Overview of Metabolism
Peds 231April 9, 2009Julie Theriot
Outline• What is metabolism and why should you care
about it?• Summary of human carbohydrate metabolism
and connections to diabetes• Metabolism in history and society: the twin
“epidemics” of obesity and diabetes• New approaches to understanding metabolic
regulation in diabetes
Metabolism: You are what you eat1. Extract components of
biological macromoleculesfrom food and rebuild intohuman tissues
2. Obtain energy stored inchemical bonds in food andconvert into a useful form
Fat energy density = 9 kcal/g2000 Calorie (kcal) per day diet = 0.5 lb of fat if stored1 lb/year weight gain = 10 excess Calories (kcal) per day
Metabolic flux: molecular synthesis anddegradation occur simultaneously
Biomolecules are constructed from a relatively small number ofbuilding blocks
Biosynthetic and degradative pathways for the same molecule tendto be segregated and reciprocally regulated
Flux through all pathways is remarkably balanced and adaptable
One typical reaction: phosphorylationof glucose (first step in glycolysis)
About 1/3 of protein domains conserved acrossall kingdoms are devoted to metabolism
Energy release by controlled oxidation
Energy released by oxidation of foodcaptured in activated carrier molecules
The metabolic web is driven bycoupling of favorable reactions(e.g. ATP hydrolysis) tounfavorable reactions (e.g.synthesis of glucose-6-phosphate)
Glycolysis and other modes of foodoxidation generate ATP and NAD(P)H
Glycogen: high density storage form of glucoseSynthesized when blood sugar is highPrimarily made in liver and muscle
tissueBroken down when blood sugar is lowGlucose from liver glycogen can be
released into bloodstream; muscleglycogen can only be used in themuscle
Well-fed rat liver Fasting rat liver
Polymer of glucose residues;Compare starch and cellulose
Gluconeogenesis converts lactate oralanine back into glucose
“Bypass enzymes” essentially allowreversal of “irreversible” steps inglycolysis
Requires net energy inputEnzymes required for gluconeogenesisare sequestered to prevent futile cycles
Expressed primarily in liverLocated in noncytoplasmic
compartments (ER, mitochondria)Regulated reciprocally with
glycolytic enzymes (e.g. AMPactivates glycolysis, inhibitsgluconeogenesis)
Also regulated by hormones
Regulation of flux through metabolicpathways:
Availability of substratesConcentration of enzymes
Balance between synthesis (usually regulated at the level oftranscription) and degradation (usually via ubiquitination)
Activity of enzymesReversible allosteric interactions
When a pathway intermediate is an allosteric effector for an enzyme in itsown pathway, it will usually inhibit upstream enzymes (feedbackinhibition) and activate downstream enzymes (feedforward activation)
Reversible covalent modifications (e.g. phosphorylation; oftendue to hormonal regulation)
Key points of pathway regulation are the first committedstep and any irreversible step (large negative ΔG)
Insulin signals the well-fed stateIncreases:
glucose uptake by muscle and adipose tissue
glycolysisglycogen synthesistriacylglycerol synthesissynthesis of DNA, RNA, protein
Decreases:gluconeogenesisglycogen breakdownfatty acid oxidationprotein degradation
Regulation of blood sugar by thepancreatic “glucostat”
Insulin also regulates glucoseuptake in muscle and fat cells
Glycolytic rate in pancreas and liver cellsdirectly reflects blood glucose levelOTHER CELLS CANNOT MEASUREBLOOD GLUCOSE!
