LMP299Y1 Lecture Notes - Pancreatic Islets, Nod Mice, Myd88

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3 Jun 2013
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Philippe.poussier@sri.utoronto.ca
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
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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
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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
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