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Sleeping1.0 Sitting1.2 Laboratory work2.5 Golf4.9 Skiing7.4 Basketball12 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

Q. Why ATP? 5P

Cell constituent Number of molecules per cell Molecules synthesized per second Molecules of ATP required per second for synthesis DNA ,000 RNA15, ,000 Polysaccharides39, ,000 Lipids15,000,00012, ,000 Proteins1,700,0001, ,120,000

Regulation of Glycolysis/Energy Sleeping/Sitting In 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 Glucose Glucose 6-phosphate Fructose 6-phosphate Fructose 1,6-bisphosphate Phosphoenolpyruvate Pyruvate PFK Pyruvate kinase

Gluconeogenesis The Liver: Gluconeogenesis

Metabolism: Overview Proteins Carbohydrates Lipids Amino acids Glucose Fatty acids Glycerol Glycolysis Pyruvate Acetyl-CoA Citric Acid Cycle CO 2 Oxidative Phosphorylation ATP NADH FADH 2 ATPH2OH2O O2O2

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

1998 Obesity Trends Among U.S. Adults 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 Langerhans 1869, islets of Langerhans Charles Best and Frederick Banting 1921, insulin History

Insulin Secretion

Insulin: Controlling Energy Function Insulin

Crosstalk between tissues Metabolic interchanges: Interconnected

1.A state in which carbohydrate and lipid metabolism are improperly regulated by insulin million worldwide/16 million in US 3.$100 billion/year/US 4.Five times increase from 1990 to Type I: insulin-dependent, autoimmune destruction of  cells 6.Type II: insulin-resistance 7.Plasma glucose (5 mM) -> Glut2 transporter ->  cell -> high ATP/ADP K + channel closed -> cell depolarized -> opening voltage sensitive Ca 2+ channel -> intracellular Ca 2+ increased -> insulin release -> Glut4 -> glucose uptake Diabetes mellitus

Impaired Insulin Release

Insulin Signaling I: Major Players

Insulin Signaling II: Glucose Uptake Pathway

PC1: prohormone convertase1 POMC: pro-opiomelanocortin Insulin Resistance

Kinases: Carbohydrate, protein, and lipid phosphorylation

Insulin Signaling III: Simplified Network

Insulin receptorInsulin mimetic Glucagon receptorLower fasting glucose  -3 Adrenergic receptorIncrease lipolysis GLP receptorIncrese insulin secretion AMP-activated kinaseIncrease glucose transport Protein kinase CBlock receptor desensitization MAP kinaseBlock receptor desensitization Ceramide activated kinaseBlock receptor desensitization I  B kinaseBlock receptor desensitization GSK-3Activate glycogen synthase PTP1bBlock receptor dephosphorylation LARBlock receptor dephosphorylation PP1Activate glycogen synthase SHIP2Increase PIP3 stimulated PTENGlucose trnasport SynipIncrease glucose transport PPAR  Insulin sensitizer HNF4Increase insulin secretion Sulfonylurea receptorIncrease insulin secretion Therapeutic Target

Why Phosphorylation? Kinases

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.”