Degeneration Of Beta Cells Research Articles

Binary Classification of Diabetic Retinopathy Using CNN Architecture

Diabetes mellitus (DM), a chronic, clinically heterogeneous condition, is becoming increasingly common all over the world. Insulin deficiency, resistance to insulin's actions on the body's surface, or both may lead to pancreatic beta-cell degeneration. Diabetes makes people more prone to its consequences, the most prevalent of which is diabetic retinopathy (DR). Deep learning algorithms surpass traditional classification models for illness diagnosis on photos of medical problems. Deep transfer learning models for medical DR detection were evaluated using the APTOS 2019 dataset. Deep transfer learning algorithms for medical diabetic retinopathy (DR) detection are being evaluated. MobileNet Convolutional Neural Networks (CNN) architecture is used to detect the DR in binary class classification tasks, which leverages pre-trained weights collected during the training process using the ImageNet database. Cohen Kappa, F1 score, recall, accuracy, and precision are some of the performance indicators used. According to the data, the given model is the most effective in terms of accuracy and training time for handling our challenges. Overall, MobileNet is a good pick. The following metrics were found to be accurate: 0.9455, precise: 0.94651, recall: 0.9455, F1 score: 0.94556, and Cohen Kappa score: 0.89083. This method might aid medical personnel in the early detection of diabetic retinopathy.

Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.

A Comprehensive insight into the effect of chromium supplementation on oxidative stress indices in diabetes mellitus: A systematic review.

Diabetes mellitus is a metabolic disorder defined as an increase in blood glucose levels (hyperglycaemia) and insufficient production or action of insulin produced by the pancreas. Chronic hyperglycaemia leads to increased reactive oxygen species (ROS) production and oxidative stress, which consequently results in insulin resistance, beta cell degeneration, dyslipidaemia, and glucose intolerance in diabetic patients. Chromium has an essential role in the metabolism of proteins, lipids, and carbohydrates through increasing insulin efficiency. This systematic review aimed to evaluate chromium supplementation's potential roles in oxidative stress indices in diabetes mellitus. A systematic search was performed in PubMed, Scopus, Google Scholar, Cochrane, and Science Direct databases until November 2020. All clinical trials and animal studies that assessed chromium's effect on oxidative stress indices in diabetes mellitus and were published in English-language journals were included. Finally, only 33 out of 633 articles met the required criteria for further analysis. Among 33 papers, 25 studies were performed on animals, and eight investigations were conducted on humans. Twenty-eight studies of chromium supplementation lead to reducing oxidative stress indices. Also, 23 studies showed that chromium supplementation markedly increased antioxidant enzymes' activity and improved levels of antioxidant indices. In conclusion, chromium supplementation decreased oxidative stress in diabetes mellitus. However, further clinical trials are suggested in a bid to determine the exact mechanisms.

PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicity-mediated impairment of insulin secretion in pancreatic beta cells.

Type 2 diabetes mellitus is characterized by insulin resistance and hypersecretion of insulin from the pancreas to compensate for decreased insulin sensitivity in the peripheral tissues. In later stages of the disease insulin-secreting beta cell degeneration commences and patients require insulin replacement therapy in order to accomplish proper regulation of their blood glucose. Endoplasmic reticulum (ER) stress in the beta cells is one of the factors contributing to this detrimental effect. Protein kinase R (PKR) is a cellular stress kinase activated by ER stress and contributing to degeneration of pancreatic islets. In order to determine whether inhibition of PKR activation by specific small molecule inhibitors of PKR ameliorates pancreatic insulin secretion capacity, we treated beta cells with two imidazole/oxindole-derived inhibitors of PKR kinase, imoxin (C16) and 2-aminopurine (2-AP), in the presence of ER stress. Our results demonstrate that PKR inhibition suppresses tunicamycin-mediated ER stress without altering the insulin production capacity of the cells. Palmitic acid-mediated suppression of insulin secretion, however, was subdued significantly by PKR inhibitor treatment through an ER stress-related mechanism. We suggest that PKR inhibitor treatment may be used to increase the insulin secretion capacity of the pancreas in later stages of diabetes.

Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates.

