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Targeting type 2 diabetes
Author: Olivia Rose-Innes
Published: 14/11/2017

Diabetes is now South Africa's third leading cause of death after heart disease and HIV/AIDS. Its causes are complex, and to combat it researchers need to better understand the interplay of multiple genes in combination with environmental factors.

For her PhD, obtained through Stellenbosch University's Division of Chemical Pathology in the Faculty of Medical and Health Sciences, Dr Zelda Vergotine set out to trace genes associated with insulin resistance, the precursor of diabetes. “I focused on insulin resistance, because that's the point where we're hoping to interrupt the development of diabetes while it is still reversible," she says.

She chose a mixed-ancestry population in Bellville South, Cape Town for her study. Following global trends, prevalence of type 2 diabetes in mixed-ancestry South Africans increased alarmingly from 10,8% to 26,4% over the past two decades – the country's second highest prevalence after that for the Indian population.

“A lot of literature concerns genes that contribute to insulin resistance, but the specific candidate genes that may predispose South Africans haven't been studied," says Vergotine.

She explains that even though the genes may have already been identified in other populations, gene-to-gene or gene-to environment interactions and certain related risk factors may influence the susceptibility to metabolic disorders in different populations.

Vergotine investigated two candidate gene variants previously associated with insulin resistance and diabetes in European Caucasians, namely PPARG (peroxisome proliferator-activated receptor gamma) and IR S1 (insulin receptor substrate). PPARG is involved in nuclear transcription, controlling activities and metabolism inside the cell. IR S1 is involved with how insulin binds to the insulin receptor protein, leading to the cascade of cellular processes that promote usage or storage of glucose.

The research uncovered that a genetic variant of PPARG , the Pro-12 allele, was strongly associated with insulin resistance: When it interacted with the additional unfavourable IR S1 variant (IR S1 Gly972Arg), it increased the risk for diabetes considerably.

“What makes the study stand out is that we found a gene-gene interaction with these two genes working together in this process. Genetic prediction of disease is greatly improved if genetic variants with strong effects are identified, either on their own or with other variants," Vergotine explains.

“By identifying genetic susceptibility for insulin resistance combined with predisposing risk factors, we can encourage high-risk patients to make use of primary lifestyle prevention programmes.

“Given its links with increased risk of developing insulin resistance and diabetes, I think the biggest issue in this particular population (although it's a national concern) is the rising obesity rate."

Spurred by a 2014 World Health Organisation report that two in five South African deaths are related to noncommunicable diseases (NCD s), the Department of Health has developed the Strategic Plan for the Prevention and Control of NCD s, naming type 2 diabetes as one of the most important. Priority has been given to reducing four key risk factors – physical inactivity, diet, and tobacco and alcohol use – responsible for driving this health crisis.


Photo: Pixabay