Raphael Scharfmann was born in Lille, France where he studied medicine. In 1986, he went to Paris, where he obtained a PhD in Developmental Physiology in 1989, under the scientific direction of Paul Czernichow. After that he did a two and a half year post doctoral training at the Salk Institute in San Diego Ca, in the laboratory of Dr Inder Verma. Back to France, he was employed as research assistant at INSERM. He is now research director at INSERM U457, in Paris. During those last years, he studied soluble factors implicated in different aspects of pancreatic development, such as proliferation, differentiation and morphogenesis. Raphael Scharfmann is author or co-author of about 35 scientific articles. He has received several prizes and awards: Research Grant Awards from the Juvenile Diabetes Foundation International in 1993, 1995, 1998; Award from the French Society of Endocrinology in 1995; Apollinaire Bouchardat Award in 1999.
Report
Back to Paris at the end of 1991, Raphael Scharfmann obtained the position of Senior Researcher (Tenure position) at INSERM (Institut National de la Santé et de la Recherche Médicale). In co-operation with Paul Czernichow, he decided to study again islet cell differentiation. Students, post docs and technicians started to work under his scientific supervision.
His hypothesis was that "identical mechanism could control the differentiation of beta and neuronal cells". This hypothesis was based on the fact that beta and neuronal cells share a large number of similarities. He thus: i). tried to understand why beta and neuronal cells share similarities; ii). studied whether factors important for the development of neuronal cells would also act on pancreatic endocrine cells; iii). tested whether beta cells, like neuronal cells would develop by default.
He proposed that identical genes were specifically expressed in beta and neuronal cells because specific transcriptional repressors were absent from both cell types. He verified this hypothesis by demonstrating that REST expression was absent from beta cells. REST is a specific repressor of genes expressed in neuronal cells such as glutamate receptors, specific adhesion molecules, brain specific sodium channels. He further confirmed this hypothesis by demonstrating that other targets of REST, which were expressed in neuronal cells, were also expressed in insulin-producing cells. These results strongly suggest that gene transcription in insulin-positive cells and in neurons could be controlled by the same transcriptional factors.
He made the original hypothesis that factors such as Nerve Growth Factor (NGF) or Neurotrophin-3 (NT-3), known to be important for the development of neuronal cells could act on pancreatic endocrine cells. He showed that functional receptors for NGF and NT-3 were expressed by beta cells. However, during pancreatic development, NGF-receptors are mainly found in immature pancreatic epithelial cells which could later differentiate into endocrine cells. Neurotrophin receptors could thus represent markers of endocrine precursor cells (Publication#5 enclosed). He next used an in vitro model where islets develop from pancreatic rudiments derived from fetal rats. He demonstrated that in that system, the islets, which develop and the putative stem cells from where the islets are budding express NGF-receptors. Moreover, the mesenchymal cells present in that culture system express NGF. NGF produced by the mesenchymal cells could thus act on the epithelial cells to induce islet morphogenesis. To test this hypothesis, he performed the culture in the presence of a specific inhibitor of the tyrosine kinase activity of neurotrophin-receptors. He demonstrated that in the presence of this inhibitor, islet development was slowed down, strongly suggesting that identical soluble factors control both islet cells and neuronal cells development.
The next hypothesis was that beta cells, like neuronal cells, develop by default. This would mean that beta stem cells would possess all the information necessary for differentiation. He thus compared the in vitro development of pancreatic epithelia from embryonic day 12 rats, grown in the presence or in the absence of their surrounding mesenchyme.
When the epithelial rudiment was cultured in the presence of its surrounding mesenchyme, both morphogenesis and cytodifferentiation of the exocrine component of the pancreas were completely achieved, while only a few immature endocrine cells developed. On the other hand, when the epithelial rudiment was cultured in the absence of mesenchyme, the exocrine tissue developed poorly, while the endocrine tissue developed actively. Moreover, the insulin-expressing cells developed in the mesenchyme-depleted rudiments appeared mature and associate into true islets. He also demonstrated that both the inductive effect of the mesenchyme on the proper development of the exocrine tissue and its repressive effect on the development of the endocrine cells are mimicked by follistatin which is expressed by E12.5 pancreatic mesenchyme. Follistatin could thus represent one of the mesenchymal factors required for the development of the exocrine tissue while exerting a repressive role on the differentiation of the endocrine cells. Taken together, these results show that no positive signals derived from surrounding tissues are necessary for proper development of the endocrine cells at specific stages of development (Publication #7 enclosed). He finally proposed an hypothesis which could explain islet morphogenesis. During embryonic life, endocrine cells would activate their own metalloproteinases. Such an activation would be controlled by Transforming Growth Factor beta endogenously produced. The active metalloproteinases would degrade the extracellular matrix and allow the association of endocrine cells into islets of Langerhans.
