Cysteine Prevents the Development of Experimental Diabetes Induced by Zinc-Binding Substances.

In experimental rabbits, cysteine injected intravenously in a dose of 1000 mg/kg temporarily bound zinc in ß cells and prevented the formation of chelate zinc complexes in response to subsequent injection of diabetogenic zinc-binding substances that induce cell destruction. Injection of cysteine to animals was associated with a sharply negative reaction to zinc in ß cells, which attests to blockade of zinc ions. Injection of cysteine few minutes after dithizone and formation of zinc-dithizone complex was followed by displacement of dithizone from the complex and prevented the development of diabetes in most animals. The most plausible mechanism of preventive effect of cysteine is the formation of 2:1 zinc-cysteine complex in ß cells with possible fixation of Zn atom between sulfur atoms from SH groups of two cysteine molecules.

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.

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.

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.

Insulin treatment improves islet function in type 2 diabetic Chinese hamsters.

To study whether normalization of hyperglycemia improves islet function in long-standing type 2 diabetes, hyperglycemic CHIG/Han subline of the genetic type 2 diabetic Chinese hamster (>15 mmol/l: n=23) were either treated with insulin implants (liberating 1 U/day) or vehicle for two weeks. Islets were isolated and incubated for 3 h in the presence of 10 mmol/l glucose with or without 0.1 mmol/l 3-isobutyl-1-methylxanthine (IBMX). Specimens were also taken for immunocytochemical analysis of insulin cells. Glucose-stimulated insulin secretion was reduced by 83% in the vehicle-treated diabetic hamsters compared to non-diabetic controls (p<0.001). This impairment was not improved by the two-week insulin treatment. IBMX potentiated glucose-stimulated insulin secretion; this effect was markedly reduced in vehicle-treated diabetics compared to controls (p<0.001). In fact, the linear relation between IBMX-potentiated and glucose-stimulated insulin secretion in controls was absent in islets from diabetic animals. The two week insulin treatment normalized this relation, although still the total insulin secretory response to IBMX and glucose was lower than in controls. Furthermore, the islet insulin content was significantly increased by the 2 week normalization of glucose and, finally, the severe degranulation and lowering of insulin staining in islet beta cells in diabetic animals were markedly improved by insulin treatment. The results suggest that two-weeks of normalization of glycemia in long-standing type 2 diabetes in non-obese Chinese hamster improves beta cell signaling induced by the cyclic AMP pathway in conjunction with improved islet insulin content and beta cell morphology.

Importance of decreased intracellular phosphate and magnesium concentrations and reduced ATPase activities in spontaneously hypertensive rats.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto (WKY) rats, and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.90+/-0.15 g/kg dry weight in SHRs versus 1.15+/-0.10 g/kg dry weight in WKY rats (p<0.05). Vascular smooth muscle phosphate content was 23.6+/-0.79 g/kg dry weight in WKY rats versus 15.81+/-1.22 g/kg dryweight in SHRs (p<0.01). In seven animals, erythrocytic ATP content was 180.2+/-102 in SHRs vs. 432+/-72 micromol/L cells in WKY rats (p< 0.01). The Na+/K+-ATPase activity was significantly decreased in hypertensive animals as compared to controls (6.49+/-2.3 vs. 12.64+/-2.9 nmol inorganic phosphate/mg protein/min (p< 0.01)). Aortic smooth muscle cells from SHRs are characterized by markedly lowered cellular phosphate and magnesium concentrations and an altered ATP metabolism, possibly due to a membrane defect or a magnesium deficit in hypertensive cells.

Islet graft-induced changes of beta-hydroxybutyrate dehydrogenase and glucose-6-phosphatase activity in liver cells of diabetic recipient rats.

It is known that the liver is a favourable site for implantation of pancreatic islets since the grafted islets remain metabolically intact and provide long-term normoglycemia in diabetic animals. However, the long-term effects exerted by the grafted tissue on the host organ are not well defined. We therefore investigated by light and electron microscopy the effects of syngeneic islets on the host organ after intraportal transplantation into the liver of streptozotocin (STZ)-induced diabetic LEW.1W rats. In addition, tissue sections of graft-bearing liver were stained by enzyme histochemical methods for beta-hydroxybutyrate dehydrogenase (HBDH) and glucose-6-phosphatase (G6Pase). At 12 weeks after transplantation, the changes seen in the hepatocytes surrounding the grafted islets were hyperproliferation and accumulation of glycogen. Hepatocytes adjacent to the implanted islets displayed increased HBDH activity, whereas G6Pase activity was variable, either decreased or increased. Increased HBDH activity was also observed in the periportal region and in liver cells extending to the central veins. The results demonstrate that intraportal islet grafts, in addition to normalizing glucose homeostasis, exert remarkable effects on the liver parenchyma of experimentally diabetic recipient rats.

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.

In search of the language switch: An fMRI study of picture naming in Spanish-English bilinguals.

For many years, researchers investigating the brain bases of bilingualism have concentrated on two basic questions. The first concerns the nature of language representation. That is, are a bilinguals' two languages represented in distinct or overlapping areas of the brain. The second basic question in the neuropsychology of bilingualism concerns the neural correlates of language switching, that is, the areas that are active when bilinguals switch from one language to the other. Performance between single-language and dual-language picture naming was compared in a group of six Spanish-English bilinguals using behavioral measures and functional magnetic resonance imaging. Participants showed slower reaction times and increased activation in the dorsolateral prefrontal cortex in the mixed language condition relative to single language condition. There was no evidence that each language was represented in different areas of the brain. Results are consistent with the view that language switching is a part of a general executive attentional system and that languages are represented in overlapping areas of the brain in early bilinguals.

Balancing bilinguals: lexical-semantic production and cognitive processing in children learning Spanish and English.

The present study investigated developmental changes in lexical production skills in early sequential bilinguals, in both Spanish (L1) and English (L2), exploring the effects of age, years of experience, and basic-level cognitive processing (specifically the ability to resist interference) within a timed picture-naming task. To assess resistance to interference, naming was compared in low competition (blocked-single language) vs. high competition (mixed-alternating language) conditions. Participants were 100 individuals, 20 at each of 5 different age levels (5-7, 8-10, 11-13, 14-16, & young adults). All had learned Spanish as a first language in the home, with formal English experience beginning at 5 years. Gains were made in both languages across age. However, there was a developmental crossover from Spanish dominance in the youngest children, through a period of relatively balanced Spanish and English skills in middle childhood, culminating in a clear pattern of English dominance among adolescents and young adults. Although all groups experienced a greater slowing of response times in the mixed-language condition relative to the blocked-language condition, developmental changes in the pattern of speed-accuracy trade-offs in the mixed condition can be interpreted to reflect a change in the ability to resist cognitive interference during word production.

Islet neuronal abnormalities associated with impaired insulin secretion in type 2 diabetes in the Chinese hamster.

This study examined the relationship between islet neurohormonal characteristics and the defective glucose-stimulated insulin secretion in genetic type 2 diabetic Chinese hamsters. Two different sublines were studied: diabetes-prone CHIG hamsters and control CHIA hamsters. The CHIG hamsters were divided into three subgroups, depending on severity of hyperglycemia. Compared to normoglycemic CHIG hamsters and control CHIA hamsters, severely hyperglycemic CHIG hamsters (glucose > 15 mmol/l) showed marked glucose intolerance during i.p. glucose tolerance test and 75% impairment of glucose-stimulated insulin secretion from isolated islets. Mildly hyperglycemic CHIG animals (glucose 7.2-15 mmol/l) showed only moderate glucose intolerance and a 60% impairment of glucose-stimulated insulin secretion from the islets. Immunostaining for neuropeptide Y and tyrosine hydroxylase (markers for adrenergic nerves) and for vasoactive intestinal peptide (marker for cholinergic nerves) revealed significant reduction in immunostaining of islets in the severely but not in the mildly hyperglycemic animals, compared to control CHIA hamsters. The study therefore provides evidence that in this model of type 2 diabetes in Chinese hamsters, severe hyperglycemia is accompanied not only by marked glucose intolerance and islet dysfunction but also by reduced islet innervation. This suggests that islet neuronal alterations may contribute to islet dysfunction in severe but not in mild diabetes.

Relationship between the histopathology of the endocrine-exocrine pancreas parenchyma and beta-cell function in the Chinese hamster CHIG/Han subline.

To investigate pancreatic histopathology in relation to islet function in type 2 diabetes, pancreatic tissue was examined at disease onset and after death in the genetically diabetic Chinese hamster CHIG/Han subline. The pancreatic islets displayed vacuolation, intraislet fibrosis, variable stages of degranulation, and beta-cell necrosis, but no insulitis. These lesions were associated with changes in immunostaining of major islet peptides, impaired glucose-stimulated (10 mM) insulin secretion, reduced islet insulin content, and the severity of hyperglycemia. The exocrine pancreas was characterized by peri- and intrapancreatic fat and mononuclear cell infiltration. Biopsy of the pancreas had a marked effect on plasma glucose such that at 2 weeks after excision, in 9 and 18% of the severely hyperglycemic hamsters, plasma glucose levels decreased to <7.2 and 15 mM, respectively, and 45% of the mildly hyperglycemic hamsters became transiently normoglycemic (<7.2 mM). The results showed that insulitis is not involved in beta-cell failure of diabetic CHIG/Han hamsters. Vacuolation of islets was the most prominent lesion associated with a functional islet abnormality and development of hyperglycemia. Attenuation of hyperglycemia after biopsy suggests that the pancreas, in type 2 diabetes, maintains the ability to respond to impairment with amelioration of the diabetic state.

Bilingual performance on the boston naming test: preliminary norms in Spanish and English.

A total of 100 young educated bilingual adults were administered the Boston Naming Test (BNT) (Kaplan, Goodglass, & Weintraub, 1983) in both Spanish and English. Three group performance scores were obtained: English only, Spanish only, and a composite score indicating the total number of items correctly named independent of language. The scores for the entire group were significantly greater in English than in Spanish. An additional set of analyses explored individual differences in picture naming performance across the two languages as measured by the BNT. For a subset of the larger group (n = 25) there were significant differences in composite over single language scoring, but no significant differences between Spanish and English. Item analyses of correct responses were conducted in both languages to explore the construct validity of the standardized administration of the BNT with this population. There was much greater variability in responses over the Spanish items for this bilingual group. The results of a correlation analysis of information obtained from the initial questionnaire with the BNT scores in each language is also reported. The practical implications of this preliminary bilingual BNT normative data are discussed.

Glucose tolerance and insulin secretion in children before and during recombinant growth hormone treatment.

This study evaluates glucose metabolism and insulin secretion in children with Ullrich-Turner syndrome (UTS), chronic renal failure (CRF) and kidney transplantation (KTx) with rh GH therapy using an intravenous glucose infusion test. Before treatment, glucose AUC was significantly increased in all patient groups when compared to normal controls. Both the early and second phases of insulin secretion were not altered. During treatment, elevated glucose AUC showed a further increase in patients with KTx but not in patients with CRF or UTS. Both the early and second insulin secretion phases rose significantly in UTS and were transiently elevated after 6 and 12 months of therapy in patients with CRF and KTx. We conclude that growth hormone therapy aggravates alteration of glucose metabolism in patients with KTx and not in children with CRF and UTS. Progressive hyperinsulinemia occurred only in patients with UTS.

[Recurrence of a stage IV neuroblastoma]. / Rezidiv eines Neuroblastoms Stadium IV.

In the follow-up of metastatic neuroblastoma mIBG scintigraphy represents the very diagnostic method. A case report of a child with a metastatic recurrence of neuroblastoma is given. Despite clear scintigraphic visualisation serum parameters remained negative. The role of additional bone scintigraphy is inconclusive even retrospectively.

Glucose transporter isoform (GLUT) 2 expression in beta-cells of long-term syngeneic islet grafts.

Syngeneic islets were transplanted into the liver of streptozotocin (STZ)-induced diabetic LEW.1W rats, and the expression of the glucose transporter isoform GLUT 2, an essential component of the glucose-sensing mechanism of the pancreatic beta-cell, was determined in the grafted islet tissue. Graft-bearing liver was obtained 12, 36, and 60 weeks after transplantation, and tissue sections were immunoperoxidase stained for GLUT 2 and major islet peptides. Islet cell aggregates of different sizes were found in the portal tract and in juxtaposition to the hepatocytes. At all time points, beta-cells in the grafts displayed GLUT 2 expression comparable to that of islets in nondiabetic rats. Islet cells containing immunoreactive insulin and islet amyloid polypeptide were plentiful, while those staining positive for glucagon and somatostatin were scarce in these grafts. The results show that beta-cells in islets engrafted in the liver, although initially exposed to chronic hyperglycemia, have the capability of stably expressing GLUT 2 over long-term periods.

[Follow up control of stage IV neuroblastoma: 123I-MIBG scintigraphy, bone scintigraphy and catecholamine metabolites]. / Verlaufskontrolle des Neuroblastoms Stadium IV: 123I-mIBG-Szintigraphie, Knochenszintigraphie und Katecholaminmetabolite.

AIM: The diagnostic value of 123I-mIBG-scintigraphy, bone scintigraphy and catecholamine metabolites in the follow up of neuroblastoma stage IV will be evaluated. METHODS: Nineteen children suffering from neuroblastoma were analysed retrospectively by 123I-mIBG-scintigraphy, bone scintigraphy and measurement of homovanillic acid, vanillic acid, neuronspecific enclose, lactate dehydrogenase, and ferritine. Follow up was 7-132 (median 36) months. RESULTS AND CONCLUSION: The significance of the methods was dependent on the time of diagnostic use. In principal, 123I-mIBG-scintigraphy has the highest diagnostic impact. For initial staging and diagnosis of recurrence a combination of all three methods can be used. On the contrary, follow up during chemotherapy is best documented by 123I-mIBG-scintigraphy, whereas bone scintigraphy is of limited and measurement of catecholamine metabolites of less diagnostic value.

Alterations in erythrocyte plasma membrane ATPase activity and adenine nucleotide content in a spontaneously diabetic subline of the Chinese hamster.

The CHIG/Han subline of the Chinese hamster develops noninsulin-dependent diabetes mellitus characterized by hyperinsulinemia and different degrees of glucose intolerance. To study whether these abnormalities could affect transmembrane cation transport activity, we determined membrane ATPase activity and ATP concentrations in red blood cells of diabetes-resistant CHIA and diabetes-susceptible CHIG sublines of the Chinese hamster. Mg(2+)-ATPase activity was increased in red blood cell membranes of diabetic hamsters compared with that of nondiabetic CHIG and the diabetes-resistant CHIA animals and correlated with plasma triglyceride and cholesterol levels. Ca(2+)-ATPase and Na+/K+ATPase activity were not significantly different between diabetic and nondiabetic hamsters, but for the Na+/K(+)-ATPase, Km was decreased and the Vmax value increased in membrane preparations from severely diabetic hamsters. Both ATP and ADP content were lower in erythrocytes from diabetic than nondiabetic hamsters. Independently of the levels of glycemia, AMP concentrations were higher in CHIG than in CHIA hamsters. While ATP/AMP ratios were found to be decreased in erythrocytes from diabetes-susceptible CHIG hamsters compared to the diabetes-resistant CHIA animals, they were significantly correlated with the levels of glycemia. Furthermore, the relationship between blood glucose levels and kidney weight in hamsters of the diabetes-susceptible CHIG subline was such, that severely hyperglycemic animals displayed the greatest increase in kidney wet weight. These results indicate that the progressive metabolic deterioration in the development of noninsulin-dependent diabetes is associated with significant changes in the activity and kinetic parameters of cellular ATPases which could probably indicate early membrane alterations which may eventually result in the late microangiopathic complications of diabetes.