1. Insulin Signaling – Insulin Resistance Elmus G. Beale, Professor Texas Tech University Health Sciences Center Paul L. Foster School of Medicine PhD, Baylor College of Med, 1977 Postdoc, University of Iowa Texas Tech SOM, 1984 – 2008 Paul L. Foster SOM, 2008 – present Expertise Adipocyte PEPCK AMPK in C. elegans Medical education

2. Themes • Insulin function / physiology • Insulin signaling • Metabolic Syndrome = Insulin Resistance Syndrome • Mechanisms of insulin resistance

3. Physiological Effects

4. Fuel Homeostasis—The Common View Glucose Insulin Target organs: Skeletal Muscle Liver White Adipose Tissue b-cells

5. Fuel Homeostasis—The Better View Glucose Insulin Target organs: Skeletal Muscle Liver White Adipose Tissue b-cells Target organs: Skeletal Muscle Liver White Adipose Tissue b-cells Fatty Acids

6. Insulin Signaling Then (1980)...

7. Insulin Signaling Now (Sort of...) Plasma Membrane GSK3 Glycogen Synthesis Akt IR IRS PI3-K PDK FOXO1 PEPCK PGC1a I eNOS Vascular Dilation TSC1/2 Outside Inside S6K Translation RHEB TOR Rap Transcript, Growth, Differen, Prot Synth IR SHC GRB2 SOS RAS RAF MEK MAPK I

8. Metabolic Syndrome =Insulin Resistance Syndrome • Obesity, lifestyle, genetics • Insulin resistance = the common etiology • Type 2 diabetes mellitus • Hyperinsulinemia insulin deficiency • Impaired glucose tolerance  hyperglycemia • Dyslipidemia • Hypertension • Cardiovascular Disease • Nephropathy • Others (PCOS, Cancer, sleep apnea, arthritis…)

9. Lipotoxicity is a Key Factor • Adipocytes can tolerate fat • High fat is toxic in Non-adipocytes • Insulin resistance • Target tissue dysfunction  metabolic syndrome • b-cell “burnout”

10. Regulators of Insulin Sensitivity • Humoral factors • Plasma Lipids • Hormones & cytokines/adipokines • Intracellular factors • Signaling pathways

11. Adipocytes Modulate Insulin Sensitivity(as do the Brain and the Gut) Adapted from TEM, 15(3), EG Beale, RE Hammer, B Antoine and C Forest, Disregulatedglyceroneogenesis: PCK1 as a candidate diabetes and obesity gene, 129-135 (2004), with permission from Elsevier.

12. Obesity and Macrophages Macrophages Adapted from TEM, 15(3), EG Beale, RE Hammer, B Antoine and C Forest, Disregulatedglyceroneogenesis: PCK1 as a candidate diabetes and obesity gene, 129-135 (2004), with permission from Elsevier.

13. Implication of Adipose Tissue • Lipodystrophy (leptin deficiency)  insulin resistance • Genetic leptin deficiency  insulin resistance • Leptin resistance (obesity)  insulin resistance • Rosiglitazone targets adipose tissue PPARg

14. Intracellular “Resistance” Candidates Plasma Membrane GSK3 Glycogen Synthesis Akt IR IRS PI3-K PDK FOXO1 PEPCK PGC1a I eNOS Vascular Dilation TSC1/2 Outside Inside S6K Translation RHEB TOR Rap Transcript, Growth, Differen, Prot Synth IR SHC GRB2 SOS RAS RAF MEK MAPK I

15. Metformin Sensitizes via AMPK(How?) Plasma Membrane GSK3 Glycogen Synthesis Akt IR IRS PI3-K PDK FOXO1 PEPCK PGC1a I eNOS Vascular Dilation TSC1/2 Via ATM & LKB1? AMPK Metformin S6K Translation Outside Inside Target? RHEB TOR Rap Transcript, Growth, Differen, Prot Synth IR SHC GRB2 SOS RAS RAF MEK MAPK I

16. Known Insulin Resistance Genes • Insulin Receptor • Insulin Receptor Substrate 1 (IRS1) • Glucokinase Regulator (GCKR) • Insulin-like Growth Factor 1 (IGF1) • PPARg • GWAS: ≤40 loci discovered to date • Majority: • Affect b-cell function; or • Are of unknown function • Minority map to insulin resistance

17. Take-home Points • Insulin has many physiological functions • Insulin resistance = common etiology for metabolic syndrome (includes nephropathy) • Insulin resistance etiologies are complex • Hyperinsulinemia • Hyperlipidemia & consequent lipotoxicity • Humeral factors (Adipose tissue, gut, macrophages) • Intracellular signaling pathways with crosstalk • PI3K – Akt pathway • Ras – MAPK pathway

18. Thank you!