1111875 (HHEX), of borderline significance (odds ratio 1.54, 95% confidence interval 0.97­2.44, p=0.052). Subjects with type 2 diabetes harbouring one or more of the risk alleles did not differ from those without genetic variation at the loci studied, with respect to age at diagnosis, blood pressure, body mass index or serum lipid levels. We conclude that risk polymorphisms identified in Caucasian populations are not associated with type 2 diabetes in this group of South African subjects of Zulu descent, with the exception of rs7903146 (TCF7L2). The genetic risk for type 2 diabetes in sub-Saharan African subjects may reside in other, as yet unidentified, genes

Toll-like receptor 3 gene polymorphisms in South African Blacks with type 1 diabetes.

Type 1 diabetes is the consequence of exposure of genetically susceptible individuals to specific environmental precipitants. The innate immune system provides the initial response to exogenous antigen and links with the adaptive immune system. The aim of this study was to assess the role of polymorphisms occurring in the cytoplasmic region of toll-like receptor (TLR) 3 gene and immediate 5' sequence, in subjects of Zulu descent with type 1 diabetes in KwaZulu-Natal, South Africa. Seventy-nine subjects with type 1 diabetes and 74 healthy normal glucose tolerant gender-matched control subjects were studied. Parts of exon 4 and exon 3/intron 3 of the TLR3 gene were studied by polymerase chain reaction, direct sequencing and restriction enzyme digestion with Bts 1. Of the nine polymorphisms studied, a significant association with type 1 diabetes was found for the major allele in the 2593 C/T polymorphism and for the minor alleles in the 2642 C/A and 2690 A/G polymorphisms, which were found to be in complete linkage disequilibrium. Correction of the P-values for the number of alleles studied, however, rendered the results no longer significant. These results suggest that polymorphisms in the TLR3 gene, which is part of the innate immune system, may be associated with type 1 diabetes in this population.

High incidence of Type 2 diabetes mellitus in South African Indians: a 10-year follow-up study.

AIMS: Previous cross-sectional studies have established that South African Indians have a high prevalence of Type 2 diabetes mellitus. A prospective community study was undertaken to determine the incidence of Type 2 diabetes and the risk factors associated with its development in a cohort of South African Indians who had been studied 10 years previously. METHODS: This is a report on 563 subjects who participated both at baseline and at the 10-year follow-up study. In the baseline study, 2479 subjects (> 15 years) were studied; using 1985 World Health Organization criteria for glucose tolerance based on 75 g oral glucose tolerance tests (OGTT), the crude prevalence of diabetes mellitus (Diabetes) was 9.8% and of impaired glucose tolerance (IGT) 5.8% (age and sex-adjusted prevalence 13% and 6.9%, respectively). RESULTS: At the 10-year follow-up study, 563 of the subjects who could be traced consented to a repeat OGTT; of these, 91 (16.2%) were classified as Diabetes and 41 (7.3%) as IGT. Of the subjects who did not have diabetes at baseline (n = 517), 49 (9.5%) progressed to diabetes (PTD) and 40 (7.7%) had IGT. The crude cumulative incidence of diabetes was 9.5% (rate of progression 0.95% per annum; incidence density 9.5/1000 person years) with an age and sex-adjusted cumulative incidence of 8.3% (rate of progression 0.95% per annum; incidence density 8.3/1000 person years). Examination of risk factors predictive of subsequent diabetes development was undertaken by analysis of baseline (year 0) variables in the 517 subjects who did not have diabetes at baseline. In multivariate analysis using a logistic regression model, the significant predictive risk factors for future diabetes included 2-h post load plasma glucose (2 PG) (P < 0.0001, odds ratio (OR) 1.7, 95% confidence interval (CI) 1.4-2.1), body mass index (BMI) (P < 0.006, OR 1.1, 95% CI 1.0-1.3) and obesity (P < 0.01, OR 4.6, 95% CI 1.4-14.7). CONCLUSIONS: This long-term study has shown that in South African Indians there is a high incidence of Type 2 diabetes, and in this population significant predictors include higher baseline blood glucose, BMI and obesity.

Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.

AIMS/HYPOTHESIS: The recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility. METHODS: To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha. RESULTS: Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions. CONCLUSION/INTERPRETATION: We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.

HLA class II antigens in South African Blacks with type I diabetes.

