The Genetics of the Glucose Intolerance Disorders

Transcription

1 The Genetics of the Glucose Intolerance Disorders JEROME I. ROTTER, M.D. DAVID L. RIMOIN, M.D., Ph.D. Torrunce, California From the Division of Medical Genetics, Department of Medicine and Pediatrics, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California. This paper was supported in part by NIH Grant AM 25834, a grant from the KROC Foundation and Clinical Investigator Award AM (J.I.R.). Requests for reprints should be addressed to Dr. J. Rotter, Division of Medical Genetics, Department of Medicine and Pediatrics, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, CA Genetic heterogeneity, the concept that diabetes can have many different causes, was fiit suggested by the existence of rare genetic syndromes with diabetes, ethnic differences in clinical features and genetic heterogeneity of animal models. Genetic heterogeneity is now considered to be firmly established by family, twin, metabolic, immunologic and HLA disease association studies that separate idiopathic diabetes into insulin-dependent types (juvenile-onset type) and noninsulin-dependent types (maturity-onset type). Further heterogeneity is being demonstrated within each of these broad groups of disorders -within insulin-dependent diabetes using the HLA antigens and immunologic studies, and within noninsulindependent diabetes using such criteria as obesity, insulin response, age of onset and chlorpropamide-primed alcohol-induced flushing. This heterogeneity has major implications for the research and care of our diabetic patients since the precise etiology, risk of complications and genetic counseling are likely to vary among these different disorders that result in diabetes. It has been clearly established in recent years that diabetes mellitus is a genetically heterogeneous group of disorders that share glucose intolerance in common [l-6]. (Heterogeneity implies that different genetic and/or environmental etiologic factors can result in similar clinical disorders.). The concept of genetic heterogeneity has significantly altered the genetic analysis of this common disorder. It is now, apparent that diabetes and glucose intolerance are not diagnostic terms but, like anemia, are simply symptom complexes or laboratory abnormalities, respectively, which can result from a number of distinct etiologic factors. Diabetes mellitus is currently classified into idiopathic diabetes mellitus and diabetes or glucose intolerance associated with genetic syndromes and other conditions [7]. The majority of cases of diabetes mellitus currently are placed into the idiopathic category, and the exact prevalence of the latter category is unknown. The idiopathic category is further subdivided into two major groups-an insulin-dependent type (often referred to as juvenile-onset diabetes] and a noninsulin-dependent type (often referred to as maturity-onset diabetes]. This separation is based on family, twin, metabolic, immunologic and HLA association studies. There is now evidence that even these major categories can be further subdivided into distinct entities. This subclassification is of major importance, because it is only through the delineation of this heterogeneity that distinct disease entities will be identified. To be meaningful, pathophysiologic studies, genetic analyses, epidemiologic prospective studies, delineation of risk factors and creation of risk tables for genetic counseling 116 January 1961 The American Journal of Medicine Volume 76

2 GENETICS OF GLIJCOSE INTOLERANCE DISORDERS-ROTTER, RIMOIN must be performed on each of the specific disease entities constituting the diabetic phenotype. For many years the genetics of diabetes mellitus was one of the most confused topics in medicine. Although familial aggregation of diabetes has been apparent for years, and classic twin studies indicated that a large component of this familial aggregation is due to genetic factors, there has been little agreement as to the specific nature of the genetic factors involved [5,6]. This confusion could in large part be explained by genetic heterogeneity. Indeed, the evidence marshalled for the concept of heterogeneity within diabetes is now overwhelming [l-6]. In 1966, the hypothesis of genetic heterogeneity was proposed based on several lines of evidence [6,8]. Indirect evidence included (1) the existence of distinct, mostly rare genetic disorders-now numbered about JO-that have glucose intolerance as one of their features: (2) genetic heterogeneity in diabetic animal models; (3) ethnic variability in prevalence and clinical features: (4) clinical variability between the thin, ketosis prone, insulin-dependent juvenile-onset diabetic subject versus the obese, nonketotic, insulin-resistant adult-onset diabetic subject; and (5) physiologic variability-the demonstration of decreased plasma insulin in those with juvenile-onset diabetes versus the relative hyperinsulinism of those with maturity-onset diabetes. In addition, some direct evidence for heterogeneity came from clinical genetic studies which suggested that juvenile-onset and adult-onset diabetes differ genetically [2,5,9]. Genetic Syndromes Associated with Glucose Intolerance. There are some 40 distinct genetic disorders associated with glucose intolerance and, in some cases, clinical diabetes (Table I) [5,6,10]. Although individually rare, these syndromes demonstrate that mutations at different loci can produce glucose intolerance. Furthermore, they illustrate the wide variety of pathogenetic mechanisms which can result in glucose intolerance. The pathogenetic mechanisms range from absolute insulin deficiency due to pancreatic degeneration, in such disorders as hereditary relapsing pancreatitis, cystic fibrosis and polyendocrine deficiency disease; to relative insulinopenia in the growth hormone deficiency syndromes; to inhibition of insulin secretion in the hereditary pheochromocytoma syndromes associated with elevated catecholamine levels; to various deficits in the interaction of insulin and its receptor in the nonketotic insulin-resistant states, in such disorders as myotonic dystrophy and the lipoatrophic diabetes syndromes; to relative insulin resistance in the hereditary syndromes associated with obesity. Even