Help me find this study please!

Type 1 and LADA
#1

I’ve read in multiple posts that once you’ve had diabetes for a certain amount of time without complications, then your chances of developing complications afterward have decreased. This may imply that there’s a genetic component to the development of complications. I think a study was conducted that demonstrated this, but I can’t find it. I want to read it. Does anyone have any knowledge of this study? Thanks!

Also, I know that a lower A1c and good control also reduces the likelihood of complications. I’m interested in looking at the stuff outside of our control right now.

#2

Not exactly what you asked for and maybe you already read this but it seems to be at least related?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956847/

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#3

Thanks! I’ll take a look.

#4

I believe that you are recalling some of the results of the Joslin Medalist Program. Several here on this message board, are 50-year medalists and have participated in the studies. (Me, I’m a total newbie, I’m only at 35 years!)

Broad outline of the Medalist program: http://www.joslin.org/medalist/50-year-medalist-study.html

My reading of the articles is not as simple as “protection is genetic”. I read that they are actively searching for biochemical and other markers that may lead to an understanding of the protection so that it can be replicated.

A specific publication might be “Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-year medalist study.” : https://www.ncbi.nlm.nih.gov/pubmed/21447665

**OBJECTIVE:
To assess complication prevalence and identify protective factors in patients with diabetes duration of ≥50 years. Characterization of a complication-free subgroup in this cohort would suggest that some individuals are protected from diabetes complications and allow identification of endogenous protective factors.

RESEARCH DESIGN AND METHODS:
Cross-sectional, observational study of 351 U.S. residents who have survived with type 1 diabetes for ≥50 years (Medalists). Retinopathy, nephropathy, neuropathy, and cardiovascular disease were assessed in relation to HbA(1c), lipids, and advanced glycation end products (AGEs). Retrospective chart review provided longitudinal ophthalmic data for a subgroup.

RESULTS:
A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Subjects with high plasma carboxyethyl-lysine and pentosidine were 7.2-fold more likely to have any complication. Of Medalists without PDR, 96% with no retinopathy progression over the first 17 years of follow-up did not experience retinopathy worsening thereafter.

CONCLUSIONS:
The Medalist population is likely enriched for protective factors against complications. These factors might prove useful to the general population with diabetes if they can be used to induce protection against long-term complications. Specific AGE combinations were strongly associated with complications, indicating a link between AGE formation or processing with development of diabetic vasculopathy.**

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#5

Thank you!!! Just a wealth of information! I appreciate you linking the specific study.

Yes! I’ve looked over some Joslin Medalist program data, but I somehow missed this study. I think I saw the outline instead. The quote below was what I was looking for. In particular, the chart below that quote indicates that low levels of CEL/Pent are protective against all forms of complications. I wonder if there’s a way to test for this.

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So much interesting stuff!

“Factors associated with individual complications were not necessarily consistent with those established for shorter duration diabetes (Supplementary Table 2). No significant relationship was found between glycemic control and any complication in the Medalist cohort.”

“Of 25 subjects with no baseline diabetic retinopathy in either eye, 11 (44%) remained free of PDR in both eyes at the last visit.”

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Thanks to all the Medalists out there that provided their data :smile:

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#6

I remember discussing this lack of complications with Richard Vaughn, a 50-year Joslin medalist. My personal opinion, with nothing to collaborate it officially, is that the old-timers all started by taking animal insulin that contained c-peptide. C-peptide is said to reduce micro-vascular damage. Our “modern” insulins contain no c-peptides.

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#7

From the Joslin 50-year medalist study.

Current and longitudinal (the past 15 years) glycemic control were unrelated to complications.

This argues against a hyperglycemic link to developing secondary diabetes complications. I’m not a scientist or academic researcher but this goes against my conclusion that good blood glucose control improves my risk of complications. It doesn’t square well with the findings of the Diabetes Control and Complications Trial, either.

I know our understanding of diabetes grows with time, but this Joslin Medalist finding creates some cognitive dissonance in me. I don’t plan to relinquish my daily effort to achieve near-normal BG levels, however. And if researchers can isolate the complication protective juice, I’d be interested in that treatment!

