Bone Morphogenetic Protein-7 (BMP-7) belongs to the transforming growth factor-β (TGFβ) family of cytokines has is known to have potent anti-inflammatory properties. It has been used in patients to treat osteoporosis clinically and has been reported to treat diabetic nephropathy in murine models. Moreover, studies show that inflammation is up-regulated in patients with pre-diabetes (PD). We, therefore, hypothesize that the administration of BMP-7 will attenuate inflammation in the heart of Streptozotocin (STZ)-induced PD mice. In this study, we divided C57Bl/6 mice into three groups: CONTROL, PD, and PD+BMP-7. CONTROL mice received intraperitoneal (i.p.) injections of Sodium Citrate Buffer while PD and PD+BMP-7 groups received i.p. injections of Streptozotocin (STZ) for two days. In addition, PD+BMP-7 mice received intravenous injections (i.v.) of BMP-7 (200µg/kg) on the last day of STZ injection and for the following two days. Animals were sacrificed 21 days post last injection and examined for levels of oxidative stress, inflammatory immune response, apoptosis, fibrosis and cardiac function. Our results indicate significant glucose intolerance in PD mice (p

Thesis (MScMedSc (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Introduction: Obesity and its associated complications, such as the metabolic syndrome, hypertension and cardiovascular disease, are escalating worldwide. In recognition of this, untested remedies advertised as anti-diabetic agents are flooding the market. Many of these products have limited efficacy, limited tolerability and significant side-effects. One remedy, claiming to have anti-diabetic properties, is DiaviteTM. DiaviteTM, a herbal product, consisting solely of the dried and ground pods of the Prosopis glandulosa tree, which is currently marketed as a food supplement with blood glucose and blood pressure stabilizing properties, as well as having the ability to enhance glucose utilization. It is already freely available from agents as well as sold over the counter at pharmacies. The producers of DiaviteTM are now seeking registration for their product from the Medicines Control Council (MCC) and, therefore, require solid scientific evidence of its effects. Aims: The aims of our study were, on request of the producing company, to determine the efficacy of DiaviteTM (P. glandulosa) as an anti-diabetic agent and possible mechanisms of action of this plant product. Methology: We utilized rat models of streptozotocin (STZ)-induced type 1 diabetes and diet-induced obese (DIO) insulin resistance. Male Wistar rats were rendered (a) type 1 diabetic after a once-off intra-peritoneal injection of STZ at a dose of 40 mg/kg and (b) insulin resistant after being on a high caloric diet (DIO) for 16 weeks. Half the animals of the type 1 diabetes model as well as the insulin resistant model were placed on DiaviteTM treatment (25 mg/kg/day) for a period of 4 – 8 weeks, depending on the model. The STZ-induced type 1 diabetic rats were sacrificed and the pancreata harvested for histological analysis. Animals on the DIO diet were sacrificed and (i) intra-peritoneal fat weight determined (ii) isolated hearts subjected to ischaemia/reperfusion to determine infarct size and protein expression profiles and (iii) cardiomyocytes prepared to determine insulin sensitivity. At the time of sacrifice blood was collected for blood glucose and serum insulin level determination, for both models. In addition, a standard toxicology study was performed in Vervet monkeys over a 3 month period. Results: In our type 1 diabetic model (blood glucose > 10 mmol/L) with a β-cell reserve, DiaviteTM treatment lead to increased serum insulin levels (p < 0.001) in both control and STZ groups as well as increased small β-cell (0 - 2500 μm2) formation (p < 0.001) in the pancreas of the STZ animals. Hearts from DiaviteTM treated control and DIO insulin resistant animals presented with smaller infarct sizes (p < 0.05) after ischaemia/reperfusion compared to their controls. DiaviteTM treatment lead to the increase of basal (p < 0.01) and insulin-stimulated (p < 0.05) glucose uptake in cardiomyocytes prepared from DIO insulin resistant animals. DiaviteTM treatment also led to significantly suppressed PTEN expression and activity (p < 0.01) in the DIO insulin resistant animals. In addition, DiaviteTM treatment had (i) no obvious detrimental effects in our rat models and (ii) no toxicity over a 3 month period in vervet monkeys. Conclusion: Our present study has shown that DiaviteTM treatment lowers fasting blood glucose levels, stimulates insulin secretion and leads to the formation of β-cells. In addition, oral consumption of DiaviteTM