Search

The conventional micromethod of fructose 2,6-bisphosphate (F-2,6-P2) determination is optimized for human peripheral blood lymphocytes. The F-2,6-P2 content in lymphocytes of healthy subjects is 0.8±0.2 pmol/106 cells or 6.7±1.1 pmol/mg protein. Preliminary findings show a decrease in the F-2,6-P2 content in lymphocytes from patients with severe diabetes mellitus.

Type-2 diabetes is characterized by impaired insulin secretion associated with excess glucagon release. Exocytosis of insulin- or glucagon-containing granules is initiated by Ca2+-influx through voltage-dependent Ca2+-channels and is modulated by the second messengers such as cAMP. Membrane capacitance measurements were used in this study to investigate the cellular mechanisms behind cAMP-regulated Ca2+-dependent exocytosis in pancreatic beta-and alpha-cells. In pancreatic beta-cells, the secretory granules have been demonstrated to co-localize with L-type Ca2+-channels. Experiments using photorelease of caged Ca2+ revealed that exocytosis of insulin-containing granules requires an increase in [Ca2+]i with a Kd of 17 µM, which is most likely achieved in the vicinity of the Ca2+-channels. It was further proved that a close association between the alpha1c L-type Ca2+-channels and the secretory granules is a prerequisite for rapid exocytosis and ensures maximum usage of Ca2+ influx in a cell with few Ca2+-channels (~500) as is the case in the beta-cell. Pharmacologically, L-type Ca2+-channels are suppressed by organic Ca2+-channel blockers such as dihydropyridines. Glacontryphan- M was isolated from the venom of Conus Marmoreus and was detected to reduce L-type Ca2+ currents and associated exocytosis. It was discovered that this novel antagonist needs the binding of Ca2+ to the Gla-residues for its function. Ca2+-dependent exocytosis in the beta-cell is enhanced by cAMP through both PKA-independent granular priming and PKA-dependent recruitment of granules from a reserve pool. This study revealed a concentration-dependent activation of the two cAMP-signalling pathways and that 5-fold higher [cAMP]i was needed for the PKA-independent mechanism. Interestingly, the sulfonylurea receptor SUR1 was required in the regulation of cAMP-stimulated PKA-independent exocytosis. This is an additional function of SUR1 apart from being a subunit of the KATP channel. Enhancement of exocytosis by cAMP in alpha-cells was discovered to involve similar mechanisms as in the beta-cell. In the present study glucagon was detected to elevate cAMP resulting in an enhanced Ca2+-dependent exocytotic response by binding to the glucagon-receptors in the plasma membrane of the alpha-cell. The stimulatory effect of glucagon was mainly mediated by PKA-dependent mechanisms, possibly due to the inability of glucagon to elevate [cAMP]i to the sufficient level needed for activation of the PKA-independent pathway. Glukos är den främsta energikällan för de flesta celler i kroppen. Det är av stor vikt att mängden glukos hålls på en jämn nivå, eftersom framförallt våra celler i hjärnan är mycket känsliga för stora variationer av glukoshalten i blodet. Regleringen av mängden glukos i blodet kontrolleras av hormonen insulin och glukagon. Insulin utsöndras från beta-celler och glukagon från alpha-celler, båda belägna i bukspottkörtels Langerhanska öar. Insulin sänker glukoshalten i blodet efter en måltid medan glukagon höjer glukoshalten då kroppen behöver tillskott av energi såsom då vi motionerar eller är under stress. Patienter med åldersdiabetes eller typ-2 diabetes har ofta en försämrad utsöndring av insulin samtidigt med en ökad sekretion av glukagon. Det vill säga kontrollen av mängden glukos i blodet är satt ur funktion. Normalt sker insulinsekretion i två faser, en första snabb fas som pågår 5-10 min följt av en långsam mer kontinuerlig fas. Patienter med åldersdiabetes saknar den första snabba fasen och den andra fasen är något reducerad. Insulin och glukagon befinner sig i små blåsor (granula) inne i repektive cell. Dessa blåsor smälter samman (fuserar) med cellens membran vid en given signal och innehållet kan komma ut i blodet. Signalen som initierar utsöndringen är ett ökat inflöde av kalcium-joner (Ca2+) genom speciella spänningskänsliga, vattenfyllda kanaler (jonkanaler) i cellens membran. Utsöndringen av hormonen kan vidare påverkas av andra substanser, ett sådan substans är cykliskt AMP (cAMP). Ett nytt läkemedel mot typ-2 diabetes som är under prövning, GLP-1, verkar bl.a. genom att öka cAMP-koncentrationen inne i cellen. I denna avhandling har de cellulära mekanismer varmed cAMP och Ca2+ påverkar utsöndringen av insulin och glukagon undersökts. Fusionen av granula med plasmamembran och därmed utsödringen av insulin (eller glukagon) har studerats på enskilda celler med en speciell teknik som kallas kapacitansmätningar. Denna teknik bygger på principen att cellens membran elektriskt kan likställas med en plattkondensator. Vidare gäller att då ytan på en kondensator ökar så ökar dess kapacitans. Detta kan utnyttjas eftersom när ett granula smälter samman med cellens membran ökar dess yta och även dess kapacitans. Det första delarbetet behandlar kopplingen mellan inflöde av Ca2+ och insulingranula. För att granula ska kunna fusera med cellmembranet krävs en hög koncentration av kalcium, mycket högre än medelkoncentrationen inuti cellen. Cellen löser detta genom att Ca2+-kanalen binder samman med insulingranula vid cellmembranet. På detta vis sker fusionen av granula snabbt samtidigt som energiåtgången för att återställa Ca2+-koncentrationen till sin vilonivå inne i cellen minimeras. I det andra delarbetet har en ny substans som utvunnits från en vattenlevande snigel, Conus Marmoreus, undersökts. Normalt är denna substans en del av snigelns gift, som används för att paralysera och fånga byten. Det visade sig att substansen blockerade de speciella Ca2+-kanaler som finns i beta-cellen. Substansen kan utnyttjas för att studera Ca2+-kanalens betydelse i olika system inte bara vid insulinsekretion. Vidare har betydelsen av cAMP för en ökad utsöndring av insulin studerats. Våra undersökningar visade på att cAMP stimulerar insulinsekretion både genom att aktivera ett protein som heter proteinkinas A (PKA) och genom att binda till ett annat protein, cAMP-GEFII. Proteinkinas A medverkar till att påskynda förflyttningen av insulingranula till cellens membran och påverkar framförallt den andra fasens insulinsekretion. Genom att binda till cAMP-GEFII stimulerar cAMP framförallt den snabba utsöndringen av insulin under den första fasen. Ett av de intressanta fynden i detta arbete berör den receptor, till vilken de antidiabetiska medicinerna sulfonylureas binder in på cellens membran. Genom att binda till denna receptor startas en kaskad som leder till utsöndring av insulin. Detta abete har visat att denna receptor också har en viktig funktion i ett av de avslutande stegen innan de insulininnehållande granula kan fusera med cellmembranet. Avslutningsvis behandlas alpha-cellen som utsöndrar glukagon. Det visade sig att cAMP förmår påverka glukagonsekretion på ett liknade sätt som i beta-cellen samt att glukagon har förmågan att stimulera sin egen sekretion åtminstone på enskilda celler. De mekanismer som har undersökts i denna avhandling påverkar framförallt första fasens insulinsekretion som saknas hos patienter med typ-2 diabetes. Dessa undersökningar är därför av stor betydelse för att förstå uppkomsten av denna sjukdom samt för att finna nya och bättre läkemedel.

