Yale researchers discover a role for Kv1.3 potassium channels in the etiology of diabetes as well as obesity

Yale researchers discover a role for Kv1.3 potassium channels in the etiology of diabetes as well as obesity

DailyUpdates 12th March 2004. Drugs targeting ion channels already generate annual sales of over $6 billion, a figure set to rise as new channels are identified and novel therapeutics that modulate these proteins are developed. Last year the voltage-gated potassium (Kv) channel, Kv1.3 was shown to regulate weight gain, Yale researchers now show that blocking this channel also increases insulin sensitivity, advancing Kv1.3 channel blockers as anti-diabetic candidates.

Identification of novel ion channels and therapeutics that target these channels are providing advances in numerous therapeutic areas including asthma, inflammation, arrhythmia and CNS disorders. Drugs targeting ion channels already generate over $6 billion in sales per annum. As described in the recent report "Ion Channel Assays in the Drug Discovery Process" the development of improved screening tools as well as highly targeted libraries of candidate channel modulators such as ChemOvation's Potassium channel enterprise library will drive this market further.

Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes and the Kv1.3 channel has been implicated in various diseases ranging from pulmonary hypertension to autoimmune disease. Recent studies have also revealed that Kv1.3-deficient mice are protected from diet-induced obesity and gain significantly less weight than littermate controls when placed on a high-fat diet. These data indicate that Kv1.3 channels may participate in the pathways that regulate body weight and represent a target for the multi billion dollar obesity therapeutics market.

Although Kv1.3-/- mice on the high-calorie diet gain weight, they remain euglycemic, with low blood insulin levels. This observation prompted Dr Gary Desir and colleagues at Yale University School of Medicine to examine the effect of Kv1.3 gene inactivation and inhibition on peripheral glucose homeostasis and insulin sensitivity.

In their Proceedings of the National Academy of Science journal article published in March 2004, this group report that Kv1.3 gene deletion and channel inhibition increase peripheral insulin sensitivity in vivo. Baseline and insulin-stimulated glucose uptake are increased in adipose tissue and skeletal muscle of Kv1.3-/- mice.

Mechanistic studies revealed that inhibition of Kv1.3 activity facilitates the translocation of the glucose transporter, GLUT4, to the plasma membrane. It also suppresses c-JUN terminal kinase activity in fat and skeletal muscle and decreases IL-6 and tumor necrosis factor secretion by adipose tissue.

Obesity and comorbid type 2 diabetes are two frequent and growing global problems. The insulin resistance syndrome was first described in 1988 and contributes to both conditions and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues.

The novel data emerging from Yale demonstrates that Kv1.3 inhibition improves insulin sensitivity in addition to reducing weight gain and does so by increasing the amount of GLUT4 at the plasma membrane. These results pinpoint a pathway through which K channels regulate peripheral glucose homeostasis, and identify Kv1.3 as a pharmacologic target for the treatment of diabetes as well as obesity.

(source DailyUpdates 12h March; for a full abstract of the original paper see Proc Natl Acad Sci U S A. 2004 Feb 23)

In this edition of DailyUpdates, LeadDiscovery also highlights a role for the N-methyl-d-aspartate receptor in the development and maintenance of human visceral pain...the therapeutic potential of KGFR blockade in the treatment of breast cancer...a novel HIV-1 viral entry inhibitor...data from a 52-week, continuation study of lamotrigine in the treatment of bipolar depression...and much more.

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