In islets from individuals with type 2 diabetes and in islets exposed to chronic elevated glucose, mitochondrial energy metabolism is impaired. Here, we studied early metabolic changes and mitochondrial adaptations in human beta cells during chronic glucose stress.Respiration and cytosolic ATP changes were measured in human islet cell clusters after culture for 4 days in 11.1 mmol/l glucose. Metabolomics was applied to analyse intracellular metabolite changes as a result of glucose stress conditions. Alterations in beta cell function were followed using insulin secretion assays or cytosolic calcium signalling after expression of the calcium probe YC3.6 specifically in beta cells of islet clusters.At early stages of glucose stress, mitochondrial energy metabolism was augmented in contrast to the previously described mitochondrial dysfunction in beta cells from islets of diabetic donors. Following chronic glucose stress, mitochondrial respiration increased (by 52.4%, p ...

Type 2 diabetes can be viewed as a failure of the pancreatic beta-cell to compensate for peripheral insulin resistance with enhanced insulin secretion. This failure is explained by both a relative loss of beta-cell mass as well as secretory defects that include enhanced basal secretion and a selective loss of sensitivity to glucose. These features are reproduced by chronic exposure of beta-cells to fatty acids (FAs), suggesting that hyperlipidemia might contribute to decompensation. Using MIN6 cells pretreated for 48 h with oleate or palmitate, we have previously defined alterations in global gene expression by transcript profiling and described additional secretory changes to those already established (Busch A-K, Cordery D, Denyer G, Biden TJ: Diabetes 51:977-987, 2002). In contrast to a modest decoupling of glucose-stimulated insulin secretion, FA pretreatment markedly enhanced the secretory response to an acute subsequent challenge with FAs. We propose that this apparent switch in sensitivity from

Understanding the molecular mechanisms behind beta cell dysfunction is essential for the development of effective and specific approaches for diabetes care and prevention. Physiological human beta cell models are needed for this work. We review the possibilities and limitations of currently availabl …

Developmental insults during gestation, such as under-nutrition, are known to restrict the number of beta cells that form in the fetal pancreas and are maintained in adulthood, leading to increased risk of type 2 diabetes. There are now substantial data indicating that glucocorticoids mediate this effect of under-nutrition on beta cell mass and that even at physiological levels they restrain fetal beta cell development in utero. There are emerging clues that this occurs downstream of endocrine commitment by neurogenin 3 but prior to terminal beta cell differentiation. Deciphering the precise mechanism will be important as it might unveil new pathways by which to manipulate beta cell mass that could be exploited as novel therapies for patients with diabetes.. ...

Analysis of Beta-Cell Gene Expression Reveals Inflammatory Signaling and Evidence of Dedifferentiation following Human Islet Isolation and Culture. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.

GSIS assays (Glucose Stimulated Insulin Secretion) have been the gold-standard for determining the functionality of a beta cell. Study of dynamic insulin release with perfusion assays is a crucial component of beta cell research. Up to now, heterogeneity in islet size and composition decreased experimental resolution, limits reproducibility and capability of using human islets for medium or large throughput GSIS screening and assay modeling. Both scientists from academia and industry are looking for large quantity of robust and functional human beta cells.. There is a growing need for better predictive tools to assess human beta cell dysfunction early in the drug development process. The authors at Novo Nordisk note in their publication, that they have now successfully used EndoC-βH1 as a screening platform for early drug discovery with regards to insulin secretion and beta cell proliferation and identified several interesting peptides and proteins. According to the authors from Novo ...

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that, together, cause the highest rate of proliferation ever observed in adult human beta cells-the cells in the pancreas that produce insulin-without harming most other cells in the body. The result is an important step toward a diabetes treatment that restores the bodys ability to produce insulin.. The finding involved one type of drug that is known to cause beta cells to proliferate and another that is already in widespread use in people with diabetes. Together, they caused the cells to proliferate at a rate of 5 to 6 percent per day. The study was published today in Science Translational Medicine online.. We are very excited about this new drug combination because for the first time ever, we are able to see rates of human beta-cell replication that are sufficient to replenish beta-cell mass in humans with diabetes, said Andrew Stewart, MD, Director of the Mount Sinai ...

Shop Pancreatic beta cell growth factor ELISA Kit, Recombinant Protein and Pancreatic beta cell growth factor Antibody at MyBioSource. Custom ELISA Kit, Recombinant Protein and Antibody are available.

Glucagon-like peptide-1 (GLP-1), an insulinotropic and glucoincretin hormone, is a potentially important therapeutic agent in the treatment of diabetes. We previously provided evidence that GLP-1 induces pancreatic beta-cell growth nonadditively with glucose in a phosphatidylinositol-3 kinase (PI-3K)-dependent manner. In the present study, we investigated the downstream effectors of PI-3K to determine the precise signal transduction pathways that mediate the action of GLP-1 on beta-cell proliferation. GLP-1 increased extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and protein kinase B activities nonadditively with glucose in pancreatic beta(INS 832/13) cells. GLP-1 also caused nuclear translocation of the atypical protein kinase C (aPKC) zeta isoform in INS as well as in dissociated normal rat beta-cells as shown by immunolocalization and Western immunoblotting analysis. Tritiated thymidine incorporation measurements showed that the p38 MAPK inhibitor SB203580

The prevalence of Diabetes Mellitus has reached epidemic proportions world-wide, and is predicted to increase rapidly in the years to come, putting a tremendous strain on health care budgets in both developed and developing countries. There are two major forms of diabetes and both are associated with decreased beta-cell mass. No treatments have been devised that increase beta-cell mass in vivo in humans, and transplantation of beta-cells is extremely limited due to lack of appropriate donors. For these reasons, increasing functional beta-cell mass in vitro, or in vivo prior to or after transplantation, has become a Holy Grail of diabetes research. Our previous studies clearly show that adult human beta-cells can be induced to replicate, and - importantly - that cells can maintain normal glucose responsiveness after cell division. However, the replication rate achieved was still low, likely due in part to the known age-related decline in the ability of the beta-cell to replicate. We propose to ...

