Genetics of insulin-dependent diabetes mellitus

IDDM is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence if IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.     

Exocrine pancreatic ductograms in insulin-dependent diabetes mellitus

OBJECTIVES: To examine the prevalence of abnormal pancreatic ductograms in patients with insulin-dependent diabetes mellitus (IDDM) and to determine the clinical characteristics of those patients. METHODS: Pancreatic exocrine morphology was studied by endoscopic retrograde pancreatography (ERP) in 43 patients with IDDM, 12 patients with islet cell antibody (ICA)-positive non-insulin-dependent diabetes mellitus (NIDDM), and 22 patients with ICA-negative NIDDM. RESULTS: ERP revealed a significantly higher prevalence of abnormal pancreatic ducts (dilation and stenosis, tortuosity, obstruction, and intraductal calculi) in the patients with IDDM (17/43, 40%) than in the patients with ICA-negative NIDDM (2/22, 9%, p = 0.018). IDDM patients who slowly progressed to insulin dependency more than 13 months after the onset of diabetes had a higher frequency of abnormal pancreatic ducts (13/22, 59%) than those who needed insulin therapy within 12 months after the onset (4/21, 19%, p = 0.016). There was no difference in duration of diabetes between the two groups. ICA-positive NIDDM patients also had a higher frequency of abnormal pancreatic ducts (7/12, 58%) than ICA-negative NIDDM patients (2/22, 9%, p = 0.0074). CONCLUSIONS: These results indicate that a high proportion of IDDM patients who have prolonged histories of non-insulin dependency with ICA suffer pancreatic exocrine impairment. A similarity between IDDM with a slowly progressive clinical course and fibrocalculous pancreatic diabetes seen in tropical countries also was suggested.     

Fusidic acid and insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is a major cause of morbidity and mortality from long-standing complications. The autoimmune nature of IDDM has encouraged use of immunosuppressive and antiinflammatory strategies to better preserve residual pancreatic beta-cell function at the time of diagnosis. Fusidic acid and its sodium salt, fusidin, is a relatively atoxic antibiotic used mainly in the treatment of staphylococcal infections. Recently, fusidin has been demonstrated to possess immunosuppressive functions in vitro and in vivo, and the drug has shown promise in preventing the disease in animal models of IDDM and in a preliminary trial in IDDM patients.     

Evidence for superantigen involvement in skin homing of T cells in atopic dermatitis

The environmental factors that contribute to the homing of T cells in skin disease is unknown. The skin lesions of atopic dermatitis (AD) are frequently colonized with superantigen (SAg), producing strains of Staphylococcus aureus. In vitro, these superantigens have the capacity to activate and expand T cells expressing specific T cell receptor BV gene segments, and also to increase their skin homing capacity via upregulation of the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA). These activities have been proposed to enhance the chronic cutaneous inflammation of AD, but an in vivo role for SAg has not been conclusively demonstrated. In this study, we sought direct evidence for in vivo SAg activity by comparing the SAg profiles of S. aureus cultured from the skin of AD subjects to the T cell receptor Vbeta repertoire of their skin homing (CLA+) T cells in peripheral blood. SAg secreting S. aureus strains were identified in six of 12 AD patients, and all of these subjects manifested significant SAg-appropriate Vbeta skewing within the CLA+ subsets of both their CD4+ and their CD8+ T cells. T cell receptor Vbeta skewing was not detectable among the overall CD4+ or CD8+ T cell subsets of these subjects, and was not present within the CLA+ T cell subsets of five patients with plaque psoriasis and 10 normal controls. T cell receptor BV genes from the presumptively SAg-expanded populations of skin homing T cells were cloned and sequenced from three subjects and, consistent with a SAg-driven effect, were found to be polyclonal. We conclude that SAg can contribute to AD pathogenesis by increasing the frequency of memory T cells able to migrate to and be activated within AD lesions.     

Evidence for cardiomyopathy in familial diabetes mellitus

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age. Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia. Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.     

Appraisal and implications of predictive testing for insulin-dependent diabetes mellitus

A patient with systemic lupus erythematosus (SLE) developed reactive hemophagocytosis. This case did not show any underlying diseases such as infection or malignancy other than SLE itself. The mechanisms inducing hemophagocytosis in SLE seem to be heterogeneous and remain to be elucidated. Although an immune complex-mediated mechanism in cases with acute lupus hemophagocytic syndrome has been proposed, we suggest the possible involvement of IL-1beta as the pathogenesis of our case.     

Peripheral osteopenia in adult patients with insulin-dependent diabetes mellitus

Alterations in bone metabolism in diabetes mellitus is a topic of special interest. Bone blood flow is increased in the distal limb of diabetic patients, which is believed to increase osteoclastic activity. We measure bone mineral density using dual-photon absorptiometry in the distal lower limb, the femoral neck, and the lumbar spine in 41 IDDM patients and in 30 control persons. In the diabetic group there was a 10% reduction of bone mineral density in the femoral neck (p < 0.01) and a 12% reduction in the distal limb (p < 0.001) compared with the control group. No significant difference was found in the lumbar spine (p = 0.22). Our data yield incidence for peripheral osteopenia in IDDM-patients, independent of any systemic bone disease such as osteoporosis. A link between decreased bone mineral density and diabetic neuropathy has been observed for the femoral neck (p < 0.001), but not for the distal limb or axial skeleton. Whether there is a common aetiological link or a casual connection between diabetic neuropathy and bone mineral density has still to be determined.     