within these individual categories, further division can be made, either by mechanism or by genetic criteria. For example, the lipoatrophic syndromes-characterized by the total or partial absence of adipose tissue, hyperlipidemia, insulin resistance, nonketotic diabetes mellitus, increased basal metabolic rate and hepatomegaly-can be further subdivided into a recessive, and several dominant and TABLE I Genetic Syndromes Associated with Glucose Intolerance Syndromes associated with pancreatic degeneration Hereditary relapsing pancreatitis Cystic fibrosis Polyendocrine deficiency disease (Schmidt syndrome) Hemochromatosis Thalassemia Alpha,-antitrypsin deficiency Hereditary endocrine disorders with glucose intolerance Isolated growth hormone deficiency Hereditary panhypopituitary dwarfism Laron dwarfism Pheochromocytoma Multiple endocrine adenomatosis I syndrome Inborn errors of metabolism with glucose Intolerance Glycogen storage disease type I (von Gierke s disease) Acute intermittent porphyria Hyperlipidemia Syndromes with nonketotic insulln-resistant early-onset diabetes mellitus Ataxia telangiectasia Myotonic dystrophy Lipoatrophic diabetes syndromes Leprechaunism Insulin resistance and acanthosis nigricans Mendenhall syndrome Hereditary neuromuscular disorders associated with glucose intolerance Muscular dystrophies Late onset proximal myopathy Huntington s chorea Machado disease Herrman syndrome Diabetes mellitus-optic atrophy, diabetes insipidus-deafness syndrome (Wolfram syndrome) Friedreich s ataxia Alstrom syndrome Laurence-Moon-Biedl syndrome Pseudo-Refsum syndrome Progeroid syndromes associated with glucose Intolerance Cockayne syndrome Werner syndrome Syndromes with glucose intolerance secondary to obesity Prader-Willi syndrome Achondroplastic dwarfism Miscellaneous syndromes associated with glucose intolerance Steroid induced ocular hypertension Epiphyseal dysplasia and infantile onset diabetes mellitus Progressive cone dystrophy, degenerative liver disease, endocrine dysfunction, and hearing defect Secretion of an abnormal insulin Cytogenetic disorders associated with glucose intolerance Down syndrome Klinefelter syndrome Turner Syndrome nongenetic forms [5,11]. Even within what is currently believed to be one genetic entity, multiple endocrine adenoma type I, an autosomal dominant disorder characterized by pituitary, parathyroid and pancreatic adenomas, a variety of different hormonal mechanisms can result in insulin antagonism. [For example, eosin- January 1981 The American Journal of Medicine Volume

3 GENETICS OF GLUCOSE INTOLERANCE DISORDERS-ROTTER, RIMOIN TABLE Ii Syndromes Associated with Insulin Receptor Defects post- Receptor Receptor Humoral receptor Syndrome Number Affinity Antagonist Defect Ataxia telangiectasia N Myotonic dystrophy N Congenital lipodystrophy N 1? - Leprechaunism Acanthosis nigricans A 7 ; I + Acanthosis nigricans B N + - Acanthosis nigricans C N N - + Werner syndrome N N - + ophilic adenomas of the pituitary may secrete growth hormone, adenomas of the adrenal gland can secrete cortisol, and nonbeta islet cells of the pancreas can produce glucagon. Each of the hormones individually is an insulin antagonist, and their excess can lead to marked glucose intolerance.] A variety of syndromes are characterized by marked insulin resistance. The pathophysiology of the resistance in many of these disorders has recently been defined by studies of the insulin receptor and its interactions (Table II) [5,12]. Another recent development is the description of a person with maturity-onset type diabetes as a consequence of secretion of an abnormal insulin [13]. Thus, each of these 40 different genetic diseases is capable of resulting in carbohydrate intolerance through a variety of different pathogepetic mechanisms. These rare syndromes clearly suggest that similar heterogeneity, both genetic and pathogenetic, may exist in idiopathic diabetes mellitus. Insulin-Dependent (Juvenile Type) versus Noninsulin-Dependent (Maturity Type) Diabetes. Heterogeneity within the more common forms of diabetes, unassociated with complex genetic syndromes, has been considered for years because of the clear clinical and physiologic distinction between the thin, ketosis prone, insulin-dependent juvenile-onset diabetic versus the obese, nonketotic, noninsulin-dependent adult-onset diabetic. A number of family studies clearly indicated that juvenile-onset and adult-onset diabetes appear to be separate disorders genetically [2,5,9]. This distinction remains when the diabetic subjects are categorized as to insulin dependence, i.e., the insulin-dependent and noninsulin-dependent types also segregate independently [14,15]. The extensive monozygotic twin studies by Pyke and his co-workers [16,17] in England strongly supported the separation of juvenile insulin-dependent and maturity noninsulin-dependent diabetes. In contrast to the usual twin studies, in which one compares concordance rates among monozygotic versus dizygotic twin pairs, Pyke and co-authors [16] examined only monozygotic twins looking for differences between the concordant and discordant pairs. Of 106 monozygotic twin pairs studied, 71 were concordant and 35 discordant. When the pairs were classified according to their age at onset of the disease, however, only 50 percent of the pairs, in whom the age of onset of diabetes in the index twin was below 40 years, were concordant as opposed to 100 percent of those in whom diabetes developed in the index twin after the age of 50 years. Of the discordant pairs, most have remained so for more than 10 years and showed no trend toward increasing concordance with time. Pyke [17] has now studied 185 twin pairs with similar results. Thus, among twin pairs with maturity-onset type of noninsulin-dependent diabetes, concordance approached 100 percent; whereas in those twin pairs with insulin-dependent juvenile-onset diabetes, concordance was only approximately 50 percent. This would suggest that there are a large group of subjects with juvenile-onset diabetes in whom, although the predisposition to diabetes can be genetically determined, nongenetic factors are of major importance. The study of insulin response to a glucose load provided early physiologic evidence for heterogeneity