Insulin resistance and pancreatic beta cell dysfunction are major contributors to the pathogenesis of diabetes. Various conditions play a role in the pathogenesis of pancreatic beta cell dysfunction and are correlated with endoplasmic reticulum (ER) stress. Pancreatic beta cells are susceptible to ER stress. Many studies have shown that increased ER stress induces pancreatic beta cell dysfunction and diabetes mellitus using genetic models of ER stress and by various stimuli. There are many reports indicating that ER stress plays an important role in the impairment of insulin biosynthesis, suggesting that reduction of ER stress could be a therapeutic target for diabetes. In this paper, we reviewed the relationship between ER stress and diabetes and how ER stress controls insulin biosynthesis.

Recent studies suggested that in older mice, beta cells lose their regenerative potential and cannot respond to mitogenic triggers. in replication rate of beta cells 64048-12-0 in young transgenic mice. Islet architecture and glucose threshold slowly normalized, indicating practical significance of compensatory beta cell replication in this establishing. Finally, administration of a small molecule glucokinase activator to older mice doubled the rate of recurrence of beta cell replication, further showing that older 64048-12-0 beta cells can respond to the mitogenic result in of enhanced glycolysis. We consider that the potential for functionally significant compensatory expansion of beta cells is definitely retained in older mice, despite a decrease in basal replication rate. test. A value < 0.05 was considered significant. Data are offered as mean H.E. RESULTS Beta Cell Mutilation in Old Mice To characterize the characteristics of beta cell mutilation in older mice, we prepared a cohort of ...

phdthesis{ef479246-001e-4db0-bb31-b145ccaa5214, abstract = {Beta cell function is an important factor in the development of both Type 1 (T1D) and Type 2 (T2D) diabetes mellitus. T1D is characterized by a primary defect in insulin secretion due to the immune-mediated beta cell destruction, however, the more common T2D beside insulin resistance also include impaired beta cell function as a consequence to abnormal glucose homeostasis. Genetic susceptibility is involved in both types of diabetes. We have studied several genetic and immunological factors affecting beta cell function. ,br/,,br, ,br/,,br, First, we tested whether single nucleotide polymorphisms (SNPs) of the human Free Fatty Acid Receptor 1 (FFAR1) are associated with T2D and insulin secretion. Another genetic study focused on FOXP3 association with T1D and the disease-related clinical parameters. The role of microRNAs (miRNAs) on beta cell function was studied in the third project using a novel genetically engineered mouse model. ...

Foodborne Cereulide Causes Beta-Cell Dysfunction and Apoptosis. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.

TY - JOUR. T1 - Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death. T2 - A Multi-laboratory Assay Comparison. AU - Speake, Cate. AU - Ylescupidez, Alyssa. AU - Neiman, Daniel. AU - Shemer, Ruth. AU - Glaser, Benjamin. AU - Tersey, Sarah A.. AU - Usmani-Brown, Sahar. AU - Clark, Pamela. AU - Wilhelm, Joshua J.. AU - Bellin, Melena D.. AU - Herold, Kevan C.. AU - Mirmira, Raghavendra G.. AU - Dor, Yuval. AU - Evans-Molina, Carmella. N1 - Funding Information: Funding Statement: This research was performed using funding provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported Human Islet Research Network Opportunity Pool Fund (HIRN, RRID:SCR_014393; https://hirnetwork.org; U01 DK104162 to CEM), and by JDRF under the Core for Assay Validation grants #3-SRA-2016-209-Q-R to S. Alice Long and 3-SRA-2019-791-S-B to CS. KCH received support from R01 DK057846, UC4 DK104205-01, and R21 AI135562. KCH and SUB have support from R43 DK116577. ...

We present evidence that, in addition to immune cell types, mouse and human pancreatic beta cells express CD40. Its expression is upregulated by proinflammatory stimuli, and signalling through this receptor activates NF-kappaB. We suggest that the effects of inflammatory stimuli that affect beta cel …

all beta cells and people with the disease would have to take insulin for life But we know that some beta cells do survive and secrete insulin even when the patients have had type 1 diabetes for 50 years says senior author Rohit N Kulkarni M D Ph D Associate Professor of Medicine at Harvard Medical School and the principle investigator of the project at Joslin In this study Joslin researchers were interested in learning exactly how immune cells could promote beta cell growth and identifying the type of cell and the mechanisms underlying this effect In a series of experiments the researchers injected NOD mice with immune cells from the pancreatic islets of donor NOD mice and assessed their effects on beta cells The immune cells tested included subtypes of B or T immune cells Dirice the lead author of the study found that it is T cells not B cells that are associated with beta cell proliferation Mice that received B cells showed no difference in beta cell growth Mice that received the T cell ...

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Increased glycemic variability has been proposed as an independent predictor of hypoglycemia in diabetic patients. Likewise, episodes of dysglycemia have been found to be predictive of diabetes in antibodypositive nondiabetic individuals. We hypothesise that an in-depth observational study comparing state-of-the-art measures of functional beta cell mass and glycemic variability will specify the relationship between both variables over a broad range of residual function and will identify treatment goals for functional beta cell mass to be reached in future beta cell therapy trials in order to avoid frequent hypoglycemia in patients and dysglycemia in risk groups. The available expertise and infrastructure (see background and (inter)national context) place the promoters of the present project in a unique position to carry out the planned experiments and support their feasibility ...