References:
Prof. Eberhard Standl,
Diabetes Research Institute & Academic Hospital Schwabing, Munich, Germany
Eberhard Standl, a graduate from Ludwig Maximilian-University in Munich 1967 soon developed a key interest in research related to the angiopathic and neuropathic complications of diabetes mellitus while he received training at the Diabetes Center in Munich-Schwabing, at the Joslin Clinic and at the New England Deaconess Hospital in Boston, USA during the early seventies. Pursuing the hypothesis that hypoxia contributed to the cellular damage soon in diabetes, he studied oxygen transport and delivery to tissues and in particular the role of high energy phosphates under various conditions, e.g. hyperglycaemia, ketoacidosis, hypoglycaemia, changes of inorganic phosphate pools, both in in-vitro and in human experiments. a concept of relative hypoxia was established which was especially apparent under conditions of high oxygen demand and physical exercise. In this latter context, by means of biopsy and catheter studies, he was also the first to issue a publication on the major impact of muscular lipid stores on the metabolism and oxygen demand in diabetes. He then explored the association of endothelial derived factors, e.g. von-Willebrand-factor protein, platelets and platelet derived factors with the vascular complications of diabetes. Studies of platelet enzyme activities indicated a broad activation of thrombocytes in diabetes and in relation to signs of endothelial dysfunction rather early on in diabetes and before the manifestation of clinical vascular disease.
Being also an angiologist by training, he introduced ultrasound Doppler and duplex techniques into the study of diabetic late complications and together with Hans Janka, who headed the prospective Schwabing study on diabetic complications, he pioneered to collect ultrasound Doppler based epidemiological data on the prevalence of peripheral vascular and also cerebrovascular disease in diabetes. Furthermore, in 1990 and 1995 he performed, within the framework of the St. Vincent process, two population based surveys on lower extremity amputations in Germany. These showed how little progress had been achieved on a nation-wide scale during this time period.
In more recent years, Eberhard Standl's group mainly concentrated on cardiovascular and cardioneuropathic disease in diabetes. After the UKPDS it is clear that metabolic control as assessed by HbA1c matters also in type 2 diabetes. Earlier on Prof. Standl and his group had performed a ten year prospective study called "The Munich General Practitioner Project" in which many of the UKPDS findings had been anticipated in epidemiological terms. It had been recorded that subjects who had died from macrovascular causes had significantly higher baseline values of fasting blood glucose, haemoglobin A1c, von-Willebrand-factor protein, urine albumin excretion and serum ß2-microglobulin. These subjects had been significantly older, exhibited more ischemic heart disease and had significantly inferior knowledge of diabetes and its treatment. In a multiple logistical regression analysis the risk factors for macrovascular death were age, haemoglobin A1c and von-Willebrand-factor protein. The data suggests that age and haemoglobin A1c are major determinants and that in addition, von-Willebrand-factor associated endothelial damage is a risk factor for macrovascular mortality in type 2 diabetic patients.
Using the innovative technique of scintigrafic detection with 123 J - Metaiodobenzylgaunidine (123-J-MIBG) cardiac sympathetic integrity was studied in both, in newly manifest and long-term subjects with type 1 as well as type 2 diabetes. This technique proved to be far more sensitive than the standard ECG-based tests for assessing cardiac autonomic neuropathy. Sympathetic dysinnervation seems to be particularly prominent in the posterior myocardial region by this method and intervention with long-term near-normoglycaemia up to 3 years leads only to a partial restoration. The results suggest that even in the early stage of type 1 diabetes cardiac sympathetic dysinnervation is composed of reversible and irreversible neuronal abnormalities. In addition, it was found that approximately a quarter of all type 1 diabetic patients with cardioneuropathy show autoimmunity against sympathetic and parasympathetic tissues, even at onset of diabetes and independent of the islet cell related autoimmunity. Meanwhile, this autoimmunity process has been demonstrated to be highly specific for type 1 diabetes and diabetic cardioneuropathy.
