T HE P UZZLE OF C OMPLEX D ISEASES NEWS 1 2 3 4 Unraveling the Causes of 5 6 nia School of Medicine in Philadelphia. 7 As the -driven epidemic of type II diabetes rages, researchers are The challenge now facing diabetes re- 8 piecing together the environmental and genetic factors behind the disease searchers, he and others note, is to sort out 9 the contribution of each factor and then use 10 “People cringe at the use of the word ‘epi- and a high risk of heart attack and stroke. that knowledge to design badly needed 11 demic’ for a chronic disease, but by all crite- Researchers are beginning to understand therapeutics. 12 ria, there’s [a diabetes 2] epidemic” in the how obesity leads to and 13 United States, says Allen Spiegel, who the other defects of diabetes. They have fin- Changing face of diabetes 14 directs the National Institute of Diabetes and gered several suspects, including fatty acids Over the years, numerous studies have point- 15 Digestive and Kidney Diseases (NIDDK) in released by fat cells. ed to obesity as a major risk factor for dia- 16 Bethesda, Maryland. But there’s more to diabetes 2 than obe- betes. “In every single racial or ethnic group, 17 The number of adults with diabetes in sity. Like cancer and heart disease, it fits the obesity raises the risk,” says David M. 18 the United States increased by 49% between profile of a complex disease: Its develop- Nathan of Massachusetts General Hospital in 19 1991 and 2000, according to data from the ment is influenced both by environment— . Even so, the risk appears to be high- 20 Centers for Disease Control and Prevention particularly by such lifestyle factors as er for some groups than for others. In partic- 21 (CDC) in Atlanta, Georgia. Type II diabetes, smoking, diet, and exercise level—and by ular, indigenous peoples tend to be hard hit. 22 formerly known as maturity-onset or non– genetics—specifically the combined effects The Pima Indians of Arizona have the high- 23 insulin-dependent diabetes, accounts for of what may be subtle alterations in several est diabetes 2 incidence in the world: 50% of 24 practically all of that increase. adults have the disease. 25 Some 16 million to 17 million Other groups in the United 26 people now have the condition, States also have higher than 27 and an equal number are average risks. The American 28 thought to be “prediabetic,” Diabetes Association esti- 29 having early symptoms but not mates that 13% of African 30 yet the full-fledged version. Americans and 10.2% of His- 31 Even children are no longer panics have diabetes, com- 32 immune to diabetes 2, which pared to about 6.5% of 33 until recently rarely affected No data whites. Researchers don’t yet 34 people before middle age. Less than 4% know what accounts for these 35 Driving this epidemic, say 4% to 6% variations, but they expect 36 Spiegel and other experts, is Above 6% that both genetic and environ- 37 the continuing increase in obe- mental factors come into play. 38 sity that is, in turn, fueled by a Recent studies also point to 39 relatively new development in some disturbing new trends. 40 human history: an ample food For one, diabetes is on the rise 41 supply coupled with a seden- in many developing countries, 42 tary lifestyle. In the past, hu- as they adopt more Western- 43 mans who wanted food “had ized lifestyles and diets. The 44 to grow it, harvest it, or hunt World Health Organization 45 it,” says diabetes researcher predicts that the number of 46 Roger Unger of the University cases worldwide—now 150 1195 (2001) 47 of Texas Southwestern Medi- million—will double by 2025. , 286 48 cal Center (UT Southwestern) And even more alarming, . 49 in Dallas. The current over- A darkening scene. The percentage of adults with diabetes increased through- obesity-driven diabetes 2 is in- 50 abundance of easily available out the United States between 1990 (top) and 2000 (bottom). creasingly striking younger

51 food is, he adds, “a surprise to people, including children—a AM. MED. ASSOC J. 52 nature,” one that our bodies aren’t designed genes. For example, not every obese person situation Spiegel describes as “potentially 53 to handle. gets diabetes 2, an indication that some are devastating,” because those who contract the 54 In diabetes 2, this manifests itself primar- more genetically susceptible than others. disease early have longer to develop the some- 1278 (2000) AND 1278 (2000)

