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The stimulant yohimbine may improve insulin secretion in type 2 diabetes patients who have a genetic risk for the disease, researchers found.
In a small study of 50 type 2 diabetes patients, those with a mutation in the ADRA2A gene had improved insulin secretion 30 minutes after a glucose load compared with those without the mutation, , of Lund University in Sweden, and colleagues .
"These findings represent the first example of pharmacological targeting of a specific disease mechanism for type 2 diabetes coupled to a common genetic variant," they wrote.
Anders told ľֱ in an email that the study is "an important proof-of-concept for personalized medicine," and the study brings "high hopes that this will open up a new avenue to treat type 2 diabetes."
Studies have shown that a single nucleotide polymorphism (SNP) in the ADRA2A gene (rs553668) causes overexpression of the alpha(2A) adrenergic receptor, leading to impaired insulin secretion. About 40% of patients with type 2 diabetes have this mutation, the researchers said.
They hypothesized that blocking this receptor with the alpha(2A) antagonist yohimbine might improve insulin secretion in patients with the mutation.
The drug is a stimulant with aphrodisiac and mild monoamine oxidase inhibitor (MAOI) effects and is currently used to treat xerostomia or sexual dysfunction.
They randomized 50 patients with type 2 diabetes to either placebo or one of two doses of yohimbine -- 10 mg or 20 mg -- and evaluated a primary endpoint of insulin response 30 minutes after a glucose load in an oral glucose tolerance test.
In mutation carriers, the 10-mg dose increased insulin secretion at 30 minutes by 20%, and the 20-mg dose upped it by 29%.
There was a clear gene-dose relationship, with the 10-mg dose increasing insulin secretion by 14% per additional risk allele and the 20-mg dose boosting it by 16% per additional risk allele.
But the drug did come with side effects, increasing both noradrenaline levels and blood pressure. Five patients also reported that the drug, which is known to be anxiogenic, gave them anxiety.
Rosengren said his team "will now try to modify the substance slightly to reduce the blood pressure elevation, then test it over longer time and finally in larger patient groups before we know whether it can be implemented clinically."
They concluded that the "insulin secretion defect in patients carrying the ADRA2A risk genotype can be corrected by alpha(2A) adrenergic receptor antagonism" and that this may provide a "new therapeutic means to target beta-cell defect in the 40% of type 2 diabetes patients who carry risk variant."
The findings also show that "knowledge of genetic risk variants can be used to guide therapeutic interventions that can directly target the underlying pathophysiology and demonstrate the potential of individualized genotype-specific treatment of type 2 diabetes."
, of the Karolinska Institute in Stockholm, cautioned in an that only about 4% of all type 2 diabetes patients are homozygous for the risk allele -- the population that garners the most benefit from this treatment.
Ostenson also noted that this type of receptor is expressed in several tissues and organs, so it may cause many undesired adverse effects, including changes in heart muscle function.