The same story here, after 12 years oral medications no longer provided enough help, insulin was needed.
-Lloyd
Mody2āthe defective thermostat variantāseems plausible. But is it consistent with my below-reference c-peptide or impaired glucose tolerance with peaks up to 250+?
I've corresponded with some Kovler folks. My sense is that they want you to pursue testing through your insurance first, and if you test negative for the standard MODY panel but fit a profile they find interesting, they may be open to doing secondary testing for more obscure monogenetic diabetes variants.
Really appreciate all the feedback! And agreed on sulfonylureas.
I'd be surprised if my diabetes didn't have some sort of monogenetic cause. I'm too odd of a standard case, in ways that seem consistent with a genetic explanation, including family history.
I checked out some threads in which April had previously posted, great MODY info! Looks like she's less active, on that topic and otherwise, these days.
So I reached out to the Kovler folks, and found them exceptionally helpful via both email and phone. I think the reason others have had different experiences is because they get inundated with inquiries from folks who don't present in the ways they associate with MODY, and it can be hard to respond to all those inquiries.
In my case, I, and my extended family, fit the MODY profile--specifically MODY2 (GCK)--awfully well, so much so that it'll be surprising if the genetic tests don't back it up. If they don't, there may be an even more rare genetic quirk, certainly it seems extremely plausible some form of genetic mutation is going on in my case.
Assuming MODY2 pans out, their clinical recommendation is basically to stop insulin, leave the meter at home, and get on with life. MODY2 is the gene defect that impairs the "thermostat" that signals the beta cells to release insulin, so instead of kicking in above, say, 90, it kicks in somewhat higher, in my case perhaps high 120s. So a MODYer will experience elevated fasting BGs and also transient post-prandial spikes, including into the 200s, though likely not higher in the absence of severe carb loads.
But a lot of evidence suggests that while insulin can reduce both the fasting BG and curb the spikes, it just doesn't matter much for MODY2s. The A1Cs basically don't budge--this is totally consistent with my experience, my untreated A1C was the same as my treated A1C, though the acid test will be whether my current untreated A1C would be the same, too. And while MODY2ers do experience both elevated fasting BGs and post-prandial spikes, evidence from older folks with the condition, who've lived with it their entire lives (the genes express themselves at birth, I suppose technically before birth), without any medication, insulin or otherwise, do not appear to manifest any complications, with the possible caveat of very modest retinal issues. No elevated risk of heart disease, kidney failure, amputations, or serious eye complications.
I don't have the gene testing results yet, and may not for several weeks, so I don't want to jump the gun. That said, I seem to fit the MODY2 profile to a T. The idea of just stopping insulin after a dozen years, stopping testing, and eating a low to moderate carb diet, staying active, and sporadically testing my A1Cs, seems scary to me, especially because I'm pretty vested in the notion that even modest and transient BG spikes can lead to complications, including damaging the beta cells. But while that notion appears to be correct for Type 1s without beta cell function, maybe it's not correct for others, including MODY2ers. Part of me fears that if we've only recently come to a relative consensus that tight control benefits Type 1s, then maybe it'll just take longer to realize that tight control benefits MODY2ers, too. But for now, the empirics seem to suggest it just doesn't.
As you can imagine, I'm struggling a bit with how to process all of this.
Just reaching out in support Niccolo. Hang in there. You have done all the right things, including asking excellent questions. Perhaps while you wait you could have a stack of novels available ;)
Thanks. It may sound weird to be stressed about the prospect of no longer managing my diabetes, at least not intensively. But change, even good change, is always hard.
And there's a lot of uncertainty associated with it. It will take some convincing for me to buy the notion that waking up at 130 in the mornings and spiking to 200 after meals isn't a problem. Arguably we're at an early stage in understanding monogenetic diabetes, so I could make a case for staying on my current regimen, even if it has little effect on my A1Cs. Or going off insulin but pursuing a very low-carb diet, which I imagine many on here would advocate.
I hear you on the novels. And there's work to be done, too, I've given myself a lot of space for the diabetes stuff recently, but the balance needs to shift back a bit toward non-diabetes stuff.
Life is uncertain and that is certain :)
My personality is highly intuitive, and am managing my diabetes well with it. Yours is more analytical and you do well with that. You ARE responding to everything just as YOU are...and it is a beautiful thing. Just stay as curious as you have been and the uncertainty will be just as interesting. And dude, please do read a novel or take a long bike ride (grin).
Thanks, I really do appreciate the support.
MODY results finally came back. I have an undocumented glucokinase (GCK) mutation. But it's in a location that would suggest MODY2, and apparently about a third of GCK mutations are novel, so basically, I appear to be MODY2.
This is the thermostat defect, i.e. my glucose thermostat is reset to a higher level. This manifests as an untreated fasting BG of maybe 140 and post-prandial spikes into the 200s.