elicits cardioprotection against an ischaemic incident. DiaviteTM treatment improves insulin sensitivity of cardiomyocytes. Furthermore, it has been established that DiaviteTM treatment has no obvious detrimental effects in either of our rat models and no short-term toxic effects over a 3 month period in Vervet monkeys (data not shown). We thus conclude that in our models, DiaviteTM proved safe and it seems as if DiaviteTM, after short-term use, is beneficial as a dietary supplement. / AFRIKAANSE OPSOMMING: Inleiding: Vetsug, en die gepaardgaande komplikasies, soos die metaboliese sindroom, hipertensie en kardiovaskulêre siektes, neem wêreldwyd toe. Daar is tans verskeie middels op die mark wat as anti-diabetiese middels geadverteer word. Baie van hierdie geadverteerde produkte het beperkte effektiwiteit en het verskeie newe-effekte. Een so ‘n middel, is DiaviteTM. DiaviteTM is 'n plantproduk, wat slegs uit die gedroogte en fyngemaakte peule van die P. glandulosa boom bestaan. Hierdie produk word tans bemark as 'n voedselaanvulling met beide bloedglukose en bloeddruk stabiliserende eienskappe, asook die vermoë om glukose gebruik te verbeter. DiaviteTM is reeds vrylik beskikbaar van agente sowel as verkrygbaar by verskeie apteke. Die produsente van DiaviteTM wil aansoek doen om registrasie vir hul produk by die Medisynebeheerraad (MCC) en hulle vereis daarom wetenskaplike bewyse van die gevolge van die gebruik van hierdie produk. Doel: Die doel van ons studie was om op versoek van die produksie maatskappy, die doeltreffendheid van DiaviteTM (P. glandulosa) as 'n anti-diabetiese behandeling te evalueer, sowel as die moontlike meganismes van werking van hierdie plantproduk. Metodes: Ons het gebruik gemaak van rot modelle van (i) streptozotocin (STZ)-geïnduseerde tipe 1 diabetes en (ii) dieet-geïnduseerde vetsugtig (DIO) insulienweerstandigheid. Manlike Wistar rotte was as (a) tipe 1 diabeties geklassifiseer na 'n eenmalige, intra-peritoneale inspuiting van STZ teen 'n dosis van 40 mg/kg en as (b) insulienweerstandig geklassifiseer, nadat hulle op 'n hoë kalorie dieet (DIO) vir 16 weke was. Die helfte van beide die tipe 1 diabetes en die insulienweerstandige groep diere was met DiaviteTM behandel (25 mg/kg/dag) vir 'n tydperk van 4 - 8 weke, afhangende van die model. Die STZ-geïnduseerde tipe 1 diabetes rotte is geslag en die pankreata geoes vir histologiese analise. Diere op die DIO dieet is geslag en (i) die intra-peritoneale vet gewig bepaal, (ii) die geïsoleerde harte blootgestel aan isgemie/herperfusie om die infarkt groottes vas te stel, sowel as die proteïenuitdrukkingsprofiele te bepaal en (iii) kardiomiosiete was berei om die insulien sensitiwiteit te bepaal. Ten tyde van die slagting is bloedmonsters geneem vir bloedglukose en serum insulien vlak bepaling, vir beide modelle. Additioneel, is 'n standaard toksologie studie met Vervet apies oor 'n 3 maande tydperk uitgevoer. Resultate: In die model van tipe 1 diabetes (bloed glukose > 10 mmol/L), met 'n β-sel reserwe, is gevind dat DiaviteTM behandeling tot verhoogde serum insulien vlakke (p < 0.001) in beide kontrole en STZ groepe lei. DiaviteTM behandeling lei ook tot ‘n hoër vlak van klein β-sel (0 - 2500 μm2) vorming (p < 0.001) in die pankreas van die STZ diere. Die harte van die DiaviteTM behandele kontrole en DIO groep het kleiner infarkt groottes (p < 0.05) getoon na isgemie/herperfusie in vergelyking met hul kontrole groepe. DiaviteTM behandeling het ook gelei tot verhoogde basal (p < 0. 01) en insulin-gestimuleerde (p < 0. 05) glukose opname in kardiomiosiete wat berei was van DIO insulinweerstandige diere. DiaviteTM behandeling het PTEN uitdrukking en aktiwiteit aansienlik onderdruk (p < 0.01) in die DIO insulienweerstandige groep diere. Daar is dus gevind dat DiaviteTM behandeling (i) geen duidelike nadelige invloed in ons rot-modelle en (ii) geen toksisiteit oor 'n 3 maande tydperk in Vervet apies getoon nie. Gevolgtrekking: Ons huidige studie toon dus dat DiaviteTM behandeling vastende bloedglukosevlakke verlaag, insulien sekresie stimuleer en die proses van β-sell vorming bevorder. Additioneel, is gewys dat wanneer DiaviteTM mondelings gebruik word, dit die hart beskerm teen isgemiese insidente. Ons het ook getoon dat DiaviteTM behandeling insuliensensitiwiteit van kardiomiosiete verhoog. Verder is daar vasgestel dat DiaviteTM behandeling geen ooglopende nadelige gevolge in beide ons rot-modelle getoon het nie en daar geen korttermyn-toksiese effekte oor 'n 3 maande tydperk in Vervet apies (data nie getoon) is nie. Ons kan dus aflei dat Diavite TM in ons modelle veilig is en na kort termyn gebruik, voordelig is as 'n dieetaanvulling.