55 ily by the body becoming resistant to the hor- Uncovering such susceptibility genes is times deadly complications. , 56 mone insulin, which is needed to metabolize much more difficult than identifying the Some of the latest data on childhood dia- 23 57 the sugar glucose, although insulin produc- single-gene defects that cause cystic fibrosis betes come from Sonia Caprio of Yale Uni- 58 tion by the β cells of the pancreas usually be- and other simple hereditary diseases. But re- versity School of Medicine and her col- DIABETES CARE

59 comes impaired, too. (By contrast, the much searchers have turned up several candidates, leagues. In a study of 167 obese children, the .,

60 less common type I diabetes is caused by a most of which are involved in either the pro- Yale team found an early warning symptom ET AL 61 complete inability to produce insulin due to duction of insulin or the body’s responses to it. of diabetes—known as impaired glucose 62 β cell destruction.) Diabetics of both types “Five years ago, nobody had a clue tolerance—in 25% of children under age 10 63 develop serious complications, including kid- [about the causes of diabetes 2]. Now, there and in 21% of those between the ages of 11 64 ney failure, blindness, damage to the feet and are almost too many ideas,” says Morris and 18. Four percent of the adolescents

65 legs serious enough to require amputation, Birnbaum of the University of Pennsylva- turned out to have previously undiagnosed, SOURCE: A. H. MOKDAD