Pancreatic beta-cell dysfunction and insulin resistance are the two hallmarks of type 2 diabetes. An early sign of beta-cell dysfunction is impaired nutrient-induced insulin release. Several insulin secretagogues act by increasing the formation of intracellular cAMP. Thus, accurate regulation of cAMP is of vital importance for the ability of the beta-cell to respond properly to these stimuli. The level of cAMP is defined by the activities of adenylyl cyclases and cAMP-degrading phosphodiesterases (PDEs). The aim of this thesis was to study the role of PDE3B in the regulation of insulin secretory processes in pancreatic beta-cells and in the regulation of overall energy homeostasis. Results in this thesis demonstrate that mice with a specific increase in beta-cell PDE3B activity (RIP-PDE3B mice) have, in comparison to control mice, a reduced insulin response to glucose as well as to glucose in combination with GLP-1, glucose intolerance and altered islet morphology. Moreover, when metabolically challenged RIP-PDE3B mice develop severe obesity and insulin resistance. The insulin secretory capacity of isolated islets from RIP-PDE3B mice was studied and a specific reduction in the first phase of glucose-stimulated insulin release was identified. An important role of beta-cell PDE3B for exocytosis and release of insulin was further demonstrated by overexpression of PDE3B and by selective inhibition of the enzyme in both insulinoma cell lines and rat pancreatic islets. Of specific interest was the marked decrease of glucose-stimulated cAMP levels and concomitant decrease in insulin release observed in cells overexpressing PDE3B. In summary, this thesis has contributed to an increased understanding for the role of beta-cell PDE3B in the regulation of insulin secretory processes. Results suggest that PDE3B regulates cAMP pools important for exocytosis of insulin-containing granules responsible for the first phase of insulin release. Also, these studies bring forward the role of cAMP in nutrient-induced insulin release. Finally, the work in this thesis demonstrates for the first time a functional role for beta-cell PDE3B in the maintenance of whole body energy homeostasis in mice. Denna avhandling är en s.k. sammanläggningsavhandling och innehåller tre delarbeten. Delarbete I är publicerat, delarbete II är under revision inför publikation och delarbete III är i manuskriptform. Syftet med mina studier har varit att undersöka regleringen av insulinsekretion från de insulinproducerande cellerna i bukspottkörteln med fokus på ett specifikt protein - fosfodiesteras 3B (PDE3B). Bakgrund Diabetes mellitus, i dagligt tal också kallad sockersjuka, är en globala folksjukdom och förekomsten av sjukdomen har ökat dramatiskt under senare år. Antalet diabetespatienter beräknades år 2001 vara drygt 150 miljoner och beräknas fördubblas till år 2025. Detta enligt siffror från den internationella diabetesfederationen (IDF). Diabetes är ett samlingsnamn på ett flertal sjukdomar som uppstår till följd av flera olika orsaker men som samtliga slutligen leder till förhöjda nivåer av socker (glukos) i blodet. Diabetes kan delas in i två huvudgrupper; typ 1 diabetes, också kallad insulinberoende diabetes eller ungdomsdiabetes, och typ 2 diabetes, också kallad icke insulinberoende diabetes eller åldersdiabetes. Typ 1 diabetes drabbar cirka 10% av diabetespatienterna och orsakas av brist på hormonet insulin. Insulin är det hormon som signalerar till kroppens vävnader att ta upp och lagra näringsämnen. Typ 1 diabetes uppstår till följd av att vårt eget immunförsvar bryter ner de insulinproducerande cellerna. Typ 2 diabetes drabbar cirka 90% av alla diabetespatienter. Antalet typ 2 diabetiker ökar snabbt i västvärlden, vilket har kopplats samman med ärftliga faktorer, fysisk inaktivitet och övervikt. Orsaken till typ 2 diabetes är inte känd, men symtomen är att utsöndringen av insulin minskar och att de vävnader, muskel, fettväv och lever, som normalt svarar på insulinsignalen blir okänsliga. Denna oförmåga att svara på insulin kallas insulinresistens. Insulin produceras i bukspottkörteln. Bukspottkörteln är belägen bakom magsäcken och består av två delar: en exokrin och en endokrin. Den exokrina delen producerar pankreassaft som innehåller enzymer vilka är viktiga för nedbrytningen av intagen föda till små beståndsdelar. Den endokrina delen består av små så kallade Langerhanska cellöar. Namnet kommer av dess upptäckare Paul Langerhans (1869). Dessa öar består av ansamlingar av olika typer av celler varav beta-cellerna är de som producerar insulin. Beta-cellerna är de enda cellerna i kroppen som kan producera och utsöndra insulin. Insulin utsöndras som svar på ökade nivåer av näringsämnen i kroppen, som till exempel efter en måltid. Insulin signalerar i sin tur till de insulinkänsliga målvävnaderna att ta upp och lagra glukos, fettsyror och aminosyror i form av kolhydrater, fett och protein. Det huvudsakliga stimulit för insulinutsöndring är glukos. Glukosmolekylen tas upp av beta-cellen där den bryts ner, vilket genererar energi i form av ATP. ATP binder till och stänger ATP-känsliga kaliumkanler i cellens cellmembran. Det minskade utflödet av kalium höjer membranpotentialen och leder till öppnandet av spänningskänsliga kalciumkanaler i cellmembranet. Detta leder till ökad koncentration av kalcium inne i cellen som i sin tur leder till insulinutsöndring. Denna glukosstimulerade insulinutsöndring påverkas av ett stort antal utifrån kommande signaler. Gemensamt för många av de signaler som kan öka den glukosstimulerade insulinutsöndringen är att de verkar via en ökning av cykliskt AMP (cAMP). cAMP är en så kallad ”second messenger” eller budbärare som för signalen vidare in i cellen och påverkar andra proteiners aktiviteter, vilket slutligen leder till en ökad glukosstimulerad insulinutsöndring. Detta kallas cAMP-potentierad glukossstimulerad insulinutsöndring. cAMP nivåerna i cellen regleras av de protein (enzym) som producerar respektive bryter ner cAMP. Enzymer som bryter ner cAMP kallas fosfodiesteraser (PDE). Det finns elva olika familjer av PDE:er och inom varje familj finns det flera subfamiljer. I min avhandling har jag studerat rollen av PDE3B i regleringen av insulinutsöndring från beta-cellerna. Resultat I delarbete I studerades uttrycket av PDE3 i odlade beta-celler och i isolerade cellöar från råtta. Vi kunde visa att i beta-celler är PDE3B det huvudsakliga enzymet av de två existerande PDE3 medlemmarna (PDE3A och PDE3B), och att PDE3B återfinns specifikt i membraner av beta-celler. Vidare undersöktes rollen av PDE3B i regleringen av glukosstimulerad och cAMP-potentierad insulinutsöndring. Dessa processer studerades i beta-celler och isolerade öar från råtta som manipulerats så att de hade en ökad mängd PDE3B. Vi kunde visa att en ökad mängd av PDE3B leder till minskad glukosstimulerad- och cAMP-potentierad insulinutsöndring i beta-celler och öar och har direkt hämmande effekter på den proccess som reglerar själva utsläppet av insulin (exocytos). Vi använde oss också av hämmare av PDE3 för att minska mängden aktivt PDE3 och kunde då visa att insulinutsöndringen istället ökade. I delarbete II studerade vi rollen av beta-cell-PDE3B för reglering av energibalansen i möss som manipulerats så att de har ett ökad mängd av PDE3B endast i beta-cellerna (transgena möss). Intravenösa glukostoleranstester utfördes vilket innebär att sövda möss belastas med glukos och under cirka en timme tas flera blodprov för bestämning av insulin- och glukosnivåer i blodet. I arbete II visade vi att mängden insulin som svar på glukos var minskad i de transgena mössen, vilket var kopplat till en försämrad förmåga att sänka blodsockret. Öar isolerades från dessa möss och vi kunde visa att den minskade mängden insulin var kopplad till en minskad utsöndring av insulin som svar på glukos. Vidare visade vi att den stimulerande effekten av cAMP på glukosstimulerad insulinutsöndring också minskade i både mössen och i de isolerade öarna. Vi fann även att många öar från transgena mössen var större än normalt och att deras cellstruktur var förändrad. I delarbete III studerade vi möss efter att de fått äta en kost rik på fett under en längre tid och så jämfördes transgena och normala kontroll möss. Det var känt sedan tidigare att kontrollmössen utvecklar fetma och insulinresistens som svar på fet kost. Våra transgena möss utvecklade fetma snabbare än kontrolldjuren trots att de inte åt mer än dessa. Vi kunde visa att de transgena mössen utsöndrade höga nivåer av insulin (hyperinsulinemi) men trots detta var glukosnivåerna ändå höga. Detta är ett tecken på att vävnader i kroppen utvecklat en lägre känslighet för insulin, det vill säga insulinresistens. Vi utförde ett så kallat intraperitonealt insulintoleranstest på mössen. Detta innebär att sövda möss ges en injektion av insulin i magen och blodprover tas under en timme för bestämningar av insulin- och glukosnivåer i blodet. Vi kunde visa att de transgena mössen var oförmögna att sänka glukosnivåerna trots insulininjektionen. Detta är en indikation på utveckling av insulinresistens. Vi studerade också öarnas storlek och struktur och fann att öarna från de transgena mössen efter fetkostbehandlingen nu var ännu större och förändringar av cellernas struktur var ännu tydligare än de vi tidigare sett i de transgena djuren på normal kost. Sammantaget tyder dessa resultat på att våra trangena möss med en ökad mängd PDE3B är mer benägna att utveckla fetma och insulinresistens än de normala mössen. Slutsats Det övergripande syftet med mina studier var att öka förståelsen för hur insulinutsöndring regleras. Detta är av betydelse för att förstå de defekter som ligger till grund för minskad utsöndring av insulin vid typ 2 diabetes och också för utvecklingen av nya läkemedel som specifikt kan öka utsöndringen av insulin. Slutsatsen av dessa studier är att mängden PDE3B är viktig för regleringen av de cAMP nivåer som påverkar insulinutsöndringen och därmed regleringen av energibalansen i kroppen. Mot bakgrunden av dessa resultat i möss vore utvecklingen av en hämmare mot PDE3B i beta-cellerna en strategi för utvecklandet av nya diabetesläkemedel.