Mr. Jean-Claude Chèvre, Institut Pasteur de Lille, Lille, France
M. Jean-Claude Chèvre was born in Bergerac, France in 1968. He studied biochemistry and genetics at the University Pierre et Marie Curie in Paris and graduated in 1993. He started his scientific career as a graduate studying for one year under the supervision of Prof. Miguel J.M. LEWIN, director of the department of biology and pathology of the digestive tract (INSERM U10, Paris, France) . During this year, he was earning his spurs in practical molecular biology by the « etablishment of a stable cellular model with inhibition of the tumor suppressor Adenomatous Polyposis Coli gene using antisens expression vector ». The purpose of this project was to confirm the assumption of a tumor suppressor function and to understand molecular mechanisms underlying this function. In 1996, J-C. Chèvre had the advisability of undertaking a Ph.D about the genetics of Maturity Onset Diabetes of the Young (MODY) under the direction of Dr Philippe Froguel, director of the laboratory of genetics of the multifactorial diseases (CNRS UPRES A 8090, Lille, France). MODY is a heterogenous subtype of type 2 diabetes characterised by early onset, usually before 25 years of age, an autosomal dominant mode of inheritance with high penetrance and a primary defect of insulin secretion. At the start of his thesis, only mutations in the glucokinase gene on chromosome 7 were known to be responsible for the MODY phenotype although two additional loci were recently mapped: MODY1 and MODY3 on chromosomes 20q and 12q respectively. As part of the collaborative work of an international academic consortium for MODY3 gene positional cloning, J-C. Chèvre searched recombination events in the at risk haplotypes of the MODY3 locus in French pedigrees. Once mutations in the hepatocyte nuclear factors-1 alpha (HNF-1a) and - 4 alpha (HNF-4a) were found to be responsible for the MODY3 and MODY1 subtypes of MODY, he identified 14 mutations in the HNF-1a gene in French MODY families and a missense mutation in the HNF-4a gene, resulting in reduced transactivation activity, in late-onset non-insulin dependant diabetes. He also searched for mutations in the insulin promoter factor 1 (IPF1)/MODY4 and hepatocyte nuclear factor-1 beta (HNF-1b)/MODY5 in families with no mutations in the 3 MODY genes previously described but no diabetogenic mutations were found in those genes. Of 67 known French MODY families, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1a gene and 11 (16%) have no mutations in the five known MODY genes (MODYx). Others groups also identified several MODY families in which diabetes is unlinked to the already known genes. As MODY is a paradigm to identify new genes implied in the pathogenesis of diabetes allowing a better understanding of the insulin secretion mechanisms and gluco-regulation, the main goal of J-C. Chèvre during the last two years was to identify new MODYx gene(s). He adopted two parallel approaches for this purpose : linkage analysis and direct mutation detection in « candidate » genes implicated in pancreatic b cell differenciation and insulin secretion, and exclusion mapping with polymorphic CA repeats or genome-wide search by random approach. He tested fifteen candidates genes encoding for transcription factors or proteins implicated in pancreatic development or function for linkage with MODY in French MODYx families using polymorphic markers. None of these loci showed evidence for linkage with MODY the French MODYx families analysed. He also screened for mutations the HNF-3beta, Nkx2.2 and Nkx6.1 coding regions and introns/exons boudaries in probands of the French MODYx families. None of the variations found in those genes was associated with early-onset diabetes. A subset of 17 MODY families did not show any linkage with known MODY loci or candidate gene regions throughout the genome. These families collected mainly in France (10 families) and also in Italy (2), Spain (1), England (2) and Denmark (2) include 214 individuals. J-C. Chèvre carried out a genome-wide screen using the basis of the ABI genome-scan sets of 413 microsatellite markers spaced at intervals of approximately 10 cM on average. Those results are currently analysed and should permit the identification of new MODY loci.
The Albert Renold Fellowship awarded by the European Association for the Study of Diabetes is gratefully acknowledged and will allow M. J-C.Chèvre to pursue his career as postdoctoral fellow in the division of molecular genetics of the department of pediatrics at the Columbia University (New-York, USA), directed by Prof. Rudolph L. Leibel. This grant gives him the great opportunity to gain experience in new techniques and methodology in the search of type 2 diabetes susceptibility genes. Using quantitative trait locus mapping (QTL), regions have been identified in the mouse and rat genome which convey susceptibility or resistance to type 2 diabetes in obese animals. J-C.Chèvre will clone the QTL's responsible for these phenotypes from the genetic intervals by monitoring the phenotype in intercross progeny to reduce the size of the responsible interval, followed by construction of physical maps and analysis of constituent genes.