Thesis (MScMedSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Diabetes Mellitus is a metabolic disease characterized by the loss of beta cells from the islets, thereby disrupting islet composition and architecture which are important components that influence islet function. The experimental technique of pancreatic duct ligation (PDL), which is thought to induce the regeneration of beta cells within the adult pancreas, was investigated as a novel treatment strategy for diabetes. This study aimed at investigating the possibility that the PDL model may have the capacity to restore normal islet composition and architecture in diabetic animals, which could make it an effective approach to reverse diabetes. Male Wistar rats (n=55) were divided into three study groups: the normal control (NC) group, the diabetic control (DC) group consisting of five subgroups (day 0, 3, 5, 10 and 30) and the experimental (EX) group consisting of four subgroups (day 3, 5, 10 and 30). The experimental group was exposed to PDL. All pancreata were divided into a P1 portion (proximal to the point of ligature) and P2 portion (distal to the point of ligature) for histological assessment. Animals’ non-fasting blood glucose levels (BGLs) and body weights were monitored. The general morphology of the tissue was studied, while an immunohistochemical (IHC) study was performed to determine insulin, pancreatic polypeptide, glucagon and somatostatin protein expression in the P1 and P2 portions of the pancreas. From the IHC slides hormone fractions, staining intensity and distribution were determined as indication of islet composition and architecture. Despite apparent morphological recovery in the islet 30 days post-PDL, islet composition and architecture remained disrupted. Compared to diabetic animals, the proximal portion of the pancreas in experimental animals had a decreased beta cell fraction and increased delta cell fraction thirty days following PDL. These observed changes in islet composition in the part of the pancreas proximal to the ligature are novel findings. There was no change in the diabetic islet composition in the portion of the pancreas distal to the ligature thirty days following PDL. Furthermore, pancreatic duct ligation did not restore body weight or normoglycemia. We conclude that STZ disrupts islet composition and architecture and this could not be restored using PDL; we therefore suggest that a comparative study using a Type 2 diabetic model, where there is limited damage to pre-existing beta cells, may yield different results. / AFRIKAANSE OPSOMMING: Diabetes Mellitus is ʼn metaboliese siekte wat deur die verlies van beta selle uit die eilande van Langerhans gekarakteriseer word. Hierdie verlies van beta selle ontwrig eiland komposisie en argitektuur, twee belangrike komponente van eiland funksie. Die eksperimentele tegnieke van pankreatiese buisafbinding (in Engels PDL), wat moontlik beta sel regenerasie in die volwasse pankreas kan induseer, is ondersoek as behandelings-strategie vir diabetes. Hierdie studie het ten doel gehad om die moontlikheid te ondersoek dat die PDL model die kapasiteit het om normale eiland komposisie en argitektuur te herstel in diabetiese diere, wat dit ʼn effektiewe benadering vir die omkeer van diabetes kan maak. Manlike Wistar rotte (n=55) was in 3 studie groepe verdeel: die normale kontrole (NC) groep, die diabetiese kontrole (DC) groep wat uit vyf subgroepe bestaan (dag 0, 3, 5, 10 en 30) en die eksperimentele (EX) groep wat uit vier subgroepe bestaan (dag 3, 5, 10 en 30). Die eksperimentele groep is aan PDL blootgestel. Alle pankreata is verdeel in ʼn P1 porsie (proksimaal tot die afbinding) en ʼn P2 porsie (distaal tot die afbinding) vir histologiese assessering. Die diere se nie-vastende bloed glukose vlakke en liggaamsgewig is gemonitor. Die algemene morfologie van die pankreas weefsel is bestudeer, terwyl ’n immunohistochemiese (IHC) studie gedoen is om insulien, pankreatiese polipeptied, glukagon en somatostatien proteïen uitdrukking in die P1 en P2 porsies van die pankreas te bepaal. Vanaf die IHC snitte is hormoon fraksie, kleur intensiteit en verspreiding bepaal as aanduidings van eiland komposisie en argitektuur. Ten spyte van ooglopende morfologiese herstel in die eilande op dag 30 na PDL, het eiland komposisie en argitektuur versteur gebly. In vergelyking met die diabetiese diere, het die proksimale deel van die pankreas van eksperimentele diere verlaagde beta sel fraksie en verhoogde delta sel fraksie getoon dertig dae na PDL. Die waarneming van veranderde komposisie in die deel van die pankreas proksimaal tot die afbinding is nuut. Daar was geen verandering in diabetiese eiland komposisie in die deel van die pankreas distaal tot die afbinding dertig dae na PDL nie. Verder het PDL nie liggaamsgewig of bloedsuiker genormaliseer nie. Ons gevolgtrekking is dat STZ eiland komposisie en argitektuur ontwrig en dat dit nie met PDL herstel kon word nie; daarom stel ons ʼn vergelykende studie in ʼn tipe 2 diabetes model voor, waar die skade aan reeds bestaande beta selle beperk is, wat ander resultate mag lewer.

Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.

A Doença de Alzheimer (DA) tem sido relacionada com danos oxidativos. O objetivo desse trabalho foi investigar o envolvimento NADPH oxidase 2 (Nox2), uma enzima que produz espécies reativas de oxigênio, na memória, na expressão de proteínas relacionadas à DA, na inflamação e morte neuronal no hipocampo na patologia Alzheimer-símile induzida por estreptozotocina (STZ), comparando os efeitos dessa droga em camundongos nocautes para Nox2 e camundongos selvagens (WT). A expressão gênica de Nox2 foi aumentada em animais WT após a injeção de STZ, além disso, esses animais apresentaram déficit de memória, aumento na fosforilação de TAU, na expressão de beta-amilóide, neurofilamentos, caspase-3 e marcadores de astrócitos e microglia, além de aumento na liberação de citocinas inflamatórias, após o tratamento. Estes efeitos não foram observados após a deleção de Nox2. A deleção de Nox2 aumentou a produção basal de IL-10, sugerindo que este pode ser um mecanismo pelo qual os camundongos nocautes são protegidos contra a patologia Alzheimer-símile induzida por STZ. / Alzheimer\'s disease (AD) has been linked to oxidative stress. The goal of this study was to investigate the involvement of NADPH oxidase 2 (nox2), an enzyme that produces reactive oxygen species, in memory, in AD-related proteins expression, inflammation and neuronal death in the hippocampus in the streptozotocin (STZ)-induced AD-like pathology by comparing the effects of that drug on mice lacking Nox2 and wild type (Wt) mice. Nox2 gene expression was increased in Wt mice after STZ injection. Moreover, these animals presented impairment in memory, increased phosphorylation of Tau and increased amyloid-&#946; protein, neurofilaments, caspase-3 and astrocyte and microglial markers expression, in addition to increased inflammatory cytokines release after treatment. Nox2 depletion prevented these effects. The baseline IL-10 levels were found increased following Nox2 deletion, suggesting that this is one mechanism by which mice lacking Nox2 are protected against STZ-induced AD-like pathology.

A doença de Alzheimer (DA) é caracterizada por déficit cognitivo, associada com prejuízos no metabolismo energético e na via de sinalização da insulina encefálicos. A injeção intracerebroventricular de baixas doses de estreptozotocina (STZ) tem sido utilizada como um modelo experimental da DA em ratos. Nesse sentido, tem sido demonstrada a participação do sistema canabinoide em processos neurodegenerativos e seus efeitos neuroprotetores e anti-inflamatórios. O objetivo deste trabalho foi caracterizar as alterações comportamentais e moleculares em modelos experimentais (in vivo e in vitro) expostos à STZ e avaliar a participação do sistema canabinoide. A STZ produziu prejuízo cognitivo, morte celular por apoptose, deficiência na resposta à insulina e alterações na via IR/PI3K, semelhantes às encontradas na DA. O agonista canabinoide ACEA foi capaz de reverter o prejuízo cognitivo, modificar as alterações proteicas da via IR/PI3K, e regular positivamente a via anti-apoptótica, gerando uma neuroproteção. / Alzheimer\'s disease (AD) is characterized by cognitive deficit associated with energy metabolism impairment and changes in insulin signaling. In this context, low doses of intracerebroventricular streptozotocin (STZ) injection has been used as an experimental model of AD in rats. Several studies have demonstrated the participation of the cannabinoid system in neurodegenerative processes and its neuroprotective and anti-inflammatory properties. Thus, the aim of this work was to characterize the molecular and behavior alterations in experimental models (in vitro and in vivo) produced by STZ exposure and evaluate the cannabinoid system participation in these models. STZ was able to induce cognitive impairment, apoptosis cell death, impaired insulin response and alterations in the IR/PI3K signaling pathway, similar to those found in AD. CB1 agonist, ACEA reversed cognitive impairment and modified some protein changes in IR/PI3K pathway caused by STZ, and positively regulate the anti-apoptotic pathway, generating neuroprotection.

