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?