Insulin resistance is a hallmark of type 2 diabetes, an increasingly common disorder. The cause of insulin resistance is supposedly failures in the processes used by insulin to signal to the interior of its target cells. These failing steps are still unknown, most probably because of incomplete knowledge of how the insulin signals are transmitted. Since insulin resistance is strongly linked to obesity, defects in lipid metabolism or other adipocyte functions, may be an important factor in the development of this pathological states. It is therefore of particular interest to study insulin signalling and lipid metabolism in adipose tissue. More specifically, the aim of this thesis was to study the regulation of adipocyte protein kinase B (PKB), an insulin-stimulated kinase that has been implicated in mediating many of insulin's metabolic as well as mitogenic effects. We have shown, that in response to insulin, adipocyte PKB translocates from the cytosol to the plasma membrane in a phosphoinositide 3-kinase (PI3-K)-dependent manner. This is believed to induce a conformational change in PKB, allowing it to be phosphorylated and activated by the upstream kinases phosphoinositide-dependent kinase (PDK) -1 and 2. We have demonstrated that PKBß in primary adipocytes is unphosphorylated prior to stimulation, and insulin mainly induces phosphorylation on Ser-474. Furthermore, protein phosphatase 2A (PP2A) was identified as the phosphatase responsible for dephosphorylation and deactivation of PKB in adipocytes. In addition, we have initiated an investigation regarding the regulation and role of PDK1 in adipocytes. Endogenous PDK1 was shown not to be activated, but to translocate from the cytosol to the membrane fraction, in response to insulin. Moreover, adenoviral-mediated expression of PDK1 was used in order to assess the role of PDK1 in primary adipocytes. A recent study has been focused on the kinase inhibitor dimethylaminopurine (DMAP), and its effects on metabolic signalling pathways in adipocytes. DMAP was demonstrated to inhibit insulin-induced glucose uptake, antilipolysis and lipogenesis. Possible molecular targets, inhibition of which may mediate the effects of DMAP, were shown to be PKB and c-jun N-terminal kinase (JNK). In summary, this thesis has provided valuable information regarding the molecular mechanisms underlying insulin-induced activation of PKB, a key component of the insulin signalling pathway.

С 8 по 12 июня 2012 г. в г. Филадельфия (США) состоялся 72-й Ежегодный конгресс Американской диабетической ассоциации (ADA), который посетили тысячи участников-членов диабетических сообществ со всего мира. Программа конгресса была разработана 33 членами комитета по планированию научных сессий под руководством M-E Patti. Кроме того, около 400 ученых и профессионалов системы здравоохранения изучили более 3000 тезисов с последующей селекцией 2000 тезисов для устных и стендовых докладов

Physical development of 710 children and adolescents with insulin-dependent diabetes mellitus (IDDM) was studied over time. The patients were divided into 3 groups: with growth rate above the 25th percentile of the age norm, with growth rate below the 10th percentile of the norm, and with growth rales between the 10th and 25th percentiles of age norm. Analysis showed that (a) the presence of manifest decompensation higher than 12 %, frequent ketoacidosis episodes is a factor of high risk of reduction of physical development rate in children and adolescents with IDDM; (b) the mean statistical rates of diabetic adolescents growth are characterized by delayed (by 1 to 2 years vs. the norm) pubertal growth skip, and this growth skip in the patients is more levelled and stretched in time, and in some cases is virtually nor manifest; (c) if good compensation is attained and maintained after previous prolonged decompensation, compensating growth rates may develop in patients of both sexes both in childhood and adolescence.

Current data on rapid and long-acting insulin analogues in the paediatric age group is limited. While several studies indicate a benefit in reducing hypoglycaemia, particularly at night, with rapid or long-acting insulin analogue treatment, the effect on long-term glycaemic control remains controversial. The continuous glucose monitoring system offers a new option for tailoring treatment with insulin analogues to achieve optimal glycaemia. In 29 adolescents with diabetes this approach confirmed the non-inferiority of postprandial rapid-acting analogue administration compared to preprandial regular insulin, but revealed significant mealtime differences, with increased analogue requirement at breakfast and dinner. Although rapid- and long-acting insulin analogues may offer potential benefits for problems frequently encountered in paediatric diabetology, their value for the individual child still has to be tested in long-term observations in daily clinical practice.

Point of care testing (POCT) is a new concept in laboratory medicine. The POCT tool helps perform the laboratory test at site giving fast result and requires only small amount of sample. It is presently and increasingly used in pediatrics. In pediatric diabetology, the use of POCT for following up of hemoglobin A1C is a new concept. At present, there are several POCT tools for this purpose. In this specific article, the author compares on important aspects (turnaround time and required amount of specimen) of 5 available POCT tools for measurement of hemoglobin A1C level. The test that is the fastest and requires the least amount of blood sample, which means the least harm to the pediatric patient is the most preferable. Here, it can be seen that there is no ideal POCT that has both properties. However, if it is standardized to compare the amount of required blood sample, the special concern in the pediatric patients, the product from multiplication shows that Siemen DCA 2000+ and Siemen DCA Vantage are the two most preferable POCT tools for hemoglobin A1C determination in pediatric diabetes mellitus management.