686 26 APRIL 2002 VOL 296 SCIENCE www.sciencemag.org T HE P UZZLE OF C OMPLEX D ISEASES 1 full-fledged diabetes 2, the team reported in cases, however, obese humans make large duced glucocorticoid hormones might foster 2 the 14 March issue of The New England quantities of but for unknown reasons diabetes development by influencing the 3 Journal of Medicine (NEJM). are resistant to its antiobesity and antidiabetes release of fatty acids and proteins by fat 4 And in a vicious cycle, a long-running effects. Researchers have recently linked cells. Last year, Eva Rask of Umeå Universi- 5 NIDDK study of Pima Indians has shown other fat-produced proteins to diabetes 2. ty Hospital in Sweden and her colleagues 6 that diabetic parents are more likely than One of these, called resistin, discovered found that the activity of a key enzyme need- 7 nondiabetics to have diabetic children. One by Lazar’s group and others, apparently coun- ed to synthesize glucocorticoids is increased 8 reason, says Clifton Bogardus of NIDDK, is teracts insulin’s effects, which suggests that it in the fat tissue of obese people. 9 because diabetes susceptibility genes can be contributes to resistance to the hormone. An- To test whether local overproduction of 10 passed down from parent to child. Another is other protein called adiponectin, identified the enzyme, known as 11β HSD-1, might 11 that, for unknown reasons, conditions in the by Philipp Scherer and his colleagues at contribute to diabetes, Jeffrey Flier of Beth 12 wombs of diabetic mothers raise the diabetes Albert Einstein College of Medicine in New Israel Deaconess Medical Center in Boston 13 risk of their offspring. and his colleagues attached the gene encod- 14 Some recent results have been en- ing the enzyme to a regulator sequence that 15 couraging, however. In a large, multi- allows it to be expressed only in fat. When 16 center clinical trial, the Diabetes Preven- the researchers introduced this gene into 17 tion Program (DPP) Research Group mice, glucocorticoid production went up in 18 found that it’s possible to stave off dia- the animals’ fat. As a result, they became 19 betes 2 in people at high risk of getting obese and developed severe insulin resis- 20 the disease. The trial included 3234 peo- tance and diabetes (Science, 7 December 21 ple, who were divided into three roughly 2001, p. 2166). Because the hormone re- 22 equal groups. The controls received a mains inside the fat cells, it may have caused 23 placebo plus standard recommendations the diabetes indirectly by promoting the re- 24 for improving their diets and exercise lease of fatty acids and decreasing adipo- 25 regimens. A drug treatment group took nectin secretion, Flier says. 26 an anti–diabetes 2 drug called met- Other researchers are also looking to 27 formin, and a second treatment group re- mouse models for clues to the disease. Sever- 28 ceived intensive counseling about eating al teams have recently shown that they can 29 better and exercising regularly. recreate some or all 30 As reported in the 7 February NEJM, of the symptoms of 31 the intensive lifestyle counseling reduced the disease in mice 32 the incidence of diabetes 2 by 58%, and High risk. Compared to by knocking out one 33 metformin treatment produced a 31% the Pima Indians of the or another of the 34 reduction. Previous studies had shown early 1900s (above), those genes encoding pro- 35 that lifestyle changes help, but they were of today (right) have a teins involved in 36 smaller and involved relatively homoge- much more serious obesi- transmitting insulin 37 neous populations. In contrast, almost ty problem—and the high- signals into the cell 38 half the participants in the DPP trial were est incidence of diabetes interior. 39 members of minority groups, including in the world. One such exam- 40 those at high risk such as African Amer- ple comes from 41 icans and Hispanics. The treatments proved York City, promotes Birnbaum’s team, 42 so effective in all groups, Nathan says, that insulin’s effects, but working with Shul- 43 the trial was halted a year early. its production decreases in obese persons. man’s. They found that knocking out the 44 Even the fatty acids released by fat cells gene for a pathway protein called Akt2 re- 45 Biochemistry of obesity may play a prominent role in promoting in- sulted in decreased glucose uptake by the an- 46 Given the firm links between obesity and di- sulin resistance, as recently shown by Gerald imals’ muscle tissue (Science, 1 June 2001, 47 abetes 2, researchers are working hard to un- Shulman of Yale University School of p. 1728). In another prime insulin target, the 48 cover the biochemical connections. They Medicine, Gunter Boden of Temple Univer- liver, the hormone could no longer suppress 49 now have several good leads to how obesity sity School of Medicine in Philadelphia, and glucose synthesis as it normally would. 50 might lead to insulin resistance and impaired others. These researchers found, for exam- Overall, Birnbaum says, the knockout mice 51 glucose tolerance. ple, that in obese people fatty acids accumu- have symptoms reminiscent of glucose intol- 52 One major discovery involves what late in muscle, a prime insulin target that re- erance in humans. 53 Mitch Lazar of the University of Pennsylva- moves glucose from the bloodstream and 54 nia Medical Center in Philadelphia calls “a stores it in the carbohydrate glycogen. Focus on β cells 55 sea change in our thinking” about fat. At one Further analysis, in which the researchers Although insulin resistance and the result- 56 time, fatty tissue was thought to be little used nuclear magnetic resonance to examine ing impairment in glucose tolerance are 57 more than a fat storage depot. But re- the muscle tissue of living patients, showed early signs of diabetes, malfunction or even 58 searchers have learned that fat cells play a that the fatty acids interfere with the pathway death of the insulin-producing β cells also 59 more dynamic role, releasing a variety of that transmits insulin signals into the muscle contributes to the disease. Ultimately about 60 hormonelike substances that circulate in the cell interior. As a result, glucose can no a third of diabetes 2 patients end up having 61 blood and affect other tissues. longer enter the cells and thus remains out of to take insulin. 62 These include proteins such as leptin, reach of the glycogen-synthesizing enzymes, Several factors seem to be involved in 63 which is best known for its role in suppressing allowing the sugar to build up in the blood— β-cell dysfunction, including some of the 64 appetite and obesity—effects that should in- a characteristic diabetes symptom. same culprits implicated in insulin resis-

65CREDITS: TO CORBIS;BOTTOM) (TOP J. CARTER/AP PAT hibit diabetes development. Except in rare Recent work suggests that locally pro- tance. For example, in experiments per-