#8

Oh I agree! I think the study demonstrates that these people may have protective qualities that enable their bodies to weather the high A1cs better than others. It’s such a small sample compared to the number diagnosed back then, right?

I imagine that of those who developed complications, the lack of regulation earlier in life may have had a bigger impact than their A1c in the last 15 years.

#9

The study I think you’re looking for is S. Bhatt, et al., “Preserved DNA Damage Checkpoint Pathway Protects Against Complications in Long-Standing Type 1 Diabetes,” Cellular Metabolism, vol. 22, no. 2, pp. 239-252 (2015). Its summary states:

The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D(disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist −C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist −C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.

In short, if you are lucky enough to have the genes providing you with efficient DNA protective machinery, then you are protected against development of serious complications.

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#10

me too!

#11

Not necessarily.
Everybody is not the same.
Assume for the sake of argument this is absolutely correct. [purely academic argument]
If somebody is genetically predisposed to these complications down the road then their glycemic control may be a critical factor.
If somebody is not predisposed to these complications down the road then their glycemic control may be of significantly less importance.
If we do not have the medical technology to know WHO IS and WHO IS NOT genetically predisposed to these longer term complications then would it not make sense for everybody to work towards the most reasonable glycemic control they can?

Maybe ?

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#12

You make good points.

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#13

Looks like both studies involved the Joslin Medalists but looked at different things when evaluating the development of complications. Both are very interesting! Though I think the one you posted contains a lot more unfamiliar words :stuck_out_tongue_closed_eyes:

Thanks for posting it!

#14

I think the medalist studies do a good job saying that recent bg’s seem unrelated to their complications. But there’s so much more that is simply unchartable/unquantifiable about a half century of past bg’s when for most of the time there were no good home measures and lab measures were incredibly intermittent.

Medalist stuides have substantial pre-selection. Only a few percent of diabetics survived those 50 years.

DCCT starts without any such pre-selection, and is much more applicable especially for microvascular complications.

Although thinking that every complication is directly related to average bg seems to be incorrect (e.g. Frozen Shoulder seems to be anti-correlated, and others like macrovascular health show some but much weaker correlatation).

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#15

There is also the complicating factor of ‘hyperglycemic memory,’ by which a history of hyperglycemia can cause permanent transformations of the DNA which continue to produce complications forever, regardless of how good the glycemic control may be later on. Patients with a long history of type 1 diabetes would have spent ten or twenty years or more living with the disease before home glucometers were invented, so their blood sugar control would have been terrible for many years, so they are more or less doomed to the hyperglycemic memory effects, unless, of course, they have the genetic luck to have inherited the protective mechanism ensuring efficient DNA repair.

For my part, I had a good 20 years of type 1 diabetes prior to the invention of home glucometers, and now, even though I’ve had an A1c in the four range for the last decade, I’m developing retinopathic complications faster than ever before in my life. What am I supposed to do to correct this, fix my blood sugar in the 1960s? A further question is, what is the point now of endangering my life from lethal hypoglycemia through strict control?

#16

I have had diabetes for over 26 years and by all rights I should have complications, especially since my BG’s were so frequently uncontrolled throughout my lifetime.
I personally believe that some of us just got “lucky” if you can call anything related to diabetes that, although I’m sure there is a scientific explanation for it that our researchers just haven’t pinned down yet.
I will however, continue to strive for good BG’s because I also have seen those that do have complications reverse some of them with good control (Dr. Bernstein is a good example of this). So I think it is a little bit of everything diet, exercise, genetics, and good BG’s.

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#17

Of course we might also say that driving for 20 years years with no accident is a good predictor of your chance of having an accident in the next year. It could be because you are extremely lucky, or maybe you stay home 98% of the time, or something else entirely.

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#18

I simply don’t believe in the concept of being doomed.

It is just not a part of my reality.

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#19

Using a CGM would drastically reduce your incidence of hypoglycemia and nearly eliminate the risk of lethal hypoglycemia.

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#20

Yeah, it’s a good question, maybe if you’re not willing to get a CGM as @beacher suggested (or even if you are), you should simply raise your A1c from 4-levels to at least in the 5s (still considered tight control) thereby lowering your hypoglycemia risk. Maybe you are in fact making suboptimal choices in balancing these factors.

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