Genetic analysis of multiply-affected families of insulin-dependent diabetes mellitus (IDDM) probands

The present study combines segregation and linkage information on 30 families ascertained through a proband and a first degree relative affected with insulin-dependent diabetes mellitus (IDDM). An autosomal dominant model with incomplete penetrance was much more likely to fit the family data than a recessive model, whether or not linkage to HLA was assumed. The lod scores for linkage to HLA were 2.46 at theta M = theta F = 0.00 for dominant and 1.45 at theta M = theta F = 0.22 for a recessive model. The results are discussed in light of heterogeneity in likelihood and lod scores when the families are grouped by familial types, which indicate that the increase in likelihood of a dominant hypothesis can be attributed to the parent-child families and not the sib-sib families.     

Blood glucose discrimination training in insulin-dependent diabetes mellitus (IDDM) patients

Self-management of insulin-dependent diabetes mellitus (IDDM) is dependent on a negative feedback loop of blood glucose (BG) fluctuations, which in turn directs treatment decisions to maintain normal BG. Although this feedback is typically accomplished by self-monitoring of blood glucose (SMBG), SMBG has limitations, and patients often rely on what their BG "feels" like. Two studies were performed to evaluate whether patients could learn to more accurately "feel"/discriminate their BG on the basis of internal cues or internal plus external BG cues. In Study I, BG Awareness Training significantly improved pre- to posttreatment BG estimation accuracy, relative to a control group. Study II replicated BG Awareness Training efficacy in improving BG estimation accuracy. Improvement in estimation accuracy was related only to initial accuracy; those who were initially less accurate improved the most. This improvement was represented in a 31% reduction in dangerous BG estimation errors and a 9% increase in accurate estimates. Resulting estimations were, however, still significantly less accurate than SMBG at the end of training.     

Blood glucose discrimination training in insulin-dependent diabetes mellitus (IDDM) patients

Self-management of insulin-dependent diabetes mellitus (IDDM) is dependent on a negative feedback loop of blood glucose (BG) fluctuations, which in turn directs treatment decisions to maintain normal BG. Although this feedback is typically accomplished by self-monitoring of blood glucose (SMBG), SMBG has limitations, and patients often rely on what their BG feels like. Two studies were performed to evaluate whether patients could learn to more accurately feel/discriminate their BG on the basis of internal cues or internal plus external BG cues. In Study I, BG Awareness Training significantly improved pre- to posttreatment BG estimation accuracy, relative to a control group. Study II replicated BG Awareness Training efficacy in improving BG estimation accuracy. Improvement in estimation accuracy was related only to initial accuracy; those who were initially less accurate improved the most. This improvement was represented in a 31% reduction in dangerous BG estimation errors and a 9% increase in accurate estimates. Resulting estimations were, however, still significantly less accurate than SMBG at the end of training.This research was supported by NIH grants AM282880, AM24177, AM22125, and RR00847 and by the Ames Company. The authors express their appreciation for the contribution made by trainers Leslie Butterfield and Linda Zimbelman, by the nursing staff at the University of Virginia's Clinical Research Center and the Diabetes and Nutrition Unit, and by Dr. James May from the Medical College of Virginia in soliciting subjects. We would also like to thank Andrea Snyder for her assistance.     

Heterozygous expression of insulin-dependent diabetes mellitus (IDDM) determinants in the HLA system.

HLA phenotypes of cases with insulin-dependent diabetes mellitus (IDDM) and identity by descent of HLA haplotypes in affected sib-pairs support an intermediate model in which morbid risk is increased by one HLA-linked IDDM determinant, and greatly increased by two determinants, which may be qualitatively different in DR3 and DR4 haplotypes. Linkage analysis allowing for gametic disequilibrium reveals no recombination in pedigrees with a DR3/DR4 propositus, but spurious recombination in the remaining pedigrees. This evidence favors interaction of unlinked IDDM determinants to produce affection in a small proportion of heterozygotes for an HLA-linked determinant. Partition of data by HLA type of the propositus (ideally by DR and the complement types jointly) is a powerful method to resolve etiological heterogeneity for HLA-associated diseases.     

Fatty liver and hyperlipidemia in IDDM (insulin-dependent diabetes mellitus) of streptozotocin-treated shrews