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1 formed on the Zucker rat, a rodent model problem in humans. At the same time, oth- Research Institute in London, Ontario, re- 2 of obesity and diabetes, Unger’s group at er researchers are searching for human ports that a mutation in one MODY gene, 3 UT Southwestern has found that fatty acids genes that confer susceptibility to diabetes which encodes a transcription factor called 4 can trigger a form of cell death called 2—a search that illustrates the problems HNF-1-α, contributes to the high incidence 5 apoptosis in β cells. posed by diseases involving multiple genes. of diabetes 2 in the Oji-Crees, an indige- 6 The fatty acids work indirectly, the UT What’s “most worrisome,” Birnbaum says, nous population of roughly 30,000 people 7 Southwestern team found: They are first “is that the disease is caused by a series of in northwestern Ontario. About 40% of 8 converted in β cells to toxic compounds insults individually so small that they will adult Oji-Cree have diabetes 2, and Hegele 9 known as ceramides. That suggests to Unger escape detection.” and his colleagues have been searching for 10 that the β-cell loss can be prevented. “If we Indeed, so far researchers have had the the culprit genes for several years. 11 block that [ceramide-producing] pathway, greatest success with a rare, single-gene The HNF-1-α gene turned up unexpected- 12 we can block apoptosis,” he says. ly when the Ontario team ana- 13 Unger also suggests that this lyzed a series of candidate 14 fatty acid toxicity may result SOME CANDIDATE DIABETES 2 GENES genes, looking to see whether 15 from the body’s insensitivity to Mutated Gene Function Effect Linked to people with the disease carry → 16 leptin. In his view, that hor- HNF-4-α, HNF-1-β Transcription Insulin MODY (human) mutations in them. In a differ- 17 mone’s job is to keep fatty acids IPF-1, NeuroD1 factors secretion ent type of analysis, the re-

18 → from accumulating in cells that HNF-1-α Transcription Insulin MODY searchers had found several 19 aren’t designed to handle them, factor secretion Oji-Cree diabetes “hot spots” in the genome that

20 such as β cells and muscle. → seem to be linked to diabetes 2 β Glucokinase Glucose Insulin MODY 21 But cells don’t have to die to metabolism secretion in the Oji-Crees. But Hegele 22 contribute to diabetes 2 patho- says that the HNF-1-α gene 23 Calpain-10 Protease Unknown Diabetes 2 in logy: They can simply fail to se- Mexican and isn’t located in any of those 24 crete the insulin needed to handle African Americans sites. The researchers exam- 25 all the glucose the body takes in. γ → ined the gene in addition to 26 PPAR- Transcription Insulin Diabetes 2 At least in mouse models, re- factor sensitivity other candidates, he adds, “just

27 searchers can duplicate that type → so we could say we looked at 28 of malfunction. Insulin receptor Transmits Insulin Human diabetes all the usual suspects.” insulin signals sensitivity (rare); mouse 29 For example, a team led by into cell and secretion models The discovery illustrates 30 Ronald Kahn of the Joslin → another problem in pinning 31 IRS1 and -2 Insulin Insulin Mouse models Diabetes Center in Boston and signaling sensitivity down the causes of complex

32 Mark Magnuson of Vanderbilt → diseases. The Hegele team 33 University School of Medicine in Akt2 Insulin Insulin Mouse models found the HNF-1-α mutation signaling sensitivity 34 Nashville, Tennessee, found that only in the Oji-Crees. Some- β → 35 they could prevent the increase in 11- -HSD Glucocorticoid Blood→ Mouse models thing similar has been seen 36 insulin secretion that normally oc- synthesis lipids, insulin with a gene that Graeme Bell sensitivity

37 curs in response to glucose inges- → → of the University of Chicago, 38 tion by specifically inactivating UCP2 ATP Insulin Mouse models Polonsky, and their colleagues β synthesis secretion 39 the insulin receptor in the cells → linked to diabetes 2 in a 40 of mice. As a result of the conse- Resistin Fat cell Insulin Mouse studies different high-diabetes popu- 41 quent block in insulin activity, “hormone” sensitivity lation: the Mexican-Ameri-

