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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.”
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