Insulin Signaling – Insulin ResistanceElmus G. Beale, ProfessorTexas Tech University Health Sciences CenterPaul 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

Themes

• Insulin function / physiology• Insulin signaling• Metabolic Syndrome = Insulin

Resistance Syndrome• Mechanisms of insulin resistance

Physiological Effects

Insulin

GlucoseUptake Glycogen

Synthesis

Gluco-neogenesis

Satiety

CellGrowth

ProteinSynthesis

& GeneExpression

Vaso-dilation

Lipogenesis

Glucose

Insulin

Fuel Homeostasis—The Common View

b-cells

Target organs:Skeletal Muscle

LiverWhite Adipose Tissue

Glucose

Insulin

Fuel Homeostasis—The Better View

b-cells

Target organs:Skeletal Muscle

LiverWhite Adipose Tissue

b-cells

Target organs:Skeletal Muscle

LiverWhite Adipose TissueFatty

Acids

Insulin Signaling Then (1980)...

Insulin Signaling Now (Sort of...)

IR IRS PI3-K PDK Akt FOXO1

GSK3

eNOS

GlycogenSynthesis

PEPCKPGC1a

VascularDilation

IR SHCGRB

2SOS

RAS MEK

Transcript,Growth,Differen,

Prot Synth

RAF MAPK

PlasmaMembrane

InsideOutside

I

I

Translation

TSC1/2

RHEBTORRap

S6K

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…)

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”

Regulators of Insulin Sensitivity

1. Humoral factors– Plasma Lipids– Hormones & cytokines/adipokines

2. Intracellular factors– Signaling pathways

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.

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.

Macrophages

Implication of Adipose Tissue

• Lipodystrophy (leptin deficiency) insulin resistance

• Genetic leptin deficiency insulin resistance• Leptin resistance (obesity) insulin resistance• Rosiglitazone targets adipose tissue PPARg

Intracellular “Resistance” Candidates

IR IRS PI3-K PDK Akt FOXO1

GSK3

eNOS

GlycogenSynthesis

PEPCKPGC1a

VascularDilation

IR SHCGRB

2SOS

RAS MEK

Transcript,Growth,Differen,

Prot Synth

RAF MAPK

PlasmaMembrane

InsideOutside

I

I

Translation

TSC1/2

RHEBTORRap

S6K

Metformin Sensitizes via AMPK(How?)

IR IRS PI3-K PDK Akt FOXO1

GSK3

eNOS

GlycogenSynthesis

PEPCKPGC1a

VascularDilation

IR SHCGRB

2SOS

RAS MEK

Transcript,Growth,Differen,

Prot Synth

RAF MAPK

PlasmaMembrane

InsideOutside

I

I

Translation

TSC1/2

RHEBTORRap

S6K

AMPKMetformin

Target?

Via ATM& LKB1?

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

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

Thank you!