Departments of Medical Sciences (M.F., U.V., F.E., P.B.-P., G.M., A.G.L., A.S.) and Obstetrics and Gynecology (L.T.), University of Milan, 20122 Milan Italy; Endocrinology and Diabetology Unit (M.F., U.V., F.E., P.B.-P., G.M., A.S.), Medical Genetics Unit (F.N., F.L.), and Neuroradiology Unit (S.A.), Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; and Endocrine Unit (A.G.L.), Istituto Clinico Humanitas IRCCS, 20089 Rozzano, Milan, Italy

Brazil is a large, populous country in South America, which has one of the biggest concentrations of people with diabetes. This article reviews the current status of diabetes care, medical education and training, and diabetes/endocrine research in Brazil. It highlights achievements in public health and research, which can be emulated by other countries. In Endocrine/Diabetes fields, a more realistic and responsible policies in terms of medical traineeship, patient education, and mainly scientific production would be mandatory to raise Brazil to a global competitive level.

N . Di Iorgi1, M .C . Salerno2, M . Cappa3, S . Loche4, G . Radetti5, D . Capaldo6, A . Allegri7, F . Napoli8, A . Calcagno7, O .B . Iovovich9, S . Noli7, S . Parodi10, M . Maghnie1 . 1DINOGMI, Endocrine Unit, IRCCS G Gaslini, University of Genova, Genova, Italy, 2Traslational Medical Sciences, Pediatric Endocrinology Unit, University Federico II, Naples, Italy, 3Unit of Endocrinology and Diabetology, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy, 4Pediatric Endocrine Unit, Ospedale Microcitemico, Cagliari, Italy, 5Pediatrics, Regional Hospital, Bolzano, Italy, 6Traslational Medical Sciences, Pediatric Endocrinology Unit, Federico II, Naples, Italy, 7DINOGMI, Endocrine Unit, University of Genova, Genova, Italy, 8Endocrine Unit, IRCCS, G Gaslini, Genova, Italy, 9Divisione di Laboratorio, IRCCS, G Gaslini, Genova, Italy, 10Institute of Electronics, Computer and Telecommunication Engineering, National Research Council of Italy, Genova, Italy

It is my greatest pleasure to introduce the papers devoted to Paediatric Endocrinology, coming in the current issue of Scripta Scientifica Medica! Paediatric Endocrinology is a relatively new but quickly and steadily developing paediatric subspecialty. While it is still unrecognized in some European countries, Paediatric Endocrinology was officially introduced in Bulgaria 20 years ago (in 1995). Even before that, many renowned paediatricians developed both endocrinology and diabetology and put the foundation for further development (professors Zhelev, Damyanova, Stanchev and others). In the 80s Prof. Lilia Peneva was the first Bulgarian paediatrician who officially joined the European Society of Paediatric Endocrinology (ESPE) and paved the way for efficient participation in the life of the biggest professional paediatric endocrine society nowadays. Since then many colleagues joined efforts in improving care for children with short stature, diabetes, rare endocrine and metabolic diseases and scientific potential grew in parallel. In 2010 the Varna Paediatric Endocrine Society (VAPES) was registered, and a year later – the Bulgarian National Society of Paediatric Endocrinology (BNSDE). Many causes have been raised and many problems solved, especially in day care. Both BNSPE and VAPES endorse the ESPE Training Syllabus (https://www.eurospe.org/education/education_training.html), and the quality and knowledge of trainees is improving constantly. This brings new successful researchers in the field, and gradually increases the number of publications in respected international journals. A good appraisal of the merit of the discipline’s development is the attraction of World renowned speakers to the annual meetings of both VAPES (www.vapesbg.org) and BNSPE (www.bnsde.org).

Background: Practicing behavior of the physicians varies from population to population due to diverse socioeconomic, cultural, and professional factors. Evidence on these issues is almost nonexistent in the developing countries. Objective: The prescribing behavior of diabetes treating physicians working in selected hospitals of the Diabetic Association of Bangladesh was studied along with the factors affecting those behaviors. Materials and Methods: This was an observational study on 818 prescriptions given by 49 physicians working in 16 health care facilities, which were photocopied by a portable photocopier. The various components of the prescription were scrutinized for presence and absence, and evaluated independently by two expert Diabetologists for their qualitative aspects. Results: The mean ± standard deviation of the total prescribing score (expressed as percentage) was 60 ± 11. Physicians scoring around or below 60% belonged more to lower age (

R O O F Vincent Braunersreuther ⁎, Fabrizio Montecucco , Mohamed Asrih , Graziano Pelli , Katia Galan , Miguel Frias , Fabienne Burger , Ana Luiza Gomez Quindere , Christophe Montessuit , Karl-Heinz Krause , Francois Mach , Vincent Jaquet f,1 a Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland b Division of Clinical Pathology, Department of Genetic Medicine and Laboratories, University Hospital, 1 rue Michel-Servet, 1211 Geneva, Switzerland c First Clinic of Internal Medicine, Department of Internal Medicine, University of Genova, 6 viale Benedetto XV, 16132 Genoa, Italy d Service of Endocrinology, Diabetology, and Nutrition, University Hospital, 4 rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland e CAPES Foundation, Ministry of Education of Brazil, Brasilia, DF 70.040-020, Brazil f Department of Pathology and Immunology, Centre Medical Universitaire, University of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland P D The authors regret that in the article referenced above the name of the third author, Mohamed Asrih, wasmisspelled. The corrected authorship is given above. The authors would like to apologise for any inconvenience caused.

