Associations of blood glucose dynamics with antihyperglycemic treatment and glycemic variability in type 1 and type 2 diabetes.

AIMS: The dynamical structure of glucose fluctuation has largely been disregarded in the contemporary management of diabetes. METHODS: In a retrospective study of patients with diabetes, we evaluated the relationship between glucose dynamics, antihyperglycemic therapy, glucose variability, and glucose exposure, while taking into account potential determinants of the complexity index. We used multiscale entropy (MSE) analysis of continuous glucose monitoring data from 131 subjects with type 1 (n = 18), type 2 diabetes (n = 102), and 11 nondiabetic control subjects. We compared the MSE complexity index derived from the glucose time series among the treatment groups, after adjusting for sex, age, diabetes duration, body mass index, and carbohydrate intake. RESULTS: In type 2 diabetic patients who were on a diet or insulin regimen with/without oral agents, the MSE index was significantly lower than in nondiabetic subjects but was lowest in the type 1 diabetes group (p < 0.001). The decline in the MSE complexity across the treatment groups correlated with increasing glucose variability and glucose exposure. Statistically, significant correlations existed between higher MSE complexity indices and better glycemic control. In multivariate regression analysis, the antidiabetic therapy was the most powerful predictor of the MSE (ß = -0.940 ± 0.242, R 2 = 0.306, p < 0.001), whereas the potential confounders failed to contribute. CONCLUSIONS: The loss of dynamical complexity in glucose homeostasis correlates more closely with therapy modalities and glucose variability than with clinical measures of glycemia. Thus, targeting the glucoregulatory system by adequate therapeutic interventions may protect against progressive worsening of diabetes control.

Incidence of type 1 diabetes in childhood before and after the reunification of Germany--an analysis of epidemiological data, 1960-2006.

OBJECTIVE: To examine the impact of rapidly changing environmental factors on the incidence of type 1 diabetes mellitus (T1D). METHOD: We compared the frequency of T1D in children before and after the reunification of Germany by means of the registries of the German Democratic Republic (GDR, 1960-1989) and of Baden-Wuerttemberg (BW, 1987-2006). The number of cases of diabetes onset in East Germany after the reunification was predicted by a mathematical model. The observed incidence rate in the Eastern part of Germany after the reunification was taken from the literature 1. RESULTS: In Germany, the incidence rate of T1D in children aged 0-14 was 7.2/100 000/year (95%-CI 6.9-7.5, GDR, 1980-1987), and 10.4/100 000/year (95%-CI 9.5-11.4, BW, 1987-1994). For the whole observation period (1960-2006), the observed incidence rates y could be described by the square of a linear function [GDR: y=(1.86 + 0.040 * (year - 1960))²; r²=0.85; BW: y=(3.03 + 0.085 * (year - 1987))², r²=0.89]. The mean rise in incidence before the reunification was less than half the mean rise after the reunification (mean slope: BW 0.085, 95%-CI 0.080-0.090 vs. GDR 0.040, 95% CI 0.036-0.044). The observed incidence for East Germany after 1989 was higher than the prediction on the basis of the GDR -registry (GDR 12.3/100 000/year vs. Saxony 15.7/100 000/year, 95%-CI 14.2-17.3, n=412; 1999-2003). CONCLUSION: We conclude that the basis for the disease progress is a genetic predisposition. Environmental factors may modify changes in incidence of type 1 diabetes but do not determine the overall risk.

Model-based decision support in diabetes care.

The model-based Karlsburg Diabetes Management System (KADIS®) has been developed as a patient-focused decision-support tool to provide evidence-based advice for physicians in their daily efforts to optimize metabolic control in diabetes care of their patients on an individualized basis. For this purpose, KADIS® was established in terms of a personalized, interactive in silico simulation procedure, implemented into a problem-related diabetes health care network and evaluated under different conditions by conducting open-label mono- and polycentric trials, and a case-control study, and last but not least, by application in routine diabetes outpatient care. The trial outcomes clearly show that the recommendations provided to the physicians by KADIS® lead to significant improvement of metabolic control. This model-based decision-support system provides an excellent tool to effectively guide physicians in personalized decision-making to achieve optimal metabolic control for their patients.

