THE PUZZLE OF COMPLEX DISEASES

NEWS
1
2
3
4
Unraveling the Causes of Diabetes
5
6 nia School of Medicine in Philadelphia.
7 As the obesity-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 insulin resistance 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— Boston. 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

Downloaded from https://www.science.org on September 29, 2023

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 No data
until recently rarely affected 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

SOURCE: A. H. MOKDAD ET AL., DIABETES CARE 23, 1278 (2000) AND J. AM. MED. ASSOC. 286, 1195 (2001)
45 it,” says diabetes researcher predicts that the number of
46 Roger Unger of the University cases worldwide—now 150
47 of Texas Southwestern Medi- million—will double by 2025.
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
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-
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-
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-
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
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,

686 26 APRIL 2002 VOL 296 SCIENCE www.sciencemag.org

 THE PUZZLE OF COMPLEX DISEASES
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 leptin 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-

Downloaded from https://www.science.org on September 29, 2023

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
CREDITS: (TOP TO BOTTOM) CORBIS; J. PAT CARTER/AP

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-
65 hibit diabetes development. Except in rare Recent work suggests that locally pro- tance. For example, in experiments per-

www.sciencemag.org SCIENCE VOL 296 26 APRIL 2002 687

 THE PUZZLE OF COMPLEX DISEASES
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- mutations in them. In a differ-

→
HNF-4-α, HNF-1-β Transcription Insulin MODY (human)
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 searchers had found several

→
HNF-1-α Transcription Insulin MODY
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

→
Glucokinase Glucose Insulin MODY
21 But β 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- isn’t located in any of those

Downloaded from https://www.science.org on September 29, 2023

Mexican and
24 crete the insulin needed to handle African Americans sites. The researchers exam-
25 all the glucose the body takes in. ined the gene in addition to
26 At least in mouse models, re-
PPAR-γ Transcription → Insulin Diabetes 2
other candidates, he adds, “just
factor sensitivity
27 searchers can duplicate that type so we could say we looked at
→

28 Insulin receptor Transmits Insulin Human diabetes

of malfunction. insulin signals sensitivity (rare); mouse
all the usual suspects.”
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-
→

35 they could prevent the increase in 11-β-HSD Glucocorticoid Blood Mouse models thing similar has been seen
→

36 synthesis lipids, insulin

insulin secretion that normally oc- sensitivity
with a gene that Graeme Bell
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
synthesis secretion
39 the insulin receptor in the β 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

 THE PUZZLE OF COMPLEX DISEASES
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
12 Lupus: Mysterious Disease encouraging, Lipsky notes, is that scientists
from disciplines other than immunology are
13 entering the field, drawn by genetic and
14
15
Holds Its Secrets Tight physiological discoveries. “You have a lot of
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-

Downloaded from https://www.science.org on September 29, 2023

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 biology 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 Environmental Drugs Viruses Bacteria them endlessly—they agree
trouble diagnosing it, and by
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 e ll 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
55 elp Autoreactive twins of lupus patients,
placed by another that may T h er 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-
impairment, psychosis
59 if each patient seems unique, ease than dizygotic twins.
60 and clinicians grumble that Animal studies sug-
ILLUSTRATION: CARIN CAIN

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

www.sciencemag.org SCIENCE VOL 296 26 APRIL 2002 689

 Unraveling the Causes of Diabetes
Jean Marx

Science 296 (5568), . DOI: 10.1126/science.296.5568.686

View the article online

https://www.science.org/doi/10.1126/science.296.5568.686
Permissions
https://www.science.org/help/reprints-and-permissions

Downloaded from https://www.science.org on September 29, 2023

Use of this article is subject to the Terms of service

Science (ISSN 1095-9203) is published by the American Association for the Advancement of Science. 1200 New York Avenue NW,
Washington, DC 20005. The title Science is a registered trademark of AAAS.

© 2002 American Association for the Advancement of Science