Hyperglycemia and insulin resistance are common in many metabolic disorders such Type 2 diabetes, obesity, and metabolic syndrome. In these chronic conditions, there is a decreased responsiveness to endogenous insulin (insulin resistance). The decreased responsiveness to insulin results in a reduction in insulin- regulated glucose disposal, which occurs mostly in skeletal muscle. Acute insulin resistance and hyperglycemia are much less studied, but are characteristic metabolic responses to infections and injuries such as surgery, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of ICU patients may reduce both morbidity and mortality associated with critical illness. However, there is some controversy concerning the proper use of intensive insulin therapy, and under what conditions it can do the most good, or conversely when it is unnecessary or harmful. Intensive insulin therapy increases the likelihood of deleterious hypoglycemic incidents, a major complication of intensive insulin therapy. Even though intensive insulin therapy is now extensively used in the ICU, little is known about the mechanisms underlying the acute onset of insulin resistance. For instance, how quickly it develops, what are the causative factors, what intracellular signaling pathways are affected, and what tissues are involved. An understanding of how this insulin resistance develops will be important in determining the proper application of intensive insulin therapy, the most advantageous time for initiation following different injuries, and may suggest new treatment protocols to increase survival of critically ill patients. For instance, is therapy to reuce insulin resistance more advantageous to the patient than intensive insulin therapy? And what tissue or tissues need to be targeted? Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post- receptor defect. Our recently published and preliminary data indicate that there are insulin receptors and post-receptor defects in insulin signaling that develop in skeletal muscle following surgical trauma and hemorrhage. The data suggests an important role for the glucocorticoids and proinflammatory cytokines, but how they interact to cause the initial development of insulin resistance is unknown. Additional preliminary data indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, skeletal muscle, liver, and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. In addition, there are time-dependent changes in the factors that maintain the insulin resistant state. We have also found these to be tissue dependent. These results may be clinically advantageous, allowing us to specifically target individual tissues with treatments less likely tha intensive insulin therapy to cause hypoglycemic incidents, and more likely to achieve the proper range of blood glucose levels in patients in the ICU. Thus, studies are proposed in this application to determine the mechanism(s) of the development of acute insulin resistance in skeletal muscle. Also, much of this application is designed to study the mechanisms of recovery of insulin sensitivity following resuscitation. Potential clinical treatments are explored that may work to reverse the mortality and morbidity related to hyperglycemia and insulin resistance in the critical care setting following injury, infection and critical illness.

Public Health Relevance

Risk factors for many chronic and critical illnesses, which often require surgical intervention, ar increased in the VA population. Following accidental injury or surgical trauma, patients in intensive care units often have high blood glucose levels, as well as high insulin levels, a symptom similar to the insulin resistance of Type 2 diabetes, even with no pre-existing symptoms of diabetes. However, little is known as to the basic reasons for this insulin resistance and the mechanisms of recovery. Skeletal muscle plays a central role in whole-body glucose metabolism. The proposed studies are vital to understand the role of skeletal muscle in the acute development of insulin resistance following injuries and infections. If we can understand how acute insulin resistance develops, and if the causative factors can be determined, it may be possible to treat the metabolic derangements following injuries to specifically correct the abnormalities, increase recovery and decrease patient morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000611-07
Application #
9339492
Study Section
Endocriniology A (ENDA)
Project Start
2009-10-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Birmingham VA Medical Center
Department
Type
DUNS #
082140880
City
Birmingham
State
AL
Country
United States
Zip Code
35233
Franklin, J Lee; Bennett, William L; Messina, Joseph L (2017) Insulin attenuates TNF?-induced hemopexin mRNA: An anti-inflammatory action of insulin in rat H4IIE hepatoma cells. Biochem Biophys Rep 9:211-216
Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A et al. (2017) Polytrauma-induced hepatic stress response and the development of liver insulin resistance. Biochim Biophys Acta Mol Basis Dis 1863:2672-2679
Franklin, J Lee; Amsler, Maggie O; Messina, Joseph L (2016) Prenylation differentially inhibits insulin-dependent immediate early gene mRNA expression. Biochem Biophys Res Commun 474:594-598
Akscyn, Robert M; Franklin, John L; Gavrikova, Tatyana A et al. (2016) Skeletal muscle atrogene expression and insulin resistance in a rat model of polytrauma. Physiol Rep 4:
Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A et al. (2015) A rat model of concurrent combined injuries (polytrauma). Int J Clin Exp Med 8:20097-110