March 20, 2013.docx

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University of Toronto St. George
Laboratory Medicine and Pathobiology

[email protected] Pancreas – type I diabetes – Pancreas is gland located under the liver and towards the back of the body and it is surrounded by the small intestine and the spleen Green ducts – connect organ with liver and with the intestine – through these ducts that bile from liver and pancreatic secretion, exocrine secretion, combine to reach the gut where they contribute to food digestion and absorption Pancreas is made up of two parts – one is the exocrine tissue, which accounts for the largest part of the organ, and it is presented by the exocrine glands the secretion of which goes from the lumen of the gland to small ducts initially, which eventually reach these large pancreatic ducts – these exocrine tissue of the pancreas,involved in the digestion of food is not involved in the ___________ process The part of the pancreas involved in type 1 diabetes is endocrine part of the gland, presented by the circular formations called islets of Langerhans and each of these islets has diameter of approx. 200 microns – contains many endocrine cells that secrete hormones and if you stain the cells for insulin in green, nuclei in blue, and glucagon hormone in red – majority of endocrine beta cells that ones that secrete insulin – majority are alpha cells (red cells that secrete glucagon – other endocrine cells that are also rare, like delta cells that secrete somatostatin, which are located between alpha cells and periphery in other part of islet – green is the target of the immune process that leads to type 1 diabetes In humans, have a million to two million islets in pancreas Classification of diabetic syndromes Type 1A is most common diabetic syndrome Vast majority of diabetic cases are type 2 diabetic syndromes, which are observed most cases in adult individuals usually people who are overweight and hese type two syndromes – even more considered as having an inflammatory component to it, it is not considered an autoimmune disease – and this accounts for roughly 90% of diabetes in the population Gestational diabetes – 2% of pregnancies – diabetic syndrome goes away after pregnancy – but big risk factor for subsequent development of type 2 later in life Type 1 – insulin dependent diabetes – patients needs exogenous insulin for the rest of their lives – Peak incidence observed around puberty – can develop at any time of life – more and more, age of onset earlier and earlier Some can die of undiagnosed type 1 diabetes – diagnosis of type 1 is relatively easy because presentation is dramatic; type 2 patients can feel well – type 1 do not, lose weight, increase quantity of urine, feel very tired, massive urine volume by excretion of large amounts of sugar that creates osmotic – also present with intestinal symptoms – and these patients will require insulin replacement for the rest of their life because their disease resuls from destruction of cells that produce insulin Soon after diagnosis, when start treating with insulin, they enter honeymoon period, where decrease amount of insulin needed to treat patients to point of stopping (becoming insulin-independent) – suggesting some recovery from the destructive process – usually transient – and after that, return to lifelong insulin-dependency Diabetes, regardless of type, is cause of the major chronic complications affecting kidneys, vessels, nerves – first cause of acquired blindness, acquired kidney failure, amputation, major source of cardiovascular disease – many of these complications can be prevented or revesred thanks to insulin treatment, if properly given – have to realize that the life of people who are type 1 diabetes is not pleasnant – because goal of treatment is to normalize the blood sugar level and this is very difficult to achieve with insulin injections under the skin or even with insulin pump that continuously administers insulin – and in order to try to mimic what the – give multiple injections of insulin per day; need to adjust dose by measuring blood sugar; this is difficult to cope with especially if happens in young child If treat yourself well, prevent onset of these complications Overall, mortality of people suffering from type 1 increased several fold from healthy individuals Type 1 diabetes is prototypical – targets beta cells exclusively Multiple risk factors – many are genetic – some environmental – Clinical disease is preceded by phase of inflammation in the pancreas islets, duration of which can vary Autoimmune disease – most patients, especially young patients are found to have circulating autoantibodies that target islets and antigens – however, these autoantibodies do not play any pathogenic role – some mysterious difficult to understand data suggesting not as black and white – in general, keep in mind that circulating autoantibodies in type 1 individuals do not contirubte to destruction of pancreatic cells; this destruction done by autoreactive T cells, most destructive when both CD4 and CD8 T cells get together In contrast to quite a few other immune-mediated diseases – there are a few lab animals that spontaneously develop disease very similar to human disease and as a consequence, these animals have proven to be very helpful to understand many steps and mechanisms of type 1 diabetes – several years ago, summary of natural history of type 1 diabetes genetically predisposed to the disease – unknown env factors trigger the disease – whether trigger is single or multiple events insultis – for a while, nto destructive – but after a while, beta cell mass decreases – during this phase of inflammation, can detect in peripheral blood T cells that show specificity for pancreatic islets – much more easily found is the presence of circulating autoantibodies, sometimes long time before onset of clinical symptoms – discuss specificity of autoantibodies – as lose beta cell mass, aftera while, can start seeing some abnormalities in the way the individual masters sugar load and the fisrt thing that is observed is that the response of insulin to glucose is ________ early phase and more sustained phase and the first thing that disappers is the first phase of insulin response – and following this, they become glucose-intolerant – they will not be able to control their blood sugar level very well – higher in normal individuals – when you have lost 80% of beta cell mass that you become clinically diabetic – the paradigm is this summary on the slide – diabetic clinically if have destroyed 80% to 90% of beta cells – this needs to be taken with grain of salt: a beta cell synthesizes insulin as a poor insulin molecule, releases it in circulation by cleaving proinsulin into two molecules, insulin and a connecting peptide called c-peptide; once a person becomes diabetic and is treated