Juan-Mateu, Jonàs et al SRp55 Regulates a Splicing Network that Controls Human Pancreatic Beta Cell Function and Survival. Diabetes (2017): db170736. Web. 22 Jan. 2018. ...

While the mechanisms by which glucose regulates insulin secretion from pancreatic beta cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralogue ChREBP, is the predominant glucose-responsive transcription factor in human pancreatic beta EndoC-βH1 cells and in human islets. In high glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes ARRDC4 and TXNIP, the latter being a protein strongly linked to beta-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human beta cells, using forskolin or the GLP-1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in beta cells that coordinates transcriptional ...

Our What?. One of the family of signals that the Huising lab studies, is named for the stress peptide Corticotropin Releasing Factor, or CRF in short. CRF was originally discovered as the principal hypothalamic factor to initiate the stress response by acting on the pituitary gland. It turns out that the insulin-producing beta cells of the pancreas can respond directly to CRF with increased insulin secretion, increased beta cell proliferation and reduced beta cell death in the face of pro-inflammatory insults, which is a promising set of beneficial characteristics united in a single molecule. Urocortin3 (Ucn3), a peptide related to CRF, is abundantly expressed by mature beta cells. We discovered that Ucn3 is co-released with insulin to trigger somatostatin release from neighboring delta cells, which in turn inhibits insulin secretion. In essence, Ucn3 triggers a negative feedback loop that attenuates insulin secretion, provided that glucose levels are successfully reduced. Ucn3 expression also ...

BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were ...

D-glucose regulates maintenance and function of pancreatic beta-cells. Several studies have shown that IRS-2, but not IRS-1, is necessary to maintain and sufficient to expand functional beta-cell mass. We therefore analyzed the expression of IRS-2 and IRS-1 in beta-cells after culture in the presence of various concentrations of D-glucose and other metabolisable or non-metabolisable hexoses. D-glucose increased Irs-2 transcription and IRS-2 accumulation in a dose-dependent manner (1.6 to 25 mmol/l), with a 3-fold increased plateau after 10 h. In contrast, the expression of IRS-1 remained unaffected. D-glucose also induced phosphorylation of IRS-2 while non-metabolisable hexoses did neither affect expression nor phosphorylation. D-glucose-mediated elevation and phosphorylation of IRS-2 were independent of autocrine insulin action although insulin itself could transiently and slightly enhance IRS-2 expression. ...

Prof. Melton stated his optimism about the future of diabetes treatment: Semmas scientists have very effectively dedicated themselves to systems that reliably generate cells indistinguishable from human pancreatic beta cells and to the invention of novel devices that are immunologically protective and surgically practical. Were very encouraged and excited about the potential this program has for diabetic patients and their families.. ...

Several groups have overexpressed Pdx1 protein in the liver of STZ-induced diabetic mice but have not succeeded in producing selective pancreatic endocrine differentiation (4,6,7,21). Instead, severe hepatitis, presumably caused by the production of exocrine enzymes such as amylase, elastase, and chymotrypsin (7), and dysmorphogenesis, such as abnormal lobe structures and multiple cystic lesions (21), were recently reported. The conclusion drawn from these in vivo animal studies is that ectopic expression of Pdx1 alone in the liver initiates both endocrine and exocrine pancreas differentiation and is insufficient to induce selective endocrine pancreas differentiation. Recent work by Zalzman et al. (22) has shown that introduction of Pdx1 into human fetal liver progenitor cells by lentivirus resulted in the expression of Ngn3, Beta2, and Nkx6.1 genes, but not Nkx2.2, Isl-1, Pax4, and Pax6 genes and was able to rescue diabetic mice, although a complete analysis was not performed. This observation ...

With an RD Lawrence Fellowship from Diabetes UK, Dr Cantley will use state-of-the-art techniques in molecular and cell biology to study the mechanisms by which ACC1 works in human and mouse beta cells in the laboratory. Specifically, he will look at the influence of ACC1 on beta cell size and number in response to metabolic challenges such as obesity and pregnancy. Dr Cantley will focus on ACC1 activity in mice, isolated mouse islets, mouse and human beta cells in the lab, and human islets. He will then monitor its impact on different aspects of beta cell function (such as insulin release, cell structure within the pancreas and the expression of genes and proteins).. ...

With a single stimulatory molecule, human insulin-producing beta cell replication can be sustained for at least four weeks in a mouse model of diabetes...

Oxidative Medicine and Cellular Longevity is a unique peer-reviewed, Open Access journal that publishes original research and review articles dealing with the cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, metabolism, cellular survival and cellular longevity. Oxidative stress impacts almost all acute and chronic progressive disorders and on a cellular basis is intimately linked to aging, cardiovascular disease, cancer, immune function, metabolism and neurodegeneration. The journal fills a significant void in todays scientific literature and serves as an international forum for the scientific community worldwide to translate pioneering

A hot topic in the type 2 diabetes world is whether we have in hand the tools to stop the decline in beta cell function that typifies this disease and, consequently, a therapy or therapies that successfully control blood glucose for many years - so-called treatment durability. Actually this is three topics. What are the specific mechanisms for the beta cell failure? Do any of our existing therapies, or those on the drawing board, reverse these mechanisms to slow or stop the beta cell failure? ...

Insufficient pancreatic beta-cell mass is fundamental to the pathogenesis of both types 1 and 2 diabetes and constitutes the basis for the goal of beta-cell replacement therapy. Current methods for isolating islets from organ donor pancreases do not come close to supplying all in need, thus providing a compelling need to find new sources of insulin-producing cells. Possible sources include generation of cells from embryonic stem cells (ESC), adult stem/precursor cells, transdifferentiation of other cell types and xenodonors. Bioengineering can be used to improve secretory performance and strengthen cells to better withstand the challenges of transplantation. Strategies include protection against hypoxia, inflammation, and immune attack.

Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, we report that metabolic stress markedly enhances macroautophagy-independent lysosomal degradation of nascent insulin granules. In different model systems of diabetes including of human origin, stress-induced nascent granule degradation (SINGD) contributes to loss of insulin along with mammalian/mechanistic Target of Rapamycin (mTOR)-dependent suppression of macroautophagy. Expression of Protein Kinase D (PKD), a negative regulator of SINGD, is reduced in diabetic β cells. Pharmacological activation of PKD counters SINGD and delays the onset of T2D. Conversely, inhibition of PKD exacerbates SINGD, mitigates insulin secretion and accelerates diabetes. Finally, reduced levels of lysosomal tetraspanin CD63 prevent SINGD, leading to increased insulin secretion. Overall, our findings

In vitro expansion of beta-cells from adult human islets could solve the tissue shortage for cell replacement therapy of diabetes. Culture of human islet cells typically results in |16 cell doublings and loss of insulin expression. Using cell lineage

Viral infections and local production of IFNgamma might contribute to beta-cell dysfunction/death in Type 1 diabetes. Double stranded RNA accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (polyinosinic-polycytidylic acid, PIC) in combination with IFNgamma results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFNgamma-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFNgamma, PIC or a combination of both agents. The gene expression profile was analyzed in duplicate with the Affymetrix RG U34A microarray.

PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

As reported by JDRF, funded scientists at the University of Pittsburgh in America have uncovered a new way to grow human beta cells in the lab.. The team led by Professor Andrew Stewart, were able to get human beta cells to divide and make more cells. Not only that, but they then managed to stop the cells dividing again. The research was published in this months issue of the journal Diabetes.. The researchers added genes called cdk and cyclin d into the beta cells. These genes make the cells divide and are usually switched off in beta cells. To deliver these genes into the cells they used a virus that can get into cells easily. Once they had enough beta cells, they added a drug to the cells which switched off the virus and stopped the cells dividing.. In the body, beta cells divide very slowly or not at all so when the immune system attacks them, the cells are not replaced. Usually in type 1 diabetes there are a few beta cells remaining and if scientists could make these cells divide they could ...

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by the loss of beta-cell secretory function and mass. The pathophysiology of beta-cell failure in T2DM involves a complex...

Human beta cell proliferation was once unthinkable, but now it is absolutely possible, says the senior author of a new study in cell cultures and in mice. The field is moving rapidly.

Its important to remember that individual cells do not last as long as people live. Cells naturally die and new cells grow within your body all the time. Research (mostly in animals) has suggested that Vildagliptin might have two separate effects on beta cells. On the one hand, it seems to cause beta cells to naturally divide and grow, and on the other hand, it seems to delay beta cells natural death, so they live longer. Both of these effects may be important to curing type-1 diabetes, but it is not clear. This is why research is important. For example, even if Vildagliptin triggers a divide-and-grow reaction, it will only be effective if there are some beta cells to start with, and we just dont know if there are enough to get things started. On the cell death side, if the autoimmune attack directly kills beta cells, then stopping natural cell death may have little impact. Those cells will be killed by autoimmunity before they can die of old age. However, if the autoimmune attack works ...

Their non-profit company, Tenth Muse Films, hopes to raise the curtain in 2017 on The Human Trial, a film that will showcase the need for sustained philanthropic investment to bring about breakthrough technologies, in this case the implantation of pancreatic cells. Their first project is focused on ViaCyte, a San Diego biotech which is trying to use a novel approach to implant pancreatic progenitor cells into people with diabetes that will mature into functional beta cells. (The filmmakers have no affiliation nor financial connection with any of the companies or entities appearing in the film.). ViaCyte is testing a product identified as a VC-01 combination device. Its a mesh pouch encapsulated in a pliable membrane which allows hormones, metabolic fluids, and oxygen to migrate, but resists immune system T-cell invasion. T-cells in people with Type 1 often target implanted beta cells, making beta cell transplant a very frustrating treatment option.. The VC-01, dubbed the teabag, is designed ...

Researchers in the lab of Gordon Weir, M.D., looked at a cellular stress mechanism called the unfolded protein response or endoplasmic reticulum (ER) stress response in beta cells. This response is triggered when the ER, part of the cells protein assembly line, struggles to fold newly formed proteins into their exactly right shapes.. Earlier studies suggested this process contributes to the high mortality and low insulin production often displayed in beta cell transplants, which aim to replace cells that the bodys own immune system kills off in type 1 diabetes.. In work reported in the journal PLoS One in June, the scientists compared healthy human beta cells from surgical donors with beta cells that had been transplanted into mice with suppressed immune systems. They found that the transplanted cells strongly activate genes that help to guard against damage from ER stress, and suppress other genes that may trigger cellular attempts to self-destruct.. Not only is this response likely to be ...

J:194010 Iglesias J, Barg S, Vallois D, Lahiri S, Roger C, Yessoufou A, Pradevand S, McDonald A, Bonal C, Reimann F, Gribble F, Debril MB, Metzger D, Chambon P, Herrera P, Rutter GA, Prentki M, Thorens B, Wahli W, PPARbeta/delta affects pancreatic beta cell mass and insulin secretion in mice. J Clin Invest. 2012 Nov 1;122(11):4105-17 ...