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8-17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8-20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

Antidiabetic Activity of Phytosaponin in STZ-Induced Type I Diabetes in Rats

Objective: The study was focused on antidiabetic activity of saponin isolated from the fruits of Momordica dioica against STZ induced Type I diabetic mellitus in rats. Methods: Saponin was isolated from methanolic extract of fruits of M. dioica and purification was achieved through fractionation method of TLC. Overnight fasting, for Type I diabetes was induced in rats by I.P. of STZ dose of 65 mg/kg b.w. During the study, body weight and fasting blood glucose level were taken. At the end of study, animals in all groups were sacrificed and biochemical parameters; Lipid profile, HbA1c, Serum insulin, pancreatic insulin, histology of pancreas, and in-vitro insulin secretion activity and proliferation of beta cells in RIN-5F cell lines were performed. Results and conclusion: Significant antidiabetic activity of saponin Momordica dioica (SMD) observed in the present investigation could be the result of decreased blood glucose levels, improved body mass, showed improvisation in lipid profile. The diabetic rats were validated by their higher HbA1c levels as compared the normal control but the treated diabetic group showed significantly decreased in the HbA1c levels. Similarly the increase in serum insulin and pancreatic insulin may facilitate to prevent diabetic complication. Diabetic pancreas of rats showed degeneration of beta cell density and disruption of normal architecture, whereas treatment group showed reversible beta cell degeneration. SMD was found to possess insulinotropic activity when rat insulinoma cell line was treated with it. Proliferation of RIN-5F was found to increase at low doses but tend to decrease with accelerating doses.

Unfolding Novel Mechanisms of Polyphenol Flavonoids for Better Glycaemic Control: Targeting Pancreatic Islet Amyloid Polypeptide (IAPP).

Type 2 diabetes (T2D) is characterised by hyperglycaemia resulting from defective insulin secretion, insulin resistance, or both. The impact of over-nutrition and reduced physical activity, evidenced by the exponential rise in obesity and the prevalence of T2D, strongly supports the implementation of lifestyle modification programs. Accordingly, an increased consumption of fruits and plant-derived foods has been advocated, as their intake is inversely correlated with T2D prevalence; this has been attributed, in part, to their contained polyphenolic compounds. Over the last decade, a body of work has focussed on establishing the mechanisms by which polyphenolic compounds exert beneficial effects to limit carbohydrate digestion, enhance insulin-mediated glucose uptake, down-regulate hepatic gluconeogenesis and decrease oxidative stress; the latter anti-oxidative property being the most documented. Novel effects on the inhibition of glucocorticoid action and the suppression of amylin misfolding and aggregation have been identified more recently. Amyloid fibrils form from spontaneously misfolded amylin, depositing in islet cells to elicit apoptosis, beta cell degeneration and decrease insulin secretion, with amyloidosis affecting up to 80% of pancreatic islet cells in T2D. Therefore, intervening with polyphenolic compounds offers a novel approach to suppressing risk or progression to T2D. This review gives an update on the emerging mechanisms related to dietary polyphenol intake for the maintenance of glycaemic control and the prevention of T2D.

Rationale for stem cell therapy for type 2 diabetes mellitus

Stem cells can be differentiated into many types of mature cells. Among degenerative diseases, type 1 diabetes mellitus (T1DM) is considered to be a good target disease for stem cell therapeutic application. Indeed, several studies have suggested that stem cells can be differentiated, both in vitro and in vivo, into beta cells which regenerate the pancreas. However, recent studies have shown that stem cell therapy can also provide benefits for type 2 diabetes mellitus (T2DM), which is not related to beta cell degeneration in the pancreas. This commentary will discuss the opportunity to use mesenchymal stem cells (MSCs) to treat T2DM, citing various stem cell therapies from recent published studies. Indeed, a current report “Expanded autologous adipose derived stem cell transplantation for type 2 diabetes mellitus, Biomedical Research and Therapy, 3(12): 1034-1044” evaluated and confirmed the positive effects of stem cell transplantation for blood glucose regulation in T2DM.

Cytological and Histochemical Studies in Rat Liver and Pancreas during Progression of Streptozotocin Induced Diabetes and Possible Protection of Certain Natural Antioxidants

Background: Diabetes mellitus is a major endocrine disorder and growing health problem in most countries. Diabetes manifested by experimental animal models exhibit high oxidative stress due to persistent and chronic hyperglycemia which increases the generation of free radicals, Streptozotocin (STZ) provides an animal model of type 1 diabetes. Thereby depleting the activities of antioxidative defense systems with alteration of antioxidant activities of enzymes such as green tea and curcumin. Aim: Biochemical histological and histochemical investigations were carried on to reveal the effect of STZ on the liver and pancreas cells. Natural antioxidants were used as a new way for ameliorated diabetic effect on the cells. Material and methods: Diabetes was induced by a single intraperitoneal injection of freshly prepared STZ dissolved in 0.05 M of sodium citrate buffer, pH=4.6, (STZ; 45 mg/kg B.wt.).Three days after degeneration of beta cells, diabetes was induced in all animals. After induction of diabetes, diabetic and normal animals were kept in metabolic cages separately. Green tea (EGCG) and curcumin are used as a natural antioxidant to improve the disorders and structural changes induced by STZ. Cellular and histochemical investigations were carried on the changes induced in pancreatic and hepatic tissues. Body weight, levels of serum glucose and insulin were calculated, and compared. For a microscopic study of degeneration of both hepatocytes and pancreatic cells of diabetic rats, tissue samples from diabetic and treated rats were collected, and pathologically examined. Results: Our investigations reveled that there was a detectable amelioration on the injures induced by STZ on both hepatocytes and pancreatic cells using green tea or curcumin with a detectable dose level. Also it can be observed that the ameliorated effect induced was a time dependant. Conformation of these results from histochemical detection of glycogen and DNA contents were detected by PAS and feulgen reactions. Conclusion: Curcumin and green tea looks to have a powerful effect against diabetic cell injury induced in both rat liver and pancreas. The ameliorating effect seems to be time dependant.

Effect of Sitagliptin and Metformin on Prediabetes Progression to Type 2 Diabetes - A Randomized, Double-Blind, Double-Arm, Multicenter Clinical Trial: Protocol for the Sitagliptin and Metformin in PreDiabetes (SiMePreD) Study

BackgroundThe high prevalence and incidence of type 2 diabetes mellitus (DM), and its associated morbidity and mortality, has prompted growing international interest and effort in the primary prevention of this disease. Primary prevention is possible since type 2 DM is preceded by prediabetes, offering a window opportunity to treat patients, and prevent the emergence of advanced disease. Sitagliptin is an oral dipeptidyl peptidase-IV inhibitor that preserves existing beta cell function and increases beta cell mass. These two effects have been demonstrated both in vitro and in animal studies, and current clinical data show that sitagliptin is safe. Metformin, a biguanide, reduces insulin resistance and inhibits hepatic gluconeogenesis, and has an excellent safety profile. The combination of metformin and sitagliptin, targeting both characteristics of prediabetes (insulin resistance and progressive beta cell degeneration), may potentially slow or halt the progression from prediabetes to type 2 DM. This paper describes the rationale and design of the Sitagliptin and Metformin in PreDiabetes (SiMePreD) study.ObjectiveThe aim of this study is to determine the effect of sitagliptin and metformin on progression from prediabetes to type 2 DM. The objectives of the study are to determine the effects of metformin and placebo on glycemic endpoints, the effects of sitagliptin and metformin on glycemic endpoints, the effects of metformin and placebo on incidence of cardiovascular disease and death, and the effects of sitagliptin and metformin on incidence of cardiovascular disease and death.MethodsThis is a randomized, double-blind, multicenter clinical study that will determine if the combination of metformin and sitagliptin is effective in preventing the progression from prediabetes to type 2 DM. The study will contain two arms (metformin/sitagliptin and metformin/placebo). Primary endpoints include the number of subjects progressing from prediabetes to type 2 DM, the number of cardiovascular events, and the number of deaths. The planned duration of the study is five years, and 410 subjects will be included in each group. Data analyses will include clinically relevant measures (eg, numbers needed to treat and numbers needed to harm) and will be performed according to the intention-to-treat principle.ResultsThis study is currently in the process of acquiring research funding.ConclusionsThe SiMePreD study is the first study to investigate the utility of sitagliptin in combination with metformin for the primary prevention of type 2 DM.

Retinoids have therapeutic action in type 2 diabetes

ObjectiveUncontrolled diabetes is associated with a compromised antioxidant state of the body. Consequentially, the reactive oxygen species generated lead to oxidative insult and associated complications. Based on this paradigm, exogenous antioxidant supplementation is thought to exert a therapeutic role in type 2 diabetes (T2-D) biology. MethodsIn the present study, the effect of vitamin A supplementation was assessed on disease progression in T2-D BALB/c mice. Animals were divided into three groups. With the exception of control, the mice in remaining groups were induced with experimental T2-D. After a 15-day treatment protocol, the mice were sacrificed and various parameters were analyzed. ResultsThe treated group evidenced a considerable improvement in total antioxidant potential and glycemic control. A therapeutic effect on beta cell degeneration as compared to the diabetic group was also found. ConclusionsThe study illustrates the antihyperglycemic and antioxidant potential of vitamin A in vivo, which has potential to serve as a dietary intervention in T2-D.

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus.

Aims/hypothesisA strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM.MethodsTwo groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements.ResultsPAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death.Conclusions/interpretationThe coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3864-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Pharmacodynamic Interaction of Garlic with Gliclazide and Ramipril on Myocardial Injury in Diabetic Rats

A B S T R A C T Concurrent therapy of herbs with conventional regimen has been extensively reported for alleviating morbidities such as diabetes and cardiac manifestations. One of unique natural remedy that carry abundant potential for ameliorating wide varieties of ailment is garlic. Present research was designed to explore the role of garlic in obviating myocardial dysfunction in diabetic animals, when combined with ramipril and/or gliclazide. Diabetic Sprague Dawley rats received garlic (250 mg kgG 1 ), ramipril (1 mg kgG 1 ) and gliclazide (10 mg kgG 1 ) orally either alone or in combination in their respective groups. At the end of treatment, heart was excised; mounted on modified Langendorff's set-up; perfused with Krebs-Henseleit solution and subjected to ischemia reperfusion injury. Significantly increased percentage recovery was recorded in heart rate and developed tension during post-ischemia in all treated animals, when compared to diabetic group. Further, depleted Superoxide Dismutase (SOD) and catalase activities were substantially inclined in treated groups. Furthermore, combination of garlic with ramipril was most effective in reverting the ischemic damage, whereas, garlic with gliclazide prevent beta cell degeneration. Moreover, histopathological observations validated biochemical and hemodynamic findings. To conclude, this preliminary observation in animals reveals the beneficial role of adding garlic to conventional regimen of gliclazide and ramipril. Further, a careful clinical evaluation of above combination would provide us an opportunity to standardize and implement in cardiovascular disease management in diabetic patient.

Pancreatic beta cell protection/regeneration with phytotherapy

Although currently available drugs are useful in controlling early onset complications of diabetes, serious late onset complications appear in a large number of patients. Considering the physiopathology of diabetes, preventing beta cell degeneration and stimulating the endogenous regeneration of islets will be essential approaches for the treatment of insulin-dependent diabetes mellitus. The current review focused on phytochemicals, the antidiabetic effect of which has been proved by pancreatic beta cell protection/regeneration. Among the hundreds of plants that have been investigated for diabetes, a small fraction has shown the regenerative property and was described in this paper. Processes of pancreatic beta cell degeneration and regeneration were described. Also, the proposed mechanisms for the protective/regenerative effects of such phytochemicals and their potential side effects were discussed.

Cytological And Histochemical Studies On Rat Liver And Pancreas During Progression Of Streptozotocin Induced Diabetes And Possible Protection Using Certain Natural Antioxidants

Background: Diabetes mellitus is a major endocrine disorder and growing health problem in most countries. Diabetes manifested by experimental animal models exhibits high oxidative stress due to persistent and chronic hyperglycemia which increases the generation of free radicals, streptozotocin (STZ) provides an animal model of type 1 diabetes. Thereby depleting the activities of antioxidative defense systems with alteration of antioxidant activities of enzymes such as green tea and curcumin . Aim : Biochemical histological and histochemical investigations were carried on to revel the effect of STZ on the liver and pancreas cells. Natural antioxidants were used as a new way for ameliorating diabetic effect on the cells Material and methods: Diabetes was induced by a single intraperitoneal injection of freshly prepared STZ dissolved in 0.05M of sodium citrate buffer, pH = 4.6, (STZ; 45 mg/kg B.wt.).Three days after degeneration of beta cells, diabetes was induced in all animals. After induction of diabetes, diabetic and normal animals were kept in metabolic cages separately. Green tea (EGCG) and curcumin are used as natural antioxidants to improve the disorders and structural changes induced by STZ. Cellular and histochemical investigations were carried on the changes induced in the pancreatic and hepatic tissues.Body weight, level of serum glucose and insulin were calculated in the control and treated groups. For detecting the degeneration of both hepatocytes and pancreatic cells of diabetic rats, tissue samples from diabetic and treated rats were collected and pathologically examined. Results: The present investigations reveled that there was a detectable amelioration on the injures induced by STZ on both hepatocytes and pancreatic cells using green tea or curcumin with a detectable dose level. Also it can be observed that the ameliorated effect induced was a time dependant. Conformation of these results from histochemical detection of polysaccharides and DNA contents were detected by PAS and Feulgen reactions. Conclusion: Curcumin and green tea look to have a powerful effect against diabetic cell injury induced in both rat liver and pancreas. The ameliorating effect seem to be time dependant.

Cytological And Histochemical Studies On Rat Liver And Pancreas During Progression Of Streptozotocin Induced Diabetes And Possible Protection Using Certain Natural Antioxidants

Background: Diabetes mellitus is a major endocrine disorder and growing health problem in most countries. Diabetes manifested by experimental animal models exhibits high oxidative stress due to persistent and chronic hyperglycemia which increases the generation of free radicals, streptozotocin (STZ) provides an animal model of type 1 diabetes. Thereby depleting the activities of antioxidative defense systems with alteration of antioxidant activities of enzymes such as green tea and curcumin . Aim : Biochemical histological and histochemical investigations were carried on to revel the effect of STZ on the liver and pancreas cells. Natural antioxidants were used as a new way for ameliorating diabetic effect on the cells Material and methods: Diabetes was induced by a single intraperitoneal injection of freshly prepared STZ dissolved in 0.05M of sodium citrate buffer, pH = 4.6, (STZ; 45 mg/kg B.wt.).Three days after degeneration of beta cells, diabetes was induced in all animals. After induction of diabetes, diabetic and normal animals were kept in metabolic cages separately. Green tea (EGCG) and curcumin are used as natural antioxidants to improve the disorders and structural changes induced by STZ. Cellular and histochemical investigations were carried on the changes induced in the pancreatic and hepatic tissues.Body weight, level of serum glucose and insulin were calculated in the control and treated groups. For detecting the degeneration of both hepatocytes and pancreatic cells of diabetic rats, tissue samples from diabetic and treated rats were collected and pathologically examined. Results: The present investigations reveled that there was a detectable amelioration on the injures induced by STZ on both hepatocytes and pancreatic cells using green tea or curcumin with a detectable dose level. Also it can be observed that the ameliorated effect induced was a time dependant. Conformation of these results from histochemical detection of polysaccharides and DNA contents were detected by PAS and Feulgen reactions. Conclusion: Curcumin and green tea look to have a powerful effect against diabetic cell injury induced in both rat liver and pancreas. The ameliorating effect seem to be time dependant.

Maternal zinc intake of Wistar rats has a protective effect in the alloxan-induced diabetic offspring

Zinc has a role in the synthesis, storage, and secretion of insulin, and has been suggested to be beneficial when used in the diabetic state. Effect of zinc intake in pregnant rats has been studied here on diabetized offspring. Pregnant rats were divided in two groups; the control group received normal food and water, and the experimental group received zinc sulfate during pregnancy and 3 weeks after offspring birth. Male offspring from the control (C) and experimental (E) groups were divided each in three groups: C1, fed with normal food and water; C2, diabetized with alloxan; C3, received zinc sulfate; E1, fed with normal food and water; E2, diabetized with alloxan; and E3, receiving zinc sulfate. After 30 days, the histological changes of pancreatic tissues were investigated by light microscopy. Body weight, blood glucose, serum insulin levels, food intake, water intake, and urine quantity were also compared between the groups. Water intake and urine quantity were decreased significantly (p < 0.01 and p < 0.001) in E2 (experimental diabetic group) in comparison with C2 (control diabetic group), but there was no significant difference in the body weight in C2 in comparison with E2, while blood glucose was decreased significantly (p < 0.001) and blood insulin level was increased significantly (p < 0.01) in E2 in comparison with C2. Microscopic evaluation of pancreas showed that E2 were protected against alloxan-induced beta-cell degeneration. In conclusion, this work showed that maternal zinc intake may influence subsequent deleterious effects of diabetes on alloxan-diabetized offspring.

Rat pancreas uptake of [11C]dihydrotetrabenazine stereoisomers

(+)-α-[(11)C]Dihydrotetrabenazine ((+)-[(11)C]DTBZ), a radioligand for the vesicular monoamine transporter type 2 (VMAT2), has been previously proposed as an in vivo marker of beta-cell degeneration in the pancreas. The stereospecificity of uptake of [(11)C]DTBZ into rat pancreas was examined here using radiolabeled forms of the (+)- and (-)-isomers. Pancreas localization of (+)-[(11)C]DTBZ could be partially blocked by prior administration of unlabeled (+)-DTBZ. Pancreatic uptake of the (-)-isomer was unexpectedly high and could not be blocked by pretreatment with (+)-DTBZ, but could be significantly reduced by treatment with racemic tetrabenazine, an in vivo source of (-)-DTBZ. These studies indicate that the inactive isomer of DTBZ does not provide a mechanism for defining the nonspecific binding of (+)-DTBZ in rat pancreas.

Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

Degeneration of pancreatic islet beta cells is increasingly ranked as a key disease mechanism in type 2 diabetes [1, 2], but it is not entirely clear what the underlying molecular processes might be and how they attack insulin production, ultimately causing type 2 diabetes [3, 4]. However, recent studies based on quantitative measurements in post mortem pancreatic tissue from humans with type 2 diabetes have reinforced earlier observations concerning the probable role of lowered beta cell numbers [5, 6] and pointed to a linkage between beta cell disappearance and beta cell apoptosis [7, 8]. ‘Glucotoxicity’ and ‘lipotoxicity’ are widely discussed possible causes of beta cell failure, but both are thought to exert their effects only after significant metabolic deterioration and functional islet impairment are already well underway [9] and so cannot be the prime movers. So what might the initiating insults be? Recent data from genome-wide association studies have highlighted the impact of particular alleles of certain susceptibility genes, giving further support to the idea that beta cell abnormalities are fundamental in the pathogenesis of this disease [4]. Some of these alleles encode variants of certain beta cell proteins linked to insulin production and/or secretion, and can hasten the development of functional islet deterioration and diabetes onset in carriers [1, 2]. However, currently identified alleles do not provide an explanation for most cases of ‘common or garden’ type 2 diabetes [10]. Against this background, Zraika et al. in this issue of Diabetologia have reviewed aspects of another, underappreciated phenomenon, which could well initiate beta cell degeneration in type 2 diabetes [11]. As they point out, it has long been known that many [8, 12–14] or perhaps most [15, 16] type 2 diabetic patients are found to have islet amyloid deposits adjacent to their beta cells [17] when post mortem pancreatic tissue is examined histologically. Although islet amyloid has also been reported to occur in numbers of humans not known to have diabetes, the author of a major study cautioned that ‘nondiabetic persons with hyaline islets may represent individuals with undiagnosed or potential diabetes’ [18]. Varying sensitivities of different histological methods may also have contributed to betweenstudy differences in prevalence estimates [11]. Islet amyloid, or hyaline as it was once known [12], has the beta cell hormone human amylin or human islet G. J. S. Cooper (*) : J. F. Aitken : S. Zhang School of Biological Sciences, and Maurice Wilkins Centre of Excellence for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand e-mail: g.cooper@auckland.ac.nz

The Sodium-Glucose Co-Transporter SGLT1 - Could Light Help Prevent Type II Diabetes?

The sodium-glucose co-transporter SGLT1 is responsible for the active transport of glucose in small intestine and kidney. Consuming food with high degrees of carbohydrates and glucose leads to a temporary, rapid increase of blood glucose levels via the absorption of glucose and galactose through SGLT1. This influences the glucose homeostasis and increases the insulin resistance of peripheral tissue. The subsequent “glucose-toxicity” leads to degeneration of beta-cells and, in last consequence, to the generation of type II diabetes. The reduction of oral glucose availability by inhibition of SGLT1 with flavonoids or other “nutraceuticals” might be one possibility to prevent type II diabetes.The transport of glucose via SGLT1 is electrogenic and coupled to the co-transport of sodium ions. Its features are examined using cell-free, solid-supported-membrane-based electrophysiology, namely the SURFE2R technology platform (IonGate Biosciences), where transporter-containing membrane fragments or vesicles are mechanically and electrically coupled to a gold-coated biochip. For SGLT1, it is important to establish a membrane potential prior to substrate application, to enhance the sensitivity of the assay. This potential can be built up via a SO4/Cl- gradient across the membrane. The following detectable transport activity is in the range of 300-1000 pA.To avoid unspecific side effects and to speed up screening, the electrochemical SO4/Cl- gradient can be replaced by a light-driven gradient. Therefore, we generated cell lines with light polarizable membranes, where the application of light generates a membrane potential. With this technique it is possible to achieve higher throughput and a better signal-to-noise ratio in drug screening.