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 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 Insulin function / physiology Insulin signaling Metabolic Syndrome = Insulin Resistance Syndrome Mechanisms of insulin resistance

3. Physiological Effects Insulin  Glucose Uptake  Glycogen Synthesis  Gluco- neogenesis  Satiety  Cell Growth  Protein Synthesis  &  Gene Expression  Vaso-dilation  Lipogenesis

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

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

6. Insulin Signaling Then (1980)...

7. Insulin Signaling Now (Sort of...) IR IRS PI3-K PDK Akt FOXO1 GSK3 eNOS Glycogen Synthesis Glycogen Synthesis PEPCK PGC1  PEPCK PGC1  Vascular Dilation Vascular Dilation IR SHC GRB2 SOS GRB2 SOS RAS MEK Transcript, Growth, Differen, Prot Synth Transcript, Growth, Differen, Prot Synth RAF MAPK Plasma Membrane InsideOutside I I I I Translation TSC 1/2 RHEB TOR Rap TOR Rap S6K

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…) 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 –  -cell “burnout” Adipocytes can tolerate fat High fat is toxic in Non-adipocytes – Insulin resistance – Target tissue dysfunction  metabolic syndrome –  -cell “burnout”

10. Regulators of Insulin Sensitivity 1.Humoral factors – Plasma Lipids – Hormones & cytokines/adipokines 2.Intracellular factors – Signaling pathways 1.Humoral factors – Plasma Lipids – Hormones & cytokines/adipokines 2.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, Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene, 129-135 (2004), with permission from Elsevier.

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

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

14. Intracellular “Resistance” Candidates IR IRS PI3-K PDK Akt FOXO1 GSK3 eNOS Glycogen Synthesis Glycogen Synthesis PEPCK PGC1  PEPCK PGC1  Vascular Dilation Vascular Dilation IR SHC GRB2 SOS GRB2 SOS RAS MEK Transcript, Growth, Differen, Prot Synth Transcript, Growth, Differen, Prot Synth RAF MAPK Plasma Membrane InsideOutside I I I I Translation TSC 1/2 RHEB TOR Rap TOR Rap S6K

15. Metformin Sensitizes via AMPK (How?) IR IRS PI3-K PDK Akt FOXO1 GSK3 eNOS Glycogen Synthesis Glycogen Synthesis PEPCK PGC1  PEPCK PGC1  Vascular Dilation Vascular Dilation IR SHC GRB2 SOS GRB2 SOS RAS MEK Transcript, Growth, Differen, Prot Synth Transcript, Growth, Differen, Prot Synth RAF MAPK Plasma Membrane InsideOutside I I I I Translation TSC 1/2 RHEB TOR Rap TOR Rap S6K AMPK Metformin Target? Via ATM & LKB1?

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