Human metabolism is coordinatelyregulated among different organs
The well-fed state The fasting state
Stages in glucose homeostasis
Diabetes: Tissuesthink that they arestarving eventhough blood sugarremains high
Chronic hyperglycemia causessevere diabetic complications
Glucose excreted in urine, massive increase inurine production, dehydration
Stress on kidneys can result in renal failureHigh blood pressure due to increase in blood
osmolytes can lead to retinopathyFrequent fungal infections due to low pH
environmentSwelling of tissues that convert glucose into
sorbitol, including lens and nerve, andmicrovascular pathologies resulting inperipheral neuropathies and retinal damage
Non-enzymatic glycosylation of blood vessellining promotes atherosclerosis, stroke, andcellulitis
HyperlipidemiaKetoacidosis (primarily in type I)
5 mM ~ 100 mg/dL
Consequences of diabetic hyperglycemia
Brownlee, 2001, Nature 414: 813
Osmotic stressPeripheral neuropathy
Buildup of glycosylatedproteins in retinal bloodvessels, kidney glomeruli
Effects on blood flow,inflammation
Effects on endothelialcells
Glycolytic pathway
Origins of diabetesType I: Destruction of insulin-producing pancreatic islet cells
(often autoimmune, can be triggered by viral infection)Type II: Related to overall metabolic state (positive feedback loop?)
Insulin resistance usually precedes beta cell dysfunction
“Metabolic syndrome”
Prevalence: Up to 25% of US adults
Considered to be a strong predictorof Type II diabetes
Metabolism in human history50,000 years:
Food was scarce and seasonal, famines were frequentMetabolic adaptations for efficient storage enabled survival
100 years:Food is abundant in many societies, year-round
Consequence: WIDESPREAD METABOLIC DISORDERS...including obesity and type 2 diabetes
An extreme case: The Pima people, southern ArizonaCaucasians in the American Southwest:
6% have type 2 diabetes, average age of onset 60
Pimas in the American Southwest:60% have type 2 diabetes, average age of onset 36
Ongoing longitudinal studies with NIH since 1963:http://diabetes.niddk.nih.gov/dm/pubs/pima/index.htm Gila River Arts Center
Flux balance gives steady-state body massBMI = body mass index (kg/m2)
1998
Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1998, 2007
(*BMI ≥30, or about 30 lbs. overweight for 5’4” person)
2007
1990
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
www.cdc.gov
Medical consequences of obesity
Note these are CORRELATIONS, not proof of causationBut, if obesity were causative, these numbers predict that a US population with BMI <25 would reduce:
-Coronary heart disease by 25%-Strokes and congestive heart failure by 35%-Type II diabetes by 70%
Obesity epidemic largely caused bychanges in environment, activity
Eat more:Increased food availability
Calories/person/day has increased 15% since 1970$ spent on food outside the home has doubled since 1970
Increased portion size12 oz. Coke at McDonald’s: king-size in 1950’s, child-size now
Increased energy density (kcal/gm)High fat foods, low fat/low cal foods
Do less:Increased sedentary leisure time activities
TV, video games, computersDecreased occupational physical activityIncreased use of automobiles
News Flash:
Cookie Monster to eatfewer cookies, more fruit
CDC
Prevalence of childhood obesity
BUT: Obesity is not the onlycontributing factor for Type II diabetes
Many overweight people are not diabeticMany diabetics are not overweightHow can we find the other genetic and environmental factors?
Frayling, 2007, Nature Rev. Genet. 8: 657
Genetic variation contributes tometabolic differences
CANDIDATE GENES:Example:Leptin knockoutmouse
Peptide secreted by adiposetissue, signals satiety
Note most obese peoplehave normal or increasedleptin levels; tissues areleptin resistant
Alternative approach, GENOME-WIDE ASSOCIATION: examinehuman variations and find correlations with obesity and type II diabetes
Predictive value may be low, but genetic variations associated withincreased risk can point the way toward new drug targets, etc.
Rate of identification of new genes is accelerating…
Challenges: Diabetes is a complex, chronic metabolic imbalanceMetabolic flux in a human is HUGE and RAPID: imbalances are
very, very small for syndromes that unfold over yearsIndividual genetic variation can produce different outcomes for the
same environmentEnvironmental variation can produce different outcomes for the
same genetic background
Most risk effects are modest
Interactions are unknown
Many genes are associatedwith beta-cell function ratherthan insulin resistance
What can we do with thisknowledge?
Florez, 2008, J. Clin. Endocrin. Metab. 93:4633
Knowledge of genes and risk factors isincomplete; interactions are complex
Doria et al., 2008, Cell Metab. 8:186
New approaches to prevention and treatment mustrely on interdisciplinary research… what will you do?