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Genotype-based treatment tested to target type 2 diabetes mechanisms
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Understanding genetic risk profiles can be useful in guiding therapeutic interventions that target disease mechanisms to help in the treatment of type 2 diabetes, according to research published in Science Translational Medicine.
Researchers at Lund University in Sweden are testing yohimbine, a previously approved but now unregistered drug, as a treatment that works to restore insulin-secreting capacity impaired by a genetic variant in ADRA2A, which encodes the alpha-2A adrenergic receptor (A2AAR) associated with type 2 diabetes.
“[Yohimbine] neutralized the effects of the risk gene,” Yunzhao Tang, a postdoctoral student at the Malmö institution, said in a press release. “The carriers of the risk gene gained the same capacity to secrete insulin as those without the risk variant.”
Tang, along with Anders Rosengren, MD, PhD, and colleagues, recruited 50 patients aged 35 to 70 years with type 2 diabetes to a randomized placebo-controlled intervention with the A2AAR antagonist yohimbine based on ADRA2A genotype; 29 patients had the high-risk allele.
The gene variant is common, with 30% of the population carrying the allele and even more among the population with type 2 diabetes, according to the press release.
Patients received either placebo or 10 mg or 20 mg of yohimbine orally during three consecutive visits with 2-week intervals. The researchers conducted oral glucose tolerance tests and collected fasting blood samples at baseline and during each visit; the primary endpoint was insulin secretion at 30 minutes (Ins30).
At baseline, patients with the risk variant demonstrated 25% lower Ins30 than those without the risk genotype. After administration of 20 mg yohimbine, Ins30 increased 29% in the risk group, offering secretion similar to patients without the variant.
In patients with the high-risk variant, corrected insulin response and disposition index were improved by 59% and 43%, respectively; this was not so with the low-risk variant. The beneficial effect seen with yohimbine did not result from improved insulin sensitivity, the researchers wrote.
“The concept of treatment personalized to the individual’s risk profile has great potential,” Rosengren said in the release. “Our results show that it is possible to block the effects of a common risk gene for type 2 diabetes.”
The researchers noted their findings provide a proof of concept; however, further investigation is warranted.
“[Yohimbine] must be modified to minimize side-effects, in this case raised blood pressure, and we need the help of a cooperation partner to achieve this,” Rosengren said. “The substance must also be tested on more patients before it can become a clinical drug.”
Disclosure: The study was supported by the Novo Nordisk Foundation, ALF Region Skåne, the EU-integrated project BetaBat and the Swedish Research Council.
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