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CANADIAN JOURNAL OF DIABETES

256

Genetics, Environment and Type 2 Diabetes in


the Oji-Cree Population of Northern Ontario

Robert A. Hegele1 MD FRCPC FACP, Lloyd C. Bartlett MD FRCSC


1
Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada

This paper was originally presented as the Young Scientist Award Lecture at the Canadian Diabetes Association/Canadian Society of
Endocrinology and Metabolism Professional Conference, October 2–5, 2002,Vancouver, British Columbia, Canada

A B S T R A C T R É S U M É

The ≈40% prevalence of type 2 diabetes and impaired glucose La prévalence du diabète de type 2 et de l’intolérance au glu-
tolerance in the Oji-Cree of Northwestern Ontario, Canada, cose chez les Oji-cri du nord-ouest de l’Ontario, au Canada,
is among the highest in the world.The most important genet- qui est d’environ 40 %, est parmi les plus élevées du monde.
ic determinant of this epidemic is the private transactivation- Le plus important déterminant génétique de cette épidémie
deficient hepatocyte nuclear factor (HNF) -1alpha G319S est la mutation privée du gène du facteur nucléaire hépato-
mutation. This mutation has a strong statistical association cyte (HNF)-1alpha G319S présentant une anomalie de trans-
with diabetes and can be used to reliably predict the onset of activation. Cette mutation a un lien statistique étroit avec le
diabetes. G319S also has a gene-dosage effect on the median diabète et peut servir à prévoir de façon sûre l’apparition du
age of diabetes onset (7 years per allele dose). However, diabète. Le gène HNF-1alpha G319S a aussi un effet sur l’âge
environmental factors play a strong role in exposing the d’apparition du diabète, chaque dose de l’allèle accélérant de
genetic susceptibility of the Oji-Cree to type 2 diabetes. For 7 ans l’âge médian d’apparition du diabète.Toutefois, les fac-
instance, among ≈5000 physician encounters with the Oji-Cree teurs environnementaux jouent un rôle important dans la
between 1942 and 1949, diabetes was documented in only susceptibilité génétique des Oji-cri au diabète de type 2. Par
2 patients. Because the genome has remained relatively exemple, au cours de quelque 5000 consultations médicales
unchanged for 3 generations, this rapid increase in the preva- par des Oji-cri entre 1942 et 1949, on n’a noté que deux cas
lence of diabetes among the Oji-Cree has most likely result- de diabète. Étant donné que le génome est resté relativement
ed from environmental changes. Recent cataclysmic changes inchangé depuis trois générations, la hausse rapide de la pré-
in the Oji-Cree way of life, i.e. reduced energy expenditure valence du diabète chez les Oji-cri est probablement le résul-
and increased caloric intake, appear to correlate with the tat de changements environnementaux. De récents
rapid increase in the prevalence of diabetes from virtually changements cataclysmiques du mode de vie des Oji-cri,
undetectable levels to the current epidemic. c’est-à-dire la baisse de la dépense énergétique et la hausse
de l’apport calorique, semblent être en corrélation avec la
hausse rapide de la prévalence du diabète, qui est passée d’un
niveau pratiquement indécelable à l’épidémie actuelle.

Address for correspondence:


Robert A. Hegele
Blackburn Cardiovascular Genetics Laboratory
Robarts Research Institute
406–100 Perth Drive
London, Ontario
N6A 5K8 Canada
Telephone: (519) 663-3461
Fax: (519) 663-3037
E-mail: hegele @ robarts.ca

CANADIAN JOURNAL OF DIABETES. 2003;27(3):256-261.


type 2 diabetes in the oji-cree
257
INTRODUCTION (HNF4, GK, HNF1A and IPF4, respectively). Using this
The prevalence of type 2 diabetes and impaired glucose tol- approach, many single nucleotide polymorphisms (SNPs)
erance in the adult Oji-Cree population in Ontario, Canada, were discovered. However, none had the attributes of a pos-
is ≈40%, among the highest prevalence in any subpopulation sible type 2 diabetes-related mutation, based on classical cri-
in the world and much higher than that in the general teria such as statistical association of the SNP with diabetes.
Canadian population (1).This high prevalence of type 2 dia- In August 1998, the candidate gene sequencing strategy
betes will challenge the country’s healthcare system, because led to identification of the MODY3 gene, namely, HNF1A,
the entire population of ≈30 000 Oji-Cree lives on reserves which encodes hepatocyte nuclear factor (HNF) -1alpha, a
dispersed across a wide, remote and harsh northern locale. transcriptional activator of many genes, including the insulin
Intervention strategies to prevent or delay the onset of type 2 gene (8). HNF1A encodes a homeobox transcription factor,
diabetes and its complications (e.g. coronary heart disease) in has been mapped to chromosome 12q24 and is expressed
this population are especially important under these circum- predominantly in the liver and the kidney, and also in the
stances (2). Understanding the factors underlying the devel- pancreas.The primary DNA sequence of the HNF1A gene was
opment of type 2 diabetes in the Oji-Cree might help to direct screened in the genomic DNA from 3 Oji-Cree subjects with
preventative strategies. One factor is the recent change in the diabetes and control subjects without diabetes. Of 10 SNPs
Oji-Cree lifestyle—characterized by increased intake of identified, only 1, HNF1A G319S, was present exclusively in
dietary fat and decreased activity levels—which has led to the Oji-Cree with diabetes who were screened (9,10). A
obesity and diabetes. Environmental risk factors, such as causative role for HNF1A G319S in type 2 diabetes in the
diet, fitness level and physical activity, are significantly asso- Oji-Cree was suggested by the following: 1) G319S altered a
ciated with type 2 diabetes in the Oji-Cree (3-6). However, glycine residue that had been conserved throughout evolu-
the very high prevalence of diabetes in this population sug- tion (9); 2) G319S had a very strong statistical association with
gests that the Oji-Cree may also have a genetic predisposition type 2 diabetes in the Oji-Cree (allele frequency of 0.21 in the
to the disease. Oji-Cree with diabetes compared to 0.09 in the Oji-Cree
without diabetes) (9), especially in adolescents (11); 3) G319S
GENETICS OF TYPE 2 DIABETES IN had a diagnostic specificity and positive predictive value of
THE OJI-CREE 97 and 95%, respectively, for the development of type 2 dia-
The search for susceptibility genes for type 2 diabetes in the betes by 50 years of age, making it the most specific genetic test
Oji-Cree began in 1996, with the collaboration of the Oji- for diabetes known in humans (12); 4) G319S had a signifi-
Cree Band Council and community members of Sandy Lake, cantly diminished ability to transactivate target gene expression
Ontario, Canada.The basic demographics of this study sample in vitro (13); and 5) each dose of the allele accelerated the age
have been reported previously (1).Two complementary exper- of onset of type 2 diabetes in the Oji-Cree by 7 years (13).
imental strategies were used concurrently: positional cloning Mutations in HNF1A can thus result in 1 of 2 very distinct
by linkage analysis and candidate gene sequencing (7,8). The phenotypes: type 2 diabetes in the Oji-Cree or MODY3.
former is the most commonly used approach to detect chro- Oji-Cree with type 2 diabetes are obese with high levels of
mosomal regions of disease susceptibility genes. In the posi- plasma insulin, indicating insulin resistance (13). In contrast,
tional cloning experiments, sibling pairs with diabetes were subjects with MODY3 are lean, with low levels of plasma
genotyped using DNA markers from across the genome to insulin resulting from defects in insulin secretion (8). In vitro
find chromosomal regions that consistently cosegregated analysis of transactivation function may explain this difference,
with the diabetes phenotype. Four markers, 1 on each of since the HNF1A G319S mutant had diminished, but not
chromosomes 6, 8, 16 and 22, showed suggestive statistical absent, residual transcriptional activity (13). Thus, Oji-Cree
linkage and association with type 2 diabetes in the Oji-Cree (7). with the G319S mutation would have relatively lower, but
None of these markers corresponded to chromosomal not absent, in vivo expression of HNF-1alpha-dependent
regions linked with type 2 diabetes in other populations. genes, including the insulin gene.The partial loss of function
These results suggested that several genetic loci conferred of HNF1A G319S would require an additional stressor to
susceptibility to type 2 diabetes in the Oji-Cree. result in a phenotype of diabetes. Unfortunately, the changes
In parallel, candidate gene sequencing was used to search in the lifestyle of the Oji-Cree during the past 100 years have
for a diabetes-related mutation. There are ≈20 candidate provided more than an adequate stress on the molecular defi-
genes for type 2 diabetes, based on the role of the gene prod- ciency imparted by HNF1A G319S. In particular, the stress of
ucts in metabolism (8). Genes were also selected as candi- obesity-induced insulin resistance was shown to have
dates because they had mutations causing rare familial exposed the partial defect in HNF1A G319S carriers, causing
diabetes syndromes, such as maturity-onset diabetes of the disease expression (13). While obese Oji-Cree subjects are
young (MODY). While type 2 diabetes in the Oji-Cree did insulin resistant, the HNF1A G319S subjects do not secrete
not resemble MODY, it was desirable to rule out mutations enough insulin to control glycemia, although their plasma
in the MODY1, MODY2, MODY3 and MODY4 genes insulin levels are relatively high (13).
CANADIAN JOURNAL OF DIABETES

258
THE ENVIRONMENT AND TYPE 2 However, traditions change. For example, introduction of
DIABETES IN THE OJI-CREE the outboard motor reduced the labour associated with tra-
Historical and photographic records suggest that many ditional forest living, as recalled by Chief Thomas Fiddler (14):
aspects of the traditional way of life in Sandy Lake were still “We were in our canoe near Caribou Lake…and we heard
intact in the 1940s (Figures 1 to 5, Appendix A). Daily life this sound coming…we saw the prospectors in 1 canoe,
was difficult, and there were hindrances to the influx of pulling 2 canoe loads of supplies. We stopped paddling. We
Western cultural influences. In Figure 1, the 2 principal could see these guys just sitting in their canoe, doing nothing.
means of transport to access the region in the 1940s, canoe This lake we were on was about a 5-mile stretch, and we just
and airplane, illustrate the geographical isolation of the watched them in amazement until they passed right out of
reserve. Winter road access for trucks and automobiles sight…The first person I saw in Berens River, I asked him if
across the frozen lake occurred >20 years later, but eventu- I could rent his motor…Immediately, I began the trip back
ally provided a more effective way to import goods, equip- driving. I didn’t work at all. I just sat there. The portages
ment and supplies. were nothing. Since then, I’ve had an outboard motor.”
The ancestors of the current inhabitants of Sandy Lake The more recent introductions of the automobile and
survived on a modest caloric intake and a narrow range of snowmobile to Sandy Lake have had a similar impact on the
food sources. Furthermore, there were periods in recorded levels of activity and exertion. Changes in the need for exer-
history in which caloric supply was inadequate to sustain sub- tion are important, since both physical activity and physical
stantial numbers of people in Sandy Lake during the harsh fitness among the current residents of Sandy Lake are inde-
winters. For example, the winter of 1899 to 1900 was par- pendently associated with fasting insulin concentration, like-
ticularly devastating, and the Manitoba Free Press,Winnipeg, ly reflecting insulin resistance (3).
Manitoba, Canada, reported the deaths from starvation of In addition, no single change to the reserve appears to
approximately 30 Aboriginal people living at or near Sandy have been more intrusive than television. One elder had a
Lake due to inadequate supply of game (14). Oral histories vivid recollection of the night that television came to Sandy
from band elders also provide striking anecdotes of the con- Lake (15): “Preceding the days of television, children had free
sequences of starvation during the winter at Sandy Lake (14): range all over the village in the evenings. In the dark, their
“When food is gone, people…eat leather, bark and lichen off voices and laughter could be heard as they ran and played.
the rock outcrops, but this food gives little strength. The shouts of the children were night music until they went
Everyone grows weak. Eventually, men sicken and cannot inside, exhausted. On the night that television came, Ennis
leave their lodges to hunt.When this happens in a family, all went outside in the evening darkness and was greeted with
but the very strong are doomed.” the strange emptiness of silence. Only the pathetic howls of
The current epidemic of diabetes in Sandy Lake has affect- a few lonely dogs rang in the quiet evening air. The glue of
ed the descendants of the very strong survivors of the merci- television has adults and children watching an alien world
less periods of caloric deprivation. Whether genetic factors every night.” As well as delivering a foreign language, culture
such as the HNF1A G319S mutation imparted a survival and attitudes directly into the living rooms of the people of
advantage is unknown and as difficult to prove as such other Sandy Lake, watching television during childhood replaced
possibilities as genetic drift or a founder effect. However, the activities that characterized an earlier time during which dia-
current caloric plenitude in Sandy Lake appears to have betes did not pose a major public health threat.
exposed a marked susceptibility to diabetes. For example, the
store on the reserve sells many processed and calorie-dense CONCLUSION
foods to the inhabitants of Sandy Lake.While it would be inac- Fifty years ago, diabetes was relatively unknown among the
curate to state that the ancestors of the current inhabitants of Oji-Cree in Sandy Lake. Currently, children as young as 12 years
Sandy Lake never consumed saturated fat and trans fatty acids, of age are developing type 2 diabetes with insulin resis-
it would be reasonable to assume that calorie-dense foods tance (11). The present high prevalence of diabetes is most
would not have been supplied in the relatively large quantities likely the result of lifestyle and cultural changes.The balance
and convenient formats that are currently available. between caloric intake and expenditure has been disrupted
Another lifestyle factor that has changed during the past 2 because of decreased activity and increased intake of total
generations of the Oji-Cree is the daily level of exertion. For calories, saturated fat and carbohydrates. This has resulted in
example, in the early 20th century, walking up to 100 km/day diet-induced obesity, a phenotype that may have its own genet-
was not uncommon for the people of Sandy Lake (14).While ic component, and has lead, in turn, to hyperinsulinemia and
the burden of carrying supplies over long distances was insulin resistance. Photographs (see Figures 1 to 5) suggest
somewhat lessened through the use of a canoe in the summer that the body mass index among the Oji-Cree in the 1940s
and a dog sled in the winter, considerable exertion was still was much lower than the current average of ≈30 kg/m2 (2).
required for both modes of transportation, at least in their This environmental change has been superimposed upon the
traditional forms. genetic predisposition to diabetes caused by mutations such
type 2 diabetes in the oji-cree
259
as HNF1A G319S. Subjects with 1 or 2 doses of the transac- in Aboriginal Canadians, with focus on the Oji-Cree of
tivation-deficient HNF1A G319S mutation develop diabetes Sandy Lake, Ontario, Canada (16). Lloyd C. Bartlett’s (LCB’s)
at earlier ages in an allele dose-dependent manner. recollections have provided first-hand confirmation of the
At the initiative of the community, clinical colleagues are substantial change in lifestyle among the inhabitants of Sandy
presently undertaking intervention efforts in Sandy Lake. Lake during the past 2 generations. Subsequent correspon-
One strategy is to improve the balance between energy dence exposed LCB’s fortuitous interest in photography.The
intake and expenditure. It is unrealistic to expect that the black-and-white images in Figures 1 to 5 serve as a powerful
Oji-Cree would choose to reverse history and live again as historical record of daily life in Sandy Lake in the 1940s.
their ancestors did. However, it might be possible to cre- Together, the compelling historical and pictorial anecdotes
atively reconstitute some aspects of the ancestral lifestyle, a substantiate, probably more convincingly than a nominal
presence that was associated with relative freedom from dia- p-value of <0.05, that relatively recent lifestyle and cultural
betes and an absence that is now associated with an epidem- changes are inextricable components of the emergence of
ic. The people of Sandy Lake have indicated their strong type 2 diabetes as a major public health issue in the Oji-Cree.
desire to take action and make a difference.This attitude is an The following questions and answers help to further recon-
encouraging predictor of success in reducing the prevalence struct the historical lifestyle of the ancestors of the present
of diabetes in this population. inhabitants of Sandy Lake.

ACKNOWLEDGEMENTS RAH: What was your connection to the Sandy Lake reserve?
Robert A. Hegele holds a Canada Research Chair in Human LCB: After I received my Doctor of Medicine degree from
Genetics and a Career Investigator award from the Heart and the University of Western Ontario, London, Ontario,
Stroke Foundation of Ontario. General support for the Canada, in 1941, I practised in the very district containing
genetic component of the Sandy Lake project was from the the present day Sandy Lake reserve for 7 years, from 1942 to
Canadian Diabetes Association (in honour of Hazel E. Kerr), 1949. During that time, I was the only medical practitioner
the Canadian Institutes of Health Research and the Canadian in that entire section of Ontario. I was based at the Berens
Genetic Diseases Network. River Mines at Favourable Lake, which is now closed. The
The authors acknowledge that almost all of the genetic mine was approximately 80 km from Sandy Lake. The
studies mentioned here were completed as part of a long- Aboriginal people from Sandy Lake often came to the mine
standing collaboration with Drs. Bernard Zinman, Stewart offices for medical assessments (Figure 2), and I also made
Harris and Anthony Hanley. frequent trips to the reserve.
The authors acknowledge the assistance of Gerry The only buildings at Sandy Lake at that time were the
Kopelow for skillful reproduction of the photographs. Hudson’s Bay Company store and the Roman Catholic
Mission. During my stay at Sandy Lake, I built a hospital near
Berens River Mines (Figure 3). A family from the communi-
APPENDIX A ty would move into the hospital and look after the sick
Recollections of Sandy Lake in the 1940s patient, while I would supply food. When a patient recov-
The authors began a surface-mail correspondence more than ered, another could move in. In this building, I first adminis-
3 years ago, following Robert A. Hegele’s (RAH’s) publica- tered penicillin, obtained from the National Research
tion of a review article about genetics and type 2 diabetes Council, via a slow intravenous drip.

