An unintended consequence of modernization is a dramatic increase in obesity and the prevalence of Metabolic Syndrome and Type 2 Diabetes (T2DM). Insulin resistance is a hallmark of these conditions. This proposal focuses on the pathogenesis of insulin resistance in skeletal muscle, as it comprises the majority of insulin sensitive tissue. High fat (HF) feeding results in insulin resistance and an increase in muscle extracellular matrix (ECM) collagen. Pharmacological or genetic manipulations that reverse or prevent the increase in ECM increases capillary density and corrects the insulin resistant state. The increase in collagen contributes to insulin resistance in skeletal muscle by binding to integrin receptors. Integrins are ubiquitously expressed dimers containing an ? (itg?) and ? (itg?) subunit. The effect of integrins depends on the specific integrin receptor and the cell typ that expresses it. A seminal finding is that the role of integrins is uniquely amplified in mice made insulin resistant by a HF diet. This key finding is likely due to the increased quantity of their ECM ligands. Insulin resistance occurs in both skeletal muscle and the vascular structures that perfuse it. Recent data suggests that insulin resistance at these sites is mediated by integrins. The hypothesis tested in the current proposal is that muscle insulin resistance in response to a HF diet occurs because ECM-Integrin interaction impedes insulin access to muscle through effects on endothelial cells and impairs insulin sensitivity by effects directly on muscle fibers. This hypothesis will be addressed in lean and HF-fed insulin resistant mice with muscle and endothelial inducible deletions of genes for the highly conserved proteins that are common to integrin receptors and their key cytosolic regulatory sites. Insulin action will be measured using the hyperinsulinemic, euglycemic clamp in the conscious mouse combined with isotopes to obtain an index of muscle glucose uptake. Indices of insulin access will be obtained by assessing conjugated-fluorescent insulin movement from the vessels, vascular reactivity, and angiogenesis. Muscle glucose uptake and metabolism will be assessed in vivo and in vitro. Experiments in Specific Aim 1 are designed to test whether integrins and the IPP contribute to muscle insulin resistance by impeding insulin access to muscle of HF-fed mice. Experiments in Specific Aim 2 will test whether integrins and the IPP contribute to muscle insulin resistance by impairing insulin sensitivity directly on the muscle itself in HF-fed mice. The experiments proposed herein will define the means by which the integrin system couples ECM remodeling to the pathology of insulin resistance and identify potential therapeutic targets for treatment of insulin resistance, Metabolic Syndrome and T2DM.

Public Health Relevance

Obesity, insulin resistance, and T2DM are critical to understand as their incidence is increasing in western and developing societies with a trajectory that is rapidly diminishing the quality of life of those afflicted and dramatically increasing the financial demand on the health care dollar. The proposed research will lead to a better understanding of the pathogenesis of skeletal muscle insulin resistance resulting from high fat feeding and the development of T2DM. With this will come improved therapies that target the underlying cause of metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054902-16A1
Application #
9105000
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Laughlin, Maren R
Project Start
1999-02-15
Project End
2021-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Hughey, Curtis C; Trefts, Elijah; Bracy, Deanna P et al. (2018) Glycine N-methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates. J Biol Chem 293:11944-11954
Williams, Ian M; McClatchey, P Mason; Bracy, Deanna P et al. (2018) Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo. Diabetes 67:1962-1975
Wasserman, David H; Wang, Thomas J; Brown, Nancy J (2018) The Vasculature in Prediabetes. Circ Res 122:1135-1150
Kjøbsted, Rasmus; Hingst, Janne R; Fentz, Joachim et al. (2018) AMPK in skeletal muscle function and metabolism. FASEB J 32:1741-1777
Lark, Daniel S; Kwan, Jamie R; McClatchey, P Mason et al. (2018) Reduced Nonexercise Activity Attenuates Negative Energy Balance in Mice Engaged in Voluntary Exercise. Diabetes 67:831-840
Hughey, Curtis C; James, Freyja D; Bracy, Deanna P et al. (2017) Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice. J Biol Chem 292:20125-20140
Williams, Ashley S; Trefts, Elijah; Lantier, Louise et al. (2017) Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance. Diabetes 66:325-334
Kang, Li; Mokshagundam, Shilpa; Reuter, Bradley et al. (2016) Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice. Diabetes 65:1590-600
Williams, Ian M; Otero, Yolanda F; Bracy, Deanna P et al. (2016) Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure. Hypertension 67:983-91
Robciuc, Marius R; Kivelä, Riikka; Williams, Ian M et al. (2016) VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications. Cell Metab 23:712-24

Showing the most recent 10 out of 63 publications