Type 2 diabetes and the metabolic syndrome are highly prevalent disorders with severe complications such as cardiovascular disease. The aetiology of type 2 diabetes and the metabolic syndrome is not known, but the interaction between genetic factors and environmental triggers is important. The aim this thesis was to identify genetic factors that may increase susceptibility to these disorders by investigating candidate genes regulating lipolysis (hormone-sensitive lipase, HSL, lipoprotein lipase, LPL and phosphodiesterase 3B, PDE3B), thermogenesis (uncoupling protein 2, UCP2) and adipogenesis (peroxisome proliferator-activated receptor gamma, PPARG). Four of the genes were screened for mutations and identified variants were tested for association in large intra-familial and case-control association studies. Variability in the UCP2 gene was not associated with alterations in basal metabolic rate or with obesity. The gene encoding HSL was associated with type 2 diabetes in a case-control study, and the LIPE marker of the HSL gene showed distorted transmission to abdominally obese offspring. The PDE3B gene was associated with hyperinsulinaemia in genotype-discordant siblings. Haplotypes including several variants on chromosome 11 were unequally transmitted to offspring with abnormal glucose tolerance. The studies also provided evidence for an interaction between a variant in the LPL gene and insulin sensitivity. In a large, family-based multi-step study we could show that genetic variability in the gene encoding PPARG is associated with a reduced risk for diabetes, supported by the consistent results in a meta-analysis on the same variant. In conclusion, variability in genes regulating lipolysis and adipogenesis increase susceptibility to type 2 diabetes and the metabolic syndrome. Prospective studies will be helpful to establish the risk associated with the potential genetic riskfactors presented in this thesis. Typ 2 diabetes (åldersdiabetes eller sockersjuka) är en av de vanligaste folksjukdomarna, som ofta medför allvarliga komplikationer. Typ 2 diabetes utvecklas under en lång tid och uppträder ofta tillsammans med andra riskfaktorer för hjärt- och kärlsjukdomar, såsom fetma, förhöjt blodtryck och förhöjda blodfetter. Denna sjukdomsbild kallas det metabola syndromet. Individer som har det metabola syndromet har 2-3 gånger ökad risk att drabbas av hjärt- och kärlsjukdomar. Typ 2 diabetes och det metabola syndromet är komplexa polygena sjukdomar, d.v.s. de är sannolikt resultatet av en kollision mellan riskfaktorer som är ärvda och som finns i livsstilen. Direkta orsaker till varför somliga individer utvecklar typ 2 diabetes är inte kända. Målet med de studier som presenteras i den här avhandlingen var att identifiera genetiska riskfaktorer som ökar risken att drabbas av typ 2 diabetes eller metabola syndromet. Vi studerade kandidat-gener som reglerar lipolys (nedbrytningen av fett), basal energiförbrukning och fettcells-utveckling, eftersom lipid- och fettcells-metabolism är av avgörande betydelse för upprätthållande av en normal glukosmetabolism. Vi identifierade mutationer och variationer i dessa kandidat-gener. Vidare studerade vi om någon specifik allel (en av flera alternativa former av en gen) eller haplotyp (en kombination av alleler på samma kromosom) av dessa gener var associerade med typ 2 diabetes eller det metabola syndromet. Uncoupling protein 2 (UCP2) är en transport-kanal i mitokondrien som reglerar frånkopplingen av elektrontransport-kedjan från ATP-syntesen. Vi visade att en vanlig variation i genen (Ala55Val; ena allelen har en alanin och den andra en valin i kodon 55) inte är associerad med förändrad basalmetabolism och att allelerna var lika vanliga hos patienter med metabola syndromet som hos friska kontroller. Vi kunde inte identifiera några ovanliga mutationer eller mer vanliga variationer i genen hos patienter med metabola syndromet. Resultaten tyder på att variationer i genen inte predisponerar för metabola syndromet eller nedsatt basalmetabolism. Hormon-känsligt lipas (HSL) är ett enzym som finns i fettväven och som reglerar rekryteringen av fett som energikälla under fasta. Vi identifierade en mutation och en relativt vanlig varation i genen hos patienter med bukfetma och förhöjda triglyderider, och visade att dessa inte var associerade med metabola syndromet. Genom att studera en genetisk markör i genen (LIPE mikrosatellit) kunde vi visa att genen var associerad med typ 2 diabetes och bukfetma hos släktingar till diabetiker. Resultaten tyder på att vissa oidentifierade varianter av genen eller närliggande gener kan predisponera för typ 2 diabetes och bukfetma. Lipoproteinlipas (LPL) är ett enzym som sitter på insidan av blodkärlen och som spjälker det fett vi äter så att kroppens vävnader kan tillgodogöra sig det. Vi studerade en variation i genen (Asn291Ser; ena allelen har aminosyran aspargin och den andra serin i kodon 291) och kunde visa att individer vars vävnader ger ett sämre svar på insulin (insulin-resistenta) hade en högre risk att utveckla störningar i fett-metabolismen om de var bärare av serin-allelen. Däremot bidrog inte serin-allelen till ökad risk för störningar i fett-metabolismen hos typ 2 diabetiker. Resultaten tyder på att serin-allelen kan vara en speciellt viktig risk-faktor för störningar i fettmetabolismen hos insulin-resistenta individer som inte har diabetes. Peroxisome proliferator-aktiverad receptor gamma (PPARg) är en transkriptionsfaktor som reglerar uttrycket av gener som är viktiga för fettcells-utvecklingen. Vi studerade en vanlig variant i genen (Pro12Ala; ena allelen har prolin och den andra alanin i kodon 12) och visade att prolin-allelen var mer frekvent hos diabetiker och nedärvdes oftare till diabetiker, vilket tyder på att prolin-allelen ökar risken att insjukna i typ 2 diabetes. Meta-analys av alla publicerade data visade övertygande att prolin-allelen var förenad med 1.25 gånger ökad risk att drabbas av diabetes. Eftersom risk-allelen är vanlig har den stor betydelse för risken av typ 2 diabetes i befolkningen. Fosfodiesteras 3B (PDE3B) finns i fettväven, levern och bukspottskörtelns insulin-producerande celler. Vi studerade en vanlig variant i exon 4 av genen, G1389A (ena allelen har en guanin och den andra en adenosin i nukleotid 1389). Homozygota bärare av A allelen hade lägre insulin-nivåer i plasma två timmar efter ett oralt glukos-tolerans-test, jämfört med syskon som har en eller inga A-alleler. Om man samtidigt har förändringar i andra gener på samma kromosom är risken ännu högre. Resultaten tyder på att haplotyper på den korta armen av kromosom 11 kan predisponera till störd insulinsekretion. Sammantaget tyder detta på att variationer i gener som reglerar lipolys och fettcells-utvecklingen kan bidra till bukfetma, typ 2 diabetes och det metabola syndromet. Prospektiva studier kommer att behövas för att fastställa om individer som bär på dessa genvarianter utvecklar diabetes tidigare och oftare än de som inte har dem.

Background and objectives Education is a key component of the care of diabetic patients. Back in 1999 we set up a network for the management of diabetics which is centred on an out-of-hospital structured therapeutic patient education (TPE) programme Its main objective is to help improve the patient9s state of health. Programme The TPE programme comprises three parts (a total of 27 h) and is implemented by trained professionals (doctors, dieticians, chiropodists, nurses) in an out-of-hospital setting. An external assessment using standards established by the French National Authority for Health (HAS) was performed from 2005 to 2007. Analysis focused on items in the patient9s file (blood pressure (BP), glycated haemoglobin (HbA1c), LDL cholesterol), health professional and patient satisfaction surveys, a quality of life questionnaire (DHP 81), and reimbursements by French national health insurance. The data were compared to the results of the 2001 ENTRED study. Results The analysis concerned 268 patients with type 2 diabetes (mean age, 65.2 years; 55.2% male). The disease had been diagnosed on average 12.1 years earlier and 31.4% of patients were on insulin. There was no difference beween our population and the ENTRED population. The satisfaction score was 8.9/10 and 6.9/10 for network patients and professionals, respectively, versus 8.4/10 and 6.4/10, respectively, for ENTRED patients and professionals. The quality of life score was 6.7/81 versus 16.3/81 for ENTRED. Annual eye examinations were performed in 83.3% of network patients versus 66.9% of ENTRED patients. At least three HbA1c measurements were made in 71% of network patients versus 51.5% of ENTRED patients. Over the three parts, an HbA1c of Discussion and conclusion The impact of the network was highly positive with regard to patient satisfaction and quality of life but less so with regard to health professional satisfaction. Working within a network helps improve professional practices. The network provides educational value for patients independently of any care they receive and this can be translated into better clinical and biological test results. The health economics analysis confirmed that the expenditure incurred by the network was offset by savings in terms of direct health expenditure. A limitation of our study was that the ENTRED study is a little outdated. In conclusion, educational support provided independently of care is effective. Contexte, objectifs La prise en charge des patients diabetiques est pluridisciplinaire et l9education est un element essentiel. Des 1999 nous avons mis en place un reseau de prise en charge des diabetique centre sur un programme structure educatif ambulatoire: le Reseau Vichy Diabete dont l9objectif principal est de faciliter l9amelioration de l9etat de sante des patients. Programme Le programme d9education therapeutique est realise en ambulatoire en 3 cycles (soit 27 heures), par des professionnels formes (medecins, dieteticiens, podologues, infirmieres). Une evaluation externe repondant au referentiel de l9HAS a porte sur la periode de fonctionnement 2005 a 2007 et a inclus 268 patients diabetiques. L9analyse a porte sur les parametres du dossier (HTA,HbA1c, LDL), des enquetes de satisfaction professionnels et patients, un questionnaire qualite de vie (DHP 81), l9analyse des depenses remboursees par l9assurance maladie. Les donnees obtenues sont comparees aux resultats de l9etude ENTRED realisee en 2001. Resultats La population est diabetique de type 2 dont 31.4% traites par insuline. L9age moyen est de 65.2 ans (55.2% sont des hommes), l9anciennete du diabete de 12.1 ans. Il n9y pas de difference avec la population ENTRED. La note de satisfaction des patients reseau est de 8.9/10 et des soignants 6.9/10 vs 8.4/10 et 6.4/10 pour ENTRED. Le score qualite de vie est de 6.7/81 vs 16.3/81. 71% des patients reseau ont eu au moins 3 dosages d9HbA1c par an vs 51.5 pour ENTRED. 83.3% vs 66.9% ont eu un FO annuel. L9HbA1c evolue favorablement au fil des cycles, 30.1% des patients en cycle 1, 36.3% en cycle 2 et 42.6% en cycle 3 ont une HbA1c Discussion/conclusion L9impact de la prise en charge reseau est tres positive sur la satisfaction et la qualite de vie des patients mais moins sur celle des professionnels. Le fonctionnement en reseau ameliore les pratiques professionnelles et demontre l9interet d9une prise en charge educative y compris sur les resultats cliniques et biologiques des patients. Par contre la reference comparative de l9etude ENTRED est probablement un peu ancienne. L9analyse economique confirme que les depenses engendrees par le reseau sont compensees par une economie en terme de depense directe de sante. Une prise en charge educative independamment du soin, demontre son efficience.

