Juvenile-onset Insulin-dependent Diabetes Mellitus Research Articles

Intrapancreatic Parenchymal Cell Transplantation as a Possible Model for the Development of a Cell-based Therapy for Type I Diabetes Mellitus

(1) Background: Transplantation of isolated islets is one of the most powerful approaches to cure insulin-dependent (type I) diabetes mellitus (IDDM). Currently, the most widely used transplantation strategy is percutaneous perfusion into the liver via the portal vein. However, this approach has several drawbacks and is often limited by the large number of islets required and hypoxic damage to the grafts. (2) Methods: In this article, we posit intrapancreatic parenchymal cell transplantation (IPPCT) as a promising strategy for cell-based therapy for IDDM. IPPCT is a very simple and convenient strategy; it involves exposing the pancreas and spleen (which is tightly associated with pancreas) to micropipette-based injection of single cells or cell clumps into the pancreatic parenchyma under observation with a dissecting microscope. (3) Results: In this work, we provide some possible experimental examples of preliminary studies of IPPCT in mouse models. (4) Conclusions: We have reported here unique experimental systems to evaluate the in vivo function of pancreatic beta-cells isolated from normal tissue or those produced in vitro using IPPCT.

Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected

Since the original description, there have been only few epidemiological studies of Wolfram syndrome (WS). Aims of the present paper are to ascertain WS prevalence and expression in a district of North-eastern Sicily, i.e. a geographic area where consanguineous unions are not very unusual. Prevalence rates of WS in the Messina district were calculated by taking into consideration both the total population (653,737) and the populations included within the 0-30year age range (202,681). We estimated the relative prevalence of WS among patients with youth-onset insulin-dependent diabetes mellitus (DM) who are currently aged under 30years (256). Global WS prevalence in our district is 1:54,478, whereas prevalence among individuals under 30 is 1:16,890 and relative prevalence among patients with juvenile-onset insulin-dependent DM is 1:22.3. When compared with the patients with insulin-dependent DM of Messina district, WS patients did not exhibit significant differences in terms of biochemical features at DM onset, whereas age at DM diagnosis was significantly earlier in WS group. (a) WS prevalence is not so infrequent as generally expected; (b) in our series, DM presented before 10years in 11/12 patients and ten cases have already developed all the four peculiar manifestations of WS by 26years; (c) 9/12 patients exhibited a homozygous frameshift/truncation mutation (Y454_L459del_fsX454), which is the one most frequently found also in patients from other Italian regions; (d) age at DM diagnosis was significantly earlier in WS group than in the patients with insulin-dependent DM of Messina district.

Endocrine and metabolic aspects of the Wolfram syndrome

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic -cells

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile-onset insulin-dependent diabetes mellitus and optic atrophy. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER) resident transmembrane protein. The Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes. Previous work suggested that the function of the WFS1 protein is connected to unfolded protein response and to intracellular Ca(2+) homeostasis. However, its precise molecular function in pancreatic β-cells remains elusive. In our present study, immunofluorescent and electron-microscopic analyses revealed that WFS1 localizes not only to ER but also to secretory granules in pancreatic β-cells. Intragranular acidification was assessed by measuring intracellular fluorescence intensity raised by the acidotrophic agent, 3-[2,4-dinitroanilino]-3'-amino-N-methyldipropyramine. Compared with wild-type β-cells, there was a 32% reduction in the intensity in WFS1-deficient β-cells, indicating the impairment of granular acidification. This phenotype may, at least partly, account for the evidence that Wfs1-null islets have impaired proinsulin processing, resulting in an increased circulating proinsulin level. Morphometric analysis using electron microscopy evidenced that the density of secretory granules attached to the plasma membrane was significantly reduced in Wfs1-null β-cells relative to that in wild-type β-cells. This may be relevant to the recent finding that granular acidification is required for the priming of secretory granules preceding exocytosis and may partly explain the fact that glucose-induced insulin secretion is profoundly impaired in young prediabetic Wfs1-null mice. These results thus provide new insights into the molecular mechanisms of β-cell dysfunction in patients with Wolfram syndrome.

