Type 2 Diabetes Mellitus in Black Zimbabweans - Metabolic Factors and Molecular Genetics.
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Objectives: The main objectives of the study were (i) to determine the prevalence of the metabolic syndrome disorders, (ii) to determine the frequency, of ApoE gene polymorphism at codons 112 and 158, of the ACE gene 287-bp insertion/deletion polymorphism, of the -308GöA mutation in the 5! region of the TNF-alpha gene, and (iii) to investigate the effects of these polymorphisms on the components of the metabolic syndrome in type 2 diabetic patients. Methods: Dyslipidaemia, obesity, hypertension, microalbuminuria, hyperinsulinaemia and insulin resistance, all intermediate traits and metabolic components found in type 2 diabetes mellitus, were determined in diabetic patients as well as non-diabetic participants. Apolipoprotein E (ApoE) gene polymorphism of the amino acid substitutions of cysteine and arginine at codons 112 and 158, angiotensin converting enzyme (ACE) gene 287-bp insertion/deletion polymorphism and the -308GöA mutation in the 5! region of the tumour necrosis factor alpha (TNF-alpha) gene were determined by the polymerase chain reaction (PCR). Polyacrylamide and agarose gels were used to electrophoretically identify the genotypes from the PCR DNA products. The genotypes from the 3 different polymorphisms were related to lipid metabolism, anthropometric measurements, microalbuminuria, hypertension, insulin resistance or hyperinsulinaemia. Results: The data in the current study clearly demonstrates a rather high prevalence of the metabolic syndrome (36%) in Black Zimbabweans with type 2 diabetes mellitus, characterised by hypertension (69%), microalbuminuria (62%), insulin resistance (57%), dyslipidaemia (47%) and obesity (31%). The nucleotide substitutions in codons 112 and 158 of the ApoE gene reveal that Zimbabweans have an unusually high frequency of e4 (29%) and e2 (11%) alleles, compared to general Caucasian and Asian populations. The E4/4 genotype has a statistically significant influence on blood total cholesterol (p < 0.05), and low density lipoprotein cholesterol (p < 0.05) in this Black population compared to other genotypes. The ApoE polymorphism has a marked influence on triglycerides and high density lipoprotein cholesterol even if this is not statistically significant. Although Black Zimbabweans have a high D (deletion) allele frequency (64%), the ACE 287-bp insertion/deletion (I/D) polymorphism, blood pressure and microalbumin levels were not statistically significant in hypertensive versus non-hypertensive and microalbuminuric versus non-albuminuric patients, respectively. The I allele had a relationship with hypertension, insulin and BMI, although this was not statistically significant. The AA genotype compared to the AG and GG genotypes of the Nco I-sensitive polymorphism (-308 GöA) in the promoter region of the TNF-alpha gene is significantly associated with BMI (p < 0.01), diastolic blood pressure (p < 0.05), and uric acid (p < 0.05) in this populace. Discussion: In the last few years it has been demonstrated that metabolic disorders investigated in this study are aetiological factors for cardiovascular and cerebrovascular disease. Obesity, insulin resistance, hyperinsulinaemia and nephropathy may aggravate the atherogenic lipid profile in most of these patients. Therefore, it may be critical to modify these risk factors in this population through therapeutic and nutritional interventions where possible, so as to reduce the risk of complications of macrovascular disease. The high prevalence of the e2 and e4 alleles is likely to be a heavy genetic burden as it has been shown to enhance susceptibility to diabetic nephropathy, coronary artery disease and Alzheimer disease in several populations. The ACE 287-bp insertion/deletion (I/D) polymorphism does not seem to play a major role in influencing blood pressure or diabetic nephropathy, despite the fact that Black Zimbabweans have a high D allele frequency. However the relation of the I allele with hypertension, insulin and BMI, although not statistically significant, suggests that its conferred risk may be much higher in the Zimbabwean Black population. Data from the current study suggests that TNF-alpha gene polymorphism may have a complex relationship with T2DM and that it may be a useful tool in determining subjects at high risk of developing the metabolic syndrome. Conclusion: The data in the current study categorically shows that genetic polymorphisms contribute to biological variation in various target tissues, and one can deduce that they are capable of influencing disease susceptibility and progression. Taken together, the findings in this study suggest that these polymorphisms could be used as potential markers in T2DM subjects at risk of developing certain metabolic complications and that they may be useful in the determination of severity of these disorders. The multiple molecular mechanism whereby these polymorphisms induce the metabolic disorders is not well understood and requires further investigation.