Background and Objectives Hopital Europeen Georges Pompidou (HEGP) is the most highly ‘computerized’ hospital of the Paris hospital network (Assistance Publique–Hopitaux de Paris (AP-HP), and provides benefit to the whole hospital community. Our objective was to assess the clinical impact of two Web-based programmes for the improvement of patient management and medical practice in diabetology. Programmes The Diabgest programme (dedicated e-mail address: diab.gest@egp.fr) is a programme for the management of gestational diabetes, which is run jointly with the maternity unit of Necker hospital. This unit is attended by 2000 patients/year. The prevalence of gestational diabetes in France is 10%. Since HEGP opened in 2000, there have been 200 gestational diabetes patients per year. Mothers-to-be benefit from a conventional medical consultation. Data are stored in a database using Advance software. The causes and consequences of gestational diabetes are calmly explained to them. A dietitian provides them with the necessary counselling on diet and a nurse teaches them how to self-monitor blood glucose. The mothers-to-be are sent a spreadsheet by e-mail in which they enter their blood glucose measurements several times a day. They return the sheet twice weekly and receive an answer from the doctor on the day of receipt. An automated colour code is used to tag normal, doubtful, or pathological readings. The system has advantages for doctors who save time and are not swamped by demands they cannot meet, and for the mothers-to-be who avoid multiplying hospital visits. This ‘electronic service on permanent duty’ allows them to ask as many questions as they wish, and thus provides reassurance and enhances psychological well-being. Appropriate treatment decisions, including initiation of insulin therapy (in 1/3rd of gestational diabetes patients, ie 3% of pregnancies), are taken promptly. Continuous ‘coaching’ and monitoring of insulin doses help rapidly achieve good glycaemic control. We have created a user-friendly Web site (www.hegp.fr/diabeto) providing simple and reassuring information for patients with diabetes. It is one of the rare hospital sites hosted by the official server of AP-HP and is not subsidised by private funds. It complies with the 8-point charter for author independence and regular updating of Heath on the Net (HON) and is certified HON. The HEGP Intranet server produces monthly statistics on numbers of visitors and visits, duration of visits and the most popular topics. Results The Diabgest programme has achieved a 100% rate of perfect births for both mothers and babies. Since its inception, there have been no cases of macrosomia, obstetric trauma, prematurity, neonatal hypoglycemia or respiratory distress syndrome. A Web-based consultation 3 month postpartum is provided to detect any recurrence of maternal diabetes (30% prevalence according to the literature). The continuous dialogue between patient and doctor throughout pregnancy has proven to be a valuable educational tool in the prevention of recurrence. When the HEPG diabetology Web site was created 2 years ago, there were a few hundred visitors each month. Currently, there are about 10 000 visitors/month, who visit the site once or twice, and read more than 350 000 pages. At least 25% stay on line for at least 30 min and 15% for 1 hour or more. Apart from the index of 200 keywords, the most consulted topics are: complications of diabetes, insulin therapy, diabetic ketoacidosis, and the causes of diabetes. Most visitors add the site to their favourite links. Its qualitative impact on the health and morale of diabetic patients is currently being assessed using questionnaires that patients are encouraged to answer. Conclusion Diabetes is a major public health issue. We have finalised two programmes that contribute towards improving the medical care and therapeutic education of diabetic patients. Contexte et objectifs L9informatique medicale contribue a l9amelioration de la qualite de la prise en charge medicale du diabete gestationnel et de l9education des patients: 2 experiences du service de diabetologie de l9HEGP. L9HEGP est deja la structure la plus « informatisee » de l9AP-HP, ce qui benefice a l9ensemble de la communaute hospitaliere. Nous presentons successivement 2 programmes informatiques supplementaires d9amelioration de la prise en charge et des pratiques medicales diabetologique dont l9impact clinique a ete evalue. Programmes Le programme Diabgest et son courriel dedie (diab.gest@egp.fr) concerne la prise en charge du diabete gestationnel en collaboration avec la maternite de l9hopital Necker. Le nombre de patientes consultant a la maternite est de 2000 par an, la prevalence du diabete gestationnel en France est de 10%. Il existe une cohorte de 200 patientes par an depuis l9ouverture de l9HEGP en 2000. Les futures mamans beneficient d9une consultation medicale conventionnelle dont les informations sont colligees sur une base de donnees sur le logiciel Advance. Causes et consequences du diabete gestationnel sont dedramatisees. La consultation dietetique permet de procurer les conseils alimentaires adequats. Enfin, les patientes beneficient par l9equipe infirmiere d9une formation a l9auto-surveillance glycemique. Elles recoivent toutes par courrier electronique un tableur informatise permettant de noter de facon pluri-quotidienne leurs releves glycemiques transmis 2 fois par semaine au medecin qui repond dans la journee. Un code couleur automatique permet de reperer les glycemies normales, douteuses ou pathologiques. Pour le medecin, c9est un gain de temps precieux et l9acces aux soins autrement serait impossible en raison d9une demande considerable. Pour la patiente enceinte, des deplacements iteratifs deraisonnables sont evites. Le contact interactif permanent leur permet de poser des questions a volonte sur cette « astreinte electronique » et de renforcer leur bien etre psychologique. Les decisions therapeutiques adequates, la mise a l9insuline (1/3 des cas des diabetes gestationnels donc 3 % des grossesses) peuvent etre prises dans des delais rapides. Le « coaching » continu de l9adaptation des doses d9insuline permet d9obtenir tres rapidement les controles parfaits necessaires. Resultats 1. Ce sont 100 % des bebes qui sont venus au monde dans d9excellentes conditions pour leurs meres et pour eux-memes : pas de macrosomie, de traumatismes obstetricaux, de prematurite, d9hypoglycemie neonatale ou de detresse respiratoire. Le programme comporte une consultation informatisee a 3 mois pour prevenir l9emergence du diabete chez la mere, dont la prevalence dans la litterature est de 30%. La strategie globale est ainsi un outil educatif de prevention. Notre deuxieme action est la creation d9un site www.hegp.fr/diabeto, destine a donner des informations simples et rassurantes aux patients. Le serveur intranet hospitalier produit des statistiques mensuelles. Nombre de visiteurs et de visites, temps passe, themes les plus consultes figurent parmi les principaux parametres analyses. 2. A sa creation il y a 2 ans le site comptait quelques centaines de visiteurs mensuels. Actuellement pres de 10 000 personnes se connectent chaque mois, 1 ou 2 fois, et lisent plus de 350 000 pages. Au moins 25 % des visiteurs restent jusqu9a 30 min et 15% une heure ou plus. Outre l9index qui repertorie par ordre alphabetique plus de 200 mots cles, les themes les plus consultes sont les complications, l9insulinotherapie, les decompensations cetosiques et les causes du diabete. La majorite des visiteurs ajoutent le site a leurs favoris. Ce site qui ne beneficie d9aucune promotion est labellise HON (Heath On the Net) car il respecte une charte en 8 points qui garantit l9independance des auteurs et des donnees regulierement mises a jour. C9est un des rares sites hospitaliers de ce type qui est heberge sur le serveur officiel de l9AP-HP. Convivial et encourageant, il seduit un nombre croissant de personnes qui y consacrent de plus en plus de temps. Sa validation qualitative par l9etude de son impact sur la sante et le moral des diabetiques est en cours par l9utilisation de questionnaires auxquels les patients sont invites a repondre. Conclusion En plus d9une informatisation poussee de l9hopital, nous avons mis au point 2 programmes contribuant a l9amelioration de la prise en charge des patients et a l9education therapeutique, enjeux majeurs de sante publique.