Current Developments in Wolfram Syndrome

Wolfram syndrome (WS), an infrequent cause of diabetes mellitus, derives its name from the physician who first reported the combination of juvenile-onset diabetes mellitus and optic atrophy. Also referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), it is an autosomal recessive neurodegenerative disease characterized by various clinical manifestations, such as diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric manifestations and gonadal disorders. The condition is very rare with an estimated prevalence of one in 770,000 of the normal population, one out of 150 cases of juvenile-onset insulin-dependent diabetes mellitus, and with a carrier frequency of one in 354. This progressive neurodegenerative disease usually results in death before the age of 50 years and many patients lead a morbid life. The pathogenesis of the disorder although unknown is ascribed to mutation of a gene on chromosome 4p encoding a transmembrane protein of undetermined function called wolframin. This review summarizes the variable presentation of the disorder, its widespread complications, poor quality of life in affected individuals, and the problems in diagnosis and treatment of the syndrome.

Autologous Hematopoietic Stem Cell Transplantation for Type I Diabetes Mellitus.

Insulin-dependent type I diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-islet cells mediated by inflammatory T cells. The pathogenic process evolves gradually for several years and becomes symptomatic when most Langerhans islands are destroyed. Antibodies against β-cell antigens (like anti-glutamic acid decarboxylase, GAD) are markers of the autoimmune reaction and levels of proinsulin C-peptide correlate with endogenous insulin secretion. Several immunosuppressive regimens have demonstrated clinical and laboratorial benefit in early onset IDDM, presumably sparing islets reserve, but most responses were transient and long term toxicity limited their continuous use. In view of durable remissions observed in various autoimmune diseases treated with high-dose immunosuppression and autologous hematopoietic stem cell transplantation (AHSCT), we started in December/03 a phase I/II trial of AHSCT in early-onset IDDM. Patients from 12–35 years old with <6 weeks from diagnosis have their peripheral blood stem cells mobilized with 2 g/m2 cyclophosphamide and 10 mcg/kg G-CSF, cryopreserved and reinfused (>2 million/kg) after conditioning with 200 mg/kg cyclophosphamide and 4,5 mg/kg rabbit antithymocyte globulin- ATG (Thymoglobuline, SangStat). End points of the study are insulin needs (U/kg/d), glycosilated hemoglobin levels, anti-GAD titers and C-peptide levels. Four patients have been transplanted and the insulin usage of the first three patients is shown in the Figure. The first patient received high dose of steroids to prevent ATG hypersensitivity and showed increasing needs of insulin after mobilization. The other two patients received minimal (#2) or no (#3) steroid dose during conditioning and showed decreasing needs of insulin after mobilization (Figure). Patient #2 presented bilateral pneumonia while pancytopenic, recovered after treatment with antibiotics and Amphotericin-B but did not require insulin therapy. A fourth patient has just been discharged from the BMT Unit. Immunologic studies in the three patients with longer follow-up showed a progressive shift from Th1 to Th2 cytokine profile after transplantation which could provide a mechanism for the modulation of the autoimmune process by high dose immunosuppression and autologous HSC. In conclusion, the preliminary results are encouraging but must be validated with a larger number of patients (12 planned in this phase) and a longer followup (5 years). [Display omitted]

Analysis of censored and incomplete survival data using flowgraph models.

Multi-state stochastic models are widely used to model stages of disease progression in survival analysis. This paper develops flowgraph models for data analysis in survival analysis. We illustrate these methods using data from a study of diabetic retinopathy consisting of 277 subjects with insulin-dependent (type I) diabetes mellitus (IDDM). These data were collected at the Eye-Kidney Clinic of the Barbara Davis Center for Childhood Diabetes at the University of Colorado Health Sciences Center.

Minute oxidative stress is sufficient to induce apoptotic death of NIT‐1 insulinoma cells

When cultured NIT-1 cells were subjected to a low level of oxidative stress (30 microM hydrogen peroxide for 15 min at 37 degrees C) several of their lysosomes ruptured, as demonstrated by intravital staining with the lysosomotropic weak base acridine orange. Such rupture is due to intralysosomal, iron-catalyzed oxidative reactions, since it was largely prevented by previous endocytotic uptake of desferrioxamine. The resultant limited leakage of lysosomal hydrolytic enzymes into the cytosol could be important for an apoptotic-type degradation/fragmentation process within initially intact plasma membranes. In contrast, extensive lysosomal rupture leads to necrosis. The development of the damage process was followed by light- and electron microscopy; and by the TUNEL-reaction. As a result of the applied oxidative stress, which is comparable to that expected to occur within the microenvironment surrounding activated macrophages under oxidative burst (e.g. during autoimmune insulitis), about 90% of the cells eventually died due to post-apoptotic secondary necrosis. The few surviving cells phagocytosed the debris from their fragmented neighbours and began to divide about 24 h after the insult. Thus the sensitivity to oxidative stress varies, perhaps as a consequence of varying amounts of intralysosomal redox-active iron, as we have found to be the case in several other cellular systems. Since the NIT-1 cells are highly differentiated, and in many ways like beta cells, we consider our result to be of value for the understanding of beta-cell death during the development of insulin-dependent (Type I) diabetes mellitus (IDDM).

Three-year follow-up on scintigraphically assessed cardiac sympathetic denervation in patients with long-term insulin-dependent (type I) diabetes mellitus

Scintigraphy using I-123-metaiodobenzylguanidine (I-123-MIBG) and Tc-99m-methoxyisobutylisonitrile (Tc-99m-MIBI) allows assessment of the cardiac sympathetic innervation and the myocardial perfusion. To investigate the natural history of cardiac sympathetic denervation in long-term diabetic patients without myocardial perfusion defects, global and regional I-123-MIBG and Tc-99m-MIBI uptake was determined (score 1–6; 1 = normal uptake, 6 = no uptake) in 22 patients with insulin-dependent (type I) diabetes mellitus (IDDM) at 3-year follow-up. All patients were treated with intensive insulin therapy and HbA 1c was 8.0% ± 1.0% at entry compared with 7.9% ± 1.1% at follow-up. Cardiac sympathetic denervation (I-123-MIBG uptake score > 2), initially observed in 18 patients, was detectable in 21 patients at follow-up. The global myocardial I-123-MIBG uptake score deteriorated in eight patients, remained unchanged in 11 and improved in three patients. The changes in mean global I-123-MIBG uptake score (3.5 ± 1.0 versus 3.8 ± 0.8) were not significant. Reduction of the anterior, lateral, posterior, septal, and apical I-123-MIBG uptake did not progress significantly during follow-up. The mean uptake score of the posterior myocardial region (4.7 ± 0.8) was smaller than the uptake score of the anterior (3.0 ± 1.1, p = 0.001), lateral (3.2 ± 0.9, p < 0.001) and septal (4.1 ± 1.1, p < 0.05) myocardial regions. At follow-up, moderate myocardial perfusion defects (global Tc-99m-MIBI uptake score = 3) were detectable in four patients. Our study demonstrates that scintigraphically assessed cardiac sympathetic denervation does neither significantly regress nor progress on the average in a group of long-term IDDM patients during a 3-year follow-up. Thus, it is concluded that cardiac sympathetic abnormalities are a persistent, yet frequent phenomenon in long-term IDDM patients.

Pharmacological approaches to the prevention of autoimmune diabetes.

Insulin-dependent (type I) diabetes mellitus (IDDM) is the consequence of a chronic cell-mediated immune attack upon the insulin-producing beta-cells. Progressive insulinopenia is characteristic of individuals who eventually develop IDDM. Autoimmunity develops because of a failure in self-nonself discrimination. Autoimmunity is usually detected when autoantibodies are present in the patient's serum. However, autoantibodies are not synonymous with disease, as many autoantibody-positive individuals show no evidence of clinical disease. Studies initiated in the early 1980s demonstrated that short term remission from IDDM could be induced or lengthened with immunosuppressive therapy. However, no long term remissions were achieved. Current prevention strategies use a combination of autoantibody marker testing and beta-cell function testing to identify individuals with 'prediabetes'. The most useful autoantibodies for prediabetes screening include islet cell autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies and IA-2 autoantibodies. Immunointervention techniques have focused on protecting beta-cells from oxidative damage and developing tolerance to beta-cell autoantigens. Environmental manipulation may also be of benefit but its effectiveness is unproven. The pharmacist of the future may be involved in dispensing autoantigens, cytokines, anti-cytokine antibodies, anti-cytokine receptor antibodies, vaccines or viral vectors for gene therapy in the prevention of IDDM.

Social Relationships Among Young Adults with Insulin‐dependent Diabetes Mellitus: Ten‐year Follow‐up of an Onset Cohort

Past cross-sectional studies have suggested that young adults with insulin-dependent (Type I) diabetes mellitus (IDDM) may experience problems in their close peer relationships. For 10 years, we have followed an onset cohort of children and adolescents with IDDM (n = 57) and an age-matched group who were originally recruited after an acute illness, accident, or injury (n = 54). Now aged 19–26 years, these two groups were compared in terms of their friendship patterns, dating and love experiences, and sense of loneliness. All subjects in both groups had at least one friend. However, the IDDM group reported fewer friendships overall. The difference was accounted for by the number of less intimate friends. The two groups had similar frequencies of current romantic partners (IDDM = 63 %; comparison group = 64 %). While dating attitude and dating assertiveness did not differ between groups, some differences were found in terms of experiences of a primary love relationship. IDDM patients experienced less trust and sense of intimate friendship in these love relationships. No differences in loneliness were found. The preponderance of our findings indicate that the two groups had similar patterns and experiences of close peer relationships. Thus, the study does not suggest that IDDM leads to serious problems in forming social relationships for these patients during the transition to young adulthood. On the other hand, the IDDM patients’ lower level of trust and intimacy within love relationships are consistent with other findings from this study suggesting specific areas of lowered self-worth that appear in social relationships. © 1997 by John Wiley & Sons, Ltd.

Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus.

IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.

Salivary peroxidase activity in whole saliva of patients with insulin-dependent (type-1) diabetes mellitus.

In this study, salivary peroxidase activity was measured in a group of 10 patients with insulin-dependent (type I) diabetes mellitus (IDDM) who had a tendency towards periodontitis. In healthy subjects (N : 10), mean salivary peroxidase activity was 0.0025 +/- 0.001 IU/ml, while in this group of type I diabetic patients it was 0.051 +/- 0.015 IU/ml, a significantly higher level (p < 0.001). Approximal plaque index (API), modified sulcus bleeding index (mod SBI) and pocket depths were assessed clinically. The values for mod SBI and API were 60% and 68% respectively for the diabetic patients while for the control group mod SBI was measured 0.0% and the value for API was 10.67% (p < 0.001). The administration of this simple and practical test may provide an early marker of a tendency towards periodontitis in IDDM patients.

Exocrine pancreatic insufficiency combined with insulin‐dependent diabetes mellitus in a juvenile German shepherd dog

Canine juvenile-onset insulin-dependent diabetes mellitus is a rare disease. While pancreatic acinar atrophy is a well known picture in the dog, the simultaneous occurrence with an endocrine insufficiency has never been clearly established. The clinical, pathological and immunohistochemical findings of a three-month-old German shepherd dog with insulin-dependent diabetes mellitus concurrent with exocrine pancreatic insufficiency are described.

Organ-specific autoimmunity

The list of organ-specific autoimmune diseases (AID) is expanding. This is particularly true for T-cell-mediated AID, the pathophysiology of which has largely been ignored until recently. The best arguments for T-cell involvement in AID, although indirect, are the presence of a local T-cell infiltrate and the dramatic sensitivity of the disease to T-cell-selective immunosuppressive agents (e.g. cyclosporin A) as in the case of insulin-dependent (type I) diabetes mellitus (IDDM) and psoriasis. This paper will review current questions concerning the etiology and pathogenesis of organ-specific AID.

Immunogenetics of Diabetes Mellitus in Chinese

Diabetes Mellitus is a syndrome of hyperglycemia with heterogeneous etiology. Previous reports from population, migration and twin studies suggested that both genetic and environmental factors are all important in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Among the genetic factors, HLA is the most important and extensively studied. As far as the non-insulin-dependent diabetes mellitus (NIDDM), the etiology remains obscure, though polygenetic factors had been mentioned. Our studies were mainly focused on the assessment of BLA association with diabetes mellitus in Chinese. Preliminary results were shown below: (A)Phenotype association of HLA with IDDM, NIDDM & Maturity-onset diabetes of the young (MODY). There was no significant association of HLA-AB,C alleles with IDDM. DR3 is better associated with IDDM than is DR4 (RR=10.25 vs 3.56) which is the reverse in Caucasian. DR6 is negatively associated with IDDM. No significant association of HLA with NIDDM & MODY. (B)DR heterozygotes association with DM and non-diabetic diseases. Both DR3/4 and 3/9 are significantly associated with juvenile-onset IDDM (RR=47.1 &15.9) and adult-onset IDDM (RR=27.5 &202). The association of DR3/4 is stronger than that DR/9 in both groups. There is no significant association of DR3/4 with NIDDM, MODY and other non-diabetic diseases. (C)Association of BlA-DQαRFLP’S with IDDM. Genomic DNA from patients and controls were digested with EcoRI, Pstl, BamHI and Hindlll and then hybridized with DQα cDNA probe. The results showed 1)significantly increased frequency of EcoRI 13.0 kb, PstIl 9.0 & 4.1 kb and HindIII 4.6 kb in patients 2)significantly decreased frequency of EcoRI 17.0 kb, PstI 17.0 & 10.0 kb, and Hindlll 9.0kb in patients 3)no significant difference in BamHI fragments between IDDM patients and controls. (D)HLA haplotype association with IDDM. IDDM patients are highly associated with DR3 haplotype but not with DR4 haplotype. AW33Bl7CW3DR3DQW2DRW52 may be a high risk haplotype for IDDM in Chinese. (E)Association of non-aspartic acid at position 57 of the HLA-DQβ chain with IDDM and NIDDM. The presence of an amino acid other than aspartic acid at position 57 of the HLA-DQB chain (NA) is highly associated with susceptibility to IDDM in Caucasion but not in Japanese. In Chinese, we demonstrated that HLA-DQB non-ASP-57 allele is significantly associated with IDDM, but not with NIDDM.

VH and V kappa segment structure of anti-insulin IgG autoantibodies in patients with insulin-dependent diabetes mellitus. Evidence for somatic selection.

In some patients with insulin-dependent (type I) diabetes mellitus (IDDM), autoantibodies to insulin are present at diagnosis. After initiation of the treatment with not only animal but also human insulin, anti-insulin, mainly IgG, autoantibodies become a major component of the autoimmune response in virtually all IDDM patients. Their structure, however, is still relatively unknown. We analyzed the structure of the VH and V kappa segments of three human IgG mAb derived from three IDDM patients. The sequences of VH genes of two IgG, mAb13 and mAb48, were 98.3 and 96.6% identical with those of the H11 and 1.9III genes (VHIII family), respectively. The sequence of the VH gene of the third IgG, mAb49, was 98.6% identical with that of the 51p1 gene (VHI family). All three IgG mAb used V kappa III segments. The V kappa III gene sequences of mAb13 and mAb49 were 97.9 and 98.9% identical, respectively, to that of the kv3g gene; the mAb48 V kappa gene sequence was 96.5% identical to that of the kv328 gene. The VH and/or V kappa segments of these anti-insulin IgG mAb are similar to Ig V genes expressed in the fetal, and adult normal and autoimmune B cell repertoires. The nucleotide differences displayed by the three anti-insulin IgG mAb VH gene sequences, when compared with those of the closest reported germ-line genes, were concentrated in the CDR (6.2 x 10(-2) and 0.8 x 10(-2) difference/base in CDR and FR, respectively; p < 0.01, chi 2 test), and yielded a significantly higher putative replacement (R) to silent (S) mutation ratio in the CDR (12.0) than in the framework (0.2). The concentration of nucleotide differences in the CDR and their high R:S putative mutation ratios were consistent with the hypothesis that these expressed VH genes underwent a process of somatic mutation and Ag-driven clonal selection. That such differences constituted somatic point-mutations was formally proved in IgG mAb13, by differentially targeted PCR amplification and Southern blot hybridization of the mAb13-producing cell line DNA. The putative germ-line gene that gave rise to the expressed VH segment was cloned using genomic DNA from PMN of the same patient whose B cells were used for the generation of this mAb. Overall, in the anti-insulin IgG mAb VH and V kappa III genes, the (putative and verified) somatic point-mutations yielded 27 amino acid replacements, of which 14 nonconserved. Four of these resulted in positively charged residues, three Arg and one His.(ABSTRACT TRUNCATED AT 400 WORDS)

Factors Influencing the Onset and Progression of Diabetic Retinopathy in Subjects with Insulin-dependent Diabetes Mellitus

The etiology of diabetic retinopathy is poorly understood. In the current study, factor associated with the onset and the progression or regression of retinopathy are evaluated. Two hundred seventy-seven subjects with insulin-dependent (type I) diabetes mellitus (IDDM) were evaluated longitudinally for retinal changes over a mean of 2.7 years. The multistate Markov model was used to analyze the influences of the duration of diabetes, a family history of hypertension, age, sex, cigarette smoking, systolic blood pressure, diastolic blood pressure, cholesterol levels, and longitudinal glycohemoglobin (GHb) values on the development and the progression or regression of retinopathy. Univariate analysis confirmed that four factors were significantly associated with the etiology and the progression or regression of diabetic retinopathy: age, duration of diabetes, mean longitudinal GHb levels (all at P < 0.01), and diastolic blood pressure (P < 0.04). However, age was no longer significant when controlled by duration of diabetes. Cigarette smoking was only associated significantly with background retinopathy (stages 2 and 3). Systolic blood pressure, sex, a family history of hypertension, and cholesterol levels were not significantly associated with retinopathy. The onset of diabetic retinopathy is associated with the duration of diabetes, mean longitudinal GHb levels, smoking, and diastolic blood pressure. A longer duration of diabetes, higher GHb values, and higher diastolic blood pressure levels are associated with an increased risk of progression and a decreased chance of regression of diabetic retinopathy.

HLA-DQβ57 in Hispanic patients with insulin-dependent diabetes mellitus

OBJECTIVE: The purpose of our study was to investigate the distribution of HLA-DQ β-chain amino acid residue 57 (HLA-DQβ57) as a genetic marker of susceptibility for insulin-dependent diabetes mellitus in the Hispanic population.STUDY DESIGN: Fifteen patients of Puerto Rican descent with juvenile-onset insulin-dependent diabetes mellitus underwent human leukocyte antigen typing for HLA-DQβ57 by polymerase chain reaction amplification of the target genomic DQ sequence followed by hybridization of the polymerase chain reaction product to phosphorus 32-labeled allele-specific oligonucleotide probes. A control group of 44 Hispanic adults without diabetes who were undergoing human leukocyte antigen typing for tissue donation were concurrently typed for comparison.RESULTS: The Hispanic insulin-dependent diabetes mellitus group showed a significant increase in homozygosity for a non-aspartate amino acid (p = 0.023) over a control group of Hispanic subjects without diabetes. A high rate of heterozygosity for aspartate (53.3%) is found in Hispanic subjects with insulin-dependent diabetes mellitus as well.CONCLUSIONS: HLA-DQβ57 in the Hispanic population has a distribution distinct from HLA-DQβ57 in the Caucasian population. A single aspartate is not protective against insulin-dependent diabetes mellitus in Hispanic subjects. (AM J OBSTET GYNECOL 1992;167:1565-70.)

Risk of early-onset proliferative retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy.

Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates greater than 30 micrograms/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR.(ABSTRACT TRUNCATED AT 250 WORDS)