Dr. Jorge Ferrer, Hospital Clinic Universitari, Spain
Dr. Jorge Ferrer studied medicine at the University of Barcelona School of Medicine, and received his MD degree in 1987. He then completed a medical residency in Endocrinology and Nutrition. In 1993 he defended his doctoral thesis at the University of Barcelona Medical School (Director, Prof. Enric Vilardell, Mentor Dr. Ramon Gomis), obtaining the University's Extraordinary Prize for the thesis with the highest qualification attained that year. Prior to the defence of his thesis he spent a short training period at the Metabolism and Endocrinology Department at the Vrije Universiteit Brussel. He next gained a Juvenile Diabetes Foundation International Postdoctoral Fellowship Award which allowed him to train with Dr. M. Alan Permutt at the Washington Universtity School of Medicine in St. Louis (1993-1995). During that period he combined research in islet-cell molecular genetics with clinical duties as Metabolism and Endocrinology Fellow at Barnes Hospital. Subsequently he worked as Harvard University Instructor in Medicine at the Laboratory of Molecular Endocrinology in Massachusetts General Hospital with Dr. Joel Habener. In 1997 he moved back to the Endocrinolgy and Nutrition Unit at the Hospital Clínic Universitari in Barcelona, where he is currently starting an independent research laboratory.
Dr. Ferrer's research has focused on the molecular genetics of pancreatic islet-cells in the context of Type 2 Diabetes Mellitus pathophysiology and genetic susceptibility. During his thesis he attempted to gain further insight into the role of pancreatic islet GLUT2 glucose transporter in diabetes. At the time several investigators had demonstrated that islet GLUT2 expression was abnormal in diverse rodent models of Type 2 diabetes, suggesting that this might be a pathophysiological mechanism underlying b-cell dysfunction. Dr. Ferrer's experiments indicated that glucose regulates islet GLUT2 protein and mRNA, and that this effect is dependent on islet glucose metabolism. These findings suggested that deranged islet glucose metabolism could represent a general mechanism involved in islet GLUT2 underexpression in animal models. He was the first to assess the expression of GLUT2 expression in human pancreatic islets of subjects with and without Type 2 diabetes, showing that while GLUT2 is clearly expressed in human pancreatic islets, the abundance is substantially lower than that found in mouse and rat islets. Furthermore, decreased expression was not found in pancreatic islets from four cadaveric organ donors with Type 2 diabetes relative to controls. These results suggested the existence of profound species-differences in the regulation and potential pathophysiological role of islet GLUT2. During that same period Dr. Ferrer collaborated in the characterization of a transgenic mouse model expressing antisense GLUT2 in pancreatic islets constructed in Dr. Fatima Bosch's lab. This model provided experimental confirmation of the role of GLUT2 expression in glucose-induced insulin secretion.
His postdoctoral training at Washington University was carried out in Dr. Alan Permutt's lab, one of the most prestigious in the field of the molecular genetics of Type 2 Diabetes. A substantial portion of his work there was aimed at the identification of novel islet candidate genes for Type 2 diabetes susceptibilty. He developed an RNA differential display strategy to identify human islet-enriched expressed sequence tags, and then used physical and radiation hybrid resources (at the time still rudimentary) to map these genes, thus integrating islet gene discovery with the emerging knowledge of Type 2 diabetes suceptibility loci. In parallel he cloned novel cDNAs endcoding known-function candidate islet genes, and used analogous strategies to map these to human chromosomes. He also searched for the cognate partner of the sulfonylurea receptor (SUR1) in the islet ATP-sensitive K+ channel, later cloned by others and coined KIR6.2. In doing so he identified other K+ channel cDNAs (now designated KIR3.2 and KIR3.4) , which when coexpressed formed heteromeric G protein-activated K+ channels, but did not associate with SUR1. He worked on the first study which identified SUR1 sequence variants associated with human Type 2 diabetes. During this period he constructed several rat and human islet-cell cDNA libraries which have been successfully used by numerous investigators in the islet research community. Subsequently, Dr. Ferrer moved to the Lab. of Molecular Endocrinology (Dr. Joel Habener, Massachusetts General Hospital), where he was able to combine his previous experience in human genetics with a highly fruitful learning experience in islet-cell transcription. There he worked on the cloning and characterization of the SUR1 promoter, as well as on the discovery of b-cell transcription factor gene IPF1 as the fourth locus responsible for autosomal dominant diabetes (MODY4). His current research in Barcelona is largely related to this experience, as he is now primarily focusing on investigating how MODY transcription factors control transcription of key pancreatic b-cell genes.
Prof. Francesco Beguinot, Federico II University of Naples, Italy
Prof. Beguinot received his M.D. in 1981 at the Federico II University in Naples, and his Ph.D. in 1986 at the University of Siena, Italy. He is a certified clinical specialist in Internal Medicine and received his clinical training at the "Federico II" University in Naples. Prof. Beguinot spent about two years as a research scientist at the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, National Institute of Health in Bethesda, and three years at the Joslin Diabetes Center in Boston, U.S.A.. After his training, Prof. Beguinot established his own laboratory at the Dipartimento di Biologia e Patologia Cellulare e Molecolare & Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R., University of Naples Medical School, where he directs a research group working in the fields of insulin action and type 2 diabetes. Prof. Beguinot's articles have been published by internationally renowned journals; he received several international scientific awards and prizes and is a member of 7 scientific societies. He is also a member of the Board of Directors of the Italian Endocrinology Society and coordinator of a research network working in the field of insulin action in type 2 diabetes, funded by the European Community.
Synopsis of Prof. Beguinot's current research activities
Using a differential cloning approach, a novel gene, PED, has recently been identified in Prof. Beguinot's laboratory [6,7]. PED is overexpressed in individuals with type 2 but not type 1 diabetes. In type 2 diabetic fibroblasts, PED overexpression persists through at least 20 generations in culture, indicating that it is not a secondary alteration due to the internal milieau of the patients, but may represent a primary genetic defect. Indeed, PED gene maps on human chromosome 1q21-22 . This same region hosts a locus in linkage with late-onset type 2 diabetes in caucasians. PED gene encodes a 15 kDa protein the levels of which are also elevated in skeletal muscle and adipose tissues, two major sites of insulin-resistance in type 2 diabetes. In differentiated L6 skeletal muscle cells and 3T3-L1 adipocytes, expression of PED cDNA to levels comparable to those detected in muscle and adipose tissues from type 2 diabetics blocks insulin-dependent translocation of GLUT4, the major insulin-stimulated glucose transporter. Insulin-stimulated glucose transport is also blocked in PED overexpressing muscle and adipose cells. PED overexpression has no effect on insulin proteosynthetic, antilipolytic, and proliferative responses. Therefore, the overexpression of PED gene may specifically generate insulin-resistance in glucose uptake in type 2 diabetes. However, the molecular mechanism through which PED controls GLUT4 intracellular trafficking and insulin-stimulated glucose transport is unknown at the present. To understand the role of PED in insulin action and in type 2 diabetes, the following objectives are presenly pursued in Prof. Beguinot's laboratory: i) to determine whether PED overexpression in type 2 diabetes originates from a proper genetic or secondary abnormalities; ii) to elucidate the molecular mechanism of PED inhibition of insulin-stimulated glucose transport; iii) to clarify the significance of PED overexpression to insulin-resistance and altered glucose tolerance in vivo.
References:
Dr. Erik Renström, Lund University, Sweden
Brief resumé of scientific work
Using a combination of electrophysiological techniques and microfluorimetry, my colleagues and I have demonstrated that the secretory capacity of the B-cell in response to a given increase in cytoplasmic Ca2+ is modulated by several cellular factors. In short, the B-cell exocytotic machinery is organized such that only a small pool of 50-100 readily releasable insulin granules (corresponding to = 1 % of the total number of granules in the B-cell) undergoes immediate fusion with the B-cell membrane when cytoplasmic Ca2+ increases. Further exocytosis requires recruitment of new secretory granules for release, a process that involves biochemical modification of the granules by hydrolysis of the glucose metabolite ATP, and is suppressed by cooling. Interestingly, 2nd phase insulin secretion in vivo shows a similar dependence on glucose and temperature, which argues that biphasic pattern of insulin secretion may occur as a result of this granular modification. The rate of granular recruitment is also regulated by protein kinase activity and granular acidification driven by the granular v-ATPase. The latter process is in turn facilitated by sulphonylurea-regulated granular Cl- fluxes.
