Insulin Signaling – Insulin Resistance
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Transcript of Insulin Signaling – Insulin Resistance
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!