in diabetes. The absolute insulinopenic response of juvenile-onset diabetic patients and the relative hyperinsulinemic response of maturity-onset diabetic patients parallels therapeutic observations of the absolute insulin requirement of the patient with juvenile-onset (insulin-dependent) diabetes in contrast to the ability to manage most patients with adult-onset diabetes with oral hypoglycemics and/or diet (insulin-independent). This, plus the immunologic and HLA observations mentioned herein, led the recent international working group of the National Institutes of Health (NIH) to use insulin dependence, rather than age at onset, as a basis of classification [7,18]. Immunologic studies have also supported this separation into insulin-dependent and noninsulin-dependent diabetic types. The first evidence was indirect, in that only insulin-dependent diabetes was found to be clinically associated with Addison s disease, certain thyroid disorders and pernicious anemia, and with increased antibodies to the thyroid, gastric mucosa, intrinsic factor and the adrenal gland [19]. Direct evidence for an autoimmune role in the pathogenesis of insulindependent diabetes came from the discovery of organ specific cell-mediated immunity to pancreatic islets and then the eventual successful demonstration of antibodies to the islet cells of the pancreas [20,21]. Although these antibodies were first detected only in insulindependent diabetic patients with coexistent autoimmune endocrine disease, it soon became apparent that they were common (60 to 80 percent) in subjects with newly diagnosed juvenile-onset diabetes. Islet cell antibody studies supported the differentiation of insulin-dependent from noninsulin-dependent diabetes, as antibodies were present in 30 to 40 percent of the former group as opposed to 5 to 8 percent of the latter. Of interest, the majority of the insulin-independent yet antibody-positive, patients appeared to become insu- 118 January 1981 The American Journal of Medicine Volume 70

4 GENETICS OF GLIJCOSE INTOLERANCE DISORDERS-ROTTER. RIMOIN lin-dependent with time. In addition, they have flat insulin responses to a glucose load. This has suggested that etiologically they belong in the insulin-dependent category [that is, they are just in an intermediate state in the development of insulin dependence) [22]. These immunologic studies have thus both separated disorders (juvenile-onset versus adult-onset) and combined others (insulin-dependent and noninsulin-dependent yet antibody-positive]. The clear and consistent association of juvenile-onset insulin-dependent, but not maturity-onset insulinindependent diabetes, with HLA antigens B8 and Bl5, has been a major argument for etiologic differences between these disorders [15,23,24]. These associations appear to be even stronger for antigens Dw3 and Dw4 of the HLA D locus [23,24]. These HLA alleles are believed to serve as markers for closely linked but as yet untypeable diabetogenic genes which may be immune response genes that are directly responsible for the patient s susceptibility to insulin-dependent diabetes. The family, twin, metabolic, immune and HLA studies clearly indicate that juvenile-onset insulindependent and maturity-onset insulin-independent diabetes are genetically distinct. The NIH National Diabetes Data Group sponsored International Workgroup on the Classification of Diabetes considered that this division between insulin-dependent type and noninsulin-dependent type diabetes is firmly established [7]. Therefore, in its classification, it has divided diabetes into an insulin-dependent type (that is, insulin dependence regardless of age at onset, therefore including the classic juvenile-onset diabetes] and a noninsulin-dependent type (classic maturity-onset diabetes, but emphasizes insulin-independent diabetes, regardless of age at onset). A few cautions are in order. First, just because we are able to separate the bulk of patients and families with diabetes into insulin-dependent and noninsulin-dependent types does not mean this phenotypic distinction is absolute. Cahill [18] has pointed out that there is at least some evidence that families of either type have more of the other type than do the general population. Part of this may be attributed to the insulin-independent phase of the insulin-dependent type (the frequency of which is not yet defined] [22]. But this observation may also hint at as yet undelineated further heterogeneity. Second, it is appropriate to point out that age at onset is still a helpful criterion in describing the diabetic phenotype. Although the distinction on the basis of insulin dependence versus independence has the greatest support, the use of age at onset as an additional, not substitute, clinical criterion has delineated further heterogeneity. Tattersall and Fajans [25,26] have described a distinct form of noninsulin-dependent diabetes which they have called maturity-onset diabetes of the young (to be discussed herein]. The recent delineation of this entity clearly demonstrates that age at onset is a useful clinical criterion. Similarly, there is tentative evidence that age at onset may still be a helpful additional classification criterion in the insulin-dependent type. Initial reports have suggested that Bl5 and Dw4 were increased principally in younger insulindependent diabetic patients whereas B8 and Dw3 were increased more prominently in older insulin-dependent diabetes patients, thus suggesting heterogeneity within insulin-dependent diabetes [24,27,28]. Heterogeneity Within Insulin-Dependent Diabetes. The various genetic studies, both clinical and those using subclinical markers such as insulin levels and islet cell antibodies, not only clearly indicate that insulin-dependent (juvenile-onset type) and noninsulin-dependent [maturity-onset type] diabetes are separate genetic disorders but also suggest that significant heterogeneity exists within these broad groups of disorders. The evidence for heterogeneity within insulin-dependent diabetes has been developing for some time. It could be inferred when the first detailed argument for heterogeneity within all of diabetes was proposed, since frank insulin-dependent diabetes was a component of certain defined genetic syndromes, such as