Search PubMed for more publications by Feyza Engin. 1. Engin, F. ER Stress and Development of Type 1 Diabetes J Investig Med. 2015.. 2. Brozzi, F., Nardelli, TR., Lopes, M., Millard, I., Barthson, J., Igoillo-Esteve, M., Grieco, FA., Villate, O., Oliveira, JM., Casimir, M., Bugliani, M., Engin, F., Hotamisligil, GS., Marchetti, PM., Eizirik, DL. Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia. 2015.. 3. Engin, F., Ngyuen T., Yermalovich A., Hotamisligil, GS. Aberrant unfolded protein response in type 2 diabetes. Sci Rep. 2014.. 4. Engin, F., Yermalovich, A., Fu, W., Ngyuen, T., Hummasti, S., Decio, L., Eizirik., Mathis, D., Hotamisligil, GS. Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Sci. Transl. Med. 2013.. 5. Engin, F., Hotamisligil, GS. Chemical modulation of ER function in metabolic diseases. Diabetes Obes. Metab. 2010. 12 Suppl 2:108-15.. 6. ...

Over the past several years, JDRF-funded researchers have found evidence that beta cell stress may play a role in the onset of T1D, and are exploring possible ways to stop it from occurring, thus potentially protecting beta cell health and maintaining normal beta cell function. In April, JDRF-funded researchers in Finland released new findings in the journal CellPress that add another piece to the puzzle of beta cell stress and T1D.

But what if other cells in the body could be coaxed into ever pancreatic beta cells? Could we possibly cure diabetes?Researchers at UCLA Larry L www.erectalis

The Effect of Rosuvastatin on Insulin Sensitivity and Pancreatic Beta-Cell Function in Nondiabetic Renal Transplant Recipients / A. Sharif, V. Ravindran, R. Moore, G. Dunseath, S. Luzio, D. Owens, K. Baboolal, Gareth Dunseath, Steve Luzio ...

Pretreatment of pancreatic beta cells with pertussis toxin resulted in a 30% increase in peak whole-cell Ca2+ currents recorded in the absence of exogenous intracellular guanine nucleotides. Intracellular application of 90 microM GTP[gamma S], by liberation from a caged precursor, resulted in 40% reduction of the peak Ca2+ current irrespective of whether the current was carried by Ca2+ or Ba2+. Effects on the delayed outward K+ current were small and restricted to a transient Ca(2+)-dependent K+ current component. Inhibition by GTP[gamma S] of the Ca2+ current was not mimicked by standard GTP and could not be prevented either by pretreatment with pertussis toxin or by inclusion of GDP[beta S] or cyclic AMP in the intracellular medium. The inhibitory effect of GTP[gamma S] could be counteracted by a prepulse to a large depolarizing voltage. A similar effect of a depolarizing prepulse was observed in control cells with no exogenous guanine nucleotides. These observations indicate that inhibition of beta

Author: Gylfe, E. et al.; Genre: Journal Article; Published in Print: 1993-08; Title: Triphasic changes of cytoplasmic CA2+ associated with early glucose effects on beta-cell membrane potential.

In This Section1 What is Type 2 Diabetes?2 Pre-diabetes3 Genetics and Beta Cell Function4 Beta Cell Function Decline and Progression to Diabetes5 Obesity and Beta Cell Function6 Beta Cell Failure7 Summary8 References What is Type 2 Diabetes? Type 2 diabetes is characterized by abnormally high blood glucose levels. The disease is multifactorial and has several risk factors, including obesity and family history. Type 2 diabetes occurs when the pancreatic beta cells that secrete insulin become dysfunctional. At first, the beta cells release large amounts of insulin to compensate for the elevated blood glucose levels. Over time the disease can progress to the point of complete beta cell failure and patients can become dependent on insulin replacement therapy. Pre-diabetes Pre-diabetes is characterized by blood glucose levels that are elevated but not high enough for a diabetes diagnosis. Typically, a hemoglobin A1c level of 5.7% - 6.4% is indicative of pre-diabetes. Patients

TY - JOUR. T1 - Hydrochlorothiazide: An hyperglycaemia-inducing agent and K-ATP channel agonist in human beta-cells and clonal insulin-secreting cells.. AU - Barnes, PD. AU - OBrien, RE. AU - Abdel-Wahab, Yasser. AU - Cosgrove, KE. AU - Flatt, Peter. AU - Dunne, MJ. PY - 1999/8. Y1 - 1999/8. M3 - Article. VL - 42. SP - 482. JO - Diabetologia. JF - Diabetologia. SN - 0012-186X. IS - Suppl.. ER - ...

Wolfram syndrome, also referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a genetic syndrome characterized by beta-cell dysfunction and apoptosis leading to diabetes, neurodegeneration and psychiatric illness. Accumulating evidence indicates that beta-cell failure and neuronal cell dysfunction in Wolframs syndrome results from a high level of ER stress in affected cells. The current treatment of Wolfram syndrome is insulin, which fails to prevent the progression of beta-cell failure.. Several studies showed that GLP-1 analogs are very effective in protecting beta-cells from ER stress. Herein, the investigators suggest studying the impact of GLP-1 analogs in the treatment of patients with Wolfram syndrome.. The investigators will Study the effects of GLP-1 analog (Exanatide) on beta-cell function and glycemic control of patients with Wolfram syndrome. Evaluation of beta cell function will be done by performing meal test and IVGTT test before starting ...

The various endocrine cell types present in mammalian Islets of Langerhans express a range of lipid-responsive G-proteln coupled receptors (GPCRs) including GPR119 and GPR120. These are each reported to be expressed In islet beta-cells and GPR 119 has been Implicated In the augmentation of glucose-stimulated insulin secretion by certain derivatives of long chain unsaturated fatty acids. By contrast GPR 120 does not appear to regulate insulin secretion and its role is unclear In addition to their ability to regulate hormone secretion long-chain fatty acids and their derivatives can also influence beta-cell viability but It IS unclear whether GPCRs are involved in mediating this response Therefore. the work undertaken in thesis has explored the possible involvement of GPR119 and GPR120 in the regulation of beta-cell viability. Long chain fatty acids exert differential effects on beta-cell viabilty according to their chain length and degree of unsaturation. Saturated molecules with chain lengths of ...

This study will compare the effects of olmesartan medoxomil and amlodipine on beta-cell function and the incidence diabetic angiopathy in type 2 diabetic

The beta cells are particularly important because they make insulin. Degeneration of the beta cells is the main cause of type I (insulin-dependent) diabetes mellitus.

Previously published gene expression analyses suggested that apoptotic function may be reduced in humans relative to chimpanzees and led to the hypothesis that this difference may contribute to the relatively larger size of the human brain and the increased propensity of humans to develop cancer. In this study, we sought to further test the hypothesis that humans maintain a reduced apoptotic function relative to chimpanzees by conducting a series of apoptotic function assays on human, chimpanzee and macaque primary fibroblastic cells. Human cells consistently displayed significantly reduced apoptotic function relative to the chimpanzee and macaque cells. These results are consistent with earlier findings indicating that apoptotic function is reduced in humans relative to chimpanzees.

Brusatol is a natural terpenoid that is capable of inducing a variety of biological effects. We presently report that this substance dramatically improves beta-cell survival when exposed to pro-inflammatory cytokines (IL-1 beta and IFN gamma) in vitro. This was observed in insulin producing rat (RIN-5AH), mouse (beta TC6) and human (EndoC-beta H1) beta-cell lines. Brusatol prevented beta-cell oxidative stress in response to cytokines and counteracted induction of iNOS on the protein level. Brusatol, however, block neither the cytokine-induced increase of iNOS mRNA, nor NF-kappa B activation, suggesting that inhibition of iNOS protein expression relies on posttranscriptional mechanism. This indicates that brusatol acts via a novel protective pathway, which may represent a more promising way of improving beta-cell function and survival.. ...

AIM/HYPOTHESIS: Increased expression of haeme-oxygenase 1 (HO1) and other antioxidant enzymes could improve pancreatic beta-cell survival under stressful conditions, including hyperglycaemia. However, how hyperglycaemia increases islet HO1 expression is not known. METHODS: Rat islets were pre-cultured for 1 week in RPMI medium containing 10 mmol x l(-1) glucose (G10), and further cultured overnight in G5-G30 plus various test substances. Islet HO1 mRNA and protein expression was measured by semiquantitative RT-PCR, western blot, and immunohistochemistry. RESULTS: Islet HO1 mRNA expression was minimal after overnight culture in G10, slightly increased in G5, and increased by five- to ten-fold in G30 in parallel with a heterogeneous increase in beta-cell HO1 protein expression. The effect of G30 was fully inhibited by agents decreasing cytosolic Ca2+ (diazoxide, nimodipine), but was only slightly reproduced by agents raising Ca2+ (tolbutamide, 30 mmol x l(-1) potassium). It was also suppressed by ...

IGFs are important regulators of pancreatic beta-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes

Preparation of Recombinant Adenoviruses. All first-generation recombinant adenoviruses were constructed according to Becker et al. (18). Generation of Ad-RIP-GFP and the bifunctional recombinant Ad-RIP-GFP-CMV-PDX-1 adenoviruses is described in Supporting Methods, which is published as supporting information on the PNAS web site.. Human Liver Cells. Adult human liver (AHL) tissues were obtained from eight different liver transplantation surgeries from 4- to 10-year-old children and three individuals ,40 years old. Fetal human livers were obtained from four deliberate abortions of 20-22 weeks of gestation. Both adult and fetal liver tissues were used with approval from the Committee on Clinical Investigations (Institutional Review Boards of Sheba Medical Center and Rabin Medical Center).. Cell Harvest and Culture Conditions. Isolation of human liver cells was performed as described (19). Briefly, liver samples were cut into thin slices (1- to 2-mm thickness), and digested by 0.03% collagenase ...

Understanding the mechanisms underlying beta-cell failure in diabetes constitutes a fundamental challenge for diabetes research. Beta-cell stress and dysfunction contributes to diabetes in both type 1 and type 2 diabetes. In this project, we are exploring the regulatory functions of intermediate filament keratins in pancreatic beta-cell biology under basal circumstances as well in diabetes. It is wellknown that mutations in keratins cause or predispose to many human liver and skin diseases, but the involvement of keratins in diabetes or in beta-cell biology is still insufficiently known. Our earlier research indicates that keratins participate in maintaining blood glucose regulation, beta-cell protein targeting, mitochondrial function and insulin content. Reduced keratin 8 levels moreover increases murine diabetes susceptibility, and early diabetes development is accompanied by keratin upregulation in the pancreatic beta-cells. Pancreatic keratins are thus involved in essential beta-cell ...

The current study demonstrates that overweight/obese adolescents meeting the ADA HbA1c diagnostic criteria (2) for prediabetes have evidence of impaired β-cell function relative to insulin sensitivity, a metabolic signal for heightened risk of type 2 diabetes (27). This finding persisted after adjustment for race and for the greater adiposity in the youth with elevated HbA1c. These data support our hypothesis that alterations in the pathophysiologic mechanisms of type 2 diabetes are evident in the ADA-recommended at-risk/prediabetes category (HbA1c 5.7 to ,6.5%).. Since the release of the HbA1c-based diagnostic criteria for prediabetes/diabetes by the ADA in 2010 (2), reports of adults and some in pediatrics have concluded that HbA1c is inferior to glycemic measures for diagnostic purposes (4-6,11). These studies evaluated the diagnostic sensitivity and specificity of HbA1c compared with glycemic measures, treating the latter as the gold standard. One such study determined that the inferior ...