University of Oxford (K.N.M.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford OX3 7LJ, United Kingdom; Medizinische Klinik und Poliklinik III (A.B.), Technische Universitat Dresden, Universitatsklinikum Carl Gustav Carus, 01307 Dresden, Germany; Endokrinologikum Ruhr (A.B.), Alter Markt 4, 44866 Bochum, Germany; and University of Bochum, University Hospital Bergmannsheil, Departments of Radiology (V.N.) and Internal Medicine, Diabetology and Endocrinology (K.N.M., H.H.K., S.H.), 44789 Bochum, Germany

Mathematical model of the glucose regulation is proposed and discussed. It is based only on the data, which are available in outpatient clinics. This model enables to predict the state of the patients health and to identificate important parameters of patients organism, which are urgent in diabetology. First Published Online: 14 Oct 2010

In any epoque and in any field of biomedicine a few major figures stand out as being particularly influential. Some because they contributed very significantly to science, some because their personalities made them natural centres of learning and research. Albert E. Renold did both and will be remembered as one of the greatest names in diabetology of this century. His curiosity, his emphatic interest in young people and their ideas, his open-mindedness and intuitive understanding of new and sometimes rather vaguely formulated concepts made conversations with Albert Renold delightful and encouraging experiences. One of us (J.N.) remembers a long conversation in Geneva several years ago where seemingly odd and certainly less than solidly substantiated ideas on the pathogenesis of insulin-dependent diabetes mellitus (IDDM) were discussed. Pointing out these shortcomings Renold said, quoting Thomas Huxley: “He who does not go beyond the facts, he will seldom get as far as the facts”. With this in mind, however, still going to the limits of the facts and probably beyond, we wish to dedicate this chapter on the pathogenesis of IDDM to the memory of Albert E. Renold.

1Department of Pain Medicine, Beaumont Hospital, Beaumont, Dublin, Ireland; 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Association of Chronic Pain Patients, Houston, TX; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; 3Arthritis Center Twente, Enschede, The Netherlands; 4Department of Endocrinology, Diabetology and Osteology, Kantonsspital St Gallen, Switzerland; 5Centro de Salud Universitario Goya, Madrid, Spain; 6Kansas University Medical Center, Kansas City, and International Clinic Research, Leawood, KS, USA; 7Service de Medecine Interne et Consultation de la Douleur, Hopital Hotel Dieu, Paris Descartes University, Paris, France; 8Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia PA, USA

The professional-scientific journal Diabetologia Croatica was first issued in 1972 and its publication continued for the past 25 years. At the beginning, the publication was bilingual (Croatian/English), whereas in 1989 it was switched to the English edition only. The journal has been issued quarterly and until now there were altogether 95 issues and 14 supplements with the total of 965 articles. Among these, 625 articles were assessed as belonging to the scientific and 340 to the professional category. Articles by the authors from the Vuk Vrhovac Institute for Diabetes, Endocrinology and Metabolic Diseases accounted for 25% of the total number of published papers, those by other authors from Croatia were represented with 43%, whereas the remaining 32% were submitted by the authors from the international community. The journal is accessible to the international medical audience through different ways. It is being referred in Excerpta Medica, Section 3. Endocrinology, Chemical Abstracts and Biological Abstracts (BIOSIS). It is also part of many library holdings. It has been successfully exchanged with many recognized journals, i.e. 57 in total so far, and 46 currently, among which there are 40 international ones. A review of the Science Citation Index (SCI) has revealed that there were 132 citations of the journal's articles in international publications until 1995.

The evaluation and treatment of critical leg ischemia has been the concern of doctors from a wide range of traditional medical specialities that includes general and vascular surgery, angiology, diabetology, cardiology, hematology, and radiology, depending on both the local circumstances and national traditions.

1329 CORRELATION OF NORMAL VERSUS ELEVATED ALT AND GGT IN AN OBESE POPULATION, ASSOCIATION WITH LIVER HISTOLOGY AND METABOLIC PARAMETERS A. Verrijken, S. Francque, I. Mertens, M. Ruppert, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal. Endocrinology, Diabetology and Metabolic Diseases, Gastroenterology and Hepatology, Abdominal Surgery, Pathology, Antwerp University Hospital, Antwerp, Belgium E-mail: an.verrijken@uza.be

The problem of finger in the patient with diabetes mellitus is important consideration in diabetology. Generally, peripheral neuropathy that manifests with finger paresthesia is common. However, some recent reports mention the concern on trigger digits in diabetic patients. In this brief article, the authors focus review and discussion on this specific topic. The searching of standard database, PubMed, on available publication on this area selecting by keywords trigger digits and diabetes mellitus was done and all derived papers were extracted and further synthesized in this review article. Epidemiology and management of the condition are the mainly focused reviewed areas and presented in this article.

After 1953, Dr. Y. Kobayashi organized a study group of chemotherapy of diabetes mellitus, and then a more broader ‘Diabetes Study Group’ sponsored by the Ministry of Education. During these group activities, the members felt the need to establish a forum to discuss various aspects of diabetology. In December 1957, an inaugural meeting of the Japan Diabetes Society (JDS) was held. The objectives of the Society were to promote the investigation and to spread the knowledge on diabetes and to thereby prevent the hazard arising from diabetes. Since that time, JDS has been admitted as a member of the International Diabetes Federation in 1958, and was approved as an incorporated association by the Ministry of Education in 1985. It has now seven regional branches. Members increased greatly and reached 7795 in March 1993. In every year, JDS has a 3-day nationwide general scientific meeting, and local meetings are held by each of its branches. The official journal ‘Tonyobyo (Journal of the Japan Diabetes Society)’ is being issued monthly. JDS edited educational books for diabetic patients, such as ‘Guidebook for the Treatment of Diabetes’, ‘The Exchange List of Foods for the Treatment of Diabetes Mellitus’ and ‘The Guidebook of Summer Camp for Diabetic Children’. In 1967, JDS began to hold a 2-day post-graduate course named ‘Progress in Diabetology’ for physicians, nurses, dieticians and other health professionals. JDS has a close connection with the Japan Association of Diabetes Care and Education, co-sponsoring the ‘diabetes week’ every year. JDS participated in the activities of International Diabetes Federation in many aspects. The first office of IDF Western Pacific Region, placed in Kobe, was supported by JDS. The 15th IDF meeting in Kobe is now being prepared by many members of the JDS.