the optic atrophy diabetes mellitus syndrome and a syndrome with epipbyseal dysplasia and infantile-onset diabetes [5,6,10]. More direct evidence came from immunologic studies which suggested that there were forms of insulin-dependent diabetes which were associated with autoimmunity and those which were not, and that this occurred on a familial basis [2%-311. On the basis of the additive risk of B8 and B15, the Danish group suggested the possibility that more than one gene in the HLA complex affected the susceptibility for insulin-dependent diabetes [32]. Subsequently Bottazzo and Doniach [33], and Irvine [19] proposed that insulin-dependent diabetes can be subdivided into autoimmune and viral-induced types, with an intermediate group in the Irvine classification. The autoimmune type would be characterized by pancreatic islet cell antibodies, which may occur years before the onset of clinical diabetes and persist for years after its onset, by the presence of other associated autoimmune endocrinopathies and antibodies, by an onset at any age and by a higher incidence in females. In contrast, the hypothesized viral-induced type would have transient islet cell antibodies at the onset of disease which disappear within the next year, would not be associated with autoimmunity, would tend to have an age at onset of less than 30 years (but which may occur later] and have an equal sex incidence. During the same period, Rotter and Rimoin [35], on the basis of an analysis of published immunologic and metabolic studies, proposed further heterogeneity among the juvenileonset insulin-dependent form of diabetes based on differential immunologic correlations with different HLA phenotypes; they postulated that the HLA B8-Dw3 and B15-Dw4 associated forms of diabetes are distinct diseases-b8-dw3, an autoimmune form, and B15-Dw4, an insulin-antibody responder type [2,5,34]. January 1981 The American Journal of Medicine Volume

5 GENETICS OF GLUCOSE INTOLERANCE DISORDERS-ROTTER. RIMOIN TABLE III Heterogeneity Within Insulin-Dependent Diabetes Mellitus Evidence B8 815 B8(Dw3)/B15(Dw4) Combined Form Relative risk for diabetes [5,24,32.35] Linkage disequilibrium [5] Insulin antibodies [ Islet cell antibodies [35, Antipancreatic cell-mediated immunity I351 Associated with other autoimmune endocrine diseases [45,46] Isolated pedigrees [5] Age of onset [24,27,28] -Additive- TRelative risk [5,24,32,35] Dw3, Drw3, Al Cw3, Dw4, Drw4 toccurrence in MZ twins [ 151 Nonresponder (no High responder (produce trisk to siblings [35] antibodies) antibodies) toccurrence in familial cases [ 15,241 Persistent Transient Increased Not increased Yes Autoimmune disorder Any age No Defect in insulin release Younger age The accumulated evidence strongly suggests that genetic heterogeneity exists even within the typical insulin-dependent juvenile-onset type of diabetes (Table III). It appears that there are at least two clearly distinct forms of juvenile-onset diabetes, one of which is associated with HLA B8 and the other with B15 [5,34]. The HLA-B8 form of the disease (autoimmune form) is characterized by an increased prevalence of pancreatic islet cell antibodies and antipancreatic cell-mediated immunity, and a lack of antibody response to exogenous insulin. A second form of juvenile-onset insulin-dependent diabetes is associated with HLA B15 and is less well characterized. It appears to be associated with the Cw3 allele of the HLA C locus and Dw4 of the D locus, it is not associated with autoimmune disease or islet cell antibodies, and it is accompanied by an increased antibody response to exogenous insulin. This disorder also appears to have an earlier age of onset than the B8-Dw3 type. Irvine et al. [38] have recently shown a direct relationship between persistent islet antibodies and lower insulin antibody levels, thus directly confirming the differential immunologic features of the two forms. There also exists a third form, the compound B8- Dw3/B15-Dw4 heterozygote [47]. This form is characterized by an increased relative risk, an increased prevalence among concordant twins, an increased prevalence among familial cases and an increased risk to sibs for diabetes [5,15,24;35]. In addition, this group may have the earliest age at onset and greater islet cell damage, as indicated by the lowest levels of measurable C-peptide [48]. There currently exists a lively debate regarding the mode of inheritance of insulin-dependent diabetes. Susceptibility to insulin-dependent diabetes has been variously proposed to be inherited in autosomal dominant, recessive or intermediate fashion, based on population studies of HLA antigens and family studies of HLA haplotypes. These studies generally proceed as follows: They start with the observation that siblings who are both affected with insulin-dependent diabetes share both HLA haplotypes more often than is expected by chance alone. (A haplotype is the set of alleles at the four closely linked HLA loci, A, B, C.and D, on one chromosome 6. Each person inherits two haplotypes, one from each parent.] If there were no linkage-association between the HLA region and insulin-dependent diabetes, affected pairs of siblings would be expected to share two haplotypes (HLA identical], one haplotype (HLA haploidentical) and 0 haplotypes (HLA nonidentical) in a ratio of 25 percent to 50 percent to 25 percent. Instead, a number of reports indicate that pairs of diabetic siblings share two haplotypes approximately 60 percent of the time, share one haplotype approximately 40 percent of the time and, in only a few cases, share no haplotypes [15,23,28,49,50,51]. This is between the 100 percent and 0 percent for two and one shared haplotypes that would be expected for simple autosomal recessive inheritance and the 50 percent and 50 percent expected for autosomal dominant inheritance. The evidence for heterogeneity reviewed here, plus the observations regarding the compound form, make an autosomal recessive hypothesis for all of insulindependent diabetes increasingly less tenable. A more restricted hypothesis would be that at least some forms of juvenile diabetes were due to inheritance of recessive susceptibility. Barbosa et al. [52] ascertained their patients in order to select two sets of families: those with