http://www.youtube.com/watch?v=6q5UoZuRZrk

Sleeping 1.0Sitting 1.2Laboratory work 2.5Golf 4.9Skiing 7.4Basketball 12

Energy Expenditure (kcal/min)

1. Energy? Glucose, protein, and fatty acid: Chemical bond!

2. Enzymes? Kinase, isomerase, and dehydrogenase: Transition state

3. Reactions? Phosphorylations, dehydration, oxidation

4. Macromolecules? Building blocks

5. Control? Energy balance and intermediates

6. Metabolic diseases? Diabetes mellitus

Metabolic Regulation

O

H

HO

HO

H

H

HO

OHHH

OH

P

O

HO-O

O-

N

NN

N

NH2

O

HOH

OP-O

O-

O

Q. Why ATP? 5P

Cell constituent

Number of molecules per cell

Molecules synthesized per second

Molecules of ATP required per second for synthesis

DNA 1 0.00083  60,000

RNA 15,000 12.5 75,000

Polysaccharides 39,000 32.5  65,000

Lipids 15,000,000 12,500.0 87,000

Proteins 1,700,000 1,400.0  2,120,000

Regulation of Glycolysis/Energy

Sleeping/SittingIn Biochemistry Class Thinking/Studying Biochemistry

Glucose

Glucose 6-phosphate

Fructose 6-phosphate

Fructose 1,6-bisphosphate

Phosphoenolpyruvate

Pyruvate

Hexokinase

Glycogen

PFK

Pyruvate kinase

ATP/AMP

ATP/AMP

Glucose

Glucose 6-phosphate

Fructose 6-phosphate

Fructose 1,6-bisphosphate

Phosphoenolpyruvate

Pyruvate

PFK

Pyruvate kinase

GluconeogenesisThe Liver: Gluconeogenesis

Metabolism: Overview

Proteins

Carbohydrates

Lipids

Amino acids

Glucose

Fatty acids Glycerol

Glycolysis

Pyruvate

Acetyl-CoA

Citric Acid Cycle

CO2

Oxidative Phosphorylation

ATPNADH

NADHFADH2

ATP H2O

O2

Type I Diabetes

• Low or absent endogenous insulin• Dependent on exogenous insulin for life• Onset generally < 30 years• 5-10% of cases of diabetes• Onset sudden

– Symptoms: 3 P’s: polyuria, polydypsia, polyphagia

Type II Diabetes

• Insulin levels may be normal, elevated or depressed– Characterized by insulin resistance, – diminished tissue sensitivity to insulin,– and impaired beta cell function (delayed or inadequate insulin release)

• Often occurs >40 years

Type II Diabetes

• Risk factors: family history, sedentary lifestyle, obesity and aging

• Controlled by weight loss, oral hypoglycemic agents and or insulin

Diabetes Trends Among Adults in the U.S.

1990 1995

2001

Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286:10.

1998

Obesity Trends Among U.S. Adults

2006

1990

No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30%

BMI 30, or about 30 lbs. overweight for 5’4” person

Q. Why is diabetes related to obesity? 5P

Carbohydrate Digestion

Paul Langerhans1869, islets of Langerhans

Charles Best and Frederick Banting1921, insulin

History

Insulin Secretion

Insulin: Controlling Energy Function

Insulin

Crosstalk between tissuesMetabolic interchanges: Interconnected

1. A state in which carbohydrate and lipid metabolism are improperly regulated by insulin

2. 143 million worldwide/16 million in US

3. $100 billion/year/US

4. Five times increase from 1990 to 2000

5. Type I: insulin-dependent, autoimmune destruction of b cells

6. Type II: insulin-resistance

7. Plasma glucose (5 mM) -> Glut2 transporter -> b cell -> high ATP/ADP

K+ channel closed -> cell depolarized -> opening voltage sensitive Ca2+ channel -> intracellular Ca2+ increased -> insulin release -> Glut4 -> glucose uptake

Diabetes mellitus

Muscle Insulin Resistance

Increased Lipolysis

Cell Compensation

Cell Decompensation

Increased GluconeogenesisImpaired Glucose Tolerance

Diabetes

Type 2 Diabetes Stage

Increased fatty acid

hyperinsulinemia

Increased glucose

Aging

Genes

Obesity

Sedentary lifestyle

Impaired Insulin Release

Insulin Signaling I: Major Players

Insulin Signaling II: Glucose Uptake Pathway

PC1: prohormone convertase1POMC: pro-opiomelanocortin

Insulin Resistance

Kinases: Carbohydrate, protein, and lipid phosphorylation

Insulin Signaling III: Simplified Network

• Insulin receptor Insulin mimetic• Glucagon receptor Lower fasting glucose• b-3 Adrenergic receptor Increase lipolysis• GLP receptor Increse insulin secretion• AMP-activated kinase Increase glucose transport• Protein kinase C Block receptor desensitization• MAP kinase Block receptor desensitization• Ceramide activated kinase Block receptor desensitization• IkB kinase Block receptor desensitization• GSK-3 Activate glycogen synthase• PTP1b Block receptor dephosphorylation• LAR Block receptor dephosphorylation• PP1 Activate glycogen synthase• SHIP2 Increase PIP3 stimulated• PTEN Glucose trnasport• Synip Increase glucose transport• PPARg Insulin sensitizer• HNF4 Increase insulin secretion• Sulfonylurea receptor Increase insulin secretion

Therapeutic Target

Why Phosphorylation? Kinases

O

O

NH

NH

HO

OH

L-783,281

O

O

NH

NH

HO

OH

L-767,827

Merck Research Lab

50, 000 synthetic compounds+natural products Insulin receptor overexpressed cell-based screening assay;IR immunopurified, tyrosine kinase activity assay

Zhang, et al. Science, 284, 974-977 (1999)

Take Home Message…

Diabetes prevention/treatment:

1. Exercise!

2. Calorie restriction?

Ralph Waldo Emerson

“Education is an admirable thing, but it is well to remember from time to time that nothing that is worth knowing can be taught.”

Oscar Wilde

“We are shut up in schools and college recitation rooms for ten or fifteen years, and come out at last with a bellyful of words and do not know a thing. The things taught in schools and colleges are not an education, but the means of education.”