Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of genetic factors in the aetiology of NIDDM has been underlined by study of family pedigrees and identical twin pairs. Although in some isolated populations and a tiny minority of Western families inheritance follows an autosomal dominant pattern, a polygenic mode of transmission predominates in Europe and North America. No genetic markers have been identified despite intensive study of the HLA system and gene polymorphisms. Environmental factors appear to play some role, but examination of the evidence for an aetiological effect of the commonly assumed factors, diet and obesity, suggests that they exert no direct effect. However, it is likely that these factors together with physical inactivity could modulate the speed of progression to symptomatic disease. Both beta cell dysfunction and tissue insulin insensitivity are important in producing the syndrome of NIDDM. Insulin insensitivity is present from very early in the time course of the syndrome, but it is clear that the disease cannot develop in the absence of beta cell dysfunction. The recent discovery of islet associated amyloid is exciting as it represents a major step in tracing the pathogenesis of NIDDM backwards towards genetic and non-genetic aetiological influences.
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PMID:Aetiology of non-insulin dependent diabetes. 267 75

This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes.
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PMID:Maturity-onset diabetes of the young (MODY). 268 21

Differences between Type 1 and Type 2 Diabetes Mellitus are briefly outlined with special emphasis on the immune mechanism in the development of juvenile diabetes. Autoimmune nature of Type 1 diabetes is based on: association with genetic markers of histocompatibility mainly with the DR3 and DR4 haplotypes of the HLA system; anomalies of the humoral and cellular immunity present in a significant percentage of Type 1 diabetic patients, its association with other autoimmune diseases; the histological features of the affected pancreas and the prevention of experimental diabetes by immunosuppression. Trials on immunotherapy with immunosuppressors (Cyclosporine A and Azathioprine) and immunomodulators (Thymic hormone) were able to achieve a 50-60% index of clinical and functional remission for more than one year. With Thymic hormone and Azathioprine in combined administration the glycemic control and residual beta-cell function one year after stopping immunotherapy exhibited positive comparative results. Other trials on immunotherapy are outlined. Side effects of immunosuppression and future prospectives for immune approaches in Type 1 diabetes are commented.
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PMID:[Immunotherapeutic management of juvenile diabetes mellitus]. 270 66

HLA antigen frequencies in 50 patients with IDDM, 56 patients with NIDDM, and 109 normal Iraqi controls were studied. Three families with one patient suffering from IDDM were also studied. No significant HLA antigens associated with NIDDM were found. Highly significant association of HLA, A1, B8, DR3, and DR4 were found in patients with IDDM as compared to normal individuals. The frequency of HLA-B5 and DR2 were significantly decreased in patients with IDDM. In contrast to previously reported findings in Caucasoids there was no significant association with B15 and a negative association with HLA-B5, not with B7. These results were compared with published findings for Arabs and other ethnic populations.
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PMID:Association of HLA antigens with diabetes mellitus in an Iraqi population. 273 9

Both early onset and late onset type II diabetes were present in one family of nine siblings. The three early onset type II diabetic siblings showed severe microvascular complications: proliferative retinopathy, diabetic nephropathy, and peripheral neuropathy. Early onset type II diabetes was not associated with any particular HLA haplotype. Early onset type II diabetes could be considered a clinical and genetic disease entity different from MODY type diabetes.
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PMID:Severe microvascular disease in type II diabetes of early onset. A family study. 275 Apr 46

To examine the relationship between HLA antigens and Type 2 non-insulin-dependent diabetes (NIDDM), 72 patients were studied and compared with 282 controls. Twenty of 72 patients had an associated non-toxic goiter. The clinical features of the goitrous diabetic patients were similar to those without goiter except that those with goiter were predominantly female (95%). Of the 46 antigens assayed, only A10 was increased in the 72 diabetics when compared with the controls (12.5 vs 5.7%, RR = 2.37, chi 2 = 4.07, p less than 0.05), but statistically this was not significant after p value correction. In the patients with goiter, antigens A2, A9, A10, B27, BW46, CW1, DR1, DR5, DR8, DRW9 showed 2 folds or greater differences in frequencies when compared to the non-goitrous diabetics. However, only A2 had a significant decrease in the former as compared with the latter (30.0 vs 59.6%, chi 2 = 5.07, p less than 0.05), but this was also statistically insignificant. The present study showed no significant HLA associations in Chinese NIDDM patients with or without non-toxic goiter, and the distribution of each antigen was not related to the presence or absence of goiter.
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PMID:HLA-A,B,C and DR antigens in Chinese with non-insulin-dependent diabetes: comparison with goitrous diabetics. 275 19

Duration of disease is the major susceptibility factor for microangiopathy. Microangiopathy does not occur without the metabolic abnormality of diabetes and there is much circumstantial evidence to implicate poor diabetic control in its pathogenesis. The rate of development and severity of complications, however, are variable even in patients with apparently similar control and about 25% of diabetics will never develop clinical evidence of microangiopathy. Studies of identical twins suggest a genetic component in the pathogenesis of retinopathy in NIDDM, and less so in IDDM, but increased capillary basement membrane thickness does not occur in the non-diabetic identical co-twins of insulin dependent diabetics. There may also be genetic heterogeneity not only of diabetes, but also of its complications, although for a given type of diabetes the prevalence of microangiopathy is often very similar in different racial groups. Associations between several different HLA molecules (particularly DR4) and microangiopathy in IDDM have been reported but not consistently confirmed. Recently the finding of an increased frequency of the B3 allotype of the fourth component of complement C4B3 in subjects with retinopathy has suggested that there is an HLA linked association. Both complement and the immunoglobulins are concerned with humoral immunity and the report of an association between a phenotype of the IgG heavy chain markers on chromosome 14 and retinopathy is of particular interest. These associations appear to be additive but independent. These reports need confirmation but provide the best evidence we have for an immunogenetic component (HLA and non-HLA linked) of the aetiology of microangiopathy, at least in IDDM. The studies of identical twins, HLA and Gm associations provide good evidence that genetic factors are involved in susceptibility to microangiopathy, at least in some diabetics, although the most relevant genes may not have been identified. Searches for better genetic markers must continue in order to identify those patients at increased risk of developing microangiopathy.
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PMID:The genetics of diabetic complications. 353 96