horizontal and those with vertical aggregation. For the purpose of linkage analysis, they then assumed recessive inheritance for the first set and dominant for the second. However, without further phenotypic distinctions, it is not clear whether these different aggregation patterns truly reflect different modes of inheritance. In addition, formal linkage analysis of the multiplex families studied by Barbosa et al. [53], assuming genetic homogeneity and autosomal recessive inheritance, was found to be consistent only with loose linkage to HLA (recombination fraction of percent [53,54]. In the absence of selection, such loose linkage is inconsistent with HLA association due to linkage disequilibrium. If the linkage between the HLA alleles and the diabetogenic susceptibility genes was not very tight, we would not expect to see the association in population [cross sectional) studies, 120 January 1981 The American Journal of Medicine Volume 70

6 GENETICS OF GLUCOSE INTOLERANCE DISORDERS-ROTTER. RIMOIN because the disequilibrium should have disappeared in just a few generations after the appearance of the diabetogenic alleles. For the most part these models ignore the increasingly documented heterogeneity within insulin-dependent diabetes. Formal genetic analyses, which fail to take this heterogeneity into account and treat insulin-dependent diabetes as one entity, probably suffer from the same defect as did earlier genetic analyses which failed to distinguish insulin-dependent from noninsulin-dependent diabetes. Other genetic models besides simple autosomal dominant or recessive ones must be developed to take this heterogeneity into account. For example, Hodge et al. [55] have recently developed a three allele model for a diabetic susceptibility locus tightly linked to the HLA complex which incorporates the immunogenetic heterogeneity observed within insulin-dependent diabetes. There were several predictions and conclusions from this modeling. First, it demonstrates that other models, besides dominant and recessive, can account for the population and HLA observations Second, in a sense, this model has both dominant and recessive features. Since only one diabetogenic allele is required for susceptibility, genetic transmission mimics dominant inheritance on a population basis. However, the familial forms often involve two alleles and, therefore, can mimic recessive inheritance within families. This kind of model should not be considered as a solution to the inheritance of insulin-dependent diabetes but as a working hypothesis to be tested in future clinical genetic and epidemiologic studies. Most recently, MacDonald [56] has argued from population genetic data that since the relative frequency of insulin-dependent diabetes in U.S. blacks is similar to the proposed fraction of gene admixture from the Caucasian population, this is most consistent with dominant inheritance of insulin-dependent diabetes susceptibility. However, the heterogeneity model can also account for these relative frequencies [57]. Heterogeneity with Noninsulin-Dependent Diabetes Mellitus (NIDDM). Clinical genetic studies have also suggested heterogeneity within the adult-onset type of diabetes. Kobberling [58] divided his probands with adult-onset diabetes into low, moderate and markedly overweight categories. He found a significantly higher frequency of affected siblings in the light proband category (38 percent] and a significantly lower frequency in the heavy proband category (10 percent]. Although Kobberling comments that one explanation for these findings could be an additive gene model, with obesity as an additional risk factor, this could also be explained by different monogenic forms with different susceptibilities, i.e., different dependence on exogenous predisposing factors. Irvine et al. [14] also suggested a difference between the nonobese and obese insulin-independent propositi in that they observed a different clinical range of diabetes in the relatives of the nonobese and obese propositi. Fajans [59] demonstrated metabolic heterogeneity in nonobese latent diabetic patients. He was able to divide his patients with latent diabetes into two broad groups, one that had an insulinopenic form of glucose intolerance, in contrast to those with high levels of plasma immunoreactive insulin. The high responders and low responders remained consistent and distinct following many years of follow-up suggesting that they represented different metabolic disorders. Fajans suggests that in the under-responder category, the lack of insulin is one of the principal determinants of abnormal glucose tolerance. On the other hand, he suggests that in the overresponder category, the hyperinsulinemia is secondary to other factors which cause glucose intolerance. Whether insulin responses will serve as a genetic marker still remains to be determined although Fajans [3] mentions that in unpublished studies the level of insulin response clusters in families. The best delineated heterogeneity within noninsulin-dependent diabetes is the distinct form of diabetes described by Tattersall and Fajans which they have called maturity-onset diabetes of the young [3,25,26] and which Pyke and colleagues refer to as a Masontype diabetes [17]. In this group of patients, the age at onset is early but they have few symptoms, no ketonuria and can be controlled without insulin, with little progression in severity of carbohydrate intolerance over 20 years or more. These patients with maturity-onset diabetes of young people (patients with maturity-onset diabetes of the young) are clearly phenotypically different from those with the classic juvenile-onset diabetes. Physiologic studies of these patients support this phenotypic differentiation, as their insulin responses to glucose loads are much more characteristic of maturity-onset diabetes. Genetic studies provided further evidence that this is a separate entity. Of the propositi with maturity-onset diabetes of the young, 85 percent had a diabetic parent, usually with a similar phenotype, 53 percent of sibs tested had diabetes, and 46 percent of the families showed three generations of direct vertical transmission of the trait, suggesting autosomal dominant inheritance. In contrast, only ll percent of the parents of those with juvenile-onset diabetes were diabetic, eight of 74 sibs were diabetic, six with similar juvenile-onset diabetes phenotype, and only 6 percent of the families showed three-generation transmission. Thus, the patients with maturity-onset diabetes of the young clearly have a distinct dominantly inherited syndrome. The delineation of this disorder most clearly demonstrates the need to carefully dissect the phenotypic differences among diabetic patients before genetic analysis is possible. If these patients with maturity-onset diabetes of the young had been classified by either their age at onset of the disease or by diabetic phenotype (insulin independence] alone, they would have been lumped together with:, classic juvenile-onset diabetes or the noninsulin-dependent type of the current NIH classification, respectively, and their January 1981 The American Journal of Medicine Volume