Relationships between glucose variability and conventional measures of glycemic control in continuously monitored patients with type 2 diabetes.

Given the importance of glucose variability in the development of diabetic complications, the present study used continuous glucose monitoring (CGM) to determine various indices of glucose variability and to investigate their relationships with conventional measures of chronic sustained hyperglycemia. We examined 53 women and 61 men, aged 36-79 years afflicted with type 2 diabetes for 1-24 years. The following indices of glycemic variability were computed from CGM data sets: mean amplitude of glycemic excursions (MAGE), CGM glucose range, interquartile range (IQR), SD-score, and average daily risk range (ADRR). CGM measurements and self-monitored blood glucose (SMBG) records were used to calculate mean CGM sensor glucose and mean SMBG, respectively. In simple correlation analysis, the indices of glucose variability showed weak correlations with HbA1c: MAGE (r=0.27, p <0.01), CGM glucose range (r=0.21, p <0.05), IQR (r=0.31, p <0.01), SD-score (r=0.34, p<0.001), and ADRR (r=0.24, p<0.05). These indices were found to differ at identical HbA1c among several patients, as reflected by diurnal excursions of different frequency and magnitude. With the exception of ADRR, stronger correlations were found between mean SMBG and the other variability indices (r=0.51-0.63, p<0.01 for all). CGM provides various indices of glycemic variability not captured by conventional measures of glycemic control. Detection of the location and the magnitude of glucose fluctuations by CGM should aid in optimal treatment of glycemic disorders in type 2 diabetes.

Impact of cytokine- and FasL-induced apoptosis in the beta-cell line NIT-1.

Cytokine- and FasL-induced pathways contribute to beta-cell death in type 1 diabetes. It remains unclear, however, whether pro-apoptotic cyto-kines or FasL have more apoptotic impact. Cytokine- and FasL-induced apoptosis were simulated using IL-1beta/IFN-gamma, Super-FasLigand and the beta-cell line NIT-1. The role of caspases was addressed using the general caspase inhibitor ZVAD. Exposure to IL-1beta/IFN-gamma induced NIT-1 cell death. FasL augmented cytokine-induced cell death accompanied by increased caspase-3 activation, DNA fragmentation, and chromatin condensation. However, FasL mediated comparable effects on the mitochondrial transmembrane potential (Deltapsi (m)) and nitrite in cytokine- and untreated cells. The cytokine-induced sequence of apoptotic events was (1) Fas, nitrite, (2) Deltapsi (m), (3) DNA fragmentation, cell death, and (4) chromatin condensation. In the presence of FasL, cell death and chromatin condensation appeared earlier implicating a compression of the apoptotic time course. General caspase inhibition using ZVAD prevented cell death, Deltapsi (m), and DNA fragmentation; however, Fas expression and nitrite were increased. In conclusion, cytokines account for the major part of cell death induced by the simultaneously action of FasL + IL-1beta/IFN-gamma. Caspases are of central importance for beta-cell death.

Efficacy of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide (P32/98) in fatty Zucker rats with incipient and manifest impaired glucose tolerance.