Type 1 diabetes mellitus is poorly characterised in many African communities, including South Africa, where little is known of the disease epidemiology. This study aimed to identify the HLA class II alleles associated with type 1 diabetes in a group of Zulu subjects in Durban, KwaZulu-Natal by PCR-SSP. The HLA alleles associated with type 1 diabetes included HLA-DQB*0302 (P<0.0001), DRB1*O9 (P<0.0001), DRB1*04 (P=0.002), DRB1*0301 (P=0.003), DQB*02 (P=0.004) and DQA*03 (P=0.035). Estimated haplotypes positively associated with type 1 diabetes included HLA-DRB1 *0301-DQA*0501, DRB1*04-DQA*03, DRB1*04-DQB*0302, DRB1*0301-DQB*0201, DQA*0501-DQB*0201 and DQA*03-DQB*0302. These findings are similar to those reported from Zimbabwe and other populations with type 1 diabetes.

Microvascular complications in South African patients with long-duration diabetes mellitus.

OBJECTIVE: To determine the prevalence of microvascular complications in South African black and Indian patients with long-duration diabetes mellitus (DM). DESIGN: A retrospective analysis was undertaken of clinical records of 219 DM patients (132 black, 87 Indian) with long-duration DM (over 10 years) attending a diabetes clinic in Durban. Data recorded on each subject included demographic details (age, gender, ethnic group, type of diabetes, age of onset and duration of diabetes), presence of retinopathy, markers of nephropathy and biochemical variables. The prevalence of complications and the clinical and biochemical parameters were evaluated for type 1 and type 2 diabetes and for each ethnic group. RESULTS: Of the 219 patients, 47 had type 1 DM (36 blacks, 11 Indians) and 172 were classified as type 2 DM (96 blacks, 76 Indians). The mean age of onset of DM was later in blacks than Indians, both for type 1 (P < 0.05) and type 2 DM (P < 0.01). In patients with type 1 DM, the prevalence of retinopathy was 53.2% (blacks 55.6%, Indians 45.5%), persistent proteinuria was found in 23.4% (blacks 25%, Indians 18.2%) and hypertension in 34%. No ethnic difference was found except for the prevalence of hypertension which was higher in blacks than Indians (41.7% v. 9.1%, P < 0.5). Onset of retinopathy from time of diabetes diagnosis occurred earlier in blacks than Indians (13.0 +/- 4.6 yrs v. 18.0 +/- 4.6 yrs, P < 0.05). For the type 2 DM group, retinopathy was found in 64.5% (black v. Indian 68.8 v. 59.2%) and persistent proteinuria in 25% (black v. Indian 30.2 v. 18.4%). Hypertension was observed in 68% and was more prevalent in blacks (84.4 v. 47.4%, P < 0.01) There was an earlier onset of retinopathy (P < 0.05) and hypertension (P < 0.01) from time of diabetes diagnosis in blacks than Indians. In the type 1 DM group retinopathy was associated with a significantly longer duration of diabetes (P < 0.05) and higher glycated haemoglobin (HbA1) (P < 0.05). For type 2 DM subjects there was a significant association between retinopathy and longer duration of diabetes (P < 0.05) and higher systolic blood pressure (P < 0.05). CONCLUSION: This study has shown that there is a high prevalence of microvascular complications in South African patients with long-duration diabetes mellitus.

Solid and cystic papillary epithelial neoplasm of the pancreas. A report of 3 cases.

This is a report of 3 female patients presenting with solid and cystic papillary epithelial neoplasms of the pancreas (SCPEN). All 3 lesions were incidental findings. SCPEN is an uncommon low-grade malignant tumour that is histologically distinct from ductal adenocarcinoma and islet cell tumour, occurs chiefly in young women, and is amenable to surgery. The cell of origin is the subject of some debate.

The significance of a positive family history in South African Indians with non-insulin-dependent diabetes (NIDDM).

A group of South African Indians with NIDDM participated in a study to evaluate the frequency of positive family histories of the disease and to determine the relative contribution of maternal or paternal genetic determinants. Information was elicited by means of an interview and recorded. Of the 1098 diabetic subjects studied 70% gave a positive family history of a first degree relative suffering from NIDDM. Three-generation transmission was recorded in 5.3% of the subjects. A significantly greater proportion of probands (40%) had a mother with NIDDM than those with a father (26%). A positive family history in an offspring was more common in female probands (10.6%) than males (5.5%). Twice as many probands with 3 generation transmission had a maternal grandmother suffering from NIDDM (2.5%) compared with those who had a paternal grandmother afflicted (1.2%) (P < 0.05), whereas the frequencies in the maternal (0.9%) and paternal (0.8%) grandfathers were similar. This study has highlighted, not only the high prevalence of a positive family history in South African Indians with NIDDM, but also a stronger maternal contribution to the putative gene responsible for the disease.