Some of you are discussing whether there are a number of distinct disease subsets and pathways that lead to type 1 diabetes diagnosis. Is there any indication at this stage of whether the patients in those groupings progress in patterned ways after the onset of their disease? E.g. could we predict a patients risk of eye involvement or maybe celiac disease, based upon the gene that triggered their diabetes and the subset they belong to?
The epidemiological patterns of T1D suggest that environmental factors contribute to the etiology of the T1D & A series of evidence supports a critical role of exogenous factors in the development of type 1 diabetes, madam u can find details from the following link
http://diabetes.diabetesjournals.org/content/54/suppl_2/S125.full
Thank you for your response Dr Ahmed, there is definitely a combination of external and genetic factors, so my question is not what is the cause (viral or otherwise) but if there are multiple causes (i.e. distinct pathways that all lead to T1D diagnosis) and whether those subsets will progress in specific ways after beta cell death and diabetes onset.
Thank you for your response too, Pankaj. I think you are right. the majority of later complications I guess are due to the patient being unable to produce insulin and needing therapy, not the imbalance that triggered the initial autoimmunity.
I think in the future the subsets of causes will be relevant for therapies that silence genes etc, but maybe not for predicting diabetes progression. Thank you both for your help : )
Hi Juliet,
the HLA-A24 (also to a lesser extent HLA-B39 and B18) susceptibility gene is an accelerant in the pre-clinical phase, providing a stable target and is also associated with more rapid loss of c-peptide (ie a marker of residual beta cells) and thus more rapid development of complications. The evidence seems to be that there are multiple viruses that affect the loss of beta cells, predominantly rotaviruses and enteroviruses see Honeyman MC Current Rev of Immunol) , both acting serially over a period of time until sufficient beta cells are lost to trigger clinical symptoms . Now that people with less full-house HLA (ie HLA-DR3,4 DQ2,8) susceptibility genes are becoming more frequent (see Fourlanos S , Harrison LC) it is likely that viruses are more important in triggering these (previously less susceptible) people. Peptides of insulin are however the the most important in initiating CD8 responses, and the INIT II trial (intranasal insulin) trial (see www.stopdiabetes.com.au ) is designed to stop pre-clinical children from progressing further in destruction of beta cells. So - yes there are multiple pathways and those with A24 may be the ones who should be treated most aggressively
post onset as they will go downhill faster.
Drs Ahmed and Bagul are correct, certainly from a classical standpoint. There are no predictors that will guide how disease will progress. I will put something heretical out there. We have been working on an area called T cell receptor revision. T cells acquire a receptor in development in the thymus. It has been assumed, incorrectly, that T cells never change their receptors after that point. We and others have solid evidence that T cells DO alter TCR expression even in the periphery. My contention is that some individuals are much more prone to this receptor revision than others. My group has evidence that diabetics are particularly susceptible to the effects of revision. The hypothesis would be that some individuals, perhaps based on their HLA configurations, are better able to revise T cells than are others. As such, new T cells with response to "new" antigens would occur. If those new antigens were "self" then the auto-aggression would progress. We follow a population of T cells called CD4+CD40+ (we also called them Th40 for a time period) that are greatly exaggerated in number in diabetes. These cells are highly diabetogenic in mouse and human studies. I would suggest that finding the right marker to follow, whether it be on T cells, B cells, other APC or even innate immune cells, and determine how those cells misbehave will be key. This idea gets to Dr. Preston's point as well. Genetics are certainly key, but environmental pressures, vivuses for example, would directly impact the immune response. Commensal gut flora for example are proving to be highly informative in this area.
Even this proposal may be difficult in its interpretation , however certain factors may have significant contribution:
1-To identify first the subset of genes involved in the particular complications
2- To monitor historical viral infection of the patient,its degree of severity
3-To study genetic background ( Family member)
4- Role of Exogenous factors ( Ecology) in the diabetic development
This may clarify the picture and can predict the complications
Dr.Mohamed.M.Elseweidy
Dear Preston,
You can read this new review..
From excess adiposity to insulin resistance: The role of free fatty acids
Cristiano Capurso, Antonio Capurso
Vascular Pharmacology
Received 6 March 2012
A b s t r a c t
With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses.
A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors.
As a consequence, more free fatty acids (FFA) are released into the portal system.
Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate readipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance.
Excess of circulating FFA, TNF-α and other factors induces insulin resistance.
FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, leading to interruption of the downstream insulin receptor (IR) signaling.
TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serinephosphorylation and tyrosine-dephosphorylation of IRS-1,
causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling.
Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes.
Can be a difference if the patient make more or less exercise?
Wow this is awesome!
Bedriniam, very interesting article, it is applicable but i was wondering more about type 1 diabetes rather than type 2. They really need to change the names to distinguish them better!
Dr Elseweidy, great summary. That sounds like personalized medicine at its best; not stopping at subsets but examining all the diverse factors and variations of an individuals health. I would put my money on this being the future, rather than a total cure that is effective across the board.
Thank you for your essay Sathya! Definitely a limitation with the genes being low penetrance as you say. Maybe we would have to focus equally on any patterns that develop as a result of certain viruses being the trigger. You highlight well how complicated it would be, maybe we could start with just looking to put two and two together. So rather than trying to map out the entire progression, just grabbing two variables and saying this gene increases risk of this complication. This virus will produce a disease that settles down so we can attempt beta cell regeneration etc etc
Dr Wagner, your hypothesis is epic! Super exciting for all autoimmune diseases and it makes so much sense when you think about how these attacks are triggered. I really hope you get some big results!
Dr Honeyman, It is incredible to get your input. Are these viruses becoming more prevalent? Why do they remain so mysterious?
If it were a series of viral infections that caused a reactionary immune malfunction and beta cell destruction, would that mean that if a patient's cells were later regenerated or transplanted the immune system would not automatically repeat the process unless exposed to certain viruses once again? Essentially, is T1D an ongoing disease, or in certain subsets is it something that 'happened'- albeit with long term consequences.
Also, as a kiwi, I am sincerely sorry to hear about Australia underperforming at the Olympics. Oh Pearson just won the hurdles, i will shutup... : D
Dear Preston and dear Peralta,
You can read this new review too..
Differential Coronary Resistance Microvessel Remodeling between Type 1 and Type 2 Diabetic Mice: Impact of Exercise Training.
Aaron J. Trask, Maria A. Delbin, Paige S. Katz, Angelina Zanesco, Pamela A. Lucchesi.
Vascular Pharmacology (2012).
ABSTRACT
The goals of the present study were to compare coronary resistance microvessel (CRM) remodeling between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mice, and to determine the impact of aerobic exercise training on CRM remodeling in diabetes.
Eight week old male mice were divided into T1DM: control sedentary (Control SD), T1DM sedentary (T1DM-SD) induced by streptozotocin, and T1DM exercise trained (T1DM-TR); T2DM: control sedentary (Db/db-SD), T2DM sedentary (db/db SD), and T2DM trained (db/db-TR).
Aerobic exercise training (TR) was performed on a mouse treadmill for 8 weeks.
CRMs were isolated and mounted on a pressure myograph to measure and record vascular remodeling and mechanics.
CRM diameters, wall thickness, stress-strain, incremental modulus remained unchanged in T1DM-SD mice compared to control, and exercise training showed no effect.
In contrast, CRMs isolated from db/db-SD mice exhibited decreased luminal diameter with thicker microvascular walls, which significantly increased the wall: lumen ratio (Db/db-SD: 5.8 ± 0.3 vs. db/db-SD: 8.9 ± 0.7, p < 0.001).
Compared to db/db-SD mice, coronary arterioles isolated from db/db-TR mice had similar internal diameter and wall thickness, while wall:lumen ratio (6.8 ± 0.2, p < 0.05) and growth index (db/db-SD: 16.2 vs. db/db-TR: 4.3, % over Db/db) were reduced.
These data show that CRMs undergo adverse inward hypertrophic remodeling only in T2DM, but not T1DM, and that aerobic exercise training can partially mitigate this process.
In some respects but the path functions tend to be too difficult to measure to a given state function... so this is why we speak in terms of probability distributions, risk factors and time lines using data and organizing said data with statistics.
I am very interested in the work of Dr Honeyman concerning the association between rotavirus and type 1 diabetes. Could a copy of the relevant article/s be sent to me at [email address deleted]
Prof Ismail Haffejee, Dept of Paediatrics, Nelson Mandela School of Medicine, Durban, South Africa.
As I know the HgbA1C is a good marker to follow the progress of Diabetes and also the treatment. The ideal value is about 6 or lower. Between 6 and 7.5 we can estimate that the diabetic complications such as eye involvement may start to develop. More than 8.5 it would be obvious.
Unfortunately currently there is no test to predict progression of type 1 diabetes , the only things we have are risk factors(family history,presence of immune markers like gad 65,anti insulin antibodies) but their presence does not tell when is the individual going to develop the disease.
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