A study in Cell Stem Cell demonstrates that a gene therapy approach can lead to the long-term survival of functional beta cells as well as normal blood glucose levels for an extended period of time in mice with type 1 diabetes. The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells.

Search PubMed for more publications by Alan Attie. Kreznar JH, Keller MP, Traeger LL, Rabaglia ME, Schueler KL, Stapleton DS, Zhao W, Vivas EI, Yandell BS, Broman AT, Hagenbuch B, Attie AD, Rey FE. Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell Rep 2017; 18:1739-1750. Attie AD, Churchill GA, Nadeau JH. How mice are indispensable for understanding obesity and diabetes genetics. Current Opinion in Endocrinology Diabetes and Obesity 2017; 24:83-91. Tian J, Keller MP, Broman AT, Kendziorski C, Yandell BS, Attie AD, Broman KW. The Dissection of Expression Quantitative Trait Locus Hotspots. Genetics 2016; 202:1563-1574. Paul PK, Rabaglia ME, Wang CY, Stapleton DS, Leng N, Kendziorski C, Lewis PW, Keller MP, Attie AD. Histone chaperone ASF1B promotes human beta-cell proliferation via recruitment of histone H3.3. Cell Cycle 2016; 15:3191-3202. Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey ...

Importantly, SIX3 and SIX2 are not expressed in mouse beta cells.. This is why it is so important to study human tissue, said Kim. Until now there has been no way of knowing the gradual changes that happen over a period of years.. Kim and his colleagues are planning to continue their studies of pancreatic and islet-cell development as part of a Stanford focus on diabetes and metabolism research. The researchers also anticipate that their gene expression data and newly described islet-cell isolation technique, coupled with the ongoing tissue procurement effort, will be helpful to others studying pancreatic development and diabetes.. This is a unique and valuable resource for researchers wishing to begin to understand how gene expression is dynamically regulated in human islet cells, said Kim. Our study charts a new road map for researchers working to use stem cells to replace human islet cells by highlighting changes that normally occur and should perhaps be taken into consideration when ...

The actions of thyroid hormone (TH) on pancreatic beta cells have not been thoroughly explored, with current knowledge being limited to the modulation of insulin secretion in response to glucose, and beta cell viability by regulation of pro-mitotic and pro-apoptotic factors. Therefore, the effects of TH on proinsulin gene expression are not known. This led us to measure: a) proinsulin mRNA expression, b) proinsulin transcripts and eEF1A protein binding to the actin cytoskeleton, c) actin cytoskeleton arrangement, and d) proinsulin mRNA poly(A) tail length modulation in INS-1E cells cultured in different media containing: i) normal fetal bovine serum - FBS (control); ii) normal FBS plus 1 M or 10 nM T3, for 12 h, and iii) FBS depleted of TH for 24 h (Tx). A decrease in proinsulin mRNA content and attachment to the cytoskeleton were observed in hypothyroid (Tx) beta cells. The amount of eEF1A protein anchored to the cytoskeleton was also reduced in hypothyroidism, and it is worth mentioning that ...

Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype ...

Genentech, a bioscience firm famous for its development of antibodies designed to combat cancer, has entered a $350 million agreement with Bayhill Therapeutics to assist in development of BHT-3021, a drug that treats type 1 diabetes by reducing or stopping immune system attacks on pancreatic beta cells.. Under the agreement, Genentech will pay $25 million in upfront to acquire an equity stake in Bayhill, plus another $325 million to finance development of BHT-3021.. Bayhills drug is based on its BHT-DNA antigen-specific immunomodulatory platform. Put simply, the drug has worked in trials by preventing T cells, the bodys immune systems soldiers from mistakenly attacking insulin-producing pancreatic islet cells.. Its done by inserting the gene for a protein that is a known target of the autoimmune system into a plasmid. (A plasmid is a small unit of DNA within a cell that can replicate itself independently of chromosomal DNA). In type 1s, the protein in question is proinsulin.. When the ...

The beta-cells of the pancreatic islets are the unique source of insulin, the main hormone for control of blood glucose and its use as an energy source in the body. A reduction in functional beta cell mass, either due to autoimmunity or prolonged insulin resistance, is a common denominator of different forms of diabetes mellitus.. Hence, a main goal of the CRTD is to protect and replace pancreatic islets in order to prevent and cure diabetes. The research is organized under the themes: ...

CD36 is increased in human islets from obese type 2 diabetes donors, and affects beta cell function by the modulation of exocytotic proteins and insulin content ...

Pancreatic beta cells help maintain normal blood glucose levels by producing the hormone insulin - the master regulator of energy (glucose). Impairment and the loss of beta cells interrupts insulin production, leading to type 1 and 2 diabetes. Using single-cell RNA sequencing, researchers at University of California San Diego School of Medicine have, for the first time, mapped out pathways that regulate beta cell growth that could be exploited to trick them to regenerate.

This Mouse Insulin (INS) ELISA kit is for the quantitative determination of Mouse Insulin concentrations in serum, plasma, cell culture supernates, tissue homogenates, cell lysates. 69+ citations.

Video created by University of Copenhagen for the course Diabetes - a Global Challenge. Inflammatory beta-cell destruction in diabetes by professor Thomas Mandrup-Poulsen. During this module we Professor Mandrup-Poulsen will guide you through ...

The ER stress in the beta cell has been implicated in type 2 diabetes, but its role in triggering beta cell dysfunction in type 1 diabetes has not been clear until now, which is why these findings are exciting, said Dr. Mirmira. Although the paper does not directly address a potential role for ER stress in the development of human T1D, what we observed in the mice is consistent with clinical observations of type 1 diabetes in people where defects in insulin secretion precede overt diabetes.. We need to look more closely at beta cells and their role in type 1 diabetes because they may be participating in their own demise, said Andrew Rakeman, Ph.D. Senior Scientist of Regeneration for JDRF. This study shows that beta cell stress is occurring at the earliest stages of the disease process, raising the intriguing possibility that beta cell stress could be part of the trigger for the autoimmune process that leads to type 1 diabetes. This is exciting because it not only teaches us something ...

Nuestros profesionales publican en revistas científicas de alto impacto con el objetivo de ofrecer a nuestros pacientes los últimos tratamientos. Clínica Universidad de Navarra.

HAMBURG, Germany , Dec. 15, 2010 (GLOBE NEWSWIRE) -- Evotec AG (Frankfurt:EVT) today announced that via its subsidiary Develogen AG it has entered into a license and collaboration agreement with MedImmune (the global biologics unit of AstraZeneca), in the diabetes therapeutic area, with a particular focus on the regeneration of insulin producing beta cells. The license gives MedImmune exclusive access to a portfolio of research programs and represents the first deal executed by Evotec on beta cell regeneration assets and capabilities.

Neogenesis, the differentiation of islet beta cells from progenitor cells present in the pancreas, can continue into postnatal life, and has been reported to occur in several animal models. Recent studies have also demonstrated neogenesis of endocrine cells in vitro from ductal structures or from islet themselves derived from adult human and animals, suggest new possibilities for generating new beta cells in culture. Such strategies might provide models to study the regulation of islet differentiation as well as providing new sources of beta cells for transplantation, but the nature of endocrine progenitors identity and the signals that regulate neogenic activity need to be elucidated. The research focus in my laboratory are: (i) the molecular events controlling pre- and postnatal beta-cell development and maturation, and (ii) the characterization of optimal culture environments for inducing progenitors to differentiate into insulin-producing islet cells, maintaining islet architecture and ...

Type 2 Diabetes Mellitus is the most common type of diabetes, accounting for more than 98% of all cases. Diabetes is intolerance to glucose: a person with diabetes is unable to utilise the glucose present in the blood and so its level remains high, in turn causing several problems. This failure to utilise glucose results from inadequate secretion of the hormone insulin, in turn resulting from failure of beta cells of the pancreas to secrete enough quantities of the hormone in response to a carb rich meal. It can also be due to inefficient action of insulin due to less responsive receptors. Ever increasing evidence suggests that beta cell failure and receptor resistance result from recurrent and prolonged increase in insulin secretion caused by high carbohydrate meals. High carb-high insulin production-insulin resistance-higher insulin production-exhaustion-failure.. At present, the drugs used for treating type 2 diabetes act by reducing receptor resistance and by increasing secretion of insulin ...

N was measured employing Mercodia ultrasensitive mouse insulin ELISA. Glucose was measured working with QuantiChrom Glucose Assay. Body weight and food

Ultra sensitive Mouse Insulin ELISA is an immunoassay for quantitative determination of insulin in mouse serum, plasma and fluid.

Promoting ectopic development of pancreatic beta cells from other cell types is one of the strategies being pursued for the treatment of diabetes. To achieve this, a detailed outline of the molecular lineage that operates in pancreatic progenitor cells to generate beta cells over other endocrine cell types is necessary. Here, we demonstrate that early transient expression of the endocrine progenitor bHLH protein Neurogenin 3 (Ngn3) favors the promotion of pancreatic beta and delta cell fates over an alpha cell fate, while later transient expression promotes ectopic development of all three endocrine cell fates. We found that short-term activation of Ngn3 in Xenopus laevis endoderm just after gastrulation was sufficient to promote both early and ectopic development of beta and delta cells. By examining gene expression changes 4 h after Ngn3 activation we identified several new downstream targets of Ngn3. We show that several of these are required for the promotion of ectopic beta cells by Ngn3 as ...

A new study has shown conclusively that a neuropeptide, melanin concentrating hormone (MCH), found in the brain and known for its role in increasing appetite in people, plays a role in the growth of insulin-producing beta cells and the secretion of insulin.

J:127412 Nir T, Melton DA, Dor Y, Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007 Sep;117(9):2553-61 ...

Goehring, I.; Sauter, N. S.; Catchpole, G.; Assmann, A.; Shu, L.; Zien, K. S.; Moehlig, M.; Pfeiffer, A. F. H.; Oberholzer, J.; Willmitzer, L. et al.; Spranger, J.; Maedler, K.: Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets (vol 54, pg 2584, 2011). Diabetologia 62 (3), pp. 553 - 554 (2019 ...

In the case of my autoimmune diabetes (LADA), Ive lost the first phase insulin response. My beta cells will still make some insulin after I eat, but...

Objective: Interleukin (IL)-1 impairs insulin secretion and induces beta-cell apoptosis. Pancreatic beta-cell IL-1 expression is increased and interleukin-1-receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes mellitus. Treatment with recombinant IL-1Ra improves glycemia and beta-cell function and reduces inflammatory markers in patients with type 2 diabetes mellitus. Here we investigated the durability of these responses.. Research Design and Methods: Among 70 ambulatory patients with type 2 diabetes and A1C and body mass index higher than 7.5% and 27, respectively, randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blinded 39 week follow-up study. Primary outcome was change in betacell function following anakinra withdrawal. Analysis was done by intention-to-treat.. Results: Thirty-nine weeks following anakinra withdrawal the proinsulin to insulin (PI/I) ratio but not ...