HLA antigens in insulin-dependent diabetes mellitus.

Diabetes mellitus is largely determined by genetic factors but environmental factors are necessary to convert genetic susceptibility into overt disease. Studies of twins show that the genetic impact in non-insulin-dependent diabetes mellitus is stronger than in insulin-dependent diabetes mellitus. The genetic factors involved in non-insulin-dependent diabetes mellitus are not known and the outcome of molecular genetic research has so far been disappointing. The major genetic susceptibility to insulin-dependent diabetes mellitus is conferred by genes in the HLA region on chromosome 6. Despite many advances in molecular genetics in insulin-dependent diabetes mellitus the serologically detectable HLA antigens and haplotypes are still the best available markers. This review describes the important developments in immunogenetics in insulin-dependent diabetes mellitus and summarises the main findings from earlier studies. Genetically the potential for primary prevention of insulin-dependent diabetes mellitus already exists and will become a reality as soon as the environmental determinants are identified. A wide application of immunogenetic methods will be needed in the prevention of insulin-dependent diabetes mellitus.     

Beta-adrenoceptor regulation in insulin-dependent diabetes mellitus.

The study was performed to determine whether the regulation of mononuclear leukocyte beta-adrenergic receptors and responses was changed in insulin-dependent diabetes mellitus (IDDM). The concentrations of noradrenaline, the beta-adrenoceptor densities, basal cAMP levels and maximal isoprenaline-induced cAMP responses were the same in the diabetic and healthy subjects. After isoprenaline-promoted receptor internalization and uncoupling, the receptor densities and the responsiveness did not differ. In the control group, a highly significant correlation existed between the number of beta-adrenoceptors and maximal isoprenaline responses, before (r = 0.99, p less than 0.01) and after (r = 0.96, p less than 0.01) receptor internalization and uncoupling. This correlation between receptor densities and responses was not present in the IDDM group, which also showed elevated levels of plasma adrenaline. This study demonstrates that IDDM subjects have an unaltered mechanism of agonist-promoted beta-adrenoceptor internalization, but indicates a partial dysfunction of the beta-adrenoceptor-coupling to adenylate cyclase.     

Platelet antioxidant enzymes in insulin-dependent diabetes mellitus.

BACKGROUND: The measurement of the peroxidase scavenging system represented by the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in blood cells of diabetic patients has, in the past, given equivocal results. Likewise, the role of these intracellular enzymatic scavengers against the oxidative stress of diabetes-associated microangiopathic complications is unknown. METHODS: Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of SOD, catalase and GSH-Px to the presence of diabetes, as well as to the presence of nephropathy and retinopathy in 35 insulin-dependent diabetic patients, as compared to 10 age-matched control subjects. RESULTS: The enzymatic activities were not changed in diabetic patients in comparison with healthy controls. After stratifying patients according to presence of nephropathy (24-h urinary albumin excretion rate persistently > or =20 microg min(-1)) or retinopathy, the group of albuminuric patients was characterized by a significant decrease in SOD activity as compared to those in the normoalbuminuric range (4.36+/-1.06 vs. 6.81+/-2.26 mU 10(-9) platelets; p=0.01). Catalase and GSH-Px did not change. No modification in platelet enzyme activities has been found in diabetic subjects with retinopathy. CONCLUSIONS: These results suggest that diabetic nephropathy, at least in its early stage, may be related to an altered redox state of platelets, as tested by the reduction in SOD activity, thus, indicating that the renal damage in these patients may be associated to a selective increase in platelet susceptibility to variation in the redox state.     

Pre-conception care and support for women with diabetes

This article discusses the National Service Framework for Diabetes: Standards (Department of Health, 2001), with the main focus on Standard 9: diabetes and pregnancy. It concentrates on pre-conception care and support for women with pre-existing diabetes to optimize the outcome of their pregnancy. The rationale for this is the need to understand how this standard affects women with diabetes during childbearing age. Following an introduction to aetiology and epidemiology of diabetes, the author examines the importance of pre-conception care for women with diabetes. An acknowledgement of the deficits within the clinical environment aids recommendations on improvement of education and knowledge for nurses. Health promotion and patient support is emphasized to facilitate an understanding of the impact of diabetes on pregnancy and the necessity of the multidisciplinary team involvement before, during and after birth.     

Total-body potassium in insulin-dependent diabetes mellitus

1. Total-body potassium and fat-free mass have been measured in 31 insulin-dependent diabetic patients and 31 age- and sex-matched normal volunteers. 2. Body mass index was significantly higher in the insulin-dependent diabetic patients (24.7 +/- 0.5 vs 23.3 +/- 0.4 kg/m2; P = 0.05). 3. Total-body potassium, uncorrected and corrected for weight and for fat-free mass, was not significantly different in the two groups (3281 +/- 141 mmol, 47.3 +/- 1.3 mmol/kg body weight, 60.9 +/- 1.0 mmol/kg fat-free mass, and 3315 +/- 143 mmol, 48.6 +/- 1.0 mmol/kg body weight, 60.4 +/- 0.8 mmol/kg fat-free mass, respectively, in diabetic patients and non-diabetic subjects). There was no relationship between blood glucose control, as assessed by glycated haemoglobin concentrations, and total-body potassium. 4. These results suggest, by contrast with previous reports, that in insulin-dependent diabetic patients, showing varying degrees of glycaemic control (glycated haemoglobin range 6.1-15.3%, mean 9.0%) that: (a) there is no significant abnormality of body potassium homoeostasis, and (b) there is no relation between total-body potassium and glycaemic control.     

Thyroid-stimulating immunoglobulins in insulin-dependent diabetes mellitus

Abstract. Increased frequencies of thyroid diseases and thyroid microsomal antibodies have been observed in insulin-dependent diabetes mellitus. However, the exact prevalence of thyroid-stimulating immunoglobulins has not been established. In the present study these antibodies were measured by both a radioreceptor and an adenylate-cyclase stimulation assay.
In forty-six patients with insulin-dependent diabetes mellitus without endogeneous insulin production (C-peptide concentration ≤ 0·06 nmol l^-1) the receptor assay was positive in ten and the stimulation assay in fifteen patients. The immunoglobulins of four patients inhibited the adenylate cyclase, and one of these was positive in the receptor assay. In nine patients with post-prandial C-peptide 0·07–0·19 nmol l^-1, five had adenylate-cyclase-stimulating antibodies, while none were positive in the receptor assay. Thyroid hormones and thyrotropin concentrations were not different in the forty-six patients without endogenous insulin production with thyroid-stimulating immunoglobulins compared with patients without these antibodies. Patients with thyroid-stimulating immunoglobulins required a daily median amount of 0·71 IE of insulin kg^-1 compared to median of 0·57 IE kg^-1 in patients without these antibodies ( P < 0·03), despite a similar degree of diabetic regulation.
The level of tri-iodothyronine was correlated to the antibody level in patients with adenylate-cyclase-stimulating antibodies. While the prognostic and possibly pathogenetic importance of these antibodies in Graves' disease have been established, their significance in insulin-dependent diabetes mellitus remains to be demonstrated.     

Plasma lipid levels in insulin-dependent diabetes mellitus

Because several recent reports have indicated a high incidence of hyperlipidemia in insulin-dependent juvenile diabetes, the plasma lipid levels were measured in a population of insulin-dependent diabetic patients to determine if hyperlipidemia is necessarily associated with diabetes. Only one patient had an elevated cholesterol concentration (greater than 220 mg. per deciliter) and two patients had an elevated triglyceride concentration (greater than 140 mg. per deciliter), giving an incidence of 6.4 per cent. A normal control group had an incidence of hyperlipidemia of 5.7 per cent. The mean cholesterol level (164 "/- 38 mg. per deciliter) of the diabetic population was significantly less than that of the normal control group (183 +/- 38 mg. per deciliter). The diabetic patients were divided into groups on the basis of 24-hour urinary glucose excretion and records of glycosuria. The serum triglyceride of the patients in group 4 (highest urinary glucose content and spills) was significantly elevated above three other groups with less glucosuria. Dietary history revealed that group 4 patients consumed a significantly higher percentage of fat. Cholesterol levels did not correlate with parameters of regulation of the diabetes.     

Modern management of insulin-dependent diabetes mellitus

Currently available treatment methods, albeit improved, remain less than totally satisfactory. New developments such as improved viability of whole organ pancreatic transplants, islet cell transplantation, immunosuppression in the treatment of new-onset diabetes, development of reliable glucose sensors to provide continuous feedback for insulin delivery devices, and alternate routes for insulin administration may drastically change diabetes treatment in the future. For now, physicians must carefully consider the risks and benefits associated with available treatments when discussing therapeutic options with patients and their families. The wide range of therapies available provides the opportunity for patient and physician to select the most appropriate treatment regimen.     

Specific immunoregulation abnormality in insulin-dependent diabetes mellitus

We evaluated antigen-nonspecific (Con A) and antigen-specific (islet cell) activation of suppressor cell function in 11 IDD patients. Compared with healthy controls, IDD was associated with both antigen-specific (n = 11, p less than 0.01) and nonspecific (n = 6, p less than 0.03) suppressor cell hypofunction. The specific defect was not present in NIDD patients and correlated negatively with the duration of the disease (r = -0.6, p less than 0.05). No relationship was found between the degree of specific suppressor cell dysfunction and diabetic control as assessed by glycosylated hemoglobin, plasma glucose values, insulin-binding capacity, or C-peptide determinations. Plasma from IDD lacked anti-suppressor cell activity. Low levels of circulating immune complexes were detected in IDD patients whose disease duration was 1 month or less. Specific suppressor cell hypofunction and/or enhanced helper cell activity in early stages of IDD could be contributing to the formation of islet cell autoantibodies, immune complexes, islet cell injury, and the diabetic state.     

Principles of immunotherapy in insulin-dependent diabetes mellitus

There is now convincing evidence that insulin-dependent (Type 1) diabetes mellitus is an immunological disease. This is derived from observations of a genetically determined predisposition, an association of recent-onset diabetes with viral infections, an inflammatory cell infiltrate affecting the islets of Langerhans, autoantibodies against islet cells, insulin, insulin receptors, and other organ-specific or non-organ-specific antigens, as well as abnormalities of cell-mediated immunity and of non-antigen specific mediators. Finally, recurrent diabetes in cases of pancreas transplantation in monozygotic twins discordant for insulin-dependent diabetes underlines the influence of an autoimmune insulitis. The current concept of the aetiopathogenesis of most cases of insulin-dependent diabetes is that in genetically susceptible individuals any form of damage to beta cells by viral, toxic, dietary or other environmental factors may initiate beta cell destruction and/or aberrant antigen expression, followed by a self-perpetuating, mostly cell-mediated autoimmune destruction of the insulin-producing cells. Successful immunoprevention in autoimmune diabetes models, on the basis of these recent concepts, led to the assumption that immunotherapy by means of immunomodulative or immunosuppressive drugs might be a possible tool in the treatment of patients with recent onset insulin-dependent (Type 1) diabetes mellitus.     

The epidemiology of insulin-dependent diabetes mellitus

Diabetes mellitus is a uniquely interesting disorder to study from an epidemiologic perspective. Information that can be gathered from carefully designed and executed epidemiologic studies carried out on a population-based group of individuals with insulin-dependent diabetes mellitus (IDDM) provides insight into this disorder that cannot be obtained by traditional methods of basic or clinical research. The application of epidemiology as an investigative tool can be illustrated in 3 important areas of diabetes mellitus: (1) the etiology of IDDM, (2) the natural history or clinical course of IDDM, and (3) long-term complications of IDDM.     

Epidemiologic studies of insulin-dependent diabetes mellitus

The incidence of insulin-dependent diabetes mellitus (IDDM) in Denmark in the years 1970--1976 was 13.3 per 100,000 in the age group 0--29 yr. This incidence is almost identical to that found in 1924 in Denmark in the same age group. The prevalence of insulin-consumers is 3.2 per 1,000. Comparison is made with incidence and prevalence data from other studies of Caucasian populations.     

Accelerated bilateral cataract formation in insulin-dependent diabetes mellitus

A 21-yr-old Caucasian man developed accelerated irreversible dense bilateral cataracts 4 wk after control of his newly diagnosed insulin-dependent diabetes mellitus (IDDM) and 12 wk after the onset of his symptoms. Although transitory cataracts have been identified in patients with newly diagnosed IDDM, there is no mention in the literature of irreversible cataract formation this soon after diagnosis (see ref. 1).     

Macrosomia in pregnancy complicated by insulin-dependent diabetes mellitus

We assessed the factors influencing the birth weight of infants born to 83 women with insulin-dependent diabetes mellitus (IDDM) over a 5-yr period. Maternal glycosylated hemoglobin (HbA1) concentrations at delivery correlated with the percentile birth-weight ratios (r = .43, P less than .001) and indicated that approximately 18% of variance in the birth weight could be ascribed to glycemic control in the third trimester. Fetal macrosomia occurred in 22 (27%) pregnancies. When 20 of these pregnancies were compared closely with 20 nonmacrosomic pregnancies in diabetic women, the mothers of macrosomic infants were found to be more obese, have a history of previous macrosomic birth, and have higher concentrations of serum human placental lactogen and urinary estriols in the third trimester. Macrosomic pregnancy was further distinguished by accelerated fetal growth (judged by serial ultrasonography) from the 32nd wk of gestation and by biochemical (but asymptomatic) hypoglycemia in the neonate. In our study, no serious neonatal morbidity could be attributed to macrosomic pregnancy. Good glycemic control was attained in both groups, and no significant differences between the groups in overall glycemic control throughout pregnancy were noted. Thus, despite good glycemic control, macrosomia remains comparatively common in modern pregnancy complicated by IDDM, and factors other than maternal hyperglycemia must contribute to its etiology.