No description available.

<p>Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which T-cells and macrophages invade the islets of Langerhans and selectively destroy the insulin producing β-cells, either directly or through the secretion of e.g. cytokines and nitric oxide (NO). This thesis has studied possible strategies to prevent T1DM. In β-cells and macrophages, NO is produced by inducible nitric oxide synthase (iNOS). </p><p>In the first study, we found that 1400W, a highly selective inhibitor of iNOS could prevent interleukin (IL)-1β induced suppression of rat islet function <i>in vitro</i>, but not diabetes induced by multiple low dose streptozotocin (MLDS), a well established animal model for autoimmune diabetes, <i>in vivo</i>. </p><p>Next, we wanted to test a new type of high affinity blocker of IL-1 action, called IL-1 trap, <i>in vitro</i>. Here we found that an IL-1 trap could prevent the suppressive effects by IL-1β on rat pancreatic islet function. Also, it was sufficient to block the action of IL-1β to prevent islet cell death induced by a combination of IL-1β, tumor necrosis factor-α and interferon-γ.</p><p>In study III, a murine IL-1 trap was found to prolong islet graft survival in the recurrence of disease (ROD) model, a T1DM model that involves syngeneic transplantation of healthy pancreatic islets to diabetic nonobese diabetic mice. Mice treated with IL-1 trap displayed an increased mRNA level of the cytokine IL-4 in isolated spleen cells. This suggests a shift towards Th2-cytokine production, which in part could explain the results. </p><p>Finally, simvastatin an anti-hypercholesterolemic drug that possesses anti-inflammatory properties e.g. by interfering with transendothelial migration of leukocytes to sites of inflammation was studied. We found that the administration of simvastatin could delay, and in some mice prevent, the onset of MLDS-diabetes, and prolong islet graft survival in the ROD model. </p>

Thesis (M.S.)--University of North Carolina at Wilmington, 2006. / Includes bibliographical references (leaves: 111-115)

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which T-cells and macrophages invade the islets of Langerhans and selectively destroy the insulin producing β-cells, either directly or through the secretion of e.g. cytokines and nitric oxide (NO). This thesis has studied possible strategies to prevent T1DM. In β-cells and macrophages, NO is produced by inducible nitric oxide synthase (iNOS). In the first study, we found that 1400W, a highly selective inhibitor of iNOS could prevent interleukin (IL)-1β induced suppression of rat islet function in vitro, but not diabetes induced by multiple low dose streptozotocin (MLDS), a well established animal model for autoimmune diabetes, in vivo. Next, we wanted to test a new type of high affinity blocker of IL-1 action, called IL-1 trap, in vitro. Here we found that an IL-1 trap could prevent the suppressive effects by IL-1β on rat pancreatic islet function. Also, it was sufficient to block the action of IL-1β to prevent islet cell death induced by a combination of IL-1β, tumor necrosis factor-α and interferon-γ. In study III, a murine IL-1 trap was found to prolong islet graft survival in the recurrence of disease (ROD) model, a T1DM model that involves syngeneic transplantation of healthy pancreatic islets to diabetic nonobese diabetic mice. Mice treated with IL-1 trap displayed an increased mRNA level of the cytokine IL-4 in isolated spleen cells. This suggests a shift towards Th2-cytokine production, which in part could explain the results. Finally, simvastatin an anti-hypercholesterolemic drug that possesses anti-inflammatory properties e.g. by interfering with transendothelial migration of leukocytes to sites of inflammation was studied. We found that the administration of simvastatin could delay, and in some mice prevent, the onset of MLDS-diabetes, and prolong islet graft survival in the ROD model.