7 GENETICS OF GLUCOSE INTOLERANCE DISORDERS-ROTTER, RIMOIN TABLE IV Heterogeneity Within Primary Diabetes Mellltus (overlapping features that may yield separate classifications) Insulih-dependent type By HLA association HLA associated BB-DwB-autoimmune type Bwl5-Dw4-Cw3Gnsulin antibbdy responder B8/B15(Dw3/Dw4) compound 7 other HLA associations? Non HLA associated By islet cell antibodies Positive Transient Persistent Negative Proposed pathogenesis Autoimmune-clinical and serologic associations Viral-mumps, rubella, coxsackie, animal models Mixed Other mechanisms Noninsulin-dependent type By obesity Nonobese Obese By age at onset Maturity-onset diabetes of the young Maturity-onset diabetes By chlorpropamide-alcohol flbshing Chlorpropamide-primed alcohol-induced flushing positive Chlorpropamide-primed alcohol-induced flushing negative distinctive pattern of inheritance would have been obscured. Fajans [3] suggests there is evidence for clinical, metabolic and possibly genetic heterogeneity even within maturity-onset diabetes of the young. Although several investigators have commented on the rarity of vascular complications iti maturity-onset diabetes of the young [25,60], a number of Fajans patients have had frequent vascular complications, a difference that may well occur on a familial basis [3]. Faj ans and co-workers [3] also report that their patients with maturity-onset diabetes of the young differ in their insulin response to a glucose load, with both hypoinsulinemic and hyperinsulinemic responses, and that there is some familial aggregation of this level of response. It is of interest that the condition in some of the hypoinsulinemic patients has progressed and that insulin is now required to control hyperglycemia. However, in contrast, Barbosa et al. [60], in a study of two families with maturity-onset diabetes of the young, found both hypoinsulinemic and hyperinsulinemic affected subjects in the same family. Finally, Barbosa et al. [61] reported that in his two families the gene for maturity-onset diabetes of the young may be linked to HLA whereas neither Nelson and Pyke [62] nor Fajans [3] were able to find any such relation in their families. A potentially exciting development regarding the genetics of maturity-onset diabetes of the young (or Mason type ) diabetes in particular, and noninsulindependent diabetes in general, has been the description by Leslie and Pyke [17,63,64] of chlorpropamide-primed alcohol-induced flushing as a purported preclinical marker of maturity-onset diabetes of the young type of diabetes. After observing that diabetic members of the original Mason family, who were being treated with chlorpropamide, experienced facial flushing after ingesting alcohol, Drs. Leslie and Pyke studied their families with maturity-onset diabetes of the young and found that most of the diabetic subjects in these families flushed after the intake of alcohol (after being primed 12 hours earlier with a tablet of chlorpropamid&) and that most of the nondiabetic subjects in these families did not. They proposed that chlorpropamide-primed alcohol-induced flushing is a dominantly inherited trait, as in their hands the subjects with such flushing also had a parent who flushed as did approximately 50 percent of their siblings and offspring, and the trait was demonstrable through three generations in two families [64]. Leslie and Pyke [17,63,64] also demonstrated that many noninsulin-dependent diabetic subjects who would not be recognized as having maturity-onset diabetes of the young type (that is, they had an adult age of onset] also had chlorpropamide-primed alcohol-induced flushing. They also observed that patients who did not have such flushing had both a higher incidence and greater severity of complications than those who did flush [65]. Leslie, Pyke and Stubbs [66] also have suggested that an increased sensitivity to enkephalins (the endogeneous opiates) is the cause of chlorpropamideprimed alcohol-induced flushing, as the flushing is reproduced in these patients with enkephalin analogues and is blocked by the specific opiate antagonist naloxone. This has led Pyke [l7] to hypothetize that the pathogenesis of chlorpropamide-primed alcohol-induced flushing in noninsulin-dependent diabetes is centrally mediated, analogous to the piqure diabetes of Claude Bernard. However, other groups of investigators have either faile$ to confirm these findings, or have only confirmed portions of them [67]. It currently is not at all * clear that chlorpropamide-primed alcohol-induced flushing predisposes to diabetes. Rather, the high incidence of chlorpropamide-primed alcohol-induced flushing in the London series of diabetic subjects may be related to specific use of chlorpropamide in that clinic. Although the absence of chlorpropamide-primed alcohol-induced flushing may indeed be associated with diabetic complications, this may reflect effect rather than cause analogous to an early form of autonomic neuropathy. Genetic factors may still be important, as the patients with chlorpropamide-primed alcoholinduced flushing did have a stronger family history of diabetes, but the genetic relationship is probably not as clearcut as originally proposed. Genetic Classification and Implications. Thus, heterogeneity within both the insulin-dependent and noninsulin dependent-types of diabetes appears ex- 122 January 1981 The American Journal of Medicine Volume 70

