http://www.hindawi.comThe latest articles from Hindawi Publishing Corporation© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/818341We examined changes in the ultrastructure and localization of major extracellular matrix components, including 5 types of collagen (type I, III, IV, VI, and VIII), laminin, fibronectin, and heparan sulfate proteoglycan in Descemet's membrane of the cornea of diabetic GK rats. In the cornea of diabetic GK rats, more long-spacing collagen fibrils were observed in Descemet's membrane than in the membrane of the nondiabetic Wistar rats. Both GK and Wistar rats showed an age-dependent increase in the density of the long-spacing collagen. Immunoelectron microscopy showed that type VIII collagen was localized in the internodal region of the long-spacing collagen, which was not labelled by any of the other antibodies used. The antidiabetic agents nateglinide and glibenclamide significantly suppressed the formation of the long-spacing collagen in the diabetic rats. Long-spacing collagen would thus be a useful indicator for studying diabetic changes in the cornea and the effect of antidiabetic agents.Yoshihiro Akimoto, Hajime Sawada, Mica Ohara-Imaizumi, Shinya Nagamatsu, and Hayato Kawakami© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/305403The relationships of renal and glomerular hypertrophies to development of hyperfiltration and proteinuria early in streptozotocin-induced diabetes were explored. Control, diabetic, phlorizin-treated controls, and diabetic male Fischer rats were used. Phlorizin (an Na+-glucose cotransport inhibitor) was given at a dose sufficient to normalize blood glucose. Inulin clearance (Cinulin) and protein excretion rate (PER) were measured. For morphometry, kidney sections were stained with periodic acid Schiff. At one week, diabetes PER increased 2.8-folds (P<.001), Cinulin increased 80% (P<.01). Kidney wet and dry weights increased 10%–12% (P<.05), and glomerular tuft area increased 9.3% (P<.001). Phlorizin prevented proteinuria, hyperfiltration, and kidney hypertrophy, but not glomerular hypertrophy. Thus, hyperfiltration, proteinuria, and whole kidney hypertrophy were related to hyperglycemia but not to glomerular growth. Diabetic glomerular hypertrophy constitutes an early event in the progression of glomerular pathology which occurs in the absence of mesangial expansion and persists even after changes in protein excretion and GFR are reversed through glycemic control.Slava Malatiali, Issam Francis, and Mario Barac-Nieto© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/165360Isolation of primary beta cells from other cells within in the pancreatic islets is of importance for many fields of islet research. However, up to now, no satisfactory method has been developed that gained high numbers of viable beta cells, without considerable alpha-cell contamination. In this study, we investigated whether rat beta cells can be isolated from nonbeta endocrine cells by manipulating the flavin adenine dinucleotide (FAD) and nicotinamide-adenine dinucleotide phosphate (NAD(P)H) autofluorescence. Beta cells were isolated from dispersed islets by flow cytometry, based on their high FAD and NAD(P)H fluorescence. To improve beta cell yield and purity, the cellular FAD and NAD(P)H contents were altered by preincubation in culture media containing varying amounts of D-glucose and amino acids. Manipulation of the cellular FAD and NAD(P)H fluorescence improves beta cell yield and purity after sorting. This method is also a fast and reliable method to measure beta cell functional viability. A conceivable application is assessing beta cell viability before transplantation.M. J. Smelt, M. M. Faas, B. J. de Haan, and P. de Vos© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/176245During the recent years, the role of C-peptide, released from the pancreatic beta cell, in regulating microvascular blood flow, has received increasing attention. In type 1 diabetic patients, intravenous application of C-peptide in physiological concentrations was shown to increase microvascular blood flow, and to improve microvascular endothelial function and the endothelial release of NO. C-peptide was shown to impact microvascular blood flow by several interactive pathways, like stimulating Na+K+ATPase or the endothelial release of NO. There is increasing evidence, that in patients with declining beta cell function, the lack of C-peptide secretion might play a putative role in the development of microvascular blood flow abnormalities, which go beyond the effects of declining insulin secretion or increased blood glucose levels.T. Forst, T. Kunt, B. Wilhelm, M. M. Weber, and A. Pfützner© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/271958Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offspring's risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22–17.6), as compared to boys of IgM-negative mothers (P<.025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood.Maria Elfving, Johan Svensson, Sami Oikarinen, Björn Jonsson, Per Olofsson, Göran Sundkvist, Bengt Lindberg, Åke Lernmark, Heikki Hyöty, and Sten-Anders Ivarsson© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/304513Exogenous administration of islet amyloid polypeptide (IAPP) has been shown to inhibit both insulin and glucagon secretion. This study examined α-cell function in mice with β-cell specific overexpression of human IAPP (hIAPP) after an oral protein gavage (75 mg whey protein/mouse). Baseline glucagon levels were higher in transgenic mice (41±4.0 pg/mL, n=6) than in wildtype animals (19±5.1 pg/mL, n=5, P=.015). In contrast, the glucagon response to protein was impaired in transgenic animals (21±2.7 pg/mL in transgenic mice versus 38±5.7 pg/mL in wildtype mice at 15 minutes; P=.027). Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (P=.018). Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2 mg/mouse) to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with β-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.Bo Ahrén and Maria Sörhede Winzell© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/230837Acute-phase serum amyloid A (A-SAA) was shown recently to correlate with obesity and insulin resistance in humans. However, the mechanisms linking obesity-associated inflammation and elevated plasma A-SAA to insulin resistance are poorly understood. Using high-fat diet- (HFD-) fed mice, we found that plasma A-SAA was increased early upon HFD feeding and was tightly associated with systemic insulin resistance. Plasma A-SAA elevation was due to induction of Saa1 and Saa2 expression in liver but not in adipose tissue. In adipose tissue Saa3 was the predominant isoform and the earliest inflammatory marker induced, suggesting it is important for initiation of adipose tissue inflammation. To assess the potential impact of A-SAA on adipose tissue insulin resistance, we treated 3T3-L1 adipocytes with recombinant A-SAA. Intriguingly, physiological levels of A-SAA caused alterations in gene expression closely resembling those observed in HFD-fed mice. Proinflammatory genes (Ccl2, Saa3) were induced while genes critical for insulin sensitivity (Irs1, Adipoq, Glut4) were down-regulated. Our data identify HFD-fed mice as a suitable model to study A-SAA as a biomarker and a novel possible mediator of insulin resistance.Ludger Scheja, Barbara Heese, Heike Zitzer, Mervyn D. Michael, Angela M. Siesky, Heike Pospisil, Ulrike Beisiegel, and Klaus Seedorf© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/256954The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP) has been intensively studied since its identification in the late 1980s. The IAPP(20–29) region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29) in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils.Sharon Gilead and Ehud Gazit© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/865850Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP) . Peptides were added in solubilized from (50 μM) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occure in cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.Johan F. Paulsson, Sebastian W. Schultz, Martin Köhler, Ingo Leibiger, Per-Olof Berggren, and Gunilla T. Westermark© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/738101The prescription of anaerobic exercise has recently been advocated for the management of diabetes; however exercise-induced signaling in diabetic muscle remains largely unexplored. Evidence from exercise studies in nondiabetics suggests that the extracellular-signal-regulated kinases (Erk1/2), p38, and c-JUN NH2-terminal kinase (Jnk) mitogen-activated protein kinases (MAPKs) are important regulators of muscle adaptation. Here, we compare the basal and the in situ contraction-induced phosphorylation of Erk1/2- p38- and Jnk-MAPK and their downstream targets (p90rsk and MAPKAP-K2) in the plantaris and soleus muscles of normal and obese (fa/fa) Zucker rats. Compared to lean animals, the time course and magnitude of Erk1/2, p90rsk and p38 phosphorylation to a single bout of contractile stimuli were greater in the plantaris of obese animals. Jnk phosphorylation in response to contractile stimuli was muscle-type dependent with greater increases in the plantaris than the soleus. These results suggest that diabetes alters intramuscular signaling processes in response to a contractile stimulus.A. Katta, D. L. Preston, S. K. Karkala, S. Asano, S. Meduru, S. P. Mupparaju, E. Yokochi, Kevin M. Rice, D. H. Desai, and E. R. Blough© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/281536The C-peptide of proinsulin is important for the biosynthesis of insulin and has for a long time been considered to be biologically inert. Animal studies have shown that some of the renal effects of the C-peptide may in part be explained by its ability to stimulate the Na,K-ATPase activity. Precisely, the C-peptide reduces diabetes-induced glomerular hyperfiltration both in animals and humans, therefore, resulting in regression of fibrosis. The tubular function is also concerned as diabetic animals supplemented with C-peptide exhibit better renal function resulting