with insulin, can no longer distinguish what is the natural insulin coming from residual beta cells to given exogenous insulin; but if measure c-peptide level, gives idea of the beta cell mass (because reflection of residual insulin secretion) – tells you that if follow c-peptide response, it is not 10% of the normal response for a few weeks and then zero; remain 30 to 40 percent of a normal individual’s response for a few years so maybe this paradigm of destroyed 80% beta cell mass when developed symptoms of type 1 diabetes is probably an exaggeration – can also return to insulin-independence in honeymoon period also suggest, close to having enough beta cells left in pancreas to control blood sugar – and as also, there is another very striking observation – there are animal models of type 1 diabetes – NOD mouse – can prevent type 1 diabetes in NOD mice; more complicated to reverse already established type 1 diabetes in this mice; people looked at the origin of the beta cells in these mice that were able to cured from type 1 diabetes by immune manipulation – the question was: has the immune manipulation allowed the mouse to rebuild a new set of beta cells OR was this reversal of diabetes the result of beta cell that already existed in the animal; in fact, these mice that recovered from type 1 diabetes through various immune treatments surprisingly, there were very few beta cells – majority of them were beta cells that existed at time of treatment, suggesting the beta cells, some of which were destroyed, but others may have been non-functional and able to recover – important because it raises possibility of reversing diabetes early so patients have enough beta cells preserved to remain non- diabetic – without need for pancreas or islet transplant that are rare procedure, not enough donors type 1 diabetes – if have several families with diabetes across several generations identical twins that have been separated at birth – if one twin develops disease, the other should, so purely genetic; on the other hand, ercombine genes to generate billions of different new genes – so the assumption that two identical twins will end up with exactly the same repertoire of T cell specificity or antibody specificity may not be important for ex. Cystic fibrosis but important for autoantibody-mediated disease – Diet, presence of infections/pathogens, Increase in Finland cannot be explained by genetic variation – clearly environmental or gene- environment interaction One of the theories to explain the changes in incidence of asthma, MS, diabetes is hygiene hypothesis – we are too clean; our immune system used to be kept busy with epidemics, but now has nothing to do – too clean, antibiotics, vaccinations, so turns to innocuous antigens or self and that’s the hygiene hypothesis – what do you think the so-called hygienic changes affect Microbiome – when change diets, microbial environemtsn, modify by what you ingest, one of the first things changed is the microbiome Microbiome – good evidence gathered in other immune mediated diseases that microbiome plays important role in susceptibility to type 1 diabetes – one example MyD88 – molecule that is downstream of the receptors that allow individual to recognize microbes – these mice deprived of ability to react to microbes, pathogenic or not, and what happens is on this Nature slide MyD88 defiicient NOD mice – mice with MyD88, whether they were male or female, 90% of females and 70 percent of males – one of two MyD88 genes present but the mice that were Myd88 knockouts were completely resistant to type 1 diabetes – - these mice kept in pathogen free environment – very clean environment, in theory devoid of any pathogenic microbe – have commensal bacteria/viruses in this pathogen free environment however, if transferred these MyD88 knockout animals into germ-free environment – completely sterile environment – protection afforded by lack of MyD88 disappeared – clearly these animals that didn’t have MyD88 were proected when they were in an environment when you have microbes and they lack these protection when they were put in protection without microbes – MyD88 KO mice clearly depending on the microbial environemtn was protected for type 1 diabetes or not – change environment, become diabetic or do not Microbiome of MyD88 KO mice VERY DIFFERENT from wildtype NOD mice – if they gave microbiome of MyD88 SPF mice to germ-free NOD mice, so colonize mice without germs with commensal bacteria of protected MyD88 – these NOD mice would not develop diabetes – microbiome that establishe din absence of MyD88 was protected In NOD , sex hormones play a role – if give male hormones to young NOD females - if castrate males, more susceptible to autoimmune disease? If put males in SPF env, protected; in germ-free env, no longer protected – Danska findings Females develop diabetes, males do not – put mom and pups in germ-free environment, both males and females develop diabetes – microbe env protective of males – transfer males to germ-free env, testosterone levels go down, show that microbiome of these mice, as they age, diverge between the two sexes and they went on to take microbiome of males, and give to young females, which got protected and their testosterone levels went up – this is to say that clearly the microbiome is probably very sensitive to major changes that had occurred in environment and that it may play an important role in type 1 diabetes like other diseases Since incidence of type 1 diabetes had increased five-hold – if can identify environemental changes – Preceded by inflammation of pancreas – darker on periphery is exonine – pancreatic islets; pale cells are endocrine Islets infiltrated by immune cells (T and B cells) Insultitis – look at pancreas of individual with insultis – severity of lesions vary from islet to islet In NOD mice – allows progression and specificity of inflammatory progress – pancreatic sections – insulitis progreses quite slowly and step wise – take pancreatic sections of NOD mice at four weeks and stain these section for insulin at top or glucagon at bottom – vast majority of pancreatic islet cells stain positive for insulin; few at periphery stain for glucagon in the 4 weeks insulin A month later – 8 weeks insulin – lots of beta cells – few alpha cells but now, can see periphery of islet, have massive infiltration which is called peri insulitis – not destructive – progressively infiltrate the whole islet and disappear once the bad job is done and if come back a few months later, at this stage, confronted with atophic islets that are not inflamed, immune cells have left, left behind islets with very few beta cells and in contrast, the majority of the cells that are left, stain clearly for glucagon – inflammatory progress leads to destruction of beta cells – Circulating antibodies sp
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