42 glucose can’t get inside the cells Adiponectin Fat cell → Insulin Mouse, human cans of Starr County, Texas. 43 to trigger release of the hormone. “hormone” sensitivity studies Genetic linkage studies by this 44 Work by Bradford Lowell’s team fingered a gene encod- 45 team at Beth Israel Deaconess ing a protein-splitting enzyme 46 Medical Center points to another possible form of the disease called MODY (for called calpain-10. But the finding has been 47 way of interfering with glucose sensing by maturity-onset diabetes of the young), al- controversial, partly because the researchers 48 the β cell and thus disrupting insulin secre- though this has led them to a susceptibility as yet have no idea how a calpain-10 mutation 49 tion. Working with mice, they found that un- gene in a larger population. Studies of might lead to diabetes 2, and partly because 50 coupling protein 2 is a negative regulator of MODY patients have uncovered some half- the linkage doesn’t show up in all study 51 insulin secretion, presumably because it de- dozen genes, each of which can, when mu- populations. For example, it’s been found in 52 creases production by the mitochondria of tated, cause MODY. “The genes involved in some French populations but not others. 53 adenosine triphosphate, the ultimate signal this syndrome all cause abnormalities of However, a team led by Michael Garant 54 for the hormone’s release. Conversely, the re- β cell function,” says Kenneth Polonsky of and Alan Shuldiner of the University of 55 searchers found that production of the pro- Washington University School of Medicine Maryland School of Medicine reported in the 56 tein is elevated in another rodent model of in St. Louis, one of the researchers studying January issue of Diabetes that mutations in 57 obesity and diabetes, the ob/ob mouse, indi- the genes. Five of them encode transcrip- the gene could account for 25% of the dia- 58 cating that it might contribute to develop- tion factors that regulate genes involved in betes 2 susceptibility of African Americans. 59 ment of diabetes. insulin production, and the mutations turn Bell doesn’t find this variability in gene im- 60 down secretion of the hormone. pact in different populations at all disconcert- 61 Susceptibility genes Only 2% or 3% of diabetes 2 patients ing. It is, he says, “what you expect in these 62 Although this and other animal work has have MODY. But in a paper published on- [susceptibility] genes for complex diseases.” 63 uncovered many potential candidates for line on 19 March by the Proceedings of the These difficulties haven’t stopped re- 64 diabetes susceptibility genes, researchers National Academy of Sciences, a team led searchers from looking for the genes. Bog- 65 still need to show that they contribute to the by Robert Hegele of the John P. Robarts ardus and his colleagues, for instance,