in reduced urinary sodium waste and protein excretion together with the reduction of the diabetes-induced glomerular hyperfiltration. The tubular effectors of C-peptide were considered to be tubule transporters, but recent studies have shown that biochemical pathways involving cellular kinases and inflammatory pathways may also be important. The matter theory concerning the C-peptide effects is a metabolic one involving the effects of the C-peptide on lipidic metabolic status.This review concentrates on the most convincing data which indicate that the C-peptide is a biologically active hormone for renal physiology.L. Rebsomen, A. Khammar, D. Raccah, and M. Tsimaratos© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/576862Starting with the epoch-making discovery of proinsulin, C-peptide has played an important interdisciplinary role, both as part of the single-chain precursor molecule and as an individual entity. In the pioneering years, fundamental systematic experiments unravelled new biochemical mechanisms and chemical structures. After the first detection of C-peptide in human serum, it quickly became a most useful independent indicator of insulin biosynthesis and secretion, finding application in a rapidly growing number of clinical investigations. A prerequisite was the development of specific immuno assays for proinsulin and C-peptide. Further milestones were: the chemical synthesis of several C-peptides and the accomplishments in the synthesis of proinsulin; the detection of preproinsulin with its bearings on understanding protein biosynthesis; the pioneering role of insulin, proinsulin, C-peptide, and mini-C-peptides in the development of recombinant DNA technology; and the discovery of the enzymes for the endoproteolytic processing of proinsulin into insulin and C-peptide, completing the pathway of biosynthesis. Today, C-peptide continues to serve as a special diagnostic tool in Diabetology and related fields. Thus, its passive role is well established. Evidence for its active role in physiology and pathophysiology is more recent and is subject of the following contributions.Dietrich Brandenburg© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/697035Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.J. W. M. Höppener, H. M. Jacobs, N. Wierup, G. Sotthewes, M. Sprong, P. de Vos, R. Berger, F. Sundler, and B. Ahrén© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/730594Aims/hypothesis. Data now indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. This study aimed to investigate the influence of C-peptide and fragments thereof on erythrocyte deformability and to elucidate the relevant signal transduction pathway. Methods. Blood samples from 23 patients with type 1 diabetes and 15 matched healthy controls were incubated with 6.6 nM of either human C-peptide, C-terminal hexapeptide, C-terminal pentapeptide, a middle fragment comprising residues 11–19 of C-peptide, or randomly scrambled C-peptide. Furthermore, red blood cells from 7 patients were incubated with C-peptide, penta- and hexapeptides with/without addition of ouabain, EDTA, or pertussis toxin. Erythrocyte deformability was measured using a laser diffractoscope in the shear stress range 0.3–60 Pa. Results. Erythrocyte deformability was impaired by 18–25% in type 1 diabetic patients compared to matched controls in the physiological shear stress range 0.6–12 Pa (P<.01–.001). C-peptide, penta- and hexapeptide all significantly improved the impaired erythrocyte deformability of type 1 diabetic patients, while the middle fragment and scrambled C-peptide had no detectable effect. Treatment of erythrocytes with ouabain or EDTA completely abolished the C-peptide, penta- and hexapeptide effects. Pertussis toxin in itself significantly increased erythrocyte deformability. Conclusion/interpretation. C-peptide and its C-terminal fragments are equally effective in improving erythrocyte deformability in type 1 diabetes. The C-terminal residues of C-peptide are causally involved in this effect. The signal transduction pathway is Ca2+-dependent and involves activation of red blood cell Na+,K+-ATPase.Thomas Hach, Thomas Forst, Thomas Kunt, Karin Ekberg, Andreas Pfützner, and John Wahren© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/421287The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet β-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced β-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of β-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer_s disease, Parkinson's disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to β-cell death in DM2.Lucie Khemtémourian, J. Antoinette Killian, Jo W. M. Höppener, and Maarten F. M. Engel© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/371716An imaging method capable of using a signal from pancreatic beta cells to determine their mass would be of immense value in monitoring the progression of diabetes as well as response to treatment. Somatostatin receptors (SSTRs) are expressed on beta cells and are a potential target for imaging. The main objective of