Protein kinase B in the diabetic heart.
This paper summarizes data from different studies all aimed at elucidating regulation of protein kinase B in the diabetic heart. Two rat models of type 2 diabetes mellitus ((i) elicited via neonatal streptozotocin injection (Stz) and (ii) Zucker fa/fa rats), were used as well as different experimental models viz isolated, Langendorff perfused hearts as well as adult ventricular myocytes. Glucose uptake was elicited by a variety of stimuli and the activation of PKB measured in tandem. Basal glucose uptake was impaired in both diabetes models while basal phosphorylation of PKB differed, showing lower levels in the Stz model but higher levels in the Zucker rats. Neither 100 nM insulin nor 10(-8) M isoproterenol could stimulate PKB phosphorylation to the same extent in the diabetic myocardium as in controls, regardless of the method used, but a combination of these stimuli resulted in an additive response. Concurrent glucose uptake however, was not additive. Wortmannin abolished both insulin and isoproterenol stimulation of glucose uptake as well as PKB phosphorylation. In contrast to the above-mentioned results, the protein tyrosine phosphatase inhibitor vanadate, alone or in combination with insulin, elicited PKB phosphorylation to the same extent in diabetic cardiomyocytes as in controls. Despite this, glucose uptake stimulated by vanadate or insulin in combination with vanadate was attenuated. The combination of insulin and vanadate may however be beneficial to the diabetic heart as it resulted in improved glucose transport. Results from the different studies can be summarized as follows: (i) dysregulation of PKB is evident in the diabetic myocardium, (ii) PKB activation is not always directly correlated with glucose uptake and (iii) insulin resistance is associated with multiple alterations in signal transduction, both above and below PKB activation.
Huisamen
Barbara
B
Department of Medical Physiology and Biochemistry, Faculty of Medicine, University of Stellenbosch, MRC Programme for Diabetes and Heart Research, Tygerberg, Republic of South Africa. bh3@maties.sun.ac.za
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011924:Rats, Zucker; D014638:Vanadates / Q000494:pharmacology
D007328:Insulin; D011518:Proto-Oncogene Proteins; D014638:Vanadates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose