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Policies in sunny countries, such as those in the Mediterranean area, do not promote vitamin D supplementation despite some studies might suggest the high prevalence of sub-optimal levels. The objective was to determine the vitamin D levels by 25-hydroxyvitamin D (25(OH)D) of a Mediterranean population and their characteristics. This population-based study included a database of public health system from all individuals living in Catalonia > 18 years who had some measure of 25(OH)D between January 2018 and April 2021. More than half million people were classified based on 25(OH)D measurements to study their characteristics. Three vitamin D categories were created: < 20 ng/ml deficiency, 20–30 ng/ml insufficiency and > 30 ng/ml optimal. Less than 10% of the population residing in Catalonia had recent 25(OH)D determinations and the majority of determinations were in ≥ 45 years and in women. Around 80% of young people with determination had sub-optimal levels but the prevalence of vitamin D supplementation prescription increased with age which was associated with better values of 25(OH)D. In a Mediterranean area 25(OH)D determinations were low despite the high prevalence of suboptimal levels in the population with recent determination. In addition, the measurements were especially concentrated in people ≥ 45 years of age and in women who were, in addition, the groups to whom the most vitamin D supplementation was prescribed. On the contrary, young people presented few determinations of 25(OH)D and, although majority of them showed sub-optimal levels, vitamin D supplementation was not prescribed in most cases. [ABSTRACT FROM AUTHOR]

Our aim was to evaluate whether fatty liver index (FLI) is associated with the risk of type 2 diabetes (T2DM) development within the Spanish adult population and according to their prediabetes status; additionally, to examine its incremental predictive value regarding traditional risk factors. A total of 2260 subjects (Prediabetes: 641 subjects, normoglycemia: 1619 subjects) from the Di@bet.es cohort study were studied. Socio-demographic, anthropometric, clinical data and survey on habits were recorded. An oral glucose tolerance test was performed and fasting determinations of glucose, lipids and insulin were made. FLI was calculated and classified into three categories: Low (< 30), intermediate (30–60) and high (> 60). In total, 143 people developed diabetes at follow-up. The presence of a high FLI category was in all cases a significant independent risk factor for the development of diabetes. The inclusion of FLI categories in prediction models based on different conventional T2DM risk factors significantly increase the prediction power of the models when all the population was considered. According to our results, FLI might be considered an early indicator of T2DM development even under normoglycemic condition. The data also suggest that FLI could provide additional information for the prediction of T2DM in models based on conventional risk factors. [ABSTRACT FROM AUTHOR]

Our aim was to determine the incidence of type 2 diabetes mellitus in a nation-wide population based cohort from Spain (di@bet.es study). The target was the Spanish population. In total 5072 people older than 18 years,were randomly selected from all over Spain). Socio-demographic and clinical data, survey on habits (physical activity and food consumption) and weight, height, waist, hip and blood pressure were recorder. A fasting blood draw and an oral glucose tolerance test were performed. Determinations of serum glucose were made. In the follow-up the same variables were collected and HbA1c was determined. A total of 2408 subjects participated in the follow-up. In total, 154 people developed diabetes (6.4% cumulative incidence in 7.5 years of follow-up). The incidence of diabetes adjusted for the structure of age and sex of the Spanish population was 11.6 cases/1000 person-years (IC95% = 11.1–12.1). The incidence of known diabetes was 3.7 cases/1000 person-years (IC95% = 2.8–4.6). The main risk factors for developing diabetes were the presence of prediabetes in cross-sectional study, age, male sex, obesity, central obesity, increase in weight, and family history of diabetes. This work provides data about population-based incidence rates of diabetes and associated risk factors in a nation-wide cohort of Spanish population. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Recent studies have shown the anti diabetic effects of oral sodium tungstate treatment in several animal models of diabetes based on short-term experiments. In this study, we examined the effectiveness of long-term tungstate treatment of streptozotocin-induced-diabetic rats. Methods. Tungstate was administered to the drinking water of rats for eight months. Results. The treatment resulted in a reduction in serum glucose concentrations in diabetic rats, but no change in glycaemia was detected in healthy rats. Alterations in the hepatic glucose metabolism due to diabetes were almost completely counteracted by tungstate treatment. The partial recovery of glucokinase activity, not found in diabetic animals, normalised glycogen and glucose 6-phosphate concentrations. Tungstate treatment also restored pyruvate kinase activity and fructose 2,6-bisphosphate concentrations. In healthy rats, tungstate treatment did not modify the majority of the hepatic parameters studied. Moreover, tungstate treatment prevented diabetes-induced morphological changes in the kidney and ocular lens and also reduced mortality. Furthermore, no hypoglycaemic episodes or undesirable side effects were observed in treated diabetic or healthy rats. In addition, there is no evidence of intolerance developing after prolonged use. Conclusion/interpretation. Tungstate could play a helpful part in the long-term treatment of diabetes. [Diabetologia (2001) 44: 507–513] [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) have been traditionally implicated in cancer progression because of their ability to degrade the extracellular matrix. However, some members of the MMP family have recently been identified as proteases with antitumor properties. Thus, it has been described that collagenase-2 (MMP-8) has a protective role in tumor and metastasis progression, but the molecular mechanisms underlying these effects are unknown. We show herein that Mmp8 expression causes a decrease in miR-21 levels that in turn leads to a reduction in tumor growth and lung metastasis formation by MDA-MB-231 (4175) breast cancer cells. By using both in vitro and in vivo models, we demonstrate that the mechanism responsible for these MMP-8 beneficial effects involves cleavage of decorin by MMP-8 and a subsequent reduction of transforming growth factor β (TGF-β) signaling that controls miR-21 levels. In addition, miR-21 downregulation induced by MMP-8 increases the levels of tumor suppressors such as programmed cell death 4, which may also contribute to the decrease in tumor formation and metastasis of breast cancer cells overexpressing this metalloproteinase. These findings reveal a new signaling pathway for cancer regulation controlled by MMP-8, and contribute to clarify the molecular mechanisms by which tumor-defying proteases may exert their protective function in cancer and metastasis. [ABSTRACT FROM AUTHOR]

Background:Despite the marked increase in cardiovascular risk factors in Spain in recent years, the prevalence and incidence of cardiovascular diseases have not risen as expected. Our objective is to examine the association between consumption of olive oil and the presence of cardiometabolic risk factors in the context of a large study representative of the Spanish population.Subjects and methods:A population-based, cross-sectional, cluster sampling study was conducted. The target population was the whole Spanish population. A total of 4572 individuals aged 18 years in 100 clusters (health centers) were randomly selected with a probability proportional to population size. The main outcome measures were clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, body mass index, waist, hip and blood pressure) and oral glucose tolerance test (OGTT) (75 g).Results:Around 90% of the Spanish population use olive oil, at least for dressing, and slightly fewer for cooking or frying. The preference for olive oil is related to age, educational level, alcohol intake, body mass index and serum glucose, insulin and lipids. People who consume olive oil (vs sunflower oil) had a lower risk of obesity (odds ratio (OR)=0.62 (95% confidence interval (CI)=0.41-0.93, P=0.02)), impaired glucose regulation (OR=0.49 (95% CI=0.28-0.86, P=0.04)), hypertriglyceridemia (OR=0.53 (95% CI=0.33-0.84, P=0.03)) and low HDL cholesterol levels (OR=0.40 (95% CI=0.26-0.59, P=0.0001)).Conclusions:The results show that consumption of olive oil has a beneficial effect on different cardiovascular risk factors, particularly in the presence of obesity, impaired glucose tolerance or a sedentary lifestyle. [ABSTRACT FROM AUTHOR]

AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1-/-)mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult (Rkip1-/-) mice after streptozotocin treatment. RESULTS: (Rkip1-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult (Rkip1-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation. Methods: A population-based, cross-sectional, cluster sampling study was carried out, with target population being the entire Spanish population. Five thousand and seventy-two participants in 100 clusters (health centres or the equivalent in each region) were randomly selected with a probability proportional to population size. Participation rate was 55.8%. Study variables were a clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, BMI, waist and hip circumference, blood pressure) and OGTT (75 g). Results: Almost 30% of the study population had some carbohydrate disturbance. The overall prevalence of diabetes mellitus adjusted for age and sex was 13.8% (95% CI 12.8, 14.7%), of which about half had unknown diabetes: 6.0% (95% CI 5.4, 6.7%). The age- and sex-adjusted prevalence rates of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG-IGT were 3.4% (95% CI 2.9, 4.0%), 9.2% (95% CI 8.2, 10.2%) and 2.2% (95% CI 1.7, 2.7%), respectively. The prevalence of diabetes and impaired glucose regulation increased significantly with age ( p < 0.0001), and was higher in men than in women ( p < 0.001). Conclusions/interpretation: The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Pancreatic beta cell hyperactivity is known to occur in obesity, particularly in insulin-resistant states. Our aim was to investigate whether changes in neuronal nitric oxide synthase (nNOS) function affect beta cell compensation in two relevant models: the Zucker fa/ fa rats and pancreatic islets from obese humans. Methods: Glucose-induced insulin response was evaluated in the isolated perfused rat pancreas and in human pancreatic islets from obese individuals. Expression of nNOS (also known as NOS1) and subcellular localisation of nNOS were studied by quantitative RT-PCR, immunoblotting, immunofluorescence and electron microscopy. Results: Pancreatic beta cells from Zucker fa/ fa rats and obese individuals were found to be hyper-responsive to glucose. Pharmacological blockade of nNOS was unable to modify beta cell response to glucose in fa/ fa rats and in islets from obese individuals, suggesting an abnormal control of insulin secretion by the enzyme. In both cases, nNOS activity in islet cell extracts remained unchanged, despite a drastic increase in nNOS protein and an enhancement in the dimer/monomer ratio, pointing to the presence of high amounts of catalytically inactive enzyme. This relative decrease in activity could be mainly related to increases in islet asymmetric dimethyl-arginine content, an endogenous inhibitor of nNOS activity. In addition, mitochondrial nNOS level was decreased, which contrasts with a strongly increased association with insulin granules. Conclusions/interpretation: Increased nNOS production and dimerisation, together with a relative decrease in catalytic activity and relocalisation, are involved in beta cell hyperactivity in insulin-resistant rats but also in human islets isolated from obese individuals. [ABSTRACT FROM AUTHOR]

Transmembrane protein 27 (TMEM27) is a membrane protein cleaved and shed by pancreatic beta cells that has been proposed as a beta cell mass biomarker. Despite reports of its possible role in insulin exocytosis and cell proliferation, its function in beta cells remains controversial. We aimed to characterise the function of TMEM27 in islets and its potential use as a beta cell mass biomarker. To determine TMEM27 function, we studied TMEM27 gene expression and localisation in human healthy and diabetic islets, the correlation of its expression with cell cycle and insulin secretion genes in human islets, its expression in tungstate-treated rats, and the effects of its overproduction on insulin secretion and proliferation in a beta cell line and islets. To elucidate its utility as a beta cell mass biomarker, we studied TMEM27 cleavage in a beta cell line, islets and primary proximal tubular cells. TMEM27 mRNA levels in islets are lower in diabetic donors than in controls. Its gene expression correlates with that of insulin and SNAPIN in human islets. TMEM27 expression is downregulated in islets of tungstate-treated rats, which exhibit decreased insulin secretion and increased proliferation. TMEM27 overproduction in a beta cell line and islets significantly enhanced glucose-induced insulin secretion, with modest or no effects on proliferation. Finally, TMEM27 is cleaved and shed by renal proximal tubular cells and pancreatic islets. Our data support a role for TMEM27 in glucose-induced insulin secretion but not in cell proliferation. The finding that its cleavage is not specific to beta cells challenges the current support for its use as a potential beta cell mass biomarker. [ABSTRACT FROM AUTHOR]

Objective:We have recently shown the in vivo anti-obesity effects of sodium tungstate. In this study, we investigate the in vitro effects of sodium tungstate on adipocyte differentiation and function.Methods:3T3-F442A cells were allowed to differentiate in the presence of sodium tungstate, and were analyzed for triglyceride (TG) accumulation, adipocyte differentiation and mitochondrial oxygen consumption.Results:Sodium tungstate treatment of adipose cells decreased TG accumulation and adipocyte differentiation. Expression of key genes for adipocyte function (aP2, ACC, fatty acid synthase (FAS) and lipoprotein lipase (LPL)) and differentiation (CCAAT enhancer-binding protein (C/EBP)α and peroxisome proliferator-activated receptor gamma (PPARγ)) was reduced by sodium tungstate, whereas C/EBPβ isoform LIP expression level was increased. TG accumulation and changes in C/EBPβ expression were partially recovered by inactivating the erk1/2 pathway. Finally, tungstate treatment increased the oxygen consumption of adipose cells without changes in the expression of oxidative genes.Conclusions:Sodium tungstate inhibits adipocyte differentiation by promoting the translation of LIP, a master dominant-negative regulator of this process, and regulates the mitochondrial oxygen consumption of adipose cells. These effects contribute to the anti-obesity activity of sodium tungstate and confirm its potential as a powerful alternative for the treatment of obesity.International Journal of Obesity (2009) 33, 534–540; doi:10.1038/ijo.2009.34; published online 3 March 2009 [ABSTRACT FROM AUTHOR]

To investigate the mechanism by which human islet amyloid polypeptide (hIAPP) fibril formation results in calcium influx across the plasma membrane of pancreatic beta cells, and its association with apoptosis. Cytoplasmic intracellular calcium concentrations ([Ca2+]i) were monitored for 2 h as the 340/380 nm fluorescence ratio in fura-2 loaded cells of the MIN6 mouse pancreatic beta cell line. Cell morphology was evaluated by transmission electron microscopy, and viability by FACS. hIAPP (10 μmol/l) increased [Ca2+]i in 21% of MIN6 cells in standard buffer, and in 8% of cells in Na+-free buffer. Transient receptor potential (TRP) channel inhibitors (gadolinium and ruthenium red) prevented the [Ca2+]i rise under both conditions, whilst nifedipine was only effective in the presence of Na+. hIAPP increased apoptosis in both insulinoma cells and islets in primary culture, and cell viability was partially rescued by ruthenium red ( p < 0.001). By RT-PCR, we detected expression of the mechanosensitive TRP cation channel subfamily V member 4 ( Trpv4) in MIN6 cells and mouse pancreas. Small interference RNA against Trpv4 prevented hIAPP-induced [Ca2+]i rises, decreased hIAPP-triggered expression of the endoplasmic reticulum (ER) stress response, and reduced hIAPP-triggered cell death by 50% ( p < 0.05). Alterations in [Ca2+]i play a key role in hIAPP-induced beta cell cytotoxicity. By electron microscopy, we detected extracellular hIAPP aggregates adjacent to irregular invaginated regions of the plasma membrane. We propose that TRPV4 channels may sense physical changes in the plasma membrane induced by hIAPP aggregation, enabling Ca2+ entry, membrane depolarisation and activation of L-type Ca2+ channels. Decreasing the activity of TRPV4 prevented hIAPP-induced [Ca2+]i changes, reduced hIAPP-triggered ER stress and improved cell viability. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes. Materials and methods: RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA1c 7.1–9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA1c of ≤7.0%. If confirmed HbA1c rises to ≥8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open. Results: Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%). Conclusions/interpretation: The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We evaluated in a double-blind study the effect of early treatment with the immunomodulatory drug fusidin in patients with newly diagnosed type 1 diabetes mellitus. Methods: Twenty-eight adults with newly diagnosed type 1 diabetes were included in the study. The patients were randomly assigned (computer-generated random number sequence) to two experimental groups. Patients allocated to the fusidin (FUS) group (n=15) received sodium fusidate (fusidin; 500 mg orally three times daily for 4 weeks). Subsequently the drug was given at the same dose and scheduled for two consecutive weeks a month followed by 2 weeks a month without the drug for 20 weeks. Subjects allocated to the placebo (PCB) group (n=13) received placebo according to the same schedule and conditions described for sodium fusidate in the FUS group. All patients received a diet adjusted to their age and BMI, and intensive insulin therapy. Results: There were no statistically significant differences between the FUS and PCB groups in beta cell function, evaluated by basal and glucagon-stimulated C-peptide values during the follow-up (24 and 48 weeks). There was also no difference between the two groups in insulin requirement after 48 weeks (0.4±0.2 and 0.4±0.2 U/kg body weight for the FUS and PCB groups, respectively). Antibody titres, including insulin autoantibodies, were similar in the two groups during the follow-up. Conclusions/interpretation: Early treatment of newly diagnosed type 1 diabetes patients with intermittently administered fusidin failed to influence the natural course of the disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE:To investigate whether the association between the metabolic syndrome (MS) and cardiovascular disease (CVD) in obese adults is influenced by the criteria used to diagnose the MS.DESIGN AND SUBJECTS:Cross-sectional study in 389 obese adults (male/female: 26%/74%; body mass index (BMI): 30.1-63.2?kg/m2; age: 18-79?y).MEASUREMENTS:To diagnose the MS by the WHO or the ATPIII criteria, body mass index, waist circumference, fasting and 2-h oral Glucose tolerance test plasma glucose, fasting plasma triglycerides and HDL cholesterol, systolic and diastolic blood pressure, 24-h albumin excretion, and fasting insulin were measured. The association between the MS diagnosed with either definition and self-referred CVD was investigated.RESULTS:The prevalence of the MS by the WHO was higher than by the ATPIII criteria (WHO 69.1%, ATPIII 49.4%; P<0.001). The MS diagnosed by the WHO criteria was significantly associated with self-referred CVD (odds ratio (OR) 5.80, 95%CI 1.35-24.95, P<0.05), whereas the ATPIIII MS was not (OR 1.34, 95%CI 0.59-3.03). An elevated blood pressure (OR 5.04, 95%CI 1.41-18.01, P<0.05) and microalbuminuria (OR 2.61, 95%CI 1.06-6.40, P<0.05) were independently associated with CVD. Consideration of the OGTT data as part of the ATPIII MS definition improved its associations with CVD (OR 4.39, 95%CI 1.29-14.94, P<0.05).CONCLUSION:The WHO criteria appear to identify a greater number of obese adults at risk for CVD. Nevertheless, the addition of an OGTT at least in nondiabetic patients with two ATPIII-defined metabolic risk factors may help to improve the association between the MS and CVD in obese adults.International Journal of Obesity (2005) 29, 668-674. doi:10.1038/sj.ijo.0802921 Published online 8 March 2005 [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Mutations in the islet amyloid polypeptide (IAPP) gene may play a potential role in the abnormal regulation or expression of the peptide. The aim of this study was to determine the functional role of the -132 G/A mutation reported in the promoter region of the IAPP gene in a population of Spanish Type 2 diabetic patients. Methods. We investigated the transcriptional activity using MIN6 cells and luciferase reporter plasmids in several culture conditions. Key regulatory elements of the IAPP promoter region were also analysed by electrophoretic mobility shift assays (EMSA). Results. The mutant construct doubled IAPP transcriptional activity (p<0.001). Both constructs showed severely reduced promoter activity (four-fold decrease) in the presence of verapamil and diazoxide. In contrast, IAPP promoter activity was doubled after incubation with forskolin or dexamethasone, regardless of the glucose concentrations in the culture media. EMSA revealed that the -132 G/A mutation increased the binding affinity through two DNA-protein complexes. In addition, a cAMP-responsive element binding protein (CREB) was identified by super-shift EMSA. Conclusions/interpretation. Our studies show that the wild-type and the mutant constructs are regulated in a similar pattern under all conditions, strongly indicating that the -132 G/A mutation increases basal but not inducible transcription. These results may be explained by new binding to the mutant region through CREB and other transcription factors not yet identified. [ABSTRACT FROM AUTHOR]

The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations. In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper. Of the study population, 9.3% had a fasting plasma glucose of ≥7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria. The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Cyclin-dependent kinase 4 (Cdk4) is crucial for beta cell development. A mutation in the gene encoding for Cdk4, Cdk4R24C, causes this kinase to be insensitive to INK4 cell cycle inhibitors and induces beta cell hyperplasia in Cdk4R24C knockin mice. We aimed to determine whether this Cdk4R24C mutation also affects proper islet function, and whether it promotes proliferation in human islets lentivirally transduced with Cdk4R24C cDNA. Methods. Our study was conducted on wild-type and Cdk4R24C knockin mice. Pancreases were morphometrically analysed. Intraperitoneal glucose tolerance tests and intravenous insulin tolerance tests were performed on wild-type and Cdk4R24C mice. We also did in vitro islet perifusion studies and islet metabolic labelling analysis. Human islets were transduced with Cdk4R24C cDNA. Results. Pancreatic islets from Cdk4R24C knockin mice exhibit a larger insulin-producing beta cell area and a higher insulin content than islets from wild-type littermates. Insulin secretion in response to glucose is faster and reaches a higher peak in Cdk4R24C mice without leading to hypoglycaemia. Conversion of proinsulin into insulin and its intermediates is similar in Cdk4R24C and wild-type mice. Glucose utilisation and oxidation measured per islet were similar in both experimental groups. Insulin secretion was faster and enhanced in Cdk4R24C islets perifused with 16.7 mmol/l glucose, with slower decay kinetics when glucose returned to 2.8 mmol/l. Moreover, human islets expressing Cdk4R24C cDNA exhibited higher beta cell proliferation. Conclusions/interpretation. Despite their hyperplastic growth, Cdk4R24C insulin-producing islet cells behave like differentiated beta cells with regard to insulin production, insulin secretion in response to glucose, and islet glucose metabolism. Therefore Cdk4 could possibly be used to engineer a source of beta cell mass for islet transplantation. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential. Methods. Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate’s action was also studied. Results. In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38. Conclusion/interpretation. These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. The electrons of the glycolysis-derived reduced form of NADH are transferred to mitochondria through the NADH shuttle system. There are two NADH shuttles: the glycerol phosphate and malate-aspartate shuttle. Mice with a targeted disruption of mitochondrial glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme of the glycerol phosphate shuttle, are not diabetic and have normal islet glucose-induced secretion. In this study, we analyzed if environmental factors, such as a high carbohydrate diet could contribute to the development of Type 2 diabetes mellitus in mice with a specific defective genetic background. Methods. The mice were fed with a high carbohydrate diet for 1 and 6 months, and several biochemical parameters were analysed. The mitochondrial respiratory activity was assayed by polarography; and the islet function was studied by islet perifusion and pancreas perfusion. Results. The high carbohydrate diet induced hyperglycaemia, hyperinsulinaemia, and islet hyperplasia in the wild-type and heterozygote mice. Activity of the respiratory chain complex I also increased in these mice. In contrast, these effects were not observed in the null mice fed with the diet; in addition, these null mice had an increased insulin sensitivity compared to wild-type mice. Conclusion/interpretation. The phenotype of the mice with an impairment of NADH shuttles does not worsen when fed a high carbohydrate diet; moreover, the diet does not compromise islet function. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the presence of mutations in the islet amyloid polypeptide (IAPP) gene in a Spanish population with type 2 diabetes and gestational diabetes mellitus (GDM). Using polymerase chain reaction single-stranded conformation polymorphism, we examined the coding region and the 5′-untranslated region (UTR) of the IAPP gene in 177 unrelated type 2 diabetic patients, 110 healthy control subjects, 38 women with GDM, and 38 gestational control subjects. Mutations were confirmed by DNA sequencing. A heterozygous C-to-A nucleotide substitution at +79 bp in intron 2 of the IAPP gene was detected. The frequencies of the +79-bp polymorphism (A allele) were 6.8% in type 2 diabetic patients, 7.7% in nondiabetic control subjects, 11.8% in women with GDM, and 9.2% in gestational control subjects. No AA genotypes were detected. Nondiabetic subjects and patients with type 2 diabetes bearing the CA genotype had lower low-density lipoprotein (LDL) cholesterol levels than subjects bearing wild genotype. Multivariate logistic regression analysis showed an independent association ( p<0.001; odds ratio: 0.33; 95% confidence interval: 0.17-0.63). We did not detect any sequence variant within exons 1 or 2. One diabetic patient was heterozygous for a silent mutation at codon 31 of exon 3 (Asn AAC→AAT). Our findings indicate that the presence of the +79-bp polymorphism of the IAPP gene in nondiabetic subjects and in patients with type 2 diabetes is associated with lower levels of LDL cholesterol. Furthermore, abnormalities of the coding regions or the 5′-UTR of the IAPP gene are not associated with type 2 diabetes or GDM in the Spanish population. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant chemokine CXCL10, also termed Interferon (IFN)-γ -inducible protein (IP)-10 is pathogenetically involved in several immunoinflammatory and autoimmune diseases. Methods. IFN-γ and IP-10 were quantified by solid-phase ELISA in sera of patients with either newly diagnosed or long-term Type I (insulin-dependent) diabetes mellitus, and in sera of their healthy first degree relatives. The latter were subdivided into "low" and "high" risk prediabetic subjects depending on whether they were negative or positive for the anti-beta-cell autoantibodies ICA and GAD. Results. Compared with healthy control subjects (18%, 9/50), those with a low risk of disease (21%, 5/24) and the group of patients with long-term Type I diabetes (24%, 12/50), IP-10 was found more frequently and at increased concentrations in both newly diagnosed Type I diabetic patients (84%, 42/50) and in those with a high risk of disease (73%, 16/22); in the latter, the IP-10 concentrations correlated with those of IFN-γ. Conclusion/interpretation. Circulating IP-10 concentrations is increased in patients with Type I diabetes, but only during the early and subclinical stage of the disease. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. To test the effects of multifunctional protein 14 (MFP14), which shares structural homology with heat shock proteins (HSPs), on the development of Type I (insulin-dependent) diabetes mellitus in NOD mice. Methods. MFP14 was given to euglycaemic female NOD mice from either the 4th to the 25th or from the 12th until the 35th week, or commencing one day before islet transplantation and until the reappearance of hyperglycaemia. Pancreata from NOD mice treated with multifunctional protein 14 for 14 consecutive weeks until 18 weeks of age were examined histologically for insulitis. Anti-CD3 and/or lipopolysaccharide (LPS)-induced blood levels of interferon (IFN)-γ, interleukin (IL)-4, IL-10, IL-12 and tumour necrosis factor (TNF)-α were measured by ELISA in 10 week-old female NOD mice treated for 6 consecutive weeks with either MFP14 or PBS. Unless otherwise stated, multifunctional protein 14 was administered daily 5 times a week at a dose of 25 μg. Control mice received PBS or, in selected experiments, heat-inactivated MFP14. Results. MFP 14 treated mice had a significantly lower incidence of spontaneous diabetes compared to control mice. The MFP14 was equally effective both upon early and late prophylaxis and the protection persisted until week 50 in mice treated from weeks 4 to 25. Insulitis was significantly reduced by the MFP14. The MFP14 also delayed recurrence of hyperglycaemia in syngeneic islet-transplanted NOD mice. Although MFP14 reduced anti-CD3 and/or LPS-induced blood levels of IFN-γ, TNF-α and IL-12 it increased IL-4 and IL-10. Conclusion/interpretation. The MFP14 could be a possible candidate for the prevention or early treatment of human Type I (insulin-dependent) diabetes mellitus. [Diabetologia (2001) 44: 839–847] [ABSTRACT FROM AUTHOR]

The effects of oral administration of tungstate to an animal model of non-insulin-dependent diabetes mellitus (NIDDM), the neonatally streptozotocin-induced diabetic rat was studied. Islet insulin content and beta-cell mass were lowered in these animals. Furthermore, the islets lost their ability to release insulin in response to an increase in glucose concentration. However, the hepatic glucose metabolism in these diabetic animals before the treatment was not significantly altered with regard to glycogen content, or glucokinase or glycogen phosphorylase activities compared with healthy animals. On the other hand, the activation state of glycogen synthase was higher although the total activity was unchanged. Moreover, a 20 % increase in the concentrations of liver glucose 6-phosphate compared to their healthy siblings was observed. Oral administration of tungstate for 15 days normalized glycaemia in these diabetic animals (4.6 vs 7.8 mmol/l). Tungstate administration was also able to normalize beta-cell insulin secretion in response to 16.7 mmol/l glucose stimulus, reaching values similar to those observed in healthy animals. Concomitantly, a partial recovery in the insulin content and in preproinsulin mRNA levels was found in the islets of treated animals, which was associated with an increase in the number of beta-cells in the pancreas (1.73 vs 0.86 %). The treatment did not change the liver parameters studied, except that it restored glucose 6-phosphate concentrations to healthy values. These data suggest that tungstate administration causes a normalization of glycaemia through the restoration of islet function. [Diabetologia (1997) 40: 143–149] [ABSTRACT FROM AUTHOR]

Although CD5+B lymphocytes are mostly committed to the production of polyreactive natural autoantibodies, CD5+B lymphocytes committed to the production of somatically mutated and monoreactive high-affinity IgM autoantibodies have been also shown. Increased proportions of CD5+B lymphocytes in some autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM), have been noticed. The present study was undertaken to analyse the differences between CD5+ and CD5-B lymphocyte subsets for production of IDDM-related autoantibodies, i.e. anti-human insulin antibodies (IA) and anti-human islet cell antibodies (ICA). For this purpose, Epstein-Barr Virus (EBV)-transformation of FACS cell-sorted CD5+ and CD5-B lymphocytes and unfractionated enriched B lymphocytes from nine IDDM patients treated exclusively with recombinant human insulin, and from four healthy control subjects was performed; a mean of 102-216 microcultures with a mean of 1,000-2,333 cells/microculture for each B-lymphocyte fraction and individual was established. Data show that both CD5+ and CD5-B-lymphocyte subsets from either normal subjects or from IDDM patients receiving recombinant human insulin, contain B lymphocytes committed to the production of IA-IgM as a common element of their repertoire. In contrast, cells committed to the production of IA-IgG were only detected among the CD5-B lymphocyte subset from some IDDM patients. Only one microculture, out of a total of 6,211 screened (from control subjects and patients), in the CD5-B-cell subset from a recently-diagnosed IDDM patient, was found to produce ICA-IgMλ. This might suggest that the frequency of circulating B lymphocytes committed to the production of ICA is very low even in IDDM patients bearing serum ICA. EBV-transformed B cells producing the ICA-IgMψ were stabilized and cloned by somatic hybridization technique. This ICA-IgMψ human monoclonal antibody, designated HY1-MB91, is not polyreactive, but shows a restricted reactivity with human pancreatic islets, failing to react with other human tissues including cerebellar cortex, and lacking rheumatoid factor and anti-DNA antibody activities. It also lacks reactivity with pancreatic islets from other mammalian species (rat, mouse and monkey) as well as with other rat tissues, including cerebellar cortex. The antigen recognized by HY1-MB91 antibody in human islet cells is a cytoplasmic component mostly found in beta cells. [Diabetologia (1995) 38:62-72] [ABSTRACT FROM AUTHOR]

Islets were isolated by automatic digestion from non-diabetic cadaveric organ donors and from Type 2 (non-insulin-dependent) diabetic subjects. The activity of FAD-glycerophosphate dehydrogenase, but not that of either glutamate dehydrogenase, glutamateoxalacetate transaminase or glutamate-pyruvate transaminase, was lower in Type 2 diabetic patients than control subjects. Hexokinase, glucokinase and glutamate decarboxylase activities were also measured in islets from control subjects. The utilization of D-[5-H]glucose, oxidation of D-[6-C]glucose and release of insulin evoked by D-glucose were all lower in Type 2 diabetic patients than control subjects. The secretory response to the combination of L-leucine and L-glutamine appeared less severely affected. Islets from Type 2 diabetic patients may thus display enzymatic, metabolic and secretory anomalies similar to those often observed in animal models of Type 2 diabetes, including a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle. [ABSTRACT FROM AUTHOR]

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Aims/hypothesis. Interleukin (IL)-18 is a cytokine primarily produced by macrophages and capable of inducing T lymphocyte synthesis of interferon (IFN)-γ. An up-regulated synthesis of IFN-γ with consequential Type I cytokine dominance has been repeatedly shown in Type I (insulin-dependent) diabetes mellitus and thought to be involved in its pathogenesis. Because increased production of IFN-γ could be secondary to a dysregulated synthesis of IL-18, we compared the circulating levels of IL-18 in patients with newly diagnosed Type I diabetes with those of non-diabetic first-degree relatives and healthy control subjects. Methods. Serum samples were obtained from healthy control subjects, patients with newly diagnosed Type I diabetes, and their healthy first-degree relatives. The latter were subdivided into “low” and “high” risk prediabetics depending on whether they were negative or positive for two or more of the anti-pancreatic autoantibodies ICA, GAD, IA-2 and IAA. Serum levels of IL-18 were measured by solid-phase ELISA. Results. Interleukin (IL)-18 was above the detection limit of 25 pg/ml in 7 of 40 (17 %) healthy control subjects, in 5 of 35 (14 %) patients and in 3 of 30 (10 %) first-degree relatives at low risk of developing Type I diabetes. In contrast, IL-18 could be detected in 19 of 28 (68 %; p < 0.0001) relatives at high risk. The mean serum level of IL-18 was higher in these individuals when compared with the low-risk relatives, patients and control subjects. Conclusion/interpretation. IL-18 serum levels are increased selectively during the early, subclinical stage of Type I diabetes. [Diabetologia (2001) 44: 309–311] [ABSTRACT FROM AUTHOR]

This study describes the effects of nicotinamide therapy on B-cell function in Type 1 (insulin-dependent) diabetes. C-peptide secretion was studied in 20 patients newly diagnosed with Type 1 diabetes at basal state and also after an i.v. glucagon stimulus. Patients were randomly allocated according to a single-blind schedule, to one of the following treatments over a 45-day period: Group 1: 10 patients, nicotinamide 1 g/day; Group 2: 10 patients, placebo. The C-peptide secretion tests were performed before treatment and on days 15, 45, 180, 365 of the follow-up. The clinical and metabolic data were similar in the two groups of patients. Basal and stimulated C-peptide levels increased by 45 days in both groups, but the increase in stimulated C-peptide response was greater in the nicotinamide group ( p<0.01). However, the B-cell function decreased after the period of nicotinamide administration. No difference in the number of clinical remissions or insulin requirement and HbA between the groups was observed. These data suggest that treatment of Type 1 diabetes with nicotinamide at diagnosis is associated with a moderate increase of C-peptide secretion recovery. [ABSTRACT FROM AUTHOR]

Islet cell antibodies, insulin antibodies and hyperglycaemia were investigated in 2291 healthy schoolchildren. Eight of the subjects had islet cell antibodies and eight had insulin antibodies. However, no schoolchild who was positive for islet cell antibodies also had insulin antibodies present. Hyperglycaemia was observed in five children but neither islet cell antibodies nor insulin antibodies could be detected in the sera from these particular subjects. [ABSTRACT FROM AUTHOR]

Viable human pancreatic islets isolated from a recent-onset Type 1 (insulin-dependent) diabetic patient were used to perform in vitro studies. Pre-proinsulin mRNA and insulin content, as well as insulin response were analysed. Insulin response to glucose and forskolin was completely absent in diabetic islets, as compared to control islets. Insulin content was reduced to only one-third of control values (395.0±3.5 vs 989.0±46.3 μU/islet) and 20.7±3.9% of islets from the diabetic pancreas contained insulin-positive cells in immunofluorescence studies. Northern blot analysis revealed a severe reduction in the content of pre-proinsulin mRNA in diabetic pancreatic tissue. Our results indicate that although markedly decreased, beta cells in human pancreatic islets at the onset of Type 1 diabetes are still present. Never-theless, pancreatic islet function is disproportionately impaired with a complete absence of an insulin response. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor reporting a study that investigates the presence of the amylin gene mutations in a group of 186 Spanish Type 2 diabetic patients and 130 non-diabetic subjects.

Presents a letter to the editor about the potential role of the G-to-A mutation in the IAAP promoter region in the pathogenesis of type II diabetes.