this study was to investigate whether pancreatic beta cells are a target for radiolabeled naphthylalanine derivatives. The molecules were subjected to in vitro and ex vivo evaluations. Pancreatic uptake of radioactivity was lower in nonobese diabetic (NOD) mice than normal mice at all time points investigated (P < .05) and correlated with the number of islets in tissue sections of both control and NOD mice. Immunohistochemical and confocal fluorescent microscopic studies showed colocalization of insulin and the conjugate radioligand in the pancreas. The results demonstrated that pancreatic uptake is receptor-mediated, and that beta cells are the primary target.John K. Amartey, Yufei Shi, Ibrahim Al-Jammaz, Celestina Esguerra, Basem Al-Otaibi, and Futwan Al-Mohanna© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/230458Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.Anders A. F. Sima, Weixian Zhang, Zhen-guo Li, and Hideki Kamiya© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/819123Patients with fulminant type 1 diabetes almost completely lack C-peptide even soon after the onset of the disease, and the deficiency continues for the rest of their life. Thus, fulminant type 1 diabetes could serve as a good model of nature to explore the physiological role of C-peptide. For example, patients with fulminant type 1 diabetes have diabetic chronic complications more frequently than those with classical autoimmune type 1 diabetes 5 years after the onset of diabetes, and the higher prevalence could be partly attributable to the complete lack of C-peptide in fulminant type 1 diabetes.Yuko Murase-Mishiba, A. Imagawa, and Toshiaki Hanafusa© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/473603In the dermis, fibroblasts play an important role in the turnover of the dermal extracellular matrix. Collagen I and III, the most important dermal proteins of the extracellular matrix, are progressively altered during ageing and diabetes. For mimicking diabetic conditions, the cultured human dermal fibroblasts were incubated with increasing amounts of AGE-modified BSA and D-glucose for 24 hours. The expression of procollagen α2(I) and procollagen α1(III) mRNA was analyzed by quantitative real-time PCR. Our data revealed that the treatment of fibroblasts with AGE-modified BSA upregulated the expression of procollagen α2(I) and procollagen α1(III) mRNA in a dose-dependent manner. High glucose levels mildly induced a profibrogenic pattern, increasing the procollagen α2(I) mRNA expression whereas there was a downregulation tendency of procollagen α1(III) mRNA.Serban Iren Andreea, Costache Marieta, and Dinischiotu Anca© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/385108Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show increased levels of C-peptide and over the last years various groups examined the effect of C-peptide in vascular cells as well as its potential role in lesion development. While some studies demonstrated beneficial effects of C-peptide, for example, by showing an inhibition of smooth muscle cell proliferation, others suggested proatherogenic mechanisms in patients with type 2 diabetes. Among them, C-peptide may facilitate the recruitment of inflammatory cells into early lesions and promote lesion progression by inducing smooth muscle cell proliferation. The following review will summarize the effects of C-peptide in vascular cells and discuss the potential role of C-peptide in atherogenesis in patients with type 2 diabetes.Nikolaus Marx and Daniel Walcher© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/769483During the recent years, multiple studies demonstrated that C-peptide is not an inert peptide, but exerts important physiological effects. C-peptide binds to cell membranes, stimulates the Na,K-ATPase and the endothelial nitric oxide (NO) synthase. Moreover, there is evidence that C-peptide decreases glomerular hyperfiltration and increases glucose utilisation. Nevertheless, there is still limited knowledge concerning mechanisms leading to an increased glucose utilisation either in rats or in humans. The aim of this paper is to give an overview over the published studies regarding C-peptide and glucose metabolism from in vitro studies to longer lasting studies in humans.B. Wilhelm, P. Kann, and A. Pfützner© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/635158C-peptide, a cleavage product of the proinsulin molecule, has long been regarded as biologically inert, serving merely as a surrogate marker for insulin release. Recent findings demonstrate both a physiological and protective role of C-peptide when administered to individuals with type I diabetes. Data indicate that C-peptide appears to bind in nanomolar concentrations to a cell surface receptor which is most likely to be G-protein coupled. Binding of C-peptide initiates multiple cellular effects, evoking a rise in intracellular calcium, increased PI-3-kinase activity, stimulation of the Na+/K+ ATPase, increased eNOS transcription, and activation of the MAPK signalling pathway. These cell signalling effects have been studied in multiple cell types from multiple tissues. Overall these observations raise the possibility that C-peptide may serve as a potential therapeutic agent for the treatment or prevention of long-term complications associated with diabetes.Claire E. Hills and Nigel J. Brunskill© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/672021Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: 4.80±1.41 (P = .009) and 2.34±1.47 (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load.A. Major-Pedersen, N. Ihlemann, T. S. Hermann, B. Christiansen, H. Dominguez, B. Kveiborg, D. B. Nielsen, O. L. Svendsen, L. Køber, and C. Torp-Pedersen© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2008/457912Recent results indicate that proinsulin C-peptide, contrary to previous views, exerts important physiological effects and shows the characteristics of a bioactive peptide. Studies in type 1 diabetes, involving animal models as well as patients, demonstrate that C-peptide in replacement doses has the ability to improve peripheral nerve function and prevent or reverse the development of nerve structural abnormalities. Peripheral nerve function, as evaluated by determination of sensory nerve conduction velocity and quantitative sensory testing, is improved by C-peptide replacement in diabetes type 1 patients with early stage neuropathy. Similarly, autonomic nerve dysfunction is ameliorated following administration of C peptide for up to 3 months. As evaluated in animal models of type 1 diabetes, the improved nerve function is accompanied by reversal or prevention of nerve structural changes, and the mechanisms of action are related to the ability of C-peptide to correct diabetes-induced reductions in endoneurial blood flow and in Na+,K+-ATPase activity and modulation of neurotrophic factors. Combining the results demonstrates that C-peptide may be a possible new treatment of neuropathy in type 1 diabetes.Karin Ekberg and Bo-Lennart Johansson© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/76271High prevalence rates of type 2 diabetes are being observed in native Canadian communities. It is believed that native populations have a higher prevalence rate of vascular complications than nonnatives. The Southern Alberta Study of Diabetic Retinopathy (DR) examined the prevalence and incidence of DR and associated metabolic abnormalities in native and nonnative subjects. Prevalence rates of DR in type 2 diabetic native and nonnative subjects were identical, with a prevalence rate of 40%. Native subjects with retinopathy, however, tended to have more advanced changes of retinopathy compared to the nonnative subjects. Key factors such as A1c, blood pressure, duration of diabetes, and lipid values were not significantly different between the two cohorts. These data indicate that ethnicity does play a role in the development and severity of DR but potential risk factors that may affect the development of retinopathy are not significantly different between native and nonnative groups.Stuart A. Ross, Anne McKenna, Sheila Mozejko, and Gordon H. Fick© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/69527Subrata Chakrabarti© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/31867 Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-κB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.Zia A. Khan and Subrata Chakrabarti© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/67435The Siraitia grosvenorii polysaccharide (SGP) from the Siraitia grosvenorii (Swingle) was isolated and purified. The therapeutic effects of SGP on diabetic rabbits induced by feeding high fat/high sucrose chow were studied. After administration of SGP for 4 weeks, the fasting blood glucose (FBG), plasma insulin levels (INS), plasma total cholesterol (TC), triglyceride (TG), and HDL-C were assayed. The results showed that administration of SGP can significantly decrease plasma total cholesterol, triglyceride, and glucose levels; and increase HDL-C levels after 4 weeks of treatment. The antihyperglycaemic effect of SGP at dose of 100 mg⋅kg−1 bw was the most significant in three dosage groups. Furthermore, SGP could restore the blood lipid levels of diabetic rabbits (P<.05). These data indicate that SGP not only ameliorates the lipid disorder, but also lowers plasma glucose levels. So SGP have obvious glucose-lowering effect on hyperglycaemic rabbits induced by feeding high fat/high sucrose chow, its mechanism may be related to amelioration of lipid metabolism and restoring the blood lipid levels of hyperglycaemic rabbits. Guo-Ping Lin, Tao Jiang, Xiao-Bo Hu, Xin-Hui Qiao, and Qin-Hui Tuo© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/95103Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-κB, increased production of nitric oxide, prostaglandin E2, IL-1β, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.Timothy S. Kern© 2008, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2007/61038The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.Mara Lorenzi© 2008, Hindawi Publishing Corporation. All rights reserved.