8 (GENETICS OF GLUCOSE INTOLERANCE DISORDERS --RO I l ER. RIMOIN tensive. A classification of the heterogeneous entities within these types is given in Table IV. It should be noted that the majority of the heterogeneity that has been described thus far is within the Caucasian, northern European racial-ethnic groups. There are clear differences in the prevalence of diabetes, many of which are explicable on the basis of diet and environment. Nevertheless, there are clear differences in the clinical phenotype of diabetes between different ethnic groups that do not appear to be totally the result of environmental differences [5,6,68]. For example, there are different ethnic groups with a low fat-high carbohydrate diet, some of whom have common vascular complications and rare ketosis, whereas in other ethnic groups with similar diet, ketosis is the usual presenting symptom, and vascular complications are rare. In addition to the clinical differences in the diabetic syndrome between ethnic groups, there can be marked differences in normal plasma glucose and insulin concentration between different populations [5]. Furthermore, there are also racial differences in the HLA diabetes association, as well as distinct types of diabetes frequent in tropical countries, namely, type J and pancreatic diabetes, that do not appear to occur in temperate zones [68,69]. This implies that the heterogeneity within diabetes may have to be defined for each ethnic group. Such ethnic differences in clinical phenotype could well be due to different genetic forms of diabetes existing in the different populations but could also be the result of the modifying effects of different genetic backgrounds on the same diabetic gene. Support for the latter concept comes from studies of the well documented genetic heterogeneity of glucose intolerance in the rodent [70]. Coleman s studies have not only documented clear genetic heterogeneity for glucose intolerance in the mouse by showing that distinct single gene mutants at different unlinked loci result in glucose intolerance, but they have also shown that the phenotypic expression of the mutant gene is influenced by the total genotype of the animal. Similarly, differences in the genetic background of human subjects could result in differences in the clinical expression of diabetes in different ethnic groups. The heterogeneity that has so far been discovered among typical diabetes mellitus probably represents just the tip of the iceberg. But even this currently demonstrable heterogeneity has immediate relevance to current research efforts into the pathogenesis and therapy of the diabetic state. Various agents, e.g., viruses, have been proposed as the inciting or promoting factors for diabetes in persons with the appropriate genetic predisposition [71]. The susceptibility to a given agent may very well depend on the heterogeneity elucidated by these studies. The longstanding debate on the efficacy of tight versus loose control in preventing vascular complications might very well be answered when this heterogeneity is taken into account in appropriately designed studies, i.e., there may be forms of diabetes in which control is vital, and others in which it is less SO, subgroups with inexorable complications, and others complication-free. There is already tentative evidence that by determining this heterogeneity, one may identify groups at increased risk for vascular complications. As regards insulin-dependent diabetes, in the British monozygotic twin study, the concordant pairs with juvenile onset diabetes were said to have complications of diabetes more frequently and more severely than the discordant pairs [72] and the concordant pairs are over-represented among the compound B8/B15, form of the disorder. In the families with insulin-dependent diabetes studied by Bottazzo et al. [31], complications were especially prevalent in those families with an aggregation of autoimmunity. Also, in treated subjects with diabetes of long duration, immune complexes have been reported to correlate with high titers of insulin antibodies, early age at onset of the disease and the presence of late diabetic complications [73]. A variety of conflicting observations regarding HLA types and complications have been reported, and so any relation to specific HLA types must be considered speculative [5]. Most exciting, as regards genetic determinants of diabetic complications, is the observation by Leslie et al. [65] that chlorpropamide-primed alcohol-induced flushing-negative patients with noninsulin-dependent diabetes had a much higher incidence of retinopathy than chlorpropamide-primed alcohol-induced flushing-positive patients. Thus, delineation of genetic heterogeneity and the search for genetic markers should have profound implications not only for understanding the genetics and etiology of diabetes but also its vascular complications. Only when each of the many disorders resulting in diabetes mellitus and/or glucose intolerance are delineated will specific prognostication and therapy be possible for all diabetic patients. Genetic Counseling in Diabetes. Given these recent advances in our knowledge of the genetics and heterogeneity of the diabetic syndrome, what is the genetic counseling we can provide at this time to our diabetic patients? First, as in all genetic counseling, an accurate diagnosis must be made. On clinical grounds one can distinguish between juvenile insulin-dependent diabetes, maturity-onset noninsulin-dependent diabetes and maturity-onset diabetes of the young. In distinguishing between these phenotypes, one already has information that can be revealed to the counselee. In a given family the increased risk for diabetes over the general population is only for that specific type of diabetes that has already occurred in the family, not for all diabetes [5]. Thus, if the index case presenting for counseling is a patient with juvenile insulin-dependent diabetes, the increased risk for that patient s relatives is for insulin-dependent diabetes. If the index case is a patient with noninsulin-dependent diabetes, the increased risk for the patient s relatives is, for the most part, for noninsulin-dependent diabetes only. Associated abnormalities or disease may suggest the rare ge- January 1981 The American Journal of Medicine Volume