AIM: Incretin enhancers are a new class of antidiabetic drugs with promising therapeutic potential for type 2 diabetes. Therapeutic intervention in prediabetes is an attractive strategy for preventing or delaying diabetes onset. The aim of the present study was to investigate the therapeutic effects of incretin enhancement on incipient impaired glucose tolerance (iIGT) and manifest IGT (mIGT) using the dipeptidyl peptidase IV (DPP-4) inhibitor P32/98- and fatty Zucker rat (ZR, fa/fa) as a model. METHODS: ZRs were classified into groups with iIGT and mIGT (n = 10 per group). P32/98 (21.61 mg/kg body weight) was administered orally to ZR with iIGT and mIGT once daily for 6 and 3 weeks respectively. Assessments included body weight, morning blood glucose and insulin, oral glucose tolerance test (oGTT; 2 g glucose/kg), plasma parameters and blood glucose day-night profile (DNP). In addition, glucose responsiveness of isolated islets and islet morphology were analysed. RESULTS: P32/98 decreased non-fasting morning blood glucose more effectively in ZR with iIGT than in ZR with mIGT. Compared with study entry, P32/98 improved DNP of blood glucose in ZR with mIGT and nearly normalized DNP in ZR with iIGT. An acute bolus of inhibitor reduced glucose load during oGTT in rats chronically treated with placebo or P32/98. In contrast to placebo-treated rats, rats receiving long-term treatment with P32/98 required less insulin during oGTT. This effect was larger in rats with iIGT vs. rats with mIGT. In isolated pancreatic islets of ZR with mIGT, treatment with P32/98 decreased pancreatic insulin content and increased glucose responsiveness, while the beta-cell volume density was unaffected. P32/98 significantly reduced triglycerides and non-esterified fatty acids. Intestinal growth was comparable between inhibitor- and placebo-treated fatty rats. CONCLUSIONS: Enhancement of incretin with the DPP-4 inhibitor P32/98 has therapeutic effects in hyperinsulinaemia, hyperglycaemia and IGT in ZR with iIGT and mIGT. Apparently, administration of P32/98 in ZR with iIGT results in more efficient beta-cell function, which is associated with less need for insulin to cope with deterioration of glucose tolerance. Importantly, P32/98 has a strong effect on dyslipidaemia in mIGT. P32/98 has no side effect on intestinal growth. Daily intake of P32/98 is a promising strategy for treatment of glucose intolerance and has the potential to prevent type 2 diabetes.

Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome.

In an attempt to more completely define the histopathologic features of the portal vein hyperperfusion or small-for-size syndrome (PHP/SFSS), we strictly identified 5 PHP/SFSS cases among 39 (5/39; 13%) adult living donor liver transplants (ALDLT) completed between 11/01 and 09/03. Living donor segments consisting of 3 right lobes, 1 left lobe, and 1 left lateral segment, with a mean allograft-to-recipient weight ratio (GRWR) of 1.0 +/- 0.3 (range 0.6 to 1.4), were transplanted without complications, initially, into 6 relatively healthy 25 to 63-year-old recipients. However, all recipients developed otherwise unexplained jaundice, coagulopathy, and ascites within 5 days after transplantation. Examination of sequential posttransplant biopsies and 3 failed allografts with clinicopathologic correlation was used in an attempt to reconstruct the sequence of events. Early findings included: (1) portal hyperperfusion resulting in portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue, which dissected into the periportal hepatic parenchyma when severe; and (2) poor hepatic arterial flow and vasospasm, which in severe cases, led to functional dearterialization, ischemic cholangitis, and parenchymal infarcts. Late sequelae in grafts surviving the initial events included small portal vein branch thrombosis with occasional luminal obliteration or recanalization, nodular regenerative hyperplasia, and biliary strictures. These findings suggest that portal hyperperfusion, venous pathology, and the arterial buffer response importantly contribute to early and late clinical and histopathologic manifestations of the small-for-size syndrome.

Improvement of glucose tolerance in Zucker diabetic fatty rats by long-term treatment with the dipeptidyl peptidase inhibitor P32/98: comparison with and combination with rosiglitazone.

AIM: The aim of this study was to investigate the effect of long-term treatment with the dipeptidyl peptidase inhibitor P32/98 and its combination with rosiglitazone on blood glucose control and islet of Langerhans histology in male Zucker diabetic fatty (ZDF) rats, when treatment begins before or after the development of overt diabetes. METHODS: ZDF rats were treated with P32/98 from the age of 9, 12 or 15 weeks. Rosiglitazone maleate was given to a separate group from the age of 13 weeks. P32/98 was given to all of these rosiglitazone-treated rats from 16 weeks of age. Rosiglitazone maleate was also given from 16 weeks of age to half the rats that were given P32/98 from 9 weeks of age. The compounds were given by oral gavage until the rats were 14 weeks old and then in the diet. The experiment was terminated at the age of 20-21 weeks. Blood glucose, plasma insulin and oral glucose tolerance were measured at intervals; islet histology was assessed terminally. RESULTS: P32/98 improved glucose tolerance after both single and multiple doses when treatment started at 9 weeks of age, also after the third week of treatment when treatment began at 12 or 15 weeks of age. P32/98 reduced daytime blood glucose when treatment began at 12 weeks. Treatment with rosiglitazone increased food intake and body weight, and after 2 weeks, reduced daytime blood glucose, water intake and the area under the glucose tolerance curve. A single dose of P32/98 markedly improved glucose tolerance in rosiglitazone-treated rats. When treatment had begun at 9 weeks of age, P32/98 stimulated insulin secretion in some glucose tolerance tests. Neither P32/98 nor rosiglitazone affected pancreatic insulin content, nor did they have clear effects on islet histology. CONCLUSION: P32/98 elicited a sustained improvement in glucose tolerance in both prediabetic and diabetic ZDF rats. The effects of P32/98 on glucose and insulin were similar to those of rosiglitazone, and in contrast to rosiglitazone, P32/98 did not increase food intake or body weight. However, neither compound was especially effective at improving diabetes in ZDF rats when treatment began at 9, 12 or 15 (P32/98) or 13 (rosiglitazone) weeks of age.

Fas ligand down-regulates cytokine-induced Fas receptor expression on insulinoma (NIT-1), but not islet cells, from autoimmune nonobese diabetic mice.

In the pathogenesis of autoimmune type 1 diabetes, the apoptosis receptor Fas appears de novo on the surface of insulin-producing beta-cells. Fas expression is thought to be induced by proinflammatory cytokines, such as IL-1beta, interferon-gamma (IFNgamma), and TNFalpha, released by islet-infiltrating mononuclear cells. To determine whether beta-cells can modulate their sensitivity to apoptosis at the level of Fas, we investigated the effect of Fas ligand (FasL) on surface expression of Fas in NIT-1 insulinoma cells from nonobese diabetic (NOD) mice prone to autoimmune diabetes and islet cells from NOD and nonautoimmune BALB/c mice. In NIT-1 insulinoma cells, Fas expression induced by the cytokine combination IL-1beta and IFNgamma was reduced in the presence of FasL, whereas in islet cells Fas expression was unaffected by FasL. The effect of FasL on NIT-1 cells was evident during and after the induction of Fas expression by IL-1beta and IFNgamma. Thus, FasL down-regulates cytokine-induced Fas expression in NOD mouse-derived NIT-1 cells, but not in NOD or BALB/c mouse islets. The ability of NIT-1 cells to down-regulate Fas receptor in response to ligation is similar to that of a variety of tumor cells, which may use this mechanism to escape destruction by cytotoxic T cells. Islets apparently cannot protect themselves against FasL-induced apoptosis by down-regulating the Fas receptor. Understanding how NIT-1 insulinoma cells down-regulate Fas receptor in response to ligation by FasL has therapeutic implications for protecting normal beta-cells in autoimmune type 1 diabetes.

Surface and intracellular Fas expression associated with cytokine-induced apoptosis in rodent islet and insulinoma cells.

During the process of insulitis in the pathogenesis of type I (insulin-dependent) diabetes mellitus, proinflammatory cytokines induce expression of the death receptor Fas on the surface of pancreatic beta-cells and thereby contribute to the enhanced susceptibility of beta-cells for apoptosis. The aim of this study was to compare cell-surface and intracellular Fas expression associated with cytokine-induced apoptosis in commonly used beta-cell models such as isolated islets and insulinoma lines derived from mouse and rat. The cell line NIT-1 responded to the interleukin (IL)-1beta+interferon (IFN)-gamma stimulus with translocation of Fas to the cell surface. Likewise, islet cells from non-obese diabetic (NOD) mice and BB/OK rats expressed increasing amounts of the Fas receptor on their surfaces after exposure to IL-1beta in combination with IFN-gamma and tumour necrosis factor-alpha. Moreover, islets obtained from BB/OK rats at an age near the onset of diabetes had an increased surface expression of Fas compared with young rats. In contrast, western blot analysis of cell lysates from cytokine-exposed islets and insulinoma cells revealed total Fas expression levels comparable to those of untreated controls. In conclusion, islets from BB/OK rats and NOD mice, in addition to NIT-1 insulinoma cells, responded to cytokine exposure with surface expression of the Fas receptor, whereas in cell lysates the levels of expression of Fas were found to be independent of cytokine exposure. Taken together, the findings indicate that cytokine-treated beta-cells might possess two pools of Fas protein, one of which is inducible by cytokines and accounts for surface Fas expression, whereas the other is constitutively expressed in cytoplasmic compartments. The underlying mechanisms, including possible interactions between these two sources of cellular Fas expression, need to be investigated in future studies.

Cell surface trafficking of Fas in NIT-1 cells and dissection of surface and total Fas expression.

The appearance of Fas receptor at the surface of pancreatic beta-cells affected by progressive insulitis strongly suggests that Fas-mediated beta-cell apoptosis plays an important role in the pathogenesis of type 1 diabetes. In support of this concept, the present study has shown that islet cells from NOD mice and the beta-cell line NIT-1 respond to the proinflammatory cytokines IL-1beta and IFN-gamma with Fas surface expression in a dose- and time-dependent manner. Moreover, the prevention of cytokine-induced surface Fas expression by actinomycin D, cycloheximide, and brefeldin A demonstrated that trafficking of Fas to the beta-cell surface requires RNA and protein synthesis and, in addition is critically dependent on intracellular protein transport. Compared with total cellular Fas protein, the amount of Fas at the cell surface was relatively small and indicated that Fas is preferentially expressed in cytoplasmic compartments of NIT-1 cells. It is concluded that inflammatory insults specifically induce translocation of Fas to the beta-cell surface and that interference with cell surface Fas expression is a new strategy to improve beta-cell survival in inflamed islets.

Peripheral arterial disease in diabetes mellitus type 1 and type 2: are there different risk factors?

BACKGROUND: Diabetic patients have increased prevalence of peripheral arterial disease (PAD). It is not clearly shown whether the prognostic factors are identical in relation to the type of diabetes. This study was done to compare the associations of PAD with risk factors and with micro- and macrovascular complications of inpatients with type 1 and type 2 diabetes. METHODS: In a retrospective cross-sectional study 1087 patients with type 1 diabetes and 1060 patients with type 2 diabetes were examined. PAD was diagnosed when ankle-brachial-pressure-index (ABI) was < 1.0. In cases with incompressible arteries (mediasclerosis) pulse wave forms were analyzed. Multivariate logistic regression analysis was applied to evaluate the impact of different variables on PAD risk, after adjusting for different variables separately. RESULTS: In both types of diabetes (type 1 vs. type 2) PAD risk (odds ratio; OR) was increased in the presence of coronary heart disease (OR 9.3 vs. 3.5), diabetic nephropathy (OR 3.0 vs. 2.8), neuropathy (OR 7.9 vs. 1.8), foot ulceration (OR 8.9 vs. 5.5), increased daily insulin requirement > 0.6 mu/kg b.w. (OR 5.2 vs. 2.9), diabetes duration of 20-29 years (OR 28.9) and > 30 years (OR 51.1) in type 1 diabetes, and diabetes duration of 10-19 years (OR 3.8) and > 20 years (OR 4.3) in type 2 diabetes. In type 2 diabetes, PAD risk was associated with microalbuminuria (OR 2.1), macroalbuminuria (OR 3.3), background retinopathy (OR 1.9), proliferative retinopathy (OR 2.8), increased triglycerides (TG) (OR 1.7) and decreased HDL-cholesterol (HDL-C > 0.90 mmol/l: OR 0.49). CONCLUSIONS: PAD risk factors and micro- and macrovascular comorbidity are very similar in type 1 and type 2 diabetes.

Maculopathy in patients with diabetes mellitus type 1 and type 2: associations with risk factors.

AIM: To examine possible relation between diabetic maculopathy and various risk factors for diabetic complications in patients with diabetes mellitus type 1 and type 2. METHODS: Cross sectional study of two cohorts of diabetic patients, comprising 1796 patients with type 1 diabetes (mean age 47 years, mean duration of diabetes 24 years) and 1563 patients with type 2 diabetes (mean age 62 years, mean duration of diabetes 16 years). Retinopathy levels (R0-RV) and maculopathy were assessed by fluorescence angiography and fundus photography and binocular biomicroscopy. Diabetic neuropathy was assessed by means of computer assisted electrocardiography and by thermal and vibratory sensory examination. Patients were classified as normoalbuminuric (<20 microg/min) or microalbuminuric (20-200 microg/min) according to their albumin excretion rates measured in urine collected overnight. Using univariate analyses, the effects of selected patient characteristics on the presence of maculopathy were evaluated. Multiple logistic regression analyses were performed to determine independent effects of risk variables on diabetic maculopathy. RESULTS: Background retinopathy (RII) was found to be present in 28% of type 1 diabetic patients and in 38% of type 2 diabetic patients. The prevalence of maculopathy in these patients was remarkably high (42% in type 1 and 53% in type 2 diabetic patients). Patients with maculopathy had significantly impaired visual acuity. Multiple logistic correlation analysis revealed that in both types of diabetes maculopathy exhibited independent associations with duration of diabetes and with neuropathy (p <0. 01); in type 1 diabetic patients there were significant associations with age at diabetes onset, serum triglyceride and total cholesterol levels (p <0.05); in type 2 diabetes with serum creatinine levels and with hypertension (p <0.05). CONCLUSIONS: Irrespective of the type of diabetes, diabetic patients with long standing diabetes have a high risk for the development of diabetic maculopathy. Diabetic maculopathy is closely associated with diabetic nephropathy and neuropathy and with several atherosclerotic risk factors which suggests that these factors might have an important role in the pathogenesis of maculopathy. However, prospective trials are necessary to evaluate the predictive value of such factors. The findings of the present cross sectional study reinforce the arguments of previous studies by others for tight control of hypertension and hyperglycaemia.

A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene.

One form of maturity-onset diabetes of the young, Type 3 (MODY3), results from mutations in the gene coding for hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor first described in the liver. MODY3 is characterized by a defective glucose-stimulated insulin secretion. Earlier observations of glycosuria with normal blood glucose levels in some MODY families suggest an additional renal manifestation of the respective genetic defect. We measured the renal threshold for glucose in five diabetic carriers of a missense mutation (Arg 272 His) in HNF-1alpha and, for comparison, in eight Type 1 diabetic patients, applying a non-invasive protocol of frequent parallel blood and urine sampling during a slow shift in blood glucose levels. We found that the mean renal threshold for glucose was lowered in the HNF-1alpha diabetic patients compared to those with Type 1 diabetes (6.5 +/- 0.9 mmol l(-1) vs 10.7 +/- 0.5 mmol l(-1); p < 0.01). This lowered glucose threshold might be an indication of an extra-pancreatic effect of HNF-1alpha gene mutations in humans. Defects in HNF-1alpha may lead to an altered tubular glucose reabsorption, possibly due to decreased expression of the renal glucose transporter proteins involved in reabsorption of glucose from the urine.

Increased prevalence of elevated urinary albumin excretion rate in type 2 diabetic patients suffering from ischemic foot lesions.

UNLABELLED: Present cross-sectional clinical study was aimed at the evaluation the prevalence of cardiovascular risk factors in Type 2-diabetics suffering from different clinical manifestations of diabetic foot lesions due to peripheral vascular disease and/or diabetic neuropathy. 1025 non-insulin-dependent (Type 2) diabetics (NIDDM) of both sexes were investigated. Patients were classified in Type II diabetes without peripheral vascular disease and foot lesions (group 0, controls), with macroangiopathic related foot lesions (group 2), with neuropathic foot lesions (group 3), and with mixed neuropathic-ischemic foot lesions (group 4). Apart from urinary albumin excretion rate (UAE), the following micro- and macroangiopathic risk factors and diseases were taken into account: Hypertension, degree of metabolic control (HbA1c), lipid concentrations, duration of diabetes, retinopathy, clinical nephropathy. RESULTS: In the total population the UAE was significantly (p < 0.01) correlated with duration of diabetes, serum creatinine, hypertension, age, lipid concentrations, HbA1c and insulin requirement. In comparison to Type II diabetic patients without peripheral vascular disease (group 0) and with neuropathic foot lesions (group 3), subjects with ischemic (group 2) and mixed neuropathic-ischemic foot lesions demonstrated an increased prevalence of pathological UAE, which was associated with a higher frequency of clinical nephropathy, retinopathy, an older age and longer duration of diabetes. It is concluded that microalbuminuria in Type 2 diabetes reflects both the existence of diabetic nephropathy and peripheral vascular disease which is often associated with the insulin resistance syndrome.

Relations between diabetic retinopathy and cardiovascular neuropathy--a cross-sectional study in IDDM and NIDDM patients.

The pathogenetic process of diabetic retinopathy and the role of different systemic risk factors in IDDM and NIDDM is not completely understood. The aim of the present cross-sectional clinical study was (1) to compare the prevalence of systemic risk factors for diabetic retinopathy in IDDM and NIDDM patients, (2) to determine relations between these risk factors and the degree of retinopathy and (3) to evaluate the relationship between retinopathy and neuropathy. The study included 1,218 IDDM and 784 NIDDM patients attending our hospital during 1994. The mean diabetes duration was 15.4 and 13.2 years, respectively. IDDM patients with proliferative retinopathy were characterized by higher mean age of 46.4 +/- 1.08 vs. 21.8 +/- 0.42 years and longer diabetes duration of 30.0 +/- 0.79 vs. 7.7 +/- 0.26 years. Among the NIDDM patients, those ones with proliferative retinopathy had the lowest mean age of 40.5 +/- 1.42 vs. 49.7 +/- 0.61 years (p < 0.01) at diabetes manifestation. There was no statistical difference between mean HbA1c concentrations in relation to retinopathy stages. Albumin excretion was increased in both IDDM and NIDDM patients with proliferative retinopathy (p < 0.01) along with increased BMI of IDDM and increased insulin requirement of NIDDM patients (p < 0.01). Multiple regression analysis showed that proliferative retinopathy with the inclusion of non-proliferative retinopathy of IDDM and NIDDM patients was significantly correlated with diabetes duration, albumin excretion, somatic and autonomic neuropathy (p < 0.01). In NIDDM patients proliferative retinopathy with the inclusion of non-proliferative retinopathy was correlated with the age at diabetes manifestation and with cholesterol levels (p < 0.05). In IDDM and NIDDM patients proliferative retinopathy was found to be correlated with somatic and autonomic neuropathy, albumin excretion (p < 0.01) and hypertension (p < 0.05). The importance of the significant correlation of autonomic neuropathy both with background and proliferative retinopathy in IDDM and NIDDM patients needs to be prospectively investigated.

Induction of islet cell surface and insulin antibodies in Balb/c mice by application of porcine insulin and Freund's adjuvant is not associated with insulitis.

To investigate whether insulin antibody (IAB) formation is associated with the appearance of islet cell cytoplasmic antibodies (ICA), islet cell surface antibodies (ICSA) and insulitis Balb/c Bln mice were immunized with porcine insulin in combination with or without Freund's adjuvant. The animals received 8 i.p. injections and were followed up to 150 days for the development of antibodies and insulitis. Mice immunized with insulin in CFA developed IAB as well as ICSA. Mice only receiving Freund's adjuvant emulsified in saline also developed ICSA. ICA were not detectable. Inflammatory infiltrates were found in the exocrine pancreatic parenchyma but not in islets. The results show that nonspecific stimulation of the immune system and the application of insulin as antigen leads to both the formation of ICSA and IAB, while insulitis was not detectable.

Primary health care of diabetic patients in a specialized outpatient setting: a DIABCARE-based analysis.

To assure health care quality requires a tool for establishing the feedback between parameters of patient management and related standards. To assess the current situation and to evaluate the DIABCARE system as a potential monitoring instrument, a retrospective study was performed in 85 randomly assigned insulin-treated patients (72% type 2) who were regularly attending the diabetes outpatient unit (total of 3,595 patients) in a township of approximately 90,000 inhabitants. 1,195 records of sequential medical visits during the years 1987 and 1990 were analyzed. -Selected results (averages in 1987 vs. 1990): (1) Visits per year 6.9 vs 7.1; (2) intensified insulin treatment in 14 vs. 27% of all patients, they were on 4.0 vs. 4.5 injections per day applying doses of 0.8 vs. 0.6 IU kg-1 d-1; (3) glycaemic control: random blood glucose 6.0 vs. 5.8 mmol/l on conventional and 6.4 vs. 5.7 mmol/l on intensified regimes, HbA1 regular measurements in 2 vs. 21% of the patients; (4) body mass index 26.4 vs. 26.6 (conventional) and 24.7 vs. 25.9 (intensified) kg/(m)2; (5) retinopathy prevalence 30 vs. 29%, in 4 vs. 29% of the patients no information; (6) nephropathy prevalence 7 vs. 11%, in 75 vs. 68% of the patients no information; (7) foot complications prevalence 6 vs. 9%, in 91 vs. 84% of the patients no pathological findings. -The DIABCARE monitor proved appropriate but too laborious. The general level of care showed a tendency towards improvement between the two investigated periods but dit not yet meet the standards which must be attained to attain the St. Vincent Declaration.

Increased prevalence of proliferative retinopathy and cardiovascular autonomic dysfunction in IDDM patients with proteinuria.

The purpose of the present cross-sectional clinical study was to evaluate the prevalence of retinopathy in Type 1 diabetic patients without nephropathy and with different degrees of nephropathy. In addition we investigated the association between retinopathy, nephropathy, and other variables, and studied the importance of cardiovascular autonomic dysfunction to these conditions. 76 Type 1 diabetic patients were investigated. All patients were initially selected on the basis of body weight, and 47 proteinuric patients were further selected for age, diabetes duration and the duration of insulin treatment (see Table 1). Proteinuric diabetic patients were categorized by degree of nephropathy, i.e. for incipient nephropathy (proteinuria of less than 0.5 g/day), for overt nephropathy (proteinuria of more than 0.5 g/day), and for renal failure (serum creatinine of more than 103 mumol/l). Retinopathy was assessed by ophthalmoscopy. Cardiovascular autonomic dysfunction (CAD) was assessed by heart rate variations, 30:15 ratios, the Valsalva maneuver, and systolic blood pressure fall upon standing. Our findings revealed increased prevalence of retinopathy in patients with more advanced stages of nephropathy. CAD abnormalities exhibited increased prevalence among proteinuric patients. Our data clearly revealed differences between proteinuric and non-proteinuric patients. In both proteinuric and non-proteinuric patients there were found correlations of retinopathy with diabetes duration, and only in proteinurics was retinopathy correlated with kidney function, systolic blood pressure and CAD findings. In patients in identical stages of nephropathy, increased prevalence of CAD abnormalities was shown in patients suffering from proliferative retinopathy. Thus our data suggest that CAD abnormalities might be related in some way to both the proliferative retinopathy and to diabetic nephropathy.

Circulating levels of placental protein 10 (PP 10) in diabetic pregnancy complicated by retinopathy.

Placental protein 10 (PP 10) is a soluble tissue antigen of the placenta. PP 10, a glycoprotein, was tested in diabetic pregnancy complicated by retinopathy. A continuous increase in PP 10 serum levels until weeks 35-36 is followed by a fall thereafter up to term. The mean of the healthy control group between 32 and 39 weeks gestation was 22 +/- 10 micrograms/l. In diabetic pregnancies complicated by retinopathy there were measured 69 +/- 24 micrograms/l in benign form and 77 +/- 26 micrograms/l in proliferative form. Both of these values are significantly (p less than 0.05) above the control values. Increased PP 10 levels in diabetic pregnancy complicated by retinopathy are probably caused by placental and amniotic leakages.