The Fight Against Type 2 Diabetes: The Promise of Genomics

Sandra Adamson Fryhofer, MD


July 11, 2014

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Hello. I'm Dr. Sandra Fryhofer. Welcome to Medicine Matters. The topic: Genomics and type 2 diabetes, a new report from the American Medical Association (AMA) Council on Science and Public Health.[1] Here is why it matters.

Type 2 diabetes is common. Nearly 26 million people already have it; 79 million more have prediabetes and are on the way to full-blown disease. Prevention and intervention are important. That is why the AMA's Improving Outcomes Group is partnering with physician practices and diabetes prevention programs. This is also why the AMA Council on Science and Public Health decided to review current genomic strategies to stave off type 2 diabetes and improve clinical care.

Let's look at risk factors. Age over 45 years increases risk 5-6 times. Body mass index (BMI) of 30 kg/m2 or more increases risk 4-5 times. Being overweight or having high blood pressure can triple diabetes risk. Having high lipid levels can quadruple it. Weight, determined by BMI, also plays a role.

There are more than 65 genetic variations that increase type 2 diabetes risk. Many affect insulin secretion rather than insulin action on tissues. These genetic variations can up type 2 diabetes risk by 10%-45%.

Family history is also a contributing factor. Having 1 first-degree or 2 second-degree relatives that have diabetes doubles or triples risk. Having 2 first-degree-affected relatives can increase risk by a factor of 5 or 6.

Several studies[2,3,4] have looked at algorithms that quantify risk with a so-called genetic risk score, or GRS. Unfortunately, it does not help that much and provides no added value to risk prediction. But could these genetic risk scores trigger patient motivation and jump-start patients to make personalized lifestyle choices that could reduce the risk for disease? That might work for some people.

Tailoring therapy on the basis of the patient's genotype is also an area with potential promise. For example, patients with genetic variants that reduce liver uptake of metformin show less glucose-lowering response, as opposed to those without this genetic variant.[5] Patients with gene variants for cytochrome P450 2C9 have decreased sulfonylurea clearance and thus have larger decreases in blood glucose.[6]

Carriers of other variants, such as PPAR-gamma, that regulate fatty-acid storage and glucose metabolism show more blood sugar lowering and lower hemoglobin A1c tests with rosiglitazone and pioglitazone therapy.[7,8]

The promise is there, but the small studies so far have not yet changed clinical practice. Genomics and its effect on diet are also quite interesting. Some patients have genetic variants that make them respond better, with lower blood sugar levels and lower lipid levels, when placed on a Mediterranean rather than a low-fat diet. Some patients have genetic variants that make them respond better to strict calorie counting and exercise. There is more on the horizon for genomics and predicting type 2 diabetes complications, such as retinopathy, peripheral neuropathy, and nephropathy, but these are not fine-tuned enough now to be helpful clinically.

In summary, genomic analysis is a rapidly advancing field, especially with the advent of next-generation sequencing and whole-genome sequencing. Genomics has many potential future uses in diabetes risk assessment, prevention, and management. The future looks very promising.

For Medicine Matters, I'm Dr. Sandra Fryhofer.


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