9 GENETICS OF GLUCOSE INTOLERANCE DISORI)ERS- ROTTER, RIMOIN nctic syndromes that include diabetes-each of which has its own risk of recurrence (5,6.10]. Once we have accurately characterized the clinical phenotype of the patient. how do we then proceed? At this stage, we must fall back for the most part on observed empiric recurrence risks, i.e., data concerning the actually observed recurrence of these disorders in a large number of families. Even these empiric recurrence risks have limitations, since for the most part they have been reported only from Caucasian populations. Even with the reservation that these empiric risks can be safely applied only to the populations from which they were derived, the most reassuring aspect of the data is the over-all low absolute risk for the development of clinical diabetes in first degree relatives, especially for insulin-dependent diabetes (51. If a child has juvenile insulin-dependent diabetes, published studies report an average risk to his siblings of 5 to 10 percent. If a parent has juvenile-onset diabetes, the risk for the offspring of having overt diabetes during the first decade of life is generally reported to be 1 to 2 percent or less. For noninsulin-dependent diabetes, the empiric recurrence risk to first degree relatives is of the order of 5 to 10 percent for clinical diabetes and 15 to 25 percent for an abnormal glucose tolerance test. Since maturity-onset diabetes of the young appears to be an autosomal dominant disorder, the offspring and siblings of such patients would be at 50 percent risk. Although the numerical risk of recurrence is relatively high in the disorder, the lower burden of this type of diabetes must be made clear to the family, since this type of diabetes appears to be milder, with fewer complications. REFERENCES Certain studies would indicate that subgroups at higher risk can theoretically bc identified [5,7]. Thus the HLA haplotype studies discussed earlier would suggest that within an insulin-dependent diabetes sibship, sibs can be classified into those who share two haplotypes with the diabetic proband and who have a higher risk for insulin-dependent diabetes than the general sibling empiric risks, sibs who share one haplotype with the proband and have approximately the same risk as the over-all empiric risk, and sibs who share no haplotypes with the proband have a decreased recurrence risk. Similarly, there have been reports of islet cell antibody positivity in ostensibly normal siblings of a patient with insulin-dependent diabetes who have gone on to have frank insulin-dependent diabetes. As regards noninsulin-dependent diabetes, the trait of chlorpropamide alcohol-induced flushing appears in Leslie and Pyke s hands to be a preclinical marker of the maturity-onset diabetes of the young or Mason type noninsulin-dependent diabetes. If confirmed by others, this could identify those at risk in younger generations who have not yet manifested the diabetes. However, for the most part these tools currently remain in the realm of research, rather than providing practical clinical tools. Advances have been so rapid that any rccommendations made here should be considered working guidelines, subject to revision as new knowledge bccomes available. In the near future we should be able to utilize many of these markers and our increasing knowledge of the genetic heterogeneity of diabetes to aid in counseling diabetic patients and their families Creutzfeldt W, Kobberling J, Nccl JV. cds: The gonetics of diabetes mellitus. Berlin: Springer-Verlag Rotter Jl, Rimoin DL. Samloff IM: Genetic heterogeneity in diabetes mellitus and peptic ulcer. In: Morton NE. Chung CS. eds. Genetic epidemiology. New York: Academic Press. 1978: Fajans SS. Cloutier MC, Crowther RI,: Clinical and ctiologic heterogeneity of idiopathic diabetes mellitus. Diabetes 1978: 27: Rotter 11: Genetic heterogeneity within diabetes mcllitus. a review. In: Sing CF. Skolnick M. cds. Genetic analysis of common diseases: applications to predictive factors in coronary heart disease. New York: Alan R. Liss, 1979: : Rotter JI. Rimoin DL: Etiology-genetics. In: Hrownlee M, ed. Handbook of diabetes mellitus. New York: Garland STPM Pros? : 1: Rimoin DL. Schimke RN: Endocrine pancreas. In: Genetic disorders of the endocrine glands. C. V. Mosby. St. Louis. 1971; National Diabetes Data Group International Workgroup: Classification of diabetes millitus and other categories if glucose intolerance. Diabetes 1979; 28: Rimoin DL: Genetics of diabetes mellitus. Diabotcs 1967: 16: Simpson NE: A review of family data. In: Crcutzfeldt W, Kobberling J. Neel JV. eds. The genetics of diabetes mellitus. Berlin: Springer -Verlag. 1976; Rimoin DL: Genetic syndromes associated with glucose intolerance. In: Creutzfeldt W. Kohberling J. Nccl JV, eds The genetics of diabetes mellitus. Berlin: Springer-Vcrlag. 1976: Kohberling J: Genetic syndromes associated with lipatrophic diabetes. fn: Creutzfeldt W. Kobberling J. Nr:cl JV, cds. The genetics of diabetes mellitus. Berlin: S$ngcr-<rorlag. 1976; Flier JS. Kahn CR. Roth J: Receptors. antireceptor antibodies and mechanisms of insulin rcsistancc. N Engl J Mcd 1979: 300: Given BD. Mako ME, Tagcr HS. et al.: Diabetes due to secration of an abnormal insulin. N Engl J Med 1980: 302: Irvine WJ. Taft AD, Holton DE. Prescott RJ, Clarke BF. Duncan LIP: Familial studies of type I and tvpc II idiopathic diabetes mellitus. Lancet 19?7: 2: 325-ii8. Cudworth AG: Type I diabetes mellitus. Diahctologia 1978; 14: Tattersall RB. Pyke DA: Uiabctcs in identical twins. Lancet 1972: 2: Pvke DA: Diabetes: the nenctic connections. Diabetolonia 1979: 77: Cahill GF. Ir: Current concents of diabetic comnlications with emphasis on hereditary factors: a brief review. In: Sing CF. Skolnick MH, cds. Genetic analysis of common tliscascs: aoolications to oredictive factors in coronaiv heart disease. cdw York: Alin R. 1.1~~. 1979; _ Irvine WI: Classification of idiopathic diabetes. Lancct 1977: I: 63% 642. Bottazzo GF, Florin-Christensen A. Doniach I): Islet-cell antibodies in diabetes mellihls with autoimmuno polycn- 124 January 1981 The American Journal of Medicine Volume 70