That sounds problematic, but there's a lot of data suggesting that it's actually not. High BGs are correlated with complications in Type 1 and 2s, but that doesn't mean they're causal, and the evidence overwhelmingly suggests that untreated MODY2ers don't suffer complications.
For example, when people have genetic testing that finds GCK mutations, there's a 50 percent chance their parents or grandparents have the same. So they'll go back and test them, and then they'll compare the relatives who have the mutation, never discovered and therefore never treated, with those who don't. And despite a lifetime of not treating the condition, the undiagnosed MODY2ers appear to have no higher risk of either macrovascular or microvascular complications (there's a little evidence there's a higher risk of early stage retinal issues). The untreated MODY2ers don't seem to have a higher risk of Type 2 diabetes, which is surprising, you would think that having your glucose thermostat reset higher would predispose you toward Type 2 when other risk factors were also present.
The treatment recommendation is to stop insulin or any other therapy, leave the meter at home, and continue to get occasional A1cs, and to reconsider that if the A1c jumps meaningfully from the elevated baseline, say 0.5 percent or more. One could carb-restrict, and that would curb post-prandial spikes a bit, but there's no evidence it makes any difference. In other words, although we have good reason to believe that post-prandial spikes *in Type 1s and 2s* are problematic, perhaps because they're a sign of other things and perhaps because they play some negative causal role in their own right, somewhat surprisingly, we have a lot of evidence that similar spikes in MODY2ers just don't have the same negative consequences.
As you can imagine, this is all a bit of a, shall we say, mind-fumble. I've been on insulin for a decade, and put a huge amount of effort into managing my blood sugars, so to be told to just leave the insulin and my test strips at home and go about my life is a rather radical change. Obviously it's a good thing, but even good change is hard.
For now, I've just disconnected from and shut down my pump. I'm going to keep the CGM running and I'll gather data, and my next A1c will be interesting, too. I can always get back on insulin if needed, and it's going to be hard to watch my BGs rise and resist the impulse to do anything about it. If it feels necessary, I can always get back on insulin, but given what I know now, that seems less likely.
I'm not sure how much sympathy I'll get here, but this really is messing with my mind a bit. I got my genetic testing results just before the recent Vegas UnConference, but I didn't have a conversation about them with one of the leading MODY researchers until today, so it's really hitting home now.
I suppose it's especially odd because I'd previously only met a few diabetics in my life, and I got to hang out and bond with a whole bunch of awesome ones the past few days in Vegas, so it sort of feels like I'm being expelled from the tribe just as I've joined it. :)
That said, I very much recognize that I'm fortunate, too, so I don't mean to mope about the fact that I apparently don't have to struggle with the things so many of us do.
Very interestingā¦ Please do continue to keep us informed on how this all goes for youā¦ Iām qiite interested in this topicā¦
Hold on! I have heard from quite a few people diagnosed with GCK MODY-2 and quite a few of them have family histories of early heart attack, sometimes very early.
There is very little to no research on the actual life-progression of MODY-2 and my guess is that the claims that it doesn't cause complications ignores these fatal incidences of heart disease.
Heart disease starts to get going when you are spending even an hour post-meal north of 150 mg/dl. With MODY-2 you've had those exposures all your life.
So don't let anyone convince you that you don't need to keep on working on those post-meal numbers.
Another really nasty set of complications that we get when we have these genetic forms of diabetes (which is what I have) is vertebral disc deterioration and tendon problems. Serious ones.
The disc problems run down the side of my family that have the heart attacks in their 50s. Those that don't die of them end up with really bad backs. I have lost all the discs in my lower back and now am losing three in my neck. This makes for permanent pain and isn't anything you want to mess with. Keeping better control could probably prevent this, but I wasn't aware I had diabetes until I was 50.
The tendon problems and the discs all happen because the blood supply to those tissues is pretty sparse so they get brittle when those tiny capillaries are clogged with even moderate amounts of glucose. My tendons can tear doing very light tasks, and it takes months for them to heal. This makes it almost impossible to exercise.
So again, don't let anyone tell you that you shouldn't be intense about controlling those post-meal numbers.
Finally, I have heard from people diagnosed with MODY-2 who tell me that though they were told cutting carbs wouldn't help at all, they tried it and it lowered their fasting glucose!
All this reiterates that the common wisdom about MODY is based on a few statemetns by some doctors in the UK made a while back and made in an environment where Good Control is defined as 7% A1cs. Since people with MODY-2 don't get those 8 and 9% A1cs, the assumptions was they didn't need treatment.
They do!
P.S. I hear from people with these oddball diagnoses because the MODY page on my web site is one of the few resources available and quite a few doctors send people there. I collect family history stories and treatment stories so that there will be more information for those of us with these conditions. Right now, after being given a diagnosis, most people get zero support from doctors because they don't really know anything about these forms of diabetes.
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Thanks for your thoughts. I know you've done good work in our community, and I know your engagement comes from a very good place. But you're using an awfully broad brush to characterize both your own assessments and the work of others.