Fully modified insulin granules bind to the intracellular synprint (synaptic protein-interacting) loop of the Ca2+-channel. This tight spatial connection enhances rapid exocytotic fusion by directing the granules to the microdomains of very high intracellular Ca2+ that develop at the inner mouth of the activated Ca2+-channels. Disruption of this connection by addition of a recombinant synprint-peptide prevents the initial rapid portion of depolarisation-evoked exocytosis. By contrast, when intracellular Ca2+ is increased independently of the L-type Ca2+-channels, by UV-flash photolysis of caged-Ca2+, exocytosis remains unaffected by the synprint peptide.
The mechanisms described above determine the time-course of exocytosis in the B-cell and enable the biphasic pattern of insulin secretion. It is therefore possible that they may be involved in the pathogenesis of the secretory defect seen in NIDDM, but this remains to be established.1999 Minkowski Prize, 34th Minkowski Lecture
Dr Raphael Scharfmann, INSERM U457, Paris, France
Since the beginning of his scientific career, Raphael Scharfmann has mainly worked on beta cell development. After 5 years at medical school, he started a PhD under the scientific direction of Paul Czernichow. He studied the synthesis and the degradation of Thyrotropin-Releasing Hormone (TRH), a peptide, expressed in hypothalamic neurons and in beta cells around birth. Raphael Scharfmann showed that TRH was synthesized in beta cells and that its maturation and its degradation were tightly controlled. During his PhD, he also worked on the implication of Growth Hormone (GH) on beta cell proliferation. He showed that GH was a potent growth factor for beta cells and demonstrated that Insulin-like growth factor-1, one of the mediators of GH-induced cell proliferation, was produced by islet cells.
He next moved to San Diego Ca, for a three year post-doctoral training at the Salk Institute, in the laboratory of Dr Verma. The objective was to establish model somatic cell systems with the potential of sustained expression of a foreign gene. Raphael Scharfmann showed that long-term expression of foreign genes in mouse embryo fibroblast implants can be achieved if a housekeeping promoter is used to drive transcription. During this period, he gained extensive experience in molecular biology technology.
1999 Castelli Pedroli Prize, 14th Camillo Golgi Lecture
1999 Albert Renold Fellowship
1999 EASD / Eli Lilly Research Fellowship in Diabetes and Metabolism
1999 EASD / Sankyo Insulin Resistance Project Award
Prof. Beguinot has a long standing interest in the mechanism of insulin signalling. In the past, he demonstrated the existance of a cross-talk mechanism involving the insulin and the IGF-1 receptor kinases which may have an important role in the transduction of insulin mitogenic effects. He has also participated in the initial studies leading to the discovery of IRS-1, and subsequently devoted his efforts to the understanding of the mechanisms which regulate the activation of this docking protein in the cells. His research group is presently focusing on the tissue-specificity of the insulin signalling network, particularly in liver and skeletal muscle tissues [1-3]. In fact, Prof. Beguinot believes that understanding the details of insulin signal transduction in these major targets for insulin action may lead to the development of more effective strategies for treating and, possibly, preventing insulin-resistance. The elucidation of PKC role in insulin action has also represented an important objective of Prof. Beguinot's research activity. In his laboratory evidence has recently been generated indicating that the insulin receptor physically associates with different PKC isoforms [4,5]. In particular, it has been recently demonstrated that PKCalpha association has an important role in directing insulin receptor intracellular trafficking [4]. Whether other PKCs convey receptor generated signals to the typical cellular effectors of insulin is presently under investigation.
1999 EASD / Amylin - Paul Langerhans Research Fellowship
for Research on the Physiology and Pathophysiology of the Beta-Cell
Loss of biphasic insulin secretion is an early sign of non-insulin-dependent diabetes mellitus (NIDDM). My research focuses on elucidating the cellular mechanisms in the insulin-releasing pancreatic B-cell that underlie this secretory pattern and their role in the development of NIDDM. Glucose induces insulin secretion via a chain of cellular events that culminates with the activation of voltage-sensitive L-type Ca2+-channels in the B-cell membrane. The resulting elevation in cytoplasmic Ca2+ is the key signal that elicits exocytosis of insulin-containing secretory dense core vesicles.
Last up-date 15 September 1999