L-cysteine, PIP3 and Insulin Signaling in Diabetes Abstract: Diabetes has become an epidemic and remains a major public health issue worldwide. The primary purpose of this application is to discover the mechanisms by which L-cysteine (LC) supplementation improves glucose homeostasis in diabetic patients. Diabetic patients have lower blood levels of L-cysteine (LC), hydrogen sulfide (H2S), and glutathione (GSH). Supplementation with cysteine-rich proteins (whey protein and ?-lactoalbumin), LC, or N-acetyl cysteine (NAC) has been shown to lower glycemia in diabetic animal studies. However, the molecular mechanism by which LC increases glucose utilization and lowers glycemia is not known. Our study demonstrated activation of PI3K and inhibition of NF-?B in the liver and reduction in blood glucose in LC supplemented ZDF rats, a model of type 2 diabetes. Further studies using an adipocyte cell model showed that LC caused PI3K activation, PTEN inhibition, and an increase in PIP3 (phosphatidylinositol-3,4,5 trisphosphate) and glucose utilization in high glucose (HG)-treated cells. The effect of LC on PIP3 and glucose utilization was prevented by PAG (propargylglycine), an inhibitor of cystathionine-?-lyase (CSE), which catalyzes H2S formation from LC. Treatment with LC, H2S, or PIP3 increased the phosphorylation of IRS1, AKT, and PKC?/?, as well as GLUT4 activation and glucose utilization in HG-treated cells. These studies provide evidence for a novel molecular mechanism by which LC can increase PIP3 and upregulate the metabolic actions of insulin, thus improving glucose metabolism. This proposal will test the hypothesis that LC upregulates both the insulin dependent (PI3K/AKT/PKC?/?) and insulin independent (SIRT1, AMPK) signaling cascades of glucose metabolism mediated by PIP3 upregulation. Data will be analyzed statistically. The understanding and validation of the mechanisms by which LC supplementation improves glucose homeostasis and lowers glycemia should support the design of clinical interventions using novel molecules (containing sulfide and cysteine moieties) to improve glucose metabolism and prevent insulin resistance (IR) in diabetes. The long-term goal is to discover a relatively low-cost dietary supplement that could be used as an adjuvant therapy for IR prevention in T2D.

Public Health Relevance

Type 2 diabetes is associated with impaired glucose metabolism. The primary purpose of this application is to discover the mechanisms by which L-cysteine (LC) supplementation improves glucose homeostasis in diabetes. Our published studies and those of other investigators have demonstrated that oral supplementation with L-cysteine is very effective at increasing glucose metabolism and reducing blood glucose. However, we need to understand the mechanisms by which L-cysteine supplementation up regulates glucose metabolism. We will perform studies with diabetic animals. These studies will increase the understanding of and provide validation for the mechanisms by which LC supplementation reduces glycemia, which should in turn lead to the design of clinical interventions using novel molecules (containing sulfide and cysteine moieties) to improve glucose metabolism and prevent CVD in diabetes. Type 2 diabetes (T2D) is treated with diet and oral hypoglycemic drugs. Intensive blood glucose control dramatically reduces the devastating complications that result from poorly controlled diabetes. However, for many patients, achieving tight glucose control is difficult with current regimens. Thus, understanding o new mechanisms is needed for the development of a novel adjuvant therapy to achieve better control of glycemia and improve the lives of the diabetic patient population. The long-term goal is to discover a relatively low-cost dietary supplement that could be used as an adjuvant therapy for CVD prevention in T2D.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT007442-01A1
Application #
8629232
Study Section
Special Emphasis Panel (ZAT1)
Program Officer
Alekel, D Lee
Project Start
2014-09-01
Project End
2016-06-30
Budget Start
2014-09-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Jain, Sushil K; Kanikarla-Marie, Preeti; Warden, Cassandra et al. (2016) L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats. Mol Nutr Food Res 60:1090-8
Kanikarla-Marie, Preeti; Jain, Sushil K (2016) 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). J Steroid Biochem Mol Biol 159:94-101
Achari, Arunkumar Elumalai; Jain, Sushil K (2016) L-Cysteine supplementation increases adiponectin synthesis and secretion, and GLUT4 and glucose utilization by upregulating disulfide bond A-like protein expression mediated by MCP-1 inhibition in 3T3-L1 adipocytes exposed to high glucose. Mol Cell Biochem 414:105-13
Kanikarla-Marie, Preeti; Jain, Sushil K (2016) Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes. Free Radic Biol Med 95:268-77
Jain, Sushil K; Kahlon, Gunjan; Bass, Pat et al. (2015) Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients? Antioxid Redox Signal 23:688-93
Manna, Prasenjit; Jain, Sushil K (2015) Phosphatidylinositol-3,4,5-triphosphate and cellular signaling: implications for obesity and diabetes. Cell Physiol Biochem 35:1253-75
Kanikarla-Marie, Preeti; Jain, Sushil K (2015) Role of Hyperketonemia in Inducing Oxidative Stress and Cellular Damage in Cultured Hepatocytes and Type 1 Diabetic Rat Liver. Cell Physiol Biochem 37:2160-70
Manna, Prasenjit; Jain, Sushil K (2015) Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies. Metab Syndr Relat Disord 13:423-44
Kanikarla-Marie, Preeti; Jain, Sushil K (2015) Hyperketonemia (acetoacetate) upregulates NADPH oxidase 4 and elevates oxidative stress, ICAM-1, and monocyte adhesivity in endothelial cells. Cell Physiol Biochem 35:364-73
Manna, Prasenjit; Jain, Sushil K (2014) Effect of PIP3 on adhesion molecules and adhesion of THP-1 monocytes to HUVEC treated with high glucose. Cell Physiol Biochem 33:1197-204

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