The heterogeneity within Type II diabetes (NIDDM) and within Maturity-Onset type Diabetes of Young people (MODY), a subset of NIDDM which is inherited in an autosomal dominant fashion, is discussed. Aspects of the definition and phenotypic expression of MODY are reviewed. Within NIDDM there are differences in patterns of inheritance between subgroups. HLA antigen associations are not found in most NIDDM populations but exist in three specific population groups with Type II diabetes. Within NIDDM and within MODY there are differences in the magnitude of insulin responses to glucose, differences in target tissue responsiveness to insulin in vivo, and differences in receptor and post-receptor effects of insulin. Structurally abnormal variant and biologically defective insulin molecules have been found in some Type II diabetic patients and in members of certain MODY families. The presence or absence of obesity may mark heterogeneous groups of Type II diabetic patients, in addition to the importance of obesity in uncovering an insulin secretory defect by causing insulin resistance. There is heterogeneity in susceptibility to vascular disease within NIDDM and MODY. The natural history of carbohydrate metabolism and of insulin secretory responses to glucose in early Type I diabetes and in MODY with low insulin secretory responses are illustrated and similarities and dissimilarities compared and contrasted. Failure to recognize young patients with MODY may contribute to incorrect diagnosis, management, and assignment of prognosis of this form of diabetes in the young by many practicing physicians. The recognition that Type I or insulin-dependent diabetes (IDDM) and Type II or noninsulin-dependent (NIDDM) differ from each other not only phenotypically but also in etiology and pathogenesis led the National Diabetes Data Group (NDDG) to devise the present nomenclature and classification of diabetes mellitus. These were adopted by the World Health Organization. As suggested by the NDDG report, the classification should be reexamined periodically to reflect improved understanding of the disease, to stimulate further research, and to be of help to practicing physicians.
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PMID:Heterogeneity within type II and MODY diabetes. 389 67

Susceptibility to IDDM is linked to the HLA-D locus on the short arm of chromosome 6, a region believed to be involved in the process of communication between cells which determines immune responses. Presumably an HLA molecule encoded by this region, unable to present a particular antigenic pathogen to the immune system, is inherited. The HLA-DR locus is quite complex, however. The gene which codes for this defective molecule may be identified by a combination of use of monoclonal antibodies and cloned gene probes which specifically hybridize to various portions of this region. Investigators are searching for HLA-DR4 containing chromosomes in IDDM which show similar patterns of restriction enzyme polymorphism. Hopefully, complete structural analysis of these related sequences will provide information about the mechanisms which confer susceptibility to develop IDDM. A strong genetic component is involved in NIDDM evidenced by a high concordance in monozygotic twins. Nevertheless, there is much evidence of genetic heterogeneity. At the present time no clear cut genetic marker has been defined. The human insulin gene has been cloned and by Southern blot hybridization analysis of peripheral leukocyte DNA, the insulin gene locus is being evaluated as a possible contributor to the genetic defect. Population studies at the present time have not identified any particular polymorphic insulin allele associated with NIDDM. Population studies are complicated by heterogeneity of NIDDM, racial and ethnic differences, and heterogeneity of insulin alleles. Linkage analysis in family studies will provide an alternative approach to population studies to determine what role if any the insulin gene plays in the genetic component of this disease. Because NIDDM is heterogeneous and perhaps polygenic in nature, these linkage analyses in families with NIDDM can be extended to other genes when they are cloned such as that coding for the insulin receptor. The familial aggregation of diabetes has long been noted (see ref. 1 for review). In relatives of diabetics, the prevalence ranges from 10-30%, while it is variously estimated to be between 0.1-3% in the general population. But familial aggregation of a trait may be caused either by genetic or environmental factors. One approach to dissecting the contribution of these factors is the study of concordance in twins. Pyke and associates observed that overall identical twins always show a higher concordance rate than dizygotic twins, irrespective of their age of diagnosis. Furthermore, they noted that identical twins of younger onset are often discordant for diabetes while identical twins of older onset are usually concordant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The genetics of type I and type II diabetes: analysis by recombinant DNA methodology. 389 68

The proliferative responses of IDDM or NIDDM patients and normal controls to monocomponent pork and beef insulins was assayed over a period of 5 days. No difference was detected in the proliferative responses between the groups. About 25-30% responded to insulin antigens by giving stimulation indices of 1.5 or higher. The exception was the HLA-B8/15 group of patients where no responses (less than or equal to 1.5) were observed. The evidence that the responses detected were insulin specific is discussed, as is the HLA and possible immune response gene linkage.
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PMID:Proliferative responses to insulin antigens in diabetics and controls. 635 May 91


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