Genotype-based treatment of type 2 diabetes with an α _2A -adrenergic receptor antagonist

Abstract

The feasibility of exploiting genomic information for individualized treatment of polygenic diseases remains uncertain. A genetic variant in ADRA2A, which encodes the α(2A)-adrenergic receptor (α(2A)AR), was recently associated with type 2 diabetes. This variant causes receptor overexpression and impaired insulin secretion; thus, we hypothesized that blocking α(2A)AR pharmacologically could improve insulin secretion in patients with the risk genotype. A total of 50 type 2 diabetes patients were recruited on the basis of ADRA2A genotype for a randomized placebo-controlled intervention study with the α(2A)AR antagonist yohimbine. The patients received 0, 10, or 20 mg of yohimbine at three separate visits. The primary endpoint was insulin secretion at 30 min (Ins30) during an oral glucose tolerance test (OGTT). Patients with the risk variant had 25% lower Ins30 than those without risk genotype. After administration of 20 mg of yohimbine, Ins30 was enhanced by 29% in the risk group, making secretion similar to patients carrying the low-risk allele. The corrected insulin response and disposition index in individuals with the high-risk (but not low-risk) allele were improved by 59 ± 18% and 43 ± 14%, respectively. The beneficial effect of yohimbine was not a consequence of improved insulin sensitivity. In summary, the data show that the insulin secretion defect in patients carrying the ADRA2A risk genotype can be corrected by α(2A)AR antagonism. The findings show that knowledge of genetic risk variants can be used to guide therapeutic interventions that directly target the underlying pathophysiology and demonstrate the potential of individualized genotype-specific treatment of type 2 diabetes.

3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling

“…In addition, a previous study suggested that ADRA2A might play a role in type 2 diabetes, seeing as ADRA2A knockout mice showed lower blood glucose levels and altered glucose homeostasis as compared to WT mice (Fagerholm et al 2004). Moreover, a single-nucleotide polymorphism at ADRA2A was identified to be a risk factor for reduced insulin secretion and type 2 diabetes (Rosengren et al 2010, Tang et al 2014.…”

Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

“…Worthy of note, our study is one of the first pharmacogenetic studies in the field of T2D, employing a recall-by-genotype design (Tang et al, 2014). It demonstrated that the effect of melatonin on glucose metabolism is dependent upon genotype.…”

“…Here, improved understanding of pathogenetic processes is required to allow tailored treatment on an individual basis. Understanding the impact of genotype, which reflects or even underlies such processes, is one way to reach this goal, but studies proving this concept are only now starting to emerge (Tang et al, 2014).…”

Alpha2A adrenergic receptor genetic variation contributes to hyperglycemia after myocardial infarction

“…(6, 8) Conceptually, inhibition of genetically defined enhanced α 2A -AR pathways has been shown to reduce hyperglycemia: a previous study demonstrated improved insulin secretion using the non-selective α 2 -AR antagonist, yohimbine, in diabetic patients treated according to their rs553668 genotype. (36) It would be interesting to consider inhibition of the α 2A -AR pathway for the prevention or treatment of stress-induced hyperglycemia and its associated morbidity and mortality, particularly for individuals with genetic risk markers. However, there is no selective α 2A -AR antagonist available for clinical use; moreover, considering that α 2 -AR antagonists such as yohimbine can increase blood pressure and sympathetic activity it would be challenging to conduct this type of study in acutely ill patients.…”