688 26 APRIL 2002 VOL 296 SCIENCE www.sciencemag.org T HE P UZZLE OF C OMPLEX D ISEASES 1 have found several hot spots in a drugs. Certain variations in the gene for a Yet other drugs are urgently needed to 2 genomewide scan for susceptibility genes transcription factor called PPAR-γ have treat the diabetes epidemic, because people 3 in the Pimas and are now trying to pin been linked to a modest increase in dia- are unlikely to cut back on food intake and 4 down the genes involved. betes risk, and researchers now know that start exercising anytime soon. Indeed, CDC 5 There are encouraging signs that sus- members of a relatively new class of drugs, has just found that more than half of the 6 ceptibility genes picked up by these scans known as the thiazolidinediones, work at U.S. population exercises little or not at all. 7 could provide good targets for antidiabetes least partly by stimulating PPAR-γ activity. –JEAN MARX 8 9 NEWS eases (NIAMS). He also predicts an intensi- 10 fied focus on emerging drug targets. Equally 11 encouraging, Lipsky notes, is that scientists 12 Lupus: Mysterious Disease from disciplines other than immunology are 13 entering the field, drawn by genetic and 14 Holds Its Secrets Tight physiological discoveries. “You have a lot of 15 new people in the mix: nephrologists, cardi- 16 Caused by an unruly immune system, lupus manifests itself in a variety of ologists, neurologists, hematologists.” A few 17 symptoms; researchers are beginning to learn what the triggers are biotech companies are also testing the wa- 18 ters, raising hope that less toxic drugs may 19 Lupus. Even the origin of the name is have been able to offer relatively few thera- soon be available. 20 uncertain. According to one tradition, the pies, and those that are available, including 21 disease was named lupus—wolf in Latin— corticosteroids and cytotoxic compounds, War within 22 because people afflicted with it had lesions are also very risky. Anyone who investigates lupus encounters a 23 that resembled wolf bites. According to an- But an explosion of new data promises striking fact, says Michael Lockshin, an im- 24 other, a classic rash on the face created a to bring lupus research out of the dol- munologist who directs the Barbara Volcker 25 wolfish appearance. It was not until 1851 drums. Molecular has unlocked a Center for Women and Rheumatic Disease at 26 that a physician gave it a medical appella- trove of information about factors that reg- the Hospital for Special Surgery in New York 27 tion: systemic lupus erythematosus. Today, ulate the immune system. Using new City: 90% of the patients are women. Black 28 this complex disease remains a mystery in mouse models of the disease, researchers women are three times as likely to get lupus 29 more than name. have begun to identify the biochemical as white. And lupus strikes primarily be- 30 The deepest puzzle lies at its core: Some- mechanisms by which lupus causes tissue tween the ages of 15 and 40, during peak fer- 31 thing in the lupus patient causes the immune damage, and they have identified a series tility. Because of this pattern, estrogen, the 32 system to go awry and turn its armament- of candidate genes that appear to be in- female sex hormone, has long been consid- 33 arium of cell-killing forces against the host. volved in lupus. Desperately needed mon- ered a key risk factor. But Lockshin says he 34 For the more than 1 million people in the ey for clinical trials may also be on the way. has heard too many simple arguments blam- 35 United States with lupus, symptoms can ap- In the past 2 years, new lupus organizations ing estrogen. Men get autoimmune diseases, 36 pear in a bewildering variety of forms, rang- have opened shop, vowing to put all their too, Lockshin points out—including lupus. 37 ing from mild to lethal. The damage can af- money into peer-reviewed science (see In some autoimmune diseases, males and 38 fect almost any organ in the body, causing sidebar on p. 690). females are equally affected. In others, males 39 arthritis, fatigue, blood clots, heart disease, “We’re going to see a lot of activity” in predominate. “There are so many anoma- 40 osteoporosis, kidney failure, and other life- lupus research, predicts Peter Lipsky, scien- lies” in the patterns of autoimmune disease, 41 threatening illnesses. Symptoms flare and tific director at the National Institute for says Lockshin, that researchers should look 42 recede over time, and more often than not, Arthritis and Musculoskeletal and Skin Dis- beyond sex hormones. 43 the disease produces a slow Although scientists 44 decline, including cognitive LUPUS have proposed a smorgas- 45 loss. Even professionals have bord of causes—and debate 46 trouble diagnosing it, and by Environmental Drugs Viruses Bacteria them endlessly—they agree triggers 47 the time a diagnosis is con- on some fundamentals. 48 firmed, the patient may have Environmental factors such 49 developed irreversible kid- as estrogen and viruses are 50 ney damage. important, but just as critical 51 The complexity of the are inherited genetic traits 52 disease also impedes clinical B c ell that make an individual’s Genetic susceptibility 53 research. One symptom may leads to hyperactive immune system susceptible 54 be “cured,” only to be re- immune response to dysregulation. Among Autoreactive 55 helper twins of lupus patients, placed by another that may T anti-DNA 56 be worse. Clinical trials are antibodies for example, monozygotic Cross-react with 57 tough because it is hard to neuronal cell twins are about 10 times 58 accumulate significant data receptors: cognitive more likely to get the dis- 59 if each patient seems unique, impairment, psychosis ease than dizygotic twins. 60 and clinicians grumble that Animal studies sug- 61 drug developers are leery of Tissue Bind to other cellular proteins, gest several ways this com- damage Kidney disease causing arthritis, skin rashes, 62 lupus trials because the pa- vascular disease, others plex interaction between 63 tients may have unrelated environment and genetics 64 medical problems that look Self-destruction. Environmental factors such as viruses interact with inherited risks might lead to chronic dis-

65ILLUSTRATION: CARIN CAIN like side effects. Doctors to create a flood of “self” antibodies that harm tissues. ease. The dominant view

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