Severe IDDM (insulin-dependent diabetes mellitus) was produced in the musk shrew (Suncus murimus, Insectivora) by a high dose (a single intraperitoneal injection of 100 mg/kg Body Weight) of streptozotocin (STZ) injection. All shrews that were administered a high dose of STZ exhibited hyperglycemia (449 +/- 16 mg/dl vs 73 +/- 4 mg/dl in controls) and hypoinsulinemia(0.25 +/- 0.07 ng/ml vs 10.96 +/- 1.97 ng/ml in controls) with ketosuria 10 days after injection. Their livers were enlarged and exhibited ayellowish-brown color with marked triglyceride (TG) accumulation (63.25 +/- 7.10 mg/g Liver vs 2.11 +/- 0.19 mg/g Liver in controls). It is probable that the increased influx of fatty acids into the liver induced by hypoinsulinemia and the low capacity of excretion of lipoprotein secretion from liver in the musk shrew resulting from a deficiency of apolipoprotein B synthesis play important roles in fatty liver formation. Hyperlipidemia was another feature in shrews with severe IDDM. The blood TG level was especially high in these shrews (899 +/- 178 mg/dl vs 23 +/- 5 mg/dl in controls). These results indicate that the IDDM shrew, induced by high doses of STZ, is a unique model characterized by fatty liver and hyperlipidemia and may be useful for studying lipid metabolism of IDDM.     

BF types and the mode of inheritance of insulin-dependent diabetes mellitus (IDDM)

Insulin-dependent diabetes mellitus (IDDM) has been found to be highly associated with a rare allele of the complement protein, properdin factor B (BF). Assuming that there is a susceptibility gene for IDDM tightly linked to the genetic locus forBF and the major histocompatibility complex (MHC), the distribution of BF types in more than 1100 North American IDDM patients strongly argues for the rejection of dominant, epistatic, and overdominant modes of inheritance. Other evidence suggesting complex modes of inheritance for IDDM is reviewed and it is concluded that our observations and published data are consistent with the idea of susceptibility to IDDM being inherited as a simple autosomal recessive trait. — C4 and C2 types, also linked toBF and theMHC, were investigated too. C4 Fs⁰ was found to be increased in association with BF F1, while C4 f⁰S and C2 B were each found to occur twice as frequently as in a control population and will be of value in defining haplotypes associated with susceptibility to IDDM.     

T-cell receptor genes and insulin-dependent diabetes mellitus (IDDM): no evidence for linkage from affected sib pairs.

Several investigators have reported an association between insulin-dependent diabetes mellitus (IDDM) and an RFLP detected with a probe for the constant region of the beta chain (C beta) of the human T-cell receptor (TCR). A likely hypothesis is that the closely linked TCR variable (V beta) region genes contribute to IDDM susceptibility and that the association with the TCR C beta locus reflects this contribution, via linkage disequilibrium between V beta and C beta. The products of the beta-chain genes might be expected to be involved in the etiology of IDDM because of the autoimmune aspects of IDDM, the known involvement of HLA, and the necessity for TCR and HLA molecules to interact in an immune response. In order to investigate the hypothesis, we tested for linkage between IDDM and V genes encoded at either the TCR beta locus on chromosome 7 or the TCR alpha locus on chromosome 14, using 36 families with multiple affected sibs. No excess sharing of haplotypes defined by V alpha or V beta gene RFLPs was observed in affected sib pairs from IDDM families. We also studied unrelated IDDM patients (N = 73) and controls (N = 45) with the C beta RFLP but were unable to confirm the reported association even when the sample was stratified by HLA-DR type. Our results are incompatible with close linkage, in the majority of families, between either the TCR alpha or TCR beta locus and a gene making a major contribution to susceptibility to IDDM.     

Erythrocyte membrane acetylcholinesterase in type 1 (insulin-dependent) diabetes mellitus.

1. The erythrocyte membrane acetylcholinesterase activity is significantly (P less than 0.001) decreased in insulin-dependent diabetes mellitus. 2. The activity is negatively correlated (r = -0.97) with the fasting blood glucose level. 3. Insulin treatment restores the activity to normal. 4. The Km of the enzyme for acetylthiocholine iodide was unchanged; however, the Vmax. was decreased, suggesting a decrease in the number of active enzyme molecules in diabetes.     

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).

A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5'' flanking polymorphism [5''FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5''FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.     

A mechanism by which primary or secondary hypothalamic involvement results in the development of insulin-dependent diabetes mellitus (IDDM)

A literature survey and hypothesis is presented in which it is concluded that an intracellular ventromedial hypothalamic (VMH) glucopenia results in a bibrachial response consisting of adenohypophysial release of growth hormone and ACTH as well as sympathetic discharge, both of which act to elevate plasma glucose and remove the VMH glucopenia. This glucopenia may occur as a result of either a deficiency of circulating insulin or alterations in the kinetic properties of the VMH cellular insulin receptor. Two mechanisms for the development of insulin dependent diabetes mellitus (IDDM) are presented: (1) a defect in VMH glucose transport and/or metabolism such that a VMH glucopenia occurs with a subsequent bibrachial response. The result of this is glucose overproduction and a chronic excess glucose stimulus will eventually cause B-cell exhaustion (primary hypothalamic involvement). (2) reduction of the B-cell population by chemical, genetic and/or viral interactions with a consequential insulopenia results in a VMH glucopenia (secondary to a reduced glucose transport into the VMH cells) and causes a bibrachial response. This VMH response may temporarily restore plasma glucose balance but a chronically enhanced counter-regulatory response to maintain this balance will eventually stress the remaining B-cell population and cause further reductions in B-cell numbers (secondary hypothalmic involvement).     

The search for heterogeneity in insulin-dependent diabetes mellitus (IDDM): linkage studies, two-locus models, and genetic heterogeneity

One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage with 27 genetic markers, including HLA, properdin factor B (BF), and glyoxalase 1(GLO) on chromosome 6, and Kidd blood group (Jk) on chromosome 2. The linkage analyses were performed under several different genetic models. An approximate correction for two-locus linkage analysis was developed and applied to four markers. Two different heterogeneity tests were implemented and applied to all the markers. One, the Predivided-Sample Test, utilizes various criteria thought to be relevant to genetic heterogeneity in IDDM. The other, the Admixture Test, looks for heterogeneity without specifying a prior how the sample should be divided. Results continued to support linkage of IDDM with three chromosome 6 markers: HLA, BF, and GLO. The total lod score for Kidd blood group, under the recessive model with 20% penetrance, is 1.63--down 1.2 from the 2.83 reported by us earlier. The only other marker whose lod score exceeded 1.0 under any model was pancreatic amylase (AMY2). The two-locus correction, which involved lowering the penetrance values used in the analysis, affected estimates of theta (recombination fraction) but did not markedly change the lod scores themselves. There was little evidence for heterogeneity within any of the lod scores, under either the Predivided-Sample Test or the Admixture Test.     

Cellular immunity in insulin-dependent diabetes mellitus (type 1)

Cell-mediated immunity was investigated with T-cell blastic transformation stimulated by phytohaemagglutinin and/or insulin in patients with diabetes mellitus type 1. T-cell blastic transformation was determined in the whole blood by the intake of labelled thymidine intake by the lymphocytic DNA. Healthy individuals and patients with diabetes mellitus type 2 served as control groups. It was found that T-cell blastic transformation stimulated with phytohaemagglutinin is markedly diminished in patients with diabetes mellitus type 1 and to a lesser degree in patients with diabetes mellitus type 2. Insulin increased T-cell blastic transformation in insulin-dependent diabetic patients but has no effect in diabetes mellitus type 2. The obtained results suggest that induction and central phases of the cell-mediated immunological response are diminished in diabetes mellitus independently on its type. Such disorders may have different etiology depending on the type of diabetes mellitus.     

Genetic markers for glutamic acid decarboxylase do not predict insulin-dependent diabetes mellitus in pairs of affected siblings

Reliable genetic and immunological markers are important in the prediction of insulin-dependent diabetes mellitus (IDDM). Since glutamic acid decarboxylase (GAD) is a candidate primary autoantigen, we examined the possible linkage between IDDM and the genes encoding GAD₆₅ (GAD2, 10p11–12) and GAD₆₇ (GAD1, 2q31) in 58 Danish IDDM affected sib pairs. The allelic inheritance of 10 polymorphic dinucleotide repeat sequences spanning the chromosomal regions of the two GAD genes, were examined by affected sib pair analysis (ASP). In addition a restriction fragment length polymorphism (RFLP) was identified in the gene encoding GAD₆₅ using the restriction enzyme PvuII. The GAD gene markers were analyzed in relation to the presence of specific HLA types and GAD autoantibodies. No evidence of linkage was found between IDDM and either of the genes encoding GAD. This was also the case when subgroups carrying specific HLA susceptibility alleles were analyzed. Nor did we observe any association between these GAD genetic markers and the presence of GAD autoantibodies. Considering the high prevalence of GAD autoantibodies in IDDM, a putative genetic association between GAD and IDDM would be expected to affect most diabetic individuals. Therefore, our data indicate that the association between GAD and IDDM is not genetically determined, and that microsatellites used in this study do not contribute to the prediction of IDDM. Received: 1 July 1996 / Revised: 21 August 1996     

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27.

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.     

Molecular pathology of insulin-dependent diabetes mellitus (type I)

Since sufficiently long time the average life expectancy in IDDM did not change. Only new data concerning the causes and pathogenesis of the disease may improve such set-back. The most promising field of creating the better insight into etiology of IDDM are molecular pathological studies. This review attempts to summarize the state of art in this area choosing the problems of clinical relevance. Many of them are controversial, disturbing the immunogenetic hypothesis of IDDM etiology, majority positively support this idea. 6 topics are critically discussed in respective sub-chapters: 1) genetic control of autoimmunization processes as pertinent to beta cells; 2) genesis, actions and clinical significance of various types of autoantibodies against autoantigens; 3) character of beta cell antigens; 4) suggested mechanism of beta cell destruction; 5) new idea of prediabetic state and 6) lessons from immunosuppressive therapeutical trials. Author brings the story of etiological mechanisms of IDDM up to date pointing that more direct and specific information is needed to be applicable in practice.