Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications.
The worldwide population afflicted with diabetes is growing at an epidemic rate. There are almost five times the number of people suffering from this disease today as compared to 10 years ago and the worldwide diabetic population is expected to exceed 300 million by the year 2028. This trend appears to be driven by the world's adoption of a "western lifestyle" comprising a combination of unhealthy dietary habits and a sedentary daily routine. Today, diabetes is the sixth leading cause of death in the United States and the death rates associated with diabetes have increased by 30% over the last decade. While medications are available to reduce blood glucose, approximately one third of the patients on oral medications will eventually fail to respond and require insulin injections. Consequently, there is a tremendous medical need for improved medications to manage this disease that demonstrate superior efficacy. Emerging knowledge regarding the underlying mechanisms that impair glucose-stimulated insulin secretion and the action of insulin on its target tissues has grown tremendously over the last two decades. During that same period of time, an understanding of the important role that phosphorylation state plays in signal transduction has drawn attention to several kinases as attractive approaches for the treatment of diabetes. Recent advances include the discovery of a"small molecule" allosteric binding site on the insulin receptor, inhibitors of glycogen synthase kinase-3(GSK-3) which improve insulin sensitivity in diabetic animal models and inhibitors of protein kinase C- beta that are presently being evaluated in clinical trials for diabetic retinopathy. This review will detail these recent discoveries and highlight emerging biological targets that hold potential to normalize blood glucose and prevent the progression of diabetes related complications.
Bullock
William H
WH
Bayer Research Center, 400 Morgan Lane, West Haven, CT, 06516-4175, USA. william.bullock.b@bayer.com
Magnuson
Steven R
SR
Choi
Soongyu
S
Gunn
David E
DE
Rudolph
Joachim
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011972:Receptor, Insulin / Q000145:classification / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D006006:Glycogen Synthase; D010770:Phosphotransferases; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases