Type 1 and Type 2 Diabetes
http://www.100md.com
《糖尿病学杂志》
the Department of Internal Medicine/Diabetology, Helsinki University Central Hospital; the Institute for Diabetes Genetics, Folkhalsan Research Center, Helsinki, Finland; and the Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
Key Words: GADA, autoantibody to GAD LADA, latent autoimmune diabetes in adults VNTR, variable number of tandem repeats
ABSTRACT
Type 1 and type 2 diabetes frequently co-occur in the same families, suggesting common genetic susceptibility. Such mixed family history is associated with an intermediate phenotype of diabetes: insulin resistance and cardiovascular complications in type 1 diabetic patients and lower BMI and less cardiovascular complications as well as lower C-peptide concentrations in type 2 diabetic patients. GAD antibody positivity is more common in type 2 diabetic patients from mixed families than from common type 2 diabetes families. The mixed family history is associated with more type 1eClike genetic (HLA and insulin gene) and phenotypic characteristics in type 2 diabetic patients, especially in the GAD antibodyeCpositive subgroup. Leaving out the extreme ends of diabetes phenotypes, young children progressing rapidly to total insulin deficiency and strongly insulin-resistant subjects mostly with non-Europid ethnic origin, a large proportion of diabetic patients may have both type 1 and type 2 processes contributing to their diabetic phenotype.
Diabetes in most cases is caused by a loss of the physical or functional -cell mass, mostly due to an autoimmune process (type 1 etiological process) and/or increased need for insulin due to insulin resistance (type 2 process) (1). Both of these major diabetes types are believed to include different stages of disease, ranging from noneCinsulin-requiring to insulin-requiring for control or survival. According to this classification adopted by the World Health Organization, it is quite possible that both processes would operate in a single patient and contribute to the phenotype of the patient. Also, factors other than autoimmunity can lead to a defective insulin response to glucose. Both major diabetes types are considered multifactorial diseases with several predisposing genetic and environmental factors, some of which could be common to both types. In populations with a high prevalence of type 1 diabetes, like in Finland, a large proportion of patients with type 2 diabetes should have inherited susceptibility genes for both types of diabetes. Also, the lifestyle changes leading to the type 2 diabetes epidemic around the world (2) may have an impact on the clinical picture of type 1 diabetes in the subjects at risk for type 2 diabetes as well. Indeed, obesity has been shown to be a risk factor for childhood type 1 diabetes (3eC6). According to the "accelerator hypothesis," there are two accelerators precipitating disease in all types of diabetes: the intrinsically high rate of -cell apoptosis and insulin resistance resulting from weight gain and physical inactivity. In addition, a third accelerator, -cell autoimmunity, would enhance the diabetic process in a subset (7). The aim of this article is to review the data on genetic interaction between type 1 and type 2 diabetes and its clinical consequences for especially type 2 diabetes.
FAMILIAL CLUSTERING OF TYPE 1 AND TYPE 2 DIABETES
Several studies have reported an increased frequency of type 2 diabetes in families with type 1 diabetes (8eC13). In Sweden, 32% of patients with type 1 diabetes reported a family history of type 2 diabetes compared with 12.5% in a nondiabetic reference group (8). The true prevalence is difficult to ascertain, because most patients are diagnosed with type 1 diabetes at an age when their parents, or grandparents, might still be too young to have developed type 2 diabetes. Also, reliable age-adjusted prevalence data for type 2 diabetes in the general population is rarely available. Of note, a parental history of type 2 diabetes was associated with an increased risk of type 1 diabetes in siblings of type 1 diabetic patients (14, 15).
In accordance with the above, frequent occurrence of type 1 diabetes in relatives of patients with type 2 diabetes has also been observed (16eC19). A total of 14% of Finnish families with more than one type 2 diabetic patient also included type 1 diabetic patients, and 5% of the type 2 diabetic probands had a first-degree relative with type 1 diabetes (19). This is clearly increased compared with the overall 0.5 to 1% prevalence of type 1 diabetes in Finland.
PHENOTYPIC CONSEQUENCES OF THE FAMILIAL CLUSTERING
The consequence of such genetic admixture for type 1 or type 2 diabetes is not known, but the existing data suggest that patients with double genetic predisposition have an intermediate phenotype. Family history for type 2 diabetes is associated with insulin resistance and cardiovascular complications in type 1 diabetic patients. In the Epidemiology of Diabetes Complications Study, the best predictors of insulin resistance in type 1 diabetes were an elevated waist-to-hip ratio, the presence of hypertension, HbA1 level, and family history of type 2 diabetes (20). Family history of type 2 diabetes was a significant risk factor for coronary artery disease (13), and parental type 2 diabetes conferred a threefold risk for nephropathy after adjustment for sex, glycemic control, and family history of hypertension (21). Furthermore, family history of type 2 diabetes and/or hypertension predicted progression of carotid intima-media thickness in a 10-year follow-up study of type 1 diabetic patients, who at baseline were 21 years old with diabetes duration of 12 years (22). Preliminary data from the FinnDiane Study showed that according to the National Cholesterol Education Program criteria for metabolic syndrome, one-third of normoalbuminuric type 1 diabetic patients had metabolic syndrome, and 14% fulfilled more than four diagnostic criteria (23).
Mixed family history has the opposite effect with respect to the phenotype of type 2 diabetes. Family history of type 1 diabetes was negatively associated with coronary artery disease in relatively young (<60 years of age) type 2 diabetic patients, and patients with such family history were leaner than those with family history for type 2 diabetes only (24). Also, type 2 diabetic patients with the type 1eCassociated HLA-DR4 allele had a lower cardiovascular mortality rate than DR4eC patients (25). Overall, the patients with mixed family history also had lower serum C-peptide concentrations, but this largely depended on the high frequency of circulating autoantibodies to GAD (GADAs) in this group, whereas the BMI and coronary artery disease association was present also in GADAeC patients (24). The frequency of GADA positivity was 18% among type 2 diabetic patients with mixed family history compared with 8% among patients with only type 2 diabetes family history (19). Thus, family history of type 1 diabetes could contribute to the heterogeneity observed in GADA+ patients (26).
LATENT AUTOIMMUNE DIABETES IN ADULTS
In two population-based studies, our Botnia study (27) and the much larger U.K. Prospective Diabetes Study (28), GADAs were present in 15eC35% of patients diagnosed with type 2 diabetes at an age younger than 45 years, and in 7eC9% of older patients (Fig. 1). We called this subgroup latent autoimmune diabetes in adults (LADA) (29) and suggested a definition based on circulating GADAs, age at diagnosis of diabetes 35 years, and no treatment with insulin during the first year after diagnosis (27). According to this definition, excluding studies selecting for lean, young-onset, or insulin-treated patients as well as hospital-based studies, the prevalence of LADA is 4.2eC13.2% among Caucasians of mainly Anglo-Celtic or Scandinavian ancestry (28eC31) and 10.2% in African-Americans (31), but lower in Japanese (1.1% [32]) and possibly in Italians (2% [33]) and Australians with Southern European ancestry (1.7% [30]).
Clinically, LADA is a heterogeneous group and the mean concentration of GADAs is lower than in individuals diagnosed with type 1 diabetes (34). When subjects commencing permanent insulin treatment during the first year after diagnosis are excluded, 50eC60% of LADA patients compared with 2% of antibody-negative patients develop marked insulin deficiency during the 6eC10 years from diagnosis (28, 35). The progression of insulin deficiency seems to be associated with younger age at onset, high levels of GADAs, and positivity for multiple autoantibodies; this group may also have other endocrine autoantibodies (27, 28, 36, 37). On the other hand, half of the patients with LADA will never need treatment with insulin and only have a mild deterioration of their maximal insulin secretory capacity compared with GADAeC patients (38). However, compared with GADAeC patients, they have less evidence of the metabolic syndrome (slightly lower BMI, better blood pressure levels, less dyslipidemia) (27, 39). It could be speculated that because of the subclinical deterioration in -cell function, a lower degree of insulin resistance precipitates diabetes in LADA compared with common type 2 diabetes (26).
IS THERE A COMMON GENETIC PREDISPOSITION
HLA class II genes.
The IDDM1 locus in the HLA class II region on chromosome 6p21 is strongly linked to type 1 diabetes (logarithm of odds score 65.8 [40, 41]). It is considered to explain 42% of the familial risk for type 1 diabetes (40). The risk associated with an HLA genotype is defined by the combination of susceptibility and protective alleles of especially DQB1, DQA1, and DRB1 genes (rev. in 42). The susceptibility DQB1 alleles 02 and 0302 were found in 49.6 and 71.1%, respectively, of Finnish type 1 diabetic patients (n = 560) compared with 25.5 and 20.6% of control subjects (n = 10,541). The protective alleles 0301 and 0602 (3) were found in 7.7 and 6.6% of patients compared with 21 and 42.2% of control subjects (42). Thus, at least one-third of the population in Finland carries at least one susceptibility allele.
Excess transmission of DR4-linked haplotypes from parents with type 2 diabetes to offspring with type 1 diabetes has been reported (43). Also, some studies have reported an increased frequency of HLA-DR4 or HLA-DR3/DR4 in patients with type 2 diabetes (44eC47). However, this increase seems to be mainly restricted to patients with relative insulin deficiency or islet cell antibodies (ICAs) and/or GADAs (27, 44, 47). Patients with LADA have an increased frequency of the type 1eCassociated susceptibility HLA alleles DQB10302 and 02 (27, 47), but the family history of type 1 diabetes could be a confounding factor. As mentioned earlier, patients with LADA have family history of type 1 diabetes more often than other phenotypically type 2 diabetic patients. Figure 2 shows the DQB1 genotype data in the Botnia study in patients diagnosed with classic type 1 diabetes and in subgroups of patients diagnosed with type 2 diabetes according to the presence of GADAs and mixed family history. Only data for adult-onset type 1 diabetes is included, because of previously published genotype differences between young-onset and adult-onset type 1 diabetes (rev. in 26). The type 2 diabetic patients from the mixed families shared an increase in the moderate-risk HLA-DQB10302/X genotype with the adult-onset type 1 diabetic patients (Fig. 2 [19]). Because they were relatives of type 1 diabetic patients, this was not unexpected. However, similar sharing of the genotype conferring the highest risk (02/0302) or absence of the genotype conferring protection [0602(3)/X] was not observed except for the GADA+ subgroup of patients from the mixed families. Thus, among the LADA patients, only those from type 1 diabetic families share the 02/0302 and 0602 (3) association with type 1 diabetic patients, whereas all LADA patients share the 0302/X association. This finding suggests that part of the observed heterogeneity among the LADA patients could be ascribed to type 1 diabetes family history.
However, the effect of type 1 diabetes family history on the diabetic phenotype is not restricted to the GADA+ group, as mentioned earlier. Sharing type 1 diabeteseCassociated risk HLA haplotype with a type 1 diabetic relative was associated with impaired insulin secretion in response to oral glucose in type 2 diabetic patients. However, no such effect was seen in type 2 diabetic patients who had similar risk haplotypes without type 1 diabetic relatives, suggesting that other genes on the short arm of chromosome 6 need to be shared (19). All in all, these data point at a genetic interaction between type 1 and type 2 diabetes that could be mediated by the HLA locus or a nearby gene.
Insulin gene.
A variable number of tandem repeats (VNTR) polymorphism in the insulin gene promoter affects the transcription level of insulin and insulin-like growth factor II genes (48eC50). The VNTR is highly variable with respect to both number and sequence of the repeats. In Caucasians, the length distribution is bimodal with 75% of short (class I) and 25% of long alleles (class III) (51). Intriguingly, the VNTR has been associated with both type 1 and type 2 diabetes. Linkage to this region on chromosome 11p15 (40, 41) and an increased frequency of either two class I alleles (Caucasians [48]) or two short class I alleles (Japanese [52]) has been shown in type 1 diabetes in several populations. The effect of the insulin gene on type 1 diabetes risk seems to be strongest in the subjects carrying moderate- or low-risk HLA genotypes, although it is detectable in all HLA risk categories (53, 54).
On the other hand, class III alleles might be associated with hyperinsulinemia, high body mass, and type 2 diabetes, but the data are controversial. A meta-analysis of small case-control studies suggested an increased frequency of class III homozygosity among the type 2 diabetic patients compared with control subjects (relative risk 1.4, P < 0.037) (55, 56). In a population-based follow-up study from the U.K., class III homozygosity increased the risk for type 2 diabetes in women (hazard ratio 4.25; 95% CI 1.76eC10.3), but not in men (57). An increased transmission of paternal class III alleles to affected offspring was seen in British patients with type 2 diabetes (58) or polycystic ovary syndrome (59), but not in Scandinavian type 2 diabetic patients (60). Moreover, class III alleles have been associated with high insulin concentrations and/or increased body mass in morbidly obese women (61) and patients with polycystic ovary syndrome (62), as well as with high birth weight and high rate of weight gain after birth (63). However, childhood obesity was associated with class I alleles and their paternal transmission (64, 65). In pigs, the syntenic region was linked to paternally inherited quantitative trait loci affecting muscle and fat mass (66, 67).
Except for the study of Huxtable et al. (58), in which GADA+ subjects were excluded, the effect of admixture of late-onset type 1 diabetes or family history of type 1 diabetes has not been studied. We examined the association between the insulin VNTR and type 2 diabetes and its sub-phenotypes, taking into account the potential of a simultaneous family history of type 1 diabetes, in 679 unrelated patients with type 2 diabetes, 148 patients with young-onset (<20 years), and 131 patients with adult-onset (20 years) type 1 diabetes and 252 nondiabetic control subjects from the Botnia study. The type 2 diabetic patients included 93 patients who had type 1 diabetic relatives (mixed type 1/2 diabetes) (24) as well as 89 GADA+ (27) and 497 GADAeC patients (60, 27) without family history for type 1 diabetes (common type 2 diabetes). As shown in Fig. 3, the type 1 diabetic patients were more often homozygous for the VNTR class IeCassociated HphI allele (76%) than the control (56%) or common type 2 diabetic subjects, irrespective of GADA positivity (53%, P = 0.0001). The type 2 diabetic patients with mixed family history had an intermediate frequency (61.3%). An increased frequency of the class IeCassociated allele was found in the U.K. Prospective Diabetes Study (47), but not in our Finnish LADA patients (27). However, the GADA+ mixed patients had a comparable I/I genotype frequency (76%) than the adult type 1 diabetic patients (75%), whereas the GADAeC mixed patients (58%) differed less from the GADAeC common type 2 diabetic patients (54%). Obviously, larger numbers of mixed patients are needed to statistically test this difference. It is possible that some of the discrepancies in the literature concerning the association between LADA and insulin VNTR reflect the degree of type 1 diabetes family history in the series.
The HphI genotype was not associated with any clinical parameters in the control, type 1 diabetic, or mixed type 2 diabetic subjects, but the small number of class III/III homozygous patients precluded their separate analysis. Although we did not find an excess of class III/III in type 2 diabetes, our data supported an association between class III alleles and body mass and insulin concentration in males but not in females. The class III allele was significantly associated with high BMI [I/I vs. I/III vs. III/III: 27.5 (5.3) vs. 28.6 (4.9) vs. 31.6 (6.6) kg/m2, P = 0.002] and fat-mass [24.5 (7.1) vs. 27.2 (7.6) vs. 27.4 (8.9)%, P = 0.001]. Men with class III alleles had higher fasting insulin concentrations than those with only class I alleles [11.1 (8.9) vs. 8.7 (8.3) mU/l, P = 0.009] and they were also more insulin resistant [homeostasis model assessment for insulin resistance: 4.71 (4.64) vs. 3.12 (4.22), P = 0.012].
Together with previous data in nondiabetic subjects (61eC67), these results support a role for the insulin gene VNTR in affecting body mass and insulin sensitivity. However, although our study and some other studies have advocated class III alleles to be associated with high in vivo insulin concentrations (61eC63), others have shown this association for class I alleles (64, 65). Moreover, in vitro, class I leads to higher expression of insulin than class III does. More studies in much larger carefully phenotyped groups and functional data are needed to solve these discrepancies.
WHERE TO GO NEXT
Except for the HLA locus, major genes contributing to diabetes have not been revealed. The common varianteCcommon disease hypothesis assumes that common single nucleotide polymorphisms (frequency >10% in the population) increase susceptibility to a polygenic disease like type 2 diabetes, but that these variants act in concert with environmental factors. During recent years, several variants have been identified in genes that increase the risk of type 2 diabetes, e.g., in the PPAR, calpain 10, and Kir 6.2 genes (60, 68eC70). Considering the data that are emerging on familial clustering of type 1 and type 2 diabetes, many of the minor genes are expected to contribute to features common to both types of diabetes. To solve this puzzle, it will be imperative to collect careful phenotypic data on all types of patients to allow stratification for various sub-phenotypes in the analyses.
REFERENCES
Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539eC553, 1998
Zimmet P, Alberti KGMM, Shaw J: Global and societal implications of the diabetes epidemic. Nature 404:782eC787, 2001
Johansson C, Samuelsson U, Ludvigsson J: A high weight gain early in life is associated with an increased risk of childhood diabetes. Diabetologia 37:91eC94, 1994
Bruining GJ: Association between infant growth before onset of juvenile type 1 diabetes and autoantibodies to IA-1. Lancet 356:655eC656, 2000
Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK, Childhood Diabetes in Finland Study Group: Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23:1755eC1760, 2000
Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ: Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care 26:2871eC2875, 2003
Wilkin TJ: The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44:914eC922, 2001
Dahlquist G, Blom L, Tuvemo T, Nystrom L, Sandstrom A, Wall S: The Swedish childhood diabetes study: results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia 32:2eC6, 1989
Pozzilli P, Visalli N, Signore A, Andreani D: Clinical remission in patients with IDDM and family history of NIDDM. Lancet 337:1165, 1991
Ramachandran A, Snehalatha C, Premila L, Mohan V, Viswanathan M: Familial aggregation in type 1 (insulin-dependent) diabetes mellitus: a study from south India. Diabet Med 7:876eC879, 1990
Teupe B, Bergis K: Epidemiological evidence for "double diabetes." Lancet 337:361eC362, 1991
Carel JC, Boitard C, Bougneres PF: Decreased insulin response to glucose in islet cell antibody-negative siblings of type 1 diabetic children. J Clin Invest 92:509eC513, 1993
Erbey JR, Kuller LH, Becker DJ, Orchard TJ: The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population. Diabetes Care 21:610eC614, 1998
Chern MM, Anderson VE, Barbosa J: Empirical risk for insulin-dependent diabetes (IDD) in sibs: further definition of genetic heterogeneity. Diabetes 31:1115eC1118, 1982
Wagener DK, Sacks JM, LaPorte RE, Macgregor JM: The Pittsburgh study of insulin-dependent diabetes mellitus: risk for diabetes among relatives of IDDM. Diabetes 31:136eC144, 1982
Gottlieb MS: Diabetes in offspring and siblings of juvenile- and maturity-onset-type diabetics. J Chronic Dis 33:331eC339, 1980
Quatraro A, Consoli G, Magno M, Caretta F, Ceriello A, Giugliano D: Analysis of diabetic family connection in subjects with insulin-dependent diabetes mellitus (IDDM). Diabete Metab 16:449eC452, 1990
Landin Olsson M, Karlsson FA, Lernmark A, Sundkvist G: Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden. Diabetes 41:1022eC1027, 1992
Li H, Lindholm E, Almgren P, Gustafsson A, Forsblom C, Groop L, Tuomi T: Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 diabetes. J Clin Endocrinol Metab 86:574eC582, 2001
Williams K, Erbey JR, Becker D, Arslanian S, Orchard TJ: Can clinical factors estimate insulin resistance in type 1 diabetes Diabetes 49:626eC632, 2000
Fagerudd JA, Pettersson-Fernholm KJ, Gronhagen-Riska C, Groop PH: The impact of a family history of type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia 42:519eC526, 1999
Makimattila S, Ylitalo K, Schlenzka A, Taskinen MR, Summanen P, Syvanne M, Yki-Jarvinen H: Family histories of type II diabetes and hypertension predict intima-media thickness in patients with type I diabetes. Diabetologia 45:711eC718, 2002
Thorn LM, Forsblom C, Fagerudd J, Thomas MC, Pettersson-Fernholm K, Saraheimo M, Waden J, Rnnback M, Rosengrd-Brlund M, af Bjrkesten C-G, Taskinen M-R, Groop P-H, the FinnDiane Study Group: Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care 28:2019eC2024, 2005
Li H, Isomaa B, Almgren P, Taskinen M-R, Groop L, Tuomi T: Consequences of a family history of type 1 or type 2 diabetes on the phenotype of patients with type 2 diabetes. Diabetes Care 23:589eC594, 2000
Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, Matikainen E, Teppo AM, Koskimies S, Groop L: Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41:1253eC1262, 1998
Tuomi T: LADA in adults: how does it differ from type 1 diabetes Int Diabetes Monitor 17:1eC5, 2005
Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissen M, Ehrnstrom BO, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC: Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150eC157, 1999
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R: UKPDS25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes: UK Prospective Diabetes Study Group. Lancet 350:1288eC1293, 1997
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359eC362, 1993
Davis T, Zimmet P, Davis W, Bruce D, Fida S, Mackay I: Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi-ethnic Australian community: the Fremantle Diabetes Study. Diabet Med 17:667eC674, 2000
Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL, Kuller LH, Trucco M: Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 49:32eC38, 2000
Kobayashi T, Nakanishi K, Okubo M, Murase T, Kosaka K: GAD antibodies seldom disappear in slowly progressive IDDM (Letter). Diabetes Care 19:1031, 1996
Bosi E, Garancini M, Poggiali F, Bonifacio E, Gallus G: Low prevalence of islet-cell autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy. Diabetologia 42:840eC844, 1999
Lundgren V, Lyssenko V, Isomaa B, Laurila E, Groop L, Tuomi T, the Botnia Study Group: GADA positivity in relatives of type 2 diabetes or LADA (Abstract). Diabetes 54 (Suppl. 2):S160, 2005
Niskanen LK, Tuomi T, Karjalainen J, Groop LC, Uusitupa MI: GAD antibodies in NIDDM: ten-year follow-up from the diagnosis. Diabetes Care 18:1557eC1565, 1995
Lohmann T, Kellner K, Verlohren H-J, Krug J, Steindorf J, Scherbaum W, Seissler J: Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 44:1005eC1010, 2001
Li X, Zhou ZG, Huang G, Yan X, Yang L, Chen XY, Wang JP: Optimal cutoff point of glutamate decarboxylase antibody titers in differentiating two subtypes of adult-onset latent autoimmune diabetes. Ann N Y Acad Sci 1037:122eC126, 2004
Carlsson L, Sundkvist G, Groop L, Tuomi T: Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J Clin Endocr Metab 85:76eC80, 2000
Tripathy D, Carlsson -L, Lehto M, Isomaa B, Tuomi T, Groop L: Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia 43:1476eC1483, 2000
Davies J, Kawaguchi Y, Bennett S, Copeman J, Cordell H, Pritchard L, Reed P, Gough S, Jenkins S, Palmer S, Balfour K, Rowe B, Farrall M, Barnett A, Bain S, Todd J: A genome-wide search for human type 1 diabetes-susceptibility genes. Nature 371:130eC136, 1994
Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P: Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. Am J Hum Genet 69:820eC830, 2001
Ilonen J, Sjoroos M, Knip M, Veijola R, Simell O, Akerblom HK, Paschou P, Bozas E, Havarani B, Malamitsi-Puchner A, Thymell J, Vazeou A, Bartsocas CS: Estimation of genetic risk for type 1 diabetes. Am J Med Genet 115:30eC36, 2002
Rich SS, Panter SS, Goetz FC, Hedlund B, Barbosa J: Shared genetic susceptibility of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin. Diabetologia 34:350eC355, 1991
Groop L, Groop P, Koskimies S: Relationship between beta-cell function and HLA-antigens in patients with type 2 diabetes. Diabetologia 29:757eC760, 1986
Rich SS, French LR, Sprafka JM, Clements JP, Goetz FC: HLA-associated susceptibility to type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study. Diabetologia 36:234eC238, 1993
Tuomilehto-Wolf E, Tuomilehto J, Hitman GA, Nissinen A, Stengard J, Pekkanen J, Kivinen P, Kaarsalo E, Karvonen MJ: Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region. BMJ 307:155eC159, 1993
Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R: Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43): UK Prospective Diabetes Study (UKPDS) Group. Diabetologia 42:608eC616, 1999
Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, Barnett AH, Bain SC, Todd JA: IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 9:415eC421, 1996
Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C: The INS 5' variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem 273:14158eC14164, 1998
Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C: Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun 9:397eC403, 1996
Bennett ST, Lucassen AM, Gough SCL, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, Nerup J, Bouzekri N, Cambon-Thomsen A, Ronningen KS, Barnett AH, Bain SC, Todd JA: Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284eC292, 1995
Awata T, Kurihara S, Kikuchi C, Takei S, Inoue I, Ishii C, Takahashi K, Negishi K, Oshida Y, Hagura R, Kanazawa Y, Katayama S: Evidence for association between class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population. Diabetes 46:1637eC1642, 1997
Laine AP, Hermann R, Knip M, Simell O, Akerblom HK, Ilonen J: The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population. Tissue Antigens 63:72eC74, 2004
Motzo C, Contu D, Cordell HJ, Lampis R, Congia M, Marrosu MG, Todd JA, Devoto M, Cucca F: Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. Diabetes 53:3286eC3291, 2004
Bennett ST, Todd JA: Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343eC370, 1996
Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J, Todd JA, Dunger DB: The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21:262eC263, 1999
Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PWF, Cupples LA: The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women. J Clin Endocrinol Metab 90:1137eC1143, 2005
Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC, Hitman GA, O’Rahilly S, Hattersley AT, McCarthy MI: Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49:126eC130, 2000
Eaves IA, Bennett ST, Forster P, Ferber KM, Ehrmann D, Wilson AJ, Bhattacharyya S, Ziegler AG, Brinkmann B, Todd JA: Transmission ratio distortion at the INS-IGF2 VNTR. Nat Genet 22:324eC325, 1999
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76eC80, 2000
Weaver JU, Kopelman PG, Hitman GA: Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. Eur J Clin Invest 22:265eC270, 1992
Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R: Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986eC990, 1997
Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST, Todd JA: Association of the INS VNTR with size at birth: ALSPAC Study Team: Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 19:98eC100, 1998
Le Stunff C, Fallin D, Bougneres P: Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat Genet 29:96eC99, 2001
Le Stunff C, Fallin D, Schork NJ, Bougneres P: The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat Genet 26:444eC446, 2000
Nezer C, Moreau L, Brouwers B, Coppieters W, Detilleux J, Hanset R, Karim L, Kvasz A, Leroy P, Georges M: An imprinted QTL with major effect on muscle mass and fat deposition maps to the IFG2 locus in pigs. Nat Genet 21:155eC156, 1999
Jeon J, Carolborg , Trnsten A, Giuffra E, Amarger V, Chardon P, Andersson-Eklund L, Andersson K, Hansson I, Lundstrm K, Andersson L: A paternally expressed QTL affecting skeletal and cardiac muscle mass in pigs maps to the IGF2 locus. Nat Genet 21:157eC158, 1999
Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the calpain 10 gene (CAPN10) is associated with type 2 diabetes mellitus. Nat Genet 26:1eC13, 2000
Florez J, Burtt N, de Bakker P, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson T, Schaffner S, Daly M, Hirschhorn J, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor (SUR1) and the islet ATP-sensitive potassium channel (KIR6.2) gene region. Diabetes 53:1360eC1368, 2004
Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P: Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 41:1511eC1515, 1998(Tiinamaija Tuomi)
Key Words: GADA, autoantibody to GAD LADA, latent autoimmune diabetes in adults VNTR, variable number of tandem repeats
ABSTRACT
Type 1 and type 2 diabetes frequently co-occur in the same families, suggesting common genetic susceptibility. Such mixed family history is associated with an intermediate phenotype of diabetes: insulin resistance and cardiovascular complications in type 1 diabetic patients and lower BMI and less cardiovascular complications as well as lower C-peptide concentrations in type 2 diabetic patients. GAD antibody positivity is more common in type 2 diabetic patients from mixed families than from common type 2 diabetes families. The mixed family history is associated with more type 1eClike genetic (HLA and insulin gene) and phenotypic characteristics in type 2 diabetic patients, especially in the GAD antibodyeCpositive subgroup. Leaving out the extreme ends of diabetes phenotypes, young children progressing rapidly to total insulin deficiency and strongly insulin-resistant subjects mostly with non-Europid ethnic origin, a large proportion of diabetic patients may have both type 1 and type 2 processes contributing to their diabetic phenotype.
Diabetes in most cases is caused by a loss of the physical or functional -cell mass, mostly due to an autoimmune process (type 1 etiological process) and/or increased need for insulin due to insulin resistance (type 2 process) (1). Both of these major diabetes types are believed to include different stages of disease, ranging from noneCinsulin-requiring to insulin-requiring for control or survival. According to this classification adopted by the World Health Organization, it is quite possible that both processes would operate in a single patient and contribute to the phenotype of the patient. Also, factors other than autoimmunity can lead to a defective insulin response to glucose. Both major diabetes types are considered multifactorial diseases with several predisposing genetic and environmental factors, some of which could be common to both types. In populations with a high prevalence of type 1 diabetes, like in Finland, a large proportion of patients with type 2 diabetes should have inherited susceptibility genes for both types of diabetes. Also, the lifestyle changes leading to the type 2 diabetes epidemic around the world (2) may have an impact on the clinical picture of type 1 diabetes in the subjects at risk for type 2 diabetes as well. Indeed, obesity has been shown to be a risk factor for childhood type 1 diabetes (3eC6). According to the "accelerator hypothesis," there are two accelerators precipitating disease in all types of diabetes: the intrinsically high rate of -cell apoptosis and insulin resistance resulting from weight gain and physical inactivity. In addition, a third accelerator, -cell autoimmunity, would enhance the diabetic process in a subset (7). The aim of this article is to review the data on genetic interaction between type 1 and type 2 diabetes and its clinical consequences for especially type 2 diabetes.
FAMILIAL CLUSTERING OF TYPE 1 AND TYPE 2 DIABETES
Several studies have reported an increased frequency of type 2 diabetes in families with type 1 diabetes (8eC13). In Sweden, 32% of patients with type 1 diabetes reported a family history of type 2 diabetes compared with 12.5% in a nondiabetic reference group (8). The true prevalence is difficult to ascertain, because most patients are diagnosed with type 1 diabetes at an age when their parents, or grandparents, might still be too young to have developed type 2 diabetes. Also, reliable age-adjusted prevalence data for type 2 diabetes in the general population is rarely available. Of note, a parental history of type 2 diabetes was associated with an increased risk of type 1 diabetes in siblings of type 1 diabetic patients (14, 15).
In accordance with the above, frequent occurrence of type 1 diabetes in relatives of patients with type 2 diabetes has also been observed (16eC19). A total of 14% of Finnish families with more than one type 2 diabetic patient also included type 1 diabetic patients, and 5% of the type 2 diabetic probands had a first-degree relative with type 1 diabetes (19). This is clearly increased compared with the overall 0.5 to 1% prevalence of type 1 diabetes in Finland.
PHENOTYPIC CONSEQUENCES OF THE FAMILIAL CLUSTERING
The consequence of such genetic admixture for type 1 or type 2 diabetes is not known, but the existing data suggest that patients with double genetic predisposition have an intermediate phenotype. Family history for type 2 diabetes is associated with insulin resistance and cardiovascular complications in type 1 diabetic patients. In the Epidemiology of Diabetes Complications Study, the best predictors of insulin resistance in type 1 diabetes were an elevated waist-to-hip ratio, the presence of hypertension, HbA1 level, and family history of type 2 diabetes (20). Family history of type 2 diabetes was a significant risk factor for coronary artery disease (13), and parental type 2 diabetes conferred a threefold risk for nephropathy after adjustment for sex, glycemic control, and family history of hypertension (21). Furthermore, family history of type 2 diabetes and/or hypertension predicted progression of carotid intima-media thickness in a 10-year follow-up study of type 1 diabetic patients, who at baseline were 21 years old with diabetes duration of 12 years (22). Preliminary data from the FinnDiane Study showed that according to the National Cholesterol Education Program criteria for metabolic syndrome, one-third of normoalbuminuric type 1 diabetic patients had metabolic syndrome, and 14% fulfilled more than four diagnostic criteria (23).
Mixed family history has the opposite effect with respect to the phenotype of type 2 diabetes. Family history of type 1 diabetes was negatively associated with coronary artery disease in relatively young (<60 years of age) type 2 diabetic patients, and patients with such family history were leaner than those with family history for type 2 diabetes only (24). Also, type 2 diabetic patients with the type 1eCassociated HLA-DR4 allele had a lower cardiovascular mortality rate than DR4eC patients (25). Overall, the patients with mixed family history also had lower serum C-peptide concentrations, but this largely depended on the high frequency of circulating autoantibodies to GAD (GADAs) in this group, whereas the BMI and coronary artery disease association was present also in GADAeC patients (24). The frequency of GADA positivity was 18% among type 2 diabetic patients with mixed family history compared with 8% among patients with only type 2 diabetes family history (19). Thus, family history of type 1 diabetes could contribute to the heterogeneity observed in GADA+ patients (26).
LATENT AUTOIMMUNE DIABETES IN ADULTS
In two population-based studies, our Botnia study (27) and the much larger U.K. Prospective Diabetes Study (28), GADAs were present in 15eC35% of patients diagnosed with type 2 diabetes at an age younger than 45 years, and in 7eC9% of older patients (Fig. 1). We called this subgroup latent autoimmune diabetes in adults (LADA) (29) and suggested a definition based on circulating GADAs, age at diagnosis of diabetes 35 years, and no treatment with insulin during the first year after diagnosis (27). According to this definition, excluding studies selecting for lean, young-onset, or insulin-treated patients as well as hospital-based studies, the prevalence of LADA is 4.2eC13.2% among Caucasians of mainly Anglo-Celtic or Scandinavian ancestry (28eC31) and 10.2% in African-Americans (31), but lower in Japanese (1.1% [32]) and possibly in Italians (2% [33]) and Australians with Southern European ancestry (1.7% [30]).
Clinically, LADA is a heterogeneous group and the mean concentration of GADAs is lower than in individuals diagnosed with type 1 diabetes (34). When subjects commencing permanent insulin treatment during the first year after diagnosis are excluded, 50eC60% of LADA patients compared with 2% of antibody-negative patients develop marked insulin deficiency during the 6eC10 years from diagnosis (28, 35). The progression of insulin deficiency seems to be associated with younger age at onset, high levels of GADAs, and positivity for multiple autoantibodies; this group may also have other endocrine autoantibodies (27, 28, 36, 37). On the other hand, half of the patients with LADA will never need treatment with insulin and only have a mild deterioration of their maximal insulin secretory capacity compared with GADAeC patients (38). However, compared with GADAeC patients, they have less evidence of the metabolic syndrome (slightly lower BMI, better blood pressure levels, less dyslipidemia) (27, 39). It could be speculated that because of the subclinical deterioration in -cell function, a lower degree of insulin resistance precipitates diabetes in LADA compared with common type 2 diabetes (26).
IS THERE A COMMON GENETIC PREDISPOSITION
HLA class II genes.
The IDDM1 locus in the HLA class II region on chromosome 6p21 is strongly linked to type 1 diabetes (logarithm of odds score 65.8 [40, 41]). It is considered to explain 42% of the familial risk for type 1 diabetes (40). The risk associated with an HLA genotype is defined by the combination of susceptibility and protective alleles of especially DQB1, DQA1, and DRB1 genes (rev. in 42). The susceptibility DQB1 alleles 02 and 0302 were found in 49.6 and 71.1%, respectively, of Finnish type 1 diabetic patients (n = 560) compared with 25.5 and 20.6% of control subjects (n = 10,541). The protective alleles 0301 and 0602 (3) were found in 7.7 and 6.6% of patients compared with 21 and 42.2% of control subjects (42). Thus, at least one-third of the population in Finland carries at least one susceptibility allele.
Excess transmission of DR4-linked haplotypes from parents with type 2 diabetes to offspring with type 1 diabetes has been reported (43). Also, some studies have reported an increased frequency of HLA-DR4 or HLA-DR3/DR4 in patients with type 2 diabetes (44eC47). However, this increase seems to be mainly restricted to patients with relative insulin deficiency or islet cell antibodies (ICAs) and/or GADAs (27, 44, 47). Patients with LADA have an increased frequency of the type 1eCassociated susceptibility HLA alleles DQB10302 and 02 (27, 47), but the family history of type 1 diabetes could be a confounding factor. As mentioned earlier, patients with LADA have family history of type 1 diabetes more often than other phenotypically type 2 diabetic patients. Figure 2 shows the DQB1 genotype data in the Botnia study in patients diagnosed with classic type 1 diabetes and in subgroups of patients diagnosed with type 2 diabetes according to the presence of GADAs and mixed family history. Only data for adult-onset type 1 diabetes is included, because of previously published genotype differences between young-onset and adult-onset type 1 diabetes (rev. in 26). The type 2 diabetic patients from the mixed families shared an increase in the moderate-risk HLA-DQB10302/X genotype with the adult-onset type 1 diabetic patients (Fig. 2 [19]). Because they were relatives of type 1 diabetic patients, this was not unexpected. However, similar sharing of the genotype conferring the highest risk (02/0302) or absence of the genotype conferring protection [0602(3)/X] was not observed except for the GADA+ subgroup of patients from the mixed families. Thus, among the LADA patients, only those from type 1 diabetic families share the 02/0302 and 0602 (3) association with type 1 diabetic patients, whereas all LADA patients share the 0302/X association. This finding suggests that part of the observed heterogeneity among the LADA patients could be ascribed to type 1 diabetes family history.
However, the effect of type 1 diabetes family history on the diabetic phenotype is not restricted to the GADA+ group, as mentioned earlier. Sharing type 1 diabeteseCassociated risk HLA haplotype with a type 1 diabetic relative was associated with impaired insulin secretion in response to oral glucose in type 2 diabetic patients. However, no such effect was seen in type 2 diabetic patients who had similar risk haplotypes without type 1 diabetic relatives, suggesting that other genes on the short arm of chromosome 6 need to be shared (19). All in all, these data point at a genetic interaction between type 1 and type 2 diabetes that could be mediated by the HLA locus or a nearby gene.
Insulin gene.
A variable number of tandem repeats (VNTR) polymorphism in the insulin gene promoter affects the transcription level of insulin and insulin-like growth factor II genes (48eC50). The VNTR is highly variable with respect to both number and sequence of the repeats. In Caucasians, the length distribution is bimodal with 75% of short (class I) and 25% of long alleles (class III) (51). Intriguingly, the VNTR has been associated with both type 1 and type 2 diabetes. Linkage to this region on chromosome 11p15 (40, 41) and an increased frequency of either two class I alleles (Caucasians [48]) or two short class I alleles (Japanese [52]) has been shown in type 1 diabetes in several populations. The effect of the insulin gene on type 1 diabetes risk seems to be strongest in the subjects carrying moderate- or low-risk HLA genotypes, although it is detectable in all HLA risk categories (53, 54).
On the other hand, class III alleles might be associated with hyperinsulinemia, high body mass, and type 2 diabetes, but the data are controversial. A meta-analysis of small case-control studies suggested an increased frequency of class III homozygosity among the type 2 diabetic patients compared with control subjects (relative risk 1.4, P < 0.037) (55, 56). In a population-based follow-up study from the U.K., class III homozygosity increased the risk for type 2 diabetes in women (hazard ratio 4.25; 95% CI 1.76eC10.3), but not in men (57). An increased transmission of paternal class III alleles to affected offspring was seen in British patients with type 2 diabetes (58) or polycystic ovary syndrome (59), but not in Scandinavian type 2 diabetic patients (60). Moreover, class III alleles have been associated with high insulin concentrations and/or increased body mass in morbidly obese women (61) and patients with polycystic ovary syndrome (62), as well as with high birth weight and high rate of weight gain after birth (63). However, childhood obesity was associated with class I alleles and their paternal transmission (64, 65). In pigs, the syntenic region was linked to paternally inherited quantitative trait loci affecting muscle and fat mass (66, 67).
Except for the study of Huxtable et al. (58), in which GADA+ subjects were excluded, the effect of admixture of late-onset type 1 diabetes or family history of type 1 diabetes has not been studied. We examined the association between the insulin VNTR and type 2 diabetes and its sub-phenotypes, taking into account the potential of a simultaneous family history of type 1 diabetes, in 679 unrelated patients with type 2 diabetes, 148 patients with young-onset (<20 years), and 131 patients with adult-onset (20 years) type 1 diabetes and 252 nondiabetic control subjects from the Botnia study. The type 2 diabetic patients included 93 patients who had type 1 diabetic relatives (mixed type 1/2 diabetes) (24) as well as 89 GADA+ (27) and 497 GADAeC patients (60, 27) without family history for type 1 diabetes (common type 2 diabetes). As shown in Fig. 3, the type 1 diabetic patients were more often homozygous for the VNTR class IeCassociated HphI allele (76%) than the control (56%) or common type 2 diabetic subjects, irrespective of GADA positivity (53%, P = 0.0001). The type 2 diabetic patients with mixed family history had an intermediate frequency (61.3%). An increased frequency of the class IeCassociated allele was found in the U.K. Prospective Diabetes Study (47), but not in our Finnish LADA patients (27). However, the GADA+ mixed patients had a comparable I/I genotype frequency (76%) than the adult type 1 diabetic patients (75%), whereas the GADAeC mixed patients (58%) differed less from the GADAeC common type 2 diabetic patients (54%). Obviously, larger numbers of mixed patients are needed to statistically test this difference. It is possible that some of the discrepancies in the literature concerning the association between LADA and insulin VNTR reflect the degree of type 1 diabetes family history in the series.
The HphI genotype was not associated with any clinical parameters in the control, type 1 diabetic, or mixed type 2 diabetic subjects, but the small number of class III/III homozygous patients precluded their separate analysis. Although we did not find an excess of class III/III in type 2 diabetes, our data supported an association between class III alleles and body mass and insulin concentration in males but not in females. The class III allele was significantly associated with high BMI [I/I vs. I/III vs. III/III: 27.5 (5.3) vs. 28.6 (4.9) vs. 31.6 (6.6) kg/m2, P = 0.002] and fat-mass [24.5 (7.1) vs. 27.2 (7.6) vs. 27.4 (8.9)%, P = 0.001]. Men with class III alleles had higher fasting insulin concentrations than those with only class I alleles [11.1 (8.9) vs. 8.7 (8.3) mU/l, P = 0.009] and they were also more insulin resistant [homeostasis model assessment for insulin resistance: 4.71 (4.64) vs. 3.12 (4.22), P = 0.012].
Together with previous data in nondiabetic subjects (61eC67), these results support a role for the insulin gene VNTR in affecting body mass and insulin sensitivity. However, although our study and some other studies have advocated class III alleles to be associated with high in vivo insulin concentrations (61eC63), others have shown this association for class I alleles (64, 65). Moreover, in vitro, class I leads to higher expression of insulin than class III does. More studies in much larger carefully phenotyped groups and functional data are needed to solve these discrepancies.
WHERE TO GO NEXT
Except for the HLA locus, major genes contributing to diabetes have not been revealed. The common varianteCcommon disease hypothesis assumes that common single nucleotide polymorphisms (frequency >10% in the population) increase susceptibility to a polygenic disease like type 2 diabetes, but that these variants act in concert with environmental factors. During recent years, several variants have been identified in genes that increase the risk of type 2 diabetes, e.g., in the PPAR, calpain 10, and Kir 6.2 genes (60, 68eC70). Considering the data that are emerging on familial clustering of type 1 and type 2 diabetes, many of the minor genes are expected to contribute to features common to both types of diabetes. To solve this puzzle, it will be imperative to collect careful phenotypic data on all types of patients to allow stratification for various sub-phenotypes in the analyses.
REFERENCES
Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539eC553, 1998
Zimmet P, Alberti KGMM, Shaw J: Global and societal implications of the diabetes epidemic. Nature 404:782eC787, 2001
Johansson C, Samuelsson U, Ludvigsson J: A high weight gain early in life is associated with an increased risk of childhood diabetes. Diabetologia 37:91eC94, 1994
Bruining GJ: Association between infant growth before onset of juvenile type 1 diabetes and autoantibodies to IA-1. Lancet 356:655eC656, 2000
Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK, Childhood Diabetes in Finland Study Group: Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23:1755eC1760, 2000
Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ: Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care 26:2871eC2875, 2003
Wilkin TJ: The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44:914eC922, 2001
Dahlquist G, Blom L, Tuvemo T, Nystrom L, Sandstrom A, Wall S: The Swedish childhood diabetes study: results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia 32:2eC6, 1989
Pozzilli P, Visalli N, Signore A, Andreani D: Clinical remission in patients with IDDM and family history of NIDDM. Lancet 337:1165, 1991
Ramachandran A, Snehalatha C, Premila L, Mohan V, Viswanathan M: Familial aggregation in type 1 (insulin-dependent) diabetes mellitus: a study from south India. Diabet Med 7:876eC879, 1990
Teupe B, Bergis K: Epidemiological evidence for "double diabetes." Lancet 337:361eC362, 1991
Carel JC, Boitard C, Bougneres PF: Decreased insulin response to glucose in islet cell antibody-negative siblings of type 1 diabetic children. J Clin Invest 92:509eC513, 1993
Erbey JR, Kuller LH, Becker DJ, Orchard TJ: The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population. Diabetes Care 21:610eC614, 1998
Chern MM, Anderson VE, Barbosa J: Empirical risk for insulin-dependent diabetes (IDD) in sibs: further definition of genetic heterogeneity. Diabetes 31:1115eC1118, 1982
Wagener DK, Sacks JM, LaPorte RE, Macgregor JM: The Pittsburgh study of insulin-dependent diabetes mellitus: risk for diabetes among relatives of IDDM. Diabetes 31:136eC144, 1982
Gottlieb MS: Diabetes in offspring and siblings of juvenile- and maturity-onset-type diabetics. J Chronic Dis 33:331eC339, 1980
Quatraro A, Consoli G, Magno M, Caretta F, Ceriello A, Giugliano D: Analysis of diabetic family connection in subjects with insulin-dependent diabetes mellitus (IDDM). Diabete Metab 16:449eC452, 1990
Landin Olsson M, Karlsson FA, Lernmark A, Sundkvist G: Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden. Diabetes 41:1022eC1027, 1992
Li H, Lindholm E, Almgren P, Gustafsson A, Forsblom C, Groop L, Tuomi T: Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 diabetes. J Clin Endocrinol Metab 86:574eC582, 2001
Williams K, Erbey JR, Becker D, Arslanian S, Orchard TJ: Can clinical factors estimate insulin resistance in type 1 diabetes Diabetes 49:626eC632, 2000
Fagerudd JA, Pettersson-Fernholm KJ, Gronhagen-Riska C, Groop PH: The impact of a family history of type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia 42:519eC526, 1999
Makimattila S, Ylitalo K, Schlenzka A, Taskinen MR, Summanen P, Syvanne M, Yki-Jarvinen H: Family histories of type II diabetes and hypertension predict intima-media thickness in patients with type I diabetes. Diabetologia 45:711eC718, 2002
Thorn LM, Forsblom C, Fagerudd J, Thomas MC, Pettersson-Fernholm K, Saraheimo M, Waden J, Rnnback M, Rosengrd-Brlund M, af Bjrkesten C-G, Taskinen M-R, Groop P-H, the FinnDiane Study Group: Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care 28:2019eC2024, 2005
Li H, Isomaa B, Almgren P, Taskinen M-R, Groop L, Tuomi T: Consequences of a family history of type 1 or type 2 diabetes on the phenotype of patients with type 2 diabetes. Diabetes Care 23:589eC594, 2000
Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, Matikainen E, Teppo AM, Koskimies S, Groop L: Risk factors for mortality in type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41:1253eC1262, 1998
Tuomi T: LADA in adults: how does it differ from type 1 diabetes Int Diabetes Monitor 17:1eC5, 2005
Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissen M, Ehrnstrom BO, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC: Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150eC157, 1999
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R: UKPDS25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes: UK Prospective Diabetes Study Group. Lancet 350:1288eC1293, 1997
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359eC362, 1993