Our understanding of MODY is certainly not based on a few statements by UK doctors who simply reference outdated A1c benchmarks. It also isn't based on a few cases of anecdotal evidence, e.g. I know someone with MODY who had a heart attack. There's been a large amount of substantive work by both the UK Exeter and Chicago Kovler groups, based on fairly intensive engagement with a pretty sizable population.
MODY is somewhat rare, and sub-types (which can vary dramatically) by definition even more so. But the UK and US groups' assessment that MODY2ers not treat is based on the pretty robust observation that untreated, advanced age MODY2ers, who've had the defect since (really since before) birth, simply don't seem to have an elevated risk of complications. Since the gene defect is only passed on 50 percent of the time, these studies are a fantastic opportunity to control for various potentially confounding variables related to genes, lifestyle, and otherwise, because one sibling will have the defective gene, one might not, and once you get a big enough pool, you can start to draw some pretty robust inferences.
This work is ongoing, and as it proceeds, it's possible that although we can pretty confidently rule out major complications for MODY2 folks, we didn't have big enough populations to be able to find more minor or less frequent ones. But we have an awful lot of information already at this point.
Kovler at Chicago likes to think of themselves as a focal point for MODY-related research and patient education, and I've found the researchers/clinicians there exceptionally helpful, including in responding patiently and thoughtfully to my deep skepticism about their treatment suggestions. So when you do get contacted by folks with MODY, I'd suggest referring them to Kovler. I also haven't found the Kovler folks to be pushing any sort of party line, they've simply provided the best information they have and engaged me in a really productive way.
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niccolo,
I have read through reams of primary MODY research and interacted with the Chicago group. I have also been contacted by several people diagnosed by the Chicago group who felt that the group there had very little to offer them once they had sequenced the gene. So I'm glad that you had a more positive experience with them, but not everyone has. Including me. (Long story I won't bore you with, but I was not at all impressed with the way they behaved.)
So my response is based on far more than a few anecdotal personal accounts. I spent a couple years combing through the research connecting blood sugar levels with various complications and that research convinced me that it doesn't matter what the cause of high blood sugars are, the effect on the body is the same. And the level at which quite a few organs start developing blood sugar-related problems is in that range between 140 and 150 mg/dl.
The group at Exeter did wonderful work to make endocrinologists aware of MODY. But when I read their studies, I find the definition they use of "good control" very depressing, in line with what my friends in the UK have to deal with when they attempt to get any medical support to control blood sugars better than that 7%.
Yes, people with 7% A1cs do better than those with 9% A1cs, but if you look at the big epidemiological studies, people with A1cs rising up out of the 5% range have a lot more heart attacks than those who can stay in the 5% range. In the population as a WHOLE, completely aside from diagnosis or diabetes.
The "robust inferences" that doctors draw in these studies are colored by the belief that there is somehow a difference between "diabetic complications" and the health issues that people who are supposedly normal suffer. But when you look at the blood sugars of those "normal" people, you find that hose at the high end of the spectrum are getting heart attacks, early kidney disease, and neuropathy. Doctors just don't connect the dots.
So it seems very likely that the "slightly" elevated blood sugars that doctors have been taught are nothing to be concerned with take a major toll on our bodies.
And if you think that somehow you are protected from the effects that happen in vitro, rodents, and humans when cells are exposed to blood sugars in that supposedly "prediabetic" range, just because your higher than normal blood sugars are caused by a failure to control the fasting glucose thermostat, you really should at least have a look at that research.
I'm actually quite sympathetic to a lot of the points you raised (and thanks for sticking with the discussion and not walking away from it!).
I've been pushing the Kovler folks on many of these points. So far I've found their responses pretty compelling. That's particularly true for the data based on "natural experiments" where familial dynamics allow finding and studying those who've lived their lives up to that point as undiagnosed, untreated MODY2ers. If those people don't manifest higher complication rates than their relatives who happened not to inherit that gene defect, that's pretty convincing.
But the devil is in the details, and one thing (among others) I'm still trying to understand better is whether they think those with MODY2 suffer fewer complications than regular Type 2s with equivalent hyperglycemia, or whether it's simply that MODY2ers suffer fewer complications as a function of their lesser hyperglycemia. The former would be much more reassuring than the latter, because there does seem to be a dose-effect relationship between blood sugar and complications in normal Type 2s (and even more so in Type 1s).
Though I do think we diabetics focus a bit too much on blood sugar--for example, my guess is hyperinsulinemia poses some real risks even when glycemia is relatively controlled. Which is partly why the standard recommendation about higher-carb, lower fat and protein diets seems kind of insane to many of us.
By all means, share studies you've found interesting. I'm happy to be a contact point in engaging the Kovler folks, because for whatever reason, they've been remarkably helpful to me (and not just one of them, either).
I have to tell you, I've long suspected I have MODY-2 but I