Figure 2. Photograph from the 1940s showing Oji-Cree people


Figure 1. Canoes and an airplane at Sandy Lake, Ontario, from Sandy Lake, Ontario, Canada, with a dog sled
Canada, in the 1940s leaving the store at Berens River Mines with supplies
CANADIAN JOURNAL OF DIABETES

260
RAH: What common medical problems did you see in Sandy Lake RAH: Did the missionaries live differently from the Aboriginal
during that era? people?
LCB: The major medical problem in those days was tuber- LCB: The missionaries did not eat the same food as the
culosis, primarily pulmonary and cervical nodal disease. Aboriginal people. The mission kept goats, and missionaries
Next were purulent otitis media and pneumonia. Deaths ate a large amount of cheese, lard and eggs. In spite of much
were frequent, mainly from tuberculosis and pneumonia, exercise, they developed the aforementioned diseases.
since this was the pre-antibiotic era. There was also some Furthermore, the missionaries had a few more comforts than
infant and child malnutrition with vitamin deficiency, and I did the Aboriginal people. For instance, the house in which
encouraged them to use cooked fish livers for infant feeding. the priest and lay brother lived had a 12-V electrical system
I often gave immunizations to the Aboriginal people at the powered by batteries charged by a windmill. They had a
hospital. With respect to lifestyle-related problems, there homemade tractor for gardening.While the snowmobile had
was very little smoking.There was not a single episode of sui- not yet been invented, the mission had a Bombardier, which
cide, mental breakdown or sexually transmitted disease that was a huge vehicle, larger than a car, with skis on the front
came to my attention.There was no alcoholism, because alco- and tracks on the back. A winter road had to be cut between
hol was forbidden. Of course, gas sniffing or drug addiction lakes for its passage. Its fuel efficiency was 36 L per 100 km.
was unheard of. Everyone was too busy trying to survive.
RAH: What was life like for the Aboriginal people of Sandy Lake
RAH: What about type 2 diabetes or cardiovascular disease in the in the 1940s?
1940s? LCB: They lived a nomadic life with no permanent
LCB: Regarding diabetes, I examined hundreds of Aboriginal dwellings. In the summer, they lived in tents by the side of
people and conducted numerous urinalyses. A conservative the lake and fished (Figure 4). When a campsite had been
estimate would be 5000 patient encounters. My records depleted, they moved on. In the winter, they dispersed to
show only 2 cases of diabetes, and I cannot recall seeing a sin- individual trap lines and lived in single-room log cabins.
gle case of coronary heart disease among the Aboriginal peo- These cabins were heated by wood in a tin stove, sometimes
ple during those 7 years. My clinical impression is that type 2 made from an oil drum (Figure 5). Logs were chinked with
diabetes was extremely uncommon among the Aboriginal moss. Sometimes a tent continued to serve as winter quar-
people in those days. ters. The floor and beds were sometimes made of small
spruce boughs.They traded their furs for a few staples at the
RAH: What was your experience with non-Aboriginals living there Hudson’s Bay Company store in Sandy Lake.
at that time?
LCB: In those years, the Roman Catholic Mission at Sandy RAH: Can you recall anything about their diet and food
Lake was staffed by a priest in whom I diagnosed coronary preparation?
heart disease, which forced him to retire.There was also a lay LCB: The main sources of protein were fish and rabbit.
brother, in whom I diagnosed rather severe type 2 diabetes. Moose was rare, and there were no deer. Food was prepared in
These anecdotal ‘control’ European patients suggest that a 2 ways. First, bannock was cooked in a frying pan with white
diagnosis of type 2 diabetes was possible, although technolo- flour, baking powder and lard, all obtained from the Hudson’s
gy and definitions have changed over the years. Bay Company in exchange for furs. Second, everything else

Figure 3. Lloyd C. Bartlett administers immunizations to Figure 4. Summer life in Sandy Lake, Ontario, Canada, in the
Aboriginal people at the hospital that he built near 1940s.The Aboriginal people lived in tent settlements
Berens River Mines in Ontario, Canada close to the lake and fished
type 2 diabetes in the oji-cree
261
was stewed in a pot or pail.This included meat, such as rab- 3. Kriska AM, Hanley AJG, Harris SB, et al. Physical activity,
bit, muskrat, moose and fish, which were gutted, but the heads physical fitness, and insulin and glucose concentrations in an
and eyes were left on. I remember seeing fish eyes floating in isolated Native Canadian population experiencing rapid
stew. A common drink was tea. In the summer, blueberries lifestyle change. Diabetes Care. 2001;24:1787-1792.
and raspberries were free for picking. All babies were breast- 4. Hanley AJG, Harris SB, Gittelsohn J, et al. Overweight among
fed. Babies were carried on the back in tikanagan packed with children and adolescents in a Native Canadian community:
dry moss instead of diapers and had no diaper rash. prevalence and associated factors. Am J Clin Nutr. 2000;
71:693-700.
RAH: Can you recall the anthropometry and activity level of the 5. Gittelsohn J, Wolever TMS, Harris SB, et al. Specific patterns
people? of food consumption and preparation are associated with dia-
LCB: You can see from the photographs that there was very betes and obesity in a Native Canadian community. J Nutr.
little obesity. The people lived a rugged, rigorous life with 1998;128:541-547.
plenty of exercise. Canoe and airplane were the 2 primary 6. Wolever TM, Hamad S, Gittelsohn J, et al. Low dietary fiber
forms of summer transportation (Figure 1). In the winter, and high protein intakes associated with newly diagnosed dia-
everyone travelled by foot on snowshoe or by dog team. It betes in a remote Aboriginal community. Am J Clin Nutr.
was not an easy life. 1997;66:1470-1474.
7. Hegele RA, Sun F, Harris SB, et al. Genome-wide scanning for
RAH: What did you do after working in Northern Ontario? type 2 diabetes susceptibility in Canadian Oji-Cree, using 190
LCB: After leaving the Sandy Lake area, I studied pathology microsatellite markers. J Hum Genet. 1999;44:10-14.
and surgery and became a Fellow of the Royal College of 8. Busch CP, Hegele RA. Genetic determinants of type 2 diabetes
Surgeons of Canada. I became the first Director of mellitus. Clin Genet. 2001;60:243-254.
Postgraduate Surgical Training at the University of Manitoba, 9. Hegele RA, Cao H, Harris SB, et al. The hepatic nuclear
Winnipeg, Manitoba, Canada, and I still have a busy practice factor-1α G319S variant is associated with early-onset type 2
in Winnipeg. I served on boards of both the Manitoba diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab.
Medical Association (MMA) and the Canadian Medical 1999;84:1077-1082.
Association and was President of the MMA from 1989 to 1990. 10. Hegele RA, Cao H, Harris SB, et al. Hepatocyte nuclear
On behalf of these organizations, I played an active role in many factor-1α G319S. A private mutation in Oji-Cree associated
public health projects both in Manitoba and nationally. with type 2 diabetes. Diabetes Care. 1999;22:524.
11. Hegele RA, Hanley AJG, Zinman B, et al.Youth-onset type 2
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Figure 5. Oji-Cree in their winter quarters.Their eyes have been


pixelated to protect their identity. Note the Christmas
tree in the background and the rabbit, probably a
future meal, hanging from the ceiling