Insulin edema in three adolescents with insulin-dependent diabetes mellitus

Three female patients with a previously poorly controlled Insulin Dependent Diabetes Mellitus (IDDM), without evidence of cardiovascular, hepatic or renal dysfunction, developed generalized edema after a substantial increase in their insulin dosage. Edema resolved in 2-3 weeks, without specific therapy. Our patient's findings met the criteria of diagnosis of insulin edema. Insulin edema during IDDM is an uncommon complication of insulin therapy (1/400) and its pathogenesis is not clarified so far; it is a transient and self-limiting condition. The diagnosis is based on exclusion of all other major causes of edema.     

Proximal tubular basement membrane width in insulin-dependent diabetes mellitus

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.     

Coping styles in youths with insulin-dependent diabetes mellitus.

The relationships between two coping styles (i.e., use of personal and interpersonal resources; ventilation and avoidance) and two health outcomes (i.e., adherence and metabolic control) were evaluated in 135 youths with insulin-dependent diabetes mellitus (IDDM). Individual characteristics (i.e., age, duration of illness) and contextual variables (i.e., stress, family relations) were used to predict coping styles. Poor adherence to treatment, older adolescent age, and long duration of IDDM were correlated with ventilation and avoidance coping. Youths with short duration of IDDM were more likely to cope through the use of personal and interpersonal resources, although this strategy was not associated with health outcomes. A multiple regression analysis indicated that high ventilation and avoidance coping was predicted by high stress, low family cohesion, and older adolescent age. In addition, the interaction between family adaptability and duration of IDDM significantly predicted ventilation and avoidance coping. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Incidence and hospitalization patterns of insulin-dependent diabetes mellitus

Data from a statewide insulin-dependent diabetes mellitus (IDDM) registry in Rhode Island show that IDDM affects young adults (20-29 yr) as frequently as adolescents and teenagers (10-19 yr). Overall incidence less than 30 yr was 14/100,000 population. Peak incidence occurred at 10-14 yr (19/100,000 population). Poor diabetic control and infection accounted for 46-62% of hospitalizations among 275 known diabetic persons. Despite a 10-yr mean duration of diabetes, only 31% of hospitalized diabetic persons less than 30 yr of age reported ever having received outpatient diabetes education of two or more hours. Readmissions 1 yr after initial registration were more frequent for known (43%) than new-onset (18%) IDDM cases. Increased risk of readmission for both groups was associated with a poverty socioeconomic status. Total direct hospitalization costs for IDDM in persons under 30 yr of age in Rhode Island was $530,000 per year of $2,245 per patient.     

New developments in treating children with insulin-dependent diabetes mellitus

A number of new developments in the management of insulin-dependent diabetes mellitus have occurred in the past several years. Primary care providers including pediatric nurse practitioners need to be aware of these developments so that they can work effectively with specialty providers in caring for children with insulin-dependent diabetes mellitus. This article discusses the implications of the Diabetes Control and Complications Trial for children and adolescents, the Diabetes Prevention Trial-Type I, and several other recent developments in caring for children with insulin-dependent diabetes mellitus.     

Relative nocturnal hypertension in children with insulin-dependent diabetes mellitus

Twenty-four-hour blood pressure and heart rate measurements were carried out in 14 newly diagnosed diabetics and in 28 diabetics with 5-13 years' duration of the disease; 8 healthy children were used as controls. Mean arterial blood pressure increased at night in 5, decreased slightly (less than 10%) in 5 and decreased markedly (more than 10%) in 18 diabetics with longer duration of the disease. The diurnal-nocturnal differences in heart rates were significantly lower in diabetics with relative "nocturnal hypertension" compared to the control group (p < 0.05). A significant negative correlation was found between maximal arterial blood pressure during physical exercise and the diurnal-nocturnal differences in mean arterial blood pressure in diabetics (r = -0.58; p < 0.02). In conclusion, we found elevated nocturnal blood pressure in a subgroup of children with longer duration of diabetes and without increased albumin excretion. However, longitudinal studies of blood pressure profiles are needed to identify the candidates for diabetic vasculopathy among diabetic children.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

BACKGROUND: Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. METHODS: We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. RESULTS: In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5 +/- 2.9 and 12.6 +/- 2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3 +/- 2.3 vs 8.6 +/- 1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5 +/- 2.1 vs 9.0 +/- 2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. CONCLUSIONS: Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Retinopathy in African Americans and whites with insulin-dependent diabetes mellitus

BACKGROUND: The development and progression of diabetic retinopathy in African Americans with insulin-dependent diabetes mellitus is not known. METHODS: Two hundred subjects with insulin-dependent diabetes mellitus with duration of diabetes 16 years or less at first visit were studied; 58 were African Americans and 142 were whites. All had gradable stereoscopic color fundus photographs (seven standard fields) from at least two visits (mean time between first and second visit was 4.1 years). Subjects with hemoglobinopathy or proliferative retinopathy or subjects who had evidence of treatment for proliferative retinopathy at first visit were excluded. Masked grading of photographs was conducted using the modified Airlie House classification scheme. RESULTS: African Americans were older, heavier, had higher systolic blood pressure (all P < .05), and marginally higher hemoglobin A1 (HbA1) values (P = .06) than the whites at first visit. African Americans had a lower rate of two steps or more progression from preexistent retinopathy (19%) than whites (43%). Progression to proliferative retinopathy or treatment was similar by race. Multivariate analysis predicting development oe progression of retinopathy, while controlling for length of follow-up, found higher HbA1 (odds ratio [OR] = 2.15), longer duration of insulin-dependent diabetes mellitus (OR = 1.69), higher serum creatinine concentration (OR = 1.59), and white race (OR = 2.62) to be independent risk factors. CONCLUSIONS: These data suggest a previously unsuspected reduction in the adjusted risk for development and progression of retinopathy in African Americans. The reason for this apparently reduced risk are not known.