J.M. Aubry1 °, F. Jermann1, M. Gex-Fabry1, L. Bockhorn2, M. Van der Linden3, N. Gervasoni4, G. Bertschy1, F.M. Rossier2, G. Bondolfi1. 1University Hospitals, Department of Psychiatry, Geneva, Switzerland; 2University Hospitals, Department of Genetics and Laboratory Medicine Service of Endocrinology and Diabetology, Geneva, Switzerland; 3University of Geneva, Cognitive Psychoplogy and Neuropsychology Unit, Geneva, Switzerland; 4University of Geneva and Clinique la Metairie, Academic Department of Psychiatry, Geneva and Nyon, Switzerland

339 NAFLD LIVER FAT SCORE STRONGLY CORRELATES WITH HISTOLOGICAL SEVERITY OF NAFLD AND NASH IN A LARGE COHORT OF PROSPECTIVELY INCLUDED OVERWEIGHT PATIENTS S. Francque, A. Verrijken, I. Mertens, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal. Department of Gastroenterology Hepatology, Department of Endocrinology, Diabetology and Metabolism, Department of Abdominal Surgery, Department of Pathology, Antwerp University Hospital, Edegem, Belgium E-mail: sven.francque@uza.be

B. Anderson, M. Peyrot, H.J. Aanstoot, K. Lange, T. Danne, L. Deeb 1 Baylor College of Medicine, Pediatrics, Houston, USA 2 Loyola College in Maryland, Dept of Sociology, Baltimore, USA 3 Diabeter, Diabetes Center for Children and Youth, Rotterdam, The Netherlands 4 Medizinische Hochschule, Medical Psychology, Hannover, Germany 5 Kinderkrankenhus Auf der Bult, Dept. of General Pediatrics and Endocrinology/Diabetology, Hannover, Germany 6 Florida State University, Dept of Behavioral and Social Medicine, Tallahassee, USA

The availability of robust biological markers of diabetes mellitus is crucial for preventing severe long-term complications. Among them are markers of non-enzymatic glycation, due to the spontaneous binding of sugars to amino groups of proteins. Glycation generates a variety of products that eventually form complex and deleterious compounds named advanced glycation end products (AGEs). HbA 1c , characterised by the binding of glucose to the N-terminal valine of hemoglobin β-chains, is the key parameter for retrospectively assessing glycaemic balance. HbA 1c level is closely linked to the development of degenerative complications. The International Federation of Clinical Chemistry (IFCC) reference method is high performance liquid chromatography (HPLC) coupled with mass spectrometry or capillary electrophoresis, which provides HbA 1c percentages lower than obtained by the currently used national glycohemoglobin standardization program (NGSP). Results should be expressed as mmol HbA 1c /mol Hb. International societies of Biology and of Diabetology have agreed to report HbA 1c results using both units, in order to ensure the best evolution of medical practices. When HbA 1c determination is not informative (alterations of haemoglobin structure or metabolism), fructosamine determination (i.e., plasma glycated proteins) is a valuable alternative. New methods for evaluating AGEs (e.g., pentosidine, carboxymethyllysine) in vitro (proteomics, LC-tandem MS) or in vivo (transdermic measurement of AGEs) represent promising fields of investigation.

These examples demonstrate the importance of a multidisciplinary approach of in vivo chemical sensors and of a tight collaboration between physico-chemists (involved in, for example, analysis, electrochemistry, polymer science) and clinicians (in the fields of diabetology, surgery and biomaterial science) to solve the numerous problems and difficulties encountered. They also show that significant improvements have been obtained allowing short-term in vivo implantation, but that very difficult problems have arisen for controlling interactions between biosensor and tissue, i.e. modifications of the 'sensor by the tissue (e.g. clotting of the external membrane or layer) as well as modifications of the tissue by the sensor (e.g. toxicity, inflammatory and immune reactions), both reactions being usually described as biocompatibility of the implant.

The continuous glucose monitor used by Murphy and colleagues can be thought of as diabetology’s answer to cardiology’s 24 hour electrocardiography monitor. It is used as an investigative tool, is attached to the patient (usually for 72 hours), and requires the user to return to hospital for its removal. The data are downloaded and examined for abnormal glucose levels and trends. The sensor is inserted through the abdominal wall, so that its glucose oxidase tip lies within subcutaneous tissue, where it measures the glucose level of interstitial fluid, not of blood. The sensor is wired to a palm sized monitor, which can be clipped to clothing. The sensor cannot be disconnected, even temporarily—for …

1 Quebec Heart Institute, Laval Hospital Research Center, Laval University, Sainte-Foy, Quebec G1V 4G5, Canada ; 2 Department of Diabetology, Metabolism, and Clinical Nutrition, University Hospital Antwerp, Faculty of Medicine (Department of Diabetology, Metabolism, and Clinical Nutrition), Edegem-Antwerp, Belgium ; 3 St Luke's-Roosevelt Hospital Center, New York, NY, USA; 4 Division of Diabetes, Nutrition, and Metabolic Disorders, CHU Sart Tilman, University of Liege, Liege, Belgium.

The prevalence of eating disorders and behaviors was evaluated in two populations of adolescents with type 1 diabetes from two cities in Italy. In this report, we will establish the relationship of these disorders with sex, BMI, socioeconomic status, metabolic control, and compliance to therapy. A total of 193 patients with type 1 diabetes aged 8–18 years (mean 13.6 ± 2.7 years; 92 female and 101 male subjects) were recruited from the pediatric diabetology units at the Second University of Naples ( n = 118, 56 female and 62 male subjects) and at the University of Parma ( n = 75, 36 female and 39 male subjects). All patients were affected by type 1 diabetes without evidence or history of other autoimmune diseases (thyroiditis, celiac disease, etc.). The distribution of sex, age at the onset of diabetes, disease duration, and BMI was statistically similar in …

Self-monitoring of blood glucose started only fifty years ago. Until then metabolic control was evaluated by means of qualitative urinary blood measure often of poor reliability. Reagent strips were the first semi quantitative tests to monitor blood glucose, and in the late seventies meters were launched on the market. Initially the use of such devices was intended for medical staff, but thanks to handiness improvement they became more and more adequate to patients and are now a necessary tool for self-blood glucose monitoring. The advanced technologies allow to develop photometric measurements but also more recently electrochemical one. In the nineties, improvements were made mainly in meters' miniaturisation, reduction of reaction time and reading, simplification of blood sampling and capillary blood laying. Although accuracy and precision concern was in the heart of considerations at the beginning of self-blood glucose monitoring, the recommendations of societies of diabetology came up in the late eighties. Now, the French drug agency: AFSSAPS asks for a control of meter before any launching on the market. According to recent publications very few meters meet reliability criteria set up by societies of diabetology in the late nineties. Finally because devices may be handled by numerous persons in hospitals, meters use as possible source of nosocomial infections have been recently questioned and is subject to very strict guidelines published by AFSSAPS.