Anti-GAD-positive patients with type 1 diabetes mellitus have higher prevalence of autoimmune thyroiditis than anti-GAD-negative patients with type 1 and type 2 diabetes mellitus

The aim of our study was to evaluate antibodies against thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO) - markers of autoimmune thyroiditis - in several groups of adult patients with type 1 and type 2 diabetes mellitus (DM). We were particularly interested whether the presence of thyroid antibodies is related to the positivity of glutamic acid decarboxylase antibodies (anti-GAD). We found elevated anti-GAD in 46 % (97/210) patients with type 1 DM. All patients with type 2 diabetes were anti-GAD-negative. At least one thyroid antibody (anti-TG and/or anti-TPO) was found in 30 % (62/210) patients with type 1 DM and 27 % (22/83) type 2 diabetes patients. The patients with type 1 DM were further grouped according to their anti-GAD status. The anti-GAD-positive patients had a higher prevalence of anti-TG antibodies than the anti-GAD-negative patients (25 % vs. 12 %, p=0.03) as well as anti-TPO antibodies (32 % vs. 12 %, p<0.001). At least one thyroid antibody was detected in 39 % (38/97) of anti-GAD-positive but only in 21 % (24/113) of anti-GAD-negative patients with type 1 DM (p=0.006). No significant difference in the frequency of thyroid antibodies was found between anti-GAD-negative patients with type 1 and type 2 DM (21 % vs. 27 %, p=0.4). The groups with or without thyroid antibodies in both type 1 and type 2 diabetic patients did not differ in actual age, the age at diabetes onset, duration of diabetes, body mass index or HbA1c level. Patients with elevated thyroid antibodies had significantly higher levels of TSH than those without thyroid antibodies (1.86 vs. 3.22 mIU/l, p=0.04 in type 1 DM; 2.06 vs. 4.89 mIU/l, p=0.003 in type 2 DM). We conclude that there is a higher frequency of thyroid-specific antibodies in anti-GAD-positive adult patients with type 1 DM than in anti-GAD-negative patients or in patients with type 2 DM. Patients with or without thyroid antibodies do not differ in age, DM onset and duration, BMI or HbA1c. Thyroid antibodies-positive patients have higher levels of thyroid stimulating hormone (TSH).     

Growth disorders in children with type 1 diabetes mellitus

The aim of the research was to analyze anthropometric variables in children with type 1 diabetes mellitus (DM) in relation with the stage of pubertal development at onset of disease and quality of metabolic control over five-year long observation. Diagnosed children were taller than their peers. This especially referred to age group between 4 and 9.5 years. On the whole, weight of the patients and healthy controls did not differ. However, the diagnosed children had substantially lower weight in puberty than healthy controls. Body mass index was significantly lower in the group of diagnosed children on the whole and in puberty. During a five-year long observation patients have had a significant retardation of growth. However, that retardation referred primarily to patients in prepuberty. Growth retardation was more pronounced with bad metabolic control. Growth was satisfactory if onset of disease had been in puberty. A significant weight gain was observed in patients in puberty whereas in those in prepuberty there was no significant change of body weight at the end of five-year long observation. Metabolic control did not affect observed changes. There were significant differences of anthropometric variables between those suffering from type 1 DM and their peers. The differences depended on the age at onset. The disease had a negative effect on growth with onset in prepuberty, whereas in puberty growth was satisfactory. However, puberty was a period in which patients increased their weight excessively. Prepuberty was a period in which growth had been significantly affected by metabolic control.     

Plasma resistin levels in patients with type 1 and type 2 diabetes mellitus and in healthy controls.

Resistin is a recently discovered hormone that is exclusively expressed in adipose tissue. Its expression in rodents was reported to be elevated or suppressed in genetic and diet-induced obesity, respectively. Resistin treatment impaired glucose tolerance and insulin action. Immunoneutralization of resistin improved insulin sensitivity, while thiazolidinedione treatment reduced resistin expression. Therefore, resistin could play a critical role in the development of obesity and type 2 diabetes. In this study were determined resistin plasma levels in humans suffering from type 1 and type 2 diabetes and in healthy controls. Plasma levels of resistin in healthy controls were 38.78 ng/ml. They were not statistically different in individuals with a broad BMI range. Resistin plasma levels in type 2 diabetes were 38.7 ng/ml, and 39.4 ng/ml in type 1 diabetes. Thiazolidinedione treatment did not influence resistin plasma levels. We conclude from our data: 1. resistin can be detected in human plasma, 2. plasma resistin levels are not different in type 1 and type 2 diabetes.     

Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus

Aims

To investigate the relationship between hyperuricemia (HUA) and the clinical backgrounds in Japanese patients with type 2 diabetes mellitus.

Methods

After a cross-sectional study evaluating the association of HUA with the clinical characteristics in 1,213 patients with type 2 diabetes mellitus, the estimated glomerular filtration rate (eGFR) and the incidence of diabetic macroangiopathies was investigated in a prospective observational study in 1,073 patients during a 3.5 year period. HUA was defined by serum uric acid levels >327 μmol/L or as patients using allopurinol.

Results

The frequency of HUA was significantly higher in the diabetic patients (32% in men and 15% in women) than in the normal controls (14% in men and 1% in women). In total, HUA was found in 299 (25%) of the patients during the cross-sectional study. Even after adjusting for sex, drinking status, treatment for diabetes mellitus, body mass index, hypertension, use of diuretics, hyperlipidemia, HbA1c and/or the eGFR, the HUA was independently associated with some diabetic complications. The eGFR was significantly reduced in HUA patients compared to those with normouricemia in the 12 months after observation was started. HUA was also an independent risk factor for coronary heart disease even after adjustment in the Cox proportional hazard model.

Conclusions

HUA is a associated with diabetic micro- and macroangiopathies. HUA is a predictor of coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. However, the influence of HUA is considered to be limited.     

Hypercalciuria in patients with diabetes mellitus type 1 and 2--studies of its pathogenesis using the oral calcium tolerance test

The study was aimed at the evaluation of changes in the urinary excretion of calcium in patients with diabetes of type I and II. The investigations were carried out in 34 patients with type I diabetes, 28 patients with type II diabetes and 30 control subjects having the normal glucose tolerance. The oral calcium tolerance test according to Pak was performed in all the patients and the controls. Besides normocalciuria, also hypercalciuria of renal origin, as well as hipercalciuria resulting from an elevated intestinal absorption of calcium have been found in diabetic patients. These disturbances occurred much more frequently in patients with type I diabetes, especially in those of age below 40.     

Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: Resistin, a peptide hormone, has been discussed controversially as a missing link between obesity and insulin resistance. In contrast to resistin mRNA expression in adipose tissue, data on human serum levels in obesity and diabetes mellitus is scarce. The physiological range of serum resistin levels, reference values or adjusted percentiles have not yet been determined, making the interpretation of serum resistin concentrations quite difficult. METHODS: Resistin serum concentrations were measured systematically by ELISA in 216 healthy controls, 555 patients with type 2 diabetes and 114 patients with type 1 diabetes. Mean values, median, and range were determined, and BMI-, gender-, and disease-adapted percentiles were calculated for all subgroups. RESULTS: Age and gender did not have any influence on resistin levels. BMI and resistin levels were positively correlated in healthy controls (p = 0.02), albeit with a weak correlation coefficient. This correlation was absent in patients with type 1 and type 2 diabetes. In both genders, healthy controls had significantly higher resistin levels than patients with type 1 and type 2 diabetes (7.9 +/- 0.2 ng/ml vs. 5.7 +/- 0.2 ng/ml and 5.5 +/- 0.1 ng/ml, respectively; p < 0.0001). There was no correlation between resistin levels and occurrence of diabetic retinopathy or nephropathy. CONCLUSIONS: Serum resistin levels can be measured by ELISA over a broad range from 0.6 ng/ml up to 27.7 ng/ml, suggesting that percentiles might be helpful in the interpretation of an individuals resistin value. While age and gender do not influence resistin levels, BMI and occurrence of diabetes have to be considered.     

Outcome of renal replacement treatment in patients with diabetes mellitus.

OBJECTIVE--To compare the outcome of renal replacement treatment in patients with diabetes mellitus and in non-diabetic patients with end stage renal failure. DESIGN--Retrospective comparison of cases and matched controls. SETTING--Renal unit, Western Infirmary, Glasgow, providing both dialysis and renal transplantation. PATIENTS--82 Diabetic patients starting renal replacement treatment between 1979 and 1988, compared with 82 matched non-diabetic controls with renal failure and 39 different matched controls undergoing renal transplantation. MAIN OUTCOME MEASURES--Patient characteristics, history of smoking, prevalence of left ventricular hypertrophy and myocardial ischaemia at start of renal replacement treatment; survival of patients with renal replacement treatment and of patients and allografts with renal transplantation. RESULTS--The overall survival of the diabetic patients during the treatment was 83%, 59%, and 50% at one, three, and five years. Survival was significantly poorer in the diabetic patients than the controls (p less than 0.001). Particularly adverse features for outcome at the start of treatment were increasing age (p less than 0.01) and current cigarette smoking (relative risk (95% confidence interval) 2.28 (0.93 to 4.84), p less than 0.05). Deaths were mainly from cardiac and vascular causes. The incidence of peritonitis in patients on continuous ambulatory peritoneal dialysis was the same in diabetic patients and controls (49% in each group remained free of peritonitis after one year), and the survival of renal allografts was not significantly worse in diabetic patients (p less than 0.5). CONCLUSIONS--Renal replacement treatment may give good results in diabetic patients, although the outlook remains less favourable than for non-diabetic patients because of coexistent, progressive vascular disease, which is more severe in older patients.     

TH1/TH2 cytokine balance in patients with both type 1 diabetes mellitus and asthma

BACKGROUND AND OBJECTIVE: T1DM and asthma are mediated by opposite arms of the cellular immune system namely T helper (Th)1 and Th2 CD4(+) cells, respectively. Our aim was to characterize the Th1/Th2 cytokine balance in patients with both T1DM and asthma. METHODS: Forty-four patients, mean age 19 years were matched by gender and age, to 4 paired groups: T1DM and asthma, asthma only, T1DM only and healthy controls. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with disease-specific recombinant antigens; glutamic acid decarboxylase and house dust mite (Der p1 antigen) for T1DM and asthma, respectively, and non-specific mitogens; phytohemaglutinin (PHA), tetanus toxin and anti-CD3 mAb. ELISPOT and ELISA technique were used to determine INF-gamma, IL-2, IL-4, IL-13 and IL-10 expression. RESULTS: Patients with T1DM and asthma demonstrated a similar cytokine pattern but lower Th1/Th2 ratio compared to patients with T1DM only. The Th2 cytokines response to Der p1 was enhanced in patients with both diseases compared to controls. The IL-10 overall secretion was higher in patients with both diseases compared to one disease only. CONCLUSION: The Th1 and Th2 secretory pattern of patients with T1DM and asthma combines features of both diseases suggesting a unique Th1/Th2 balance.     

Activated lymphocytes in patients with newly diagnosed type 1 (insulin-dependent) diabetes mellitus

The expression of activation antigens (transferrin receptor, IL-2 receptor and Ia antigen) on circulating T lymphocytes from Japanese children with Type 1 diabetes was studied using five monoclonal antibodies (Ab), OKT9, anti-Tac Ab, OKIa1, anti-human HLA-DR Ab and OKT3. For detecting Ia positive T cells, the dual staining technique using OKT3 and anti-Ia antibody was employed. Four out of six patients (67%) with newly diagnosed Type 1 diabetes showed a raised level of either OKT9 or Tac positive cells when examined at diagnosis. These patients, however, rapidly lost these activation antigens after the insulin therapy was started. In contrast, in 32 long-standing patients, only 2 (6%) had a high percentage of OKT9 positive cells and none of them demonstrated Tac positive cells. One out of six newly diagnosed patients or three out of 21 long-standing patients had a significantly high percentage of Ia-positive T cells compared with normal subjects. In poorly controlled long-standing patients whose HbA1 value was higher than 14%, none of them had an increased number of activated lymphocytes. Therefore, it is unlikely that insulin deficiency and hyperglycemia were responsible for the changes observed in these studies. Activated lymphocytes might be related to activation of the immune system involved in pathogenesis of Type 1 diabetes.     

Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus

Androgen receptor (AR) mediates a wide range of cellular processes, such as proliferation, differentiation and apoptosis. Here we sought to identify whether AR was located in pancreatic beta-cells and investigate its functions in type 1 diabetes induced by multiple low doses of streptozotocin. Double/triple immunofluorescence, Western blot and semi-quantitative RT-PCR were carried out to determine variances of AR expression in beta-cells and correlation between AR and apoptosis/proliferation of beta-cells with progress of diabetes. In addition, in vitro primary beta-cells from control mice were cultured for 3 days or 6 days with compound stimulation in order to further identify effect of AR on beta-cell apoptosis and proliferation. AR expression in beta-cells peaked in control and 1-day diabetic mice, gradually and significantly decreased, even disappeared in diabetic mice with progress of diabetes. TUNEL-positive beta-cells were concomitant with overexpression of AR, and Ki67-positive beta-cells showed extremely weak, even negative AR staining. In vitro, AR could mediate beta-cell apoptosis, and AR antagonist flutamide contributed to beta-cell proliferation. In conclusion, AR is abundantly expressed in pancreatic beta-cell cytoplasm of control mice. With progress of type 1 diabetes, decrement of AR expression in diabetic mice contributes to prohibit beta-cells from apoptosis, and is strongly associated with beta-cell proliferation.     

The challenge of type 1 diabetes mellitus

Diabetes mellitus is a heterogeneous group of diseases characterized by high blood glucose levels due to defects in insulin secretion, insulin action, or both. With the number of cases expected to increase rapidly in the years to come, diabetes is a growing health challenge worldwide. Of the approximately 16 million diabetics in the United States, about 1.5 million suffer from type 1 diabetes. In this catabolic disorder afflicting predominantly young individuals, blood insulin is almost completely absent, leading to hyperglycemia and alterations in lipid metabolism. Type 1 diabetes is thought to be induced by a toxic or infectious insult that occurs in genetically predisposed individuals. With recent advances in the understanding of the involved immunology and cellular and molecular mechanisms, researchers strive to battle the disease with new preventive and corrective strategies.     

Growth and body composition in type 1 diabetes mellitus

Over the last 50 years the prognosis for growth and pubertal development in children with type 1 diabetes mellitus (T1DM) has improved considerably. The early reports of Mauriac's syndrome were related not only to relative deficiency of insulin but also reduced caloric intake. Improved insulin delivery and liberalisation of caloric intake has resulted in improved growth, but subtle abnormalities persist. The frequently reported increased height at diagnosis may relate to prior hyperinsulinaemia and genetic background with respect to lDDM2 the insulin gene VNTR. Subsequent growth faltering is thought to be related to impairment of the GH/IGF-1 axis but children with T1DM are also more at risk of hypothyroidism and coeliac disease. At puberty, persisting abnormalities of the GH/IGF-1 axis and our inability to reverse these totally, even with intensified insulin therapy, contribute to the blunted pubertal growth in the girls but abnormal sex steroid concentrations may also be important. Intensification of insulin therapy may result in leptin resistance and excessive gains in fat mass, particularly in girls. Although it is likely that most children with T1DM will have normal final heights, this excessive weight gain in girls may lead to problems with compliance. Furthermore, hyperinsulinaemia in these subjects may also lead to ovarian hyperandrogenism, increased early risk of microvascular complications and long-term risk of cardiovascular disease.     

Blood glucose level neural model for type 1 diabetes mellitus patients

This paper deals with the blood glucose level modeling for Type 1 Diabetes Mellitus (T1DM) patients. The model is developed using a recurrent neural network trained with an extended Kalman filter based algorithm in order to develop an affine model, which captures the nonlinear behavior of the blood glucose metabolism. The goal is to derive a dynamical mathematical model for the T1DM as the response of a patient to meal and subcutaneous insulin infusion. Experimental data given by continuous glucose monitoring system is utilized for identification and for testing the applicability of the proposed scheme to T1DM subjects.     

Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus

We tested the generally accepted concept that increased gluconeogenesis (GNG) and endogenous glucose production (EGP) are the main reasons for postabsorptive hyperglycemia in patients with type 2 diabetes mellitus (T2DM). GNG was measured with the (2)H(2)O method by use of both the C5-to-C2 ratio (C5/C2, with gas chromatography-mass spectrometry) and the C5-to-(2)H(2)O ratio (C5/(2)H(2)O, with isotope ratio mass spectrometry), and EGP was measured with 3-[(3)H]glucose in 27 patients with T2DM [13 with fasting plasma glucose (FPG) >10 mM and 14 with FPG <10 mM] and in 7 weight- and age-matched nondiabetic controls. The results showed 1) that GNG could be determined accurately with (2)H(2)O by using either C5/C2 or C5/(2)H(2)O; 2) that whereas after an overnight fast of 16 h, GNG was higher in the entire group of patients with T2DM than in controls (6.4 vs. 5.0 micromol. kg(-1). min(-1) or 60.4 vs. 51.4% of EGP, P < 0.02), GNG was within normal limits (less than the mean +/- 2 SD of controls or <65.3%) in 11/14 (79%) patients with mild to moderate hyperglycemia (FPG <10 mM) and in 5/13 (38%) of patients with severe hyperglycemia (FPG 10-20 mM); 3) that elevated GNG in T2DM was associated with a 43% decrease in prehepatic insulin secretion, i.e., with hepatic insulin deficiency; and 4) that FPG correlated significantly with glucose clearance (insulin resistance) (r = 0.70) and with GNG (r = 0.50) or EGP (r = 0.45). We conclude 1) that peripheral insulin resistance is at least as important as GNG (and EGP) as a cause of postabsorptive hyperglycemia in T2DM and 2) that GNG and EGP in T2DM are increased under conditions of significant hepatic insulin deficiency and thus probably represent a late event in the course of T2DM.