Davis T, Zimmet P, Davis W, Bruce D, Fida S, Mackay I: Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi-ethnic Australian community: the Fremantle Diabetes Study. Diabet Med 17:667eC674, 2000
Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL, Kuller LH, Trucco M: Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 49:32eC38, 2000
Kobayashi T, Nakanishi K, Okubo M, Murase T, Kosaka K: GAD antibodies seldom disappear in slowly progressive IDDM (Letter). Diabetes Care 19:1031, 1996
Bosi E, Garancini M, Poggiali F, Bonifacio E, Gallus G: Low prevalence of islet-cell autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy. Diabetologia 42:840eC844, 1999
Lundgren V, Lyssenko V, Isomaa B, Laurila E, Groop L, Tuomi T, the Botnia Study Group: GADA positivity in relatives of type 2 diabetes or LADA (Abstract). Diabetes 54 (Suppl. 2):S160, 2005
Niskanen LK, Tuomi T, Karjalainen J, Groop LC, Uusitupa MI: GAD antibodies in NIDDM: ten-year follow-up from the diagnosis. Diabetes Care 18:1557eC1565, 1995
Lohmann T, Kellner K, Verlohren H-J, Krug J, Steindorf J, Scherbaum W, Seissler J: Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 44:1005eC1010, 2001
Li X, Zhou ZG, Huang G, Yan X, Yang L, Chen XY, Wang JP: Optimal cutoff point of glutamate decarboxylase antibody titers in differentiating two subtypes of adult-onset latent autoimmune diabetes. Ann N Y Acad Sci 1037:122eC126, 2004
Carlsson L, Sundkvist G, Groop L, Tuomi T: Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J Clin Endocr Metab 85:76eC80, 2000
Tripathy D, Carlsson -L, Lehto M, Isomaa B, Tuomi T, Groop L: Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia 43:1476eC1483, 2000
Davies J, Kawaguchi Y, Bennett S, Copeman J, Cordell H, Pritchard L, Reed P, Gough S, Jenkins S, Palmer S, Balfour K, Rowe B, Farrall M, Barnett A, Bain S, Todd J: A genome-wide search for human type 1 diabetes-susceptibility genes. Nature 371:130eC136, 1994
Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P: Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. Am J Hum Genet 69:820eC830, 2001
Ilonen J, Sjoroos M, Knip M, Veijola R, Simell O, Akerblom HK, Paschou P, Bozas E, Havarani B, Malamitsi-Puchner A, Thymell J, Vazeou A, Bartsocas CS: Estimation of genetic risk for type 1 diabetes. Am J Med Genet 115:30eC36, 2002
Rich SS, Panter SS, Goetz FC, Hedlund B, Barbosa J: Shared genetic susceptibility of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin. Diabetologia 34:350eC355, 1991
Groop L, Groop P, Koskimies S: Relationship between beta-cell function and HLA-antigens in patients with type 2 diabetes. Diabetologia 29:757eC760, 1986
Rich SS, French LR, Sprafka JM, Clements JP, Goetz FC: HLA-associated susceptibility to type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study. Diabetologia 36:234eC238, 1993
Tuomilehto-Wolf E, Tuomilehto J, Hitman GA, Nissinen A, Stengard J, Pekkanen J, Kivinen P, Kaarsalo E, Karvonen MJ: Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region. BMJ 307:155eC159, 1993
Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R: Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43): UK Prospective Diabetes Study (UKPDS) Group. Diabetologia 42:608eC616, 1999
Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, Barnett AH, Bain SC, Todd JA: IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 9:415eC421, 1996
Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C: The INS 5' variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem 273:14158eC14164, 1998
Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C: Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun 9:397eC403, 1996
Bennett ST, Lucassen AM, Gough SCL, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, Nerup J, Bouzekri N, Cambon-Thomsen A, Ronningen KS, Barnett AH, Bain SC, Todd JA: Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284eC292, 1995
Awata T, Kurihara S, Kikuchi C, Takei S, Inoue I, Ishii C, Takahashi K, Negishi K, Oshida Y, Hagura R, Kanazawa Y, Katayama S: Evidence for association between class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population. Diabetes 46:1637eC1642, 1997
Laine AP, Hermann R, Knip M, Simell O, Akerblom HK, Ilonen J: The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population. Tissue Antigens 63:72eC74, 2004
Motzo C, Contu D, Cordell HJ, Lampis R, Congia M, Marrosu MG, Todd JA, Devoto M, Cucca F: Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. Diabetes 53:3286eC3291, 2004
Bennett ST, Todd JA: Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343eC370, 1996
Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J, Todd JA, Dunger DB: The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21:262eC263, 1999
Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PWF, Cupples LA: The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women. J Clin Endocrinol Metab 90:1137eC1143, 2005
Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC, Hitman GA, O’Rahilly S, Hattersley AT, McCarthy MI: Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49:126eC130, 2000
Eaves IA, Bennett ST, Forster P, Ferber KM, Ehrmann D, Wilson AJ, Bhattacharyya S, Ziegler AG, Brinkmann B, Todd JA: Transmission ratio distortion at the INS-IGF2 VNTR. Nat Genet 22:324eC325, 1999
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76eC80, 2000
Weaver JU, Kopelman PG, Hitman GA: Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. Eur J Clin Invest 22:265eC270, 1992
Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R: Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986eC990, 1997
Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST, Todd JA: Association of the INS VNTR with size at birth: ALSPAC Study Team: Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 19:98eC100, 1998
Le Stunff C, Fallin D, Bougneres P: Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat Genet 29:96eC99, 2001
Le Stunff C, Fallin D, Schork NJ, Bougneres P: The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat Genet 26:444eC446, 2000
Nezer C, Moreau L, Brouwers B, Coppieters W, Detilleux J, Hanset R, Karim L, Kvasz A, Leroy P, Georges M: An imprinted QTL with major effect on muscle mass and fat deposition maps to the IFG2 locus in pigs. Nat Genet 21:155eC156, 1999
Jeon J, Carolborg , Trnsten A, Giuffra E, Amarger V, Chardon P, Andersson-Eklund L, Andersson K, Hansson I, Lundstrm K, Andersson L: A paternally expressed QTL affecting skeletal and cardiac muscle mass in pigs maps to the IGF2 locus. Nat Genet 21:157eC158, 1999
Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the calpain 10 gene (CAPN10) is associated with type 2 diabetes mellitus. Nat Genet 26:1eC13, 2000
Florez J, Burtt N, de Bakker P, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson T, Schaffner S, Daly M, Hirschhorn J, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor (SUR1) and the islet ATP-sensitive potassium channel (KIR6.2) gene region. Diabetes 53:1360eC1368, 2004
Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P: Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 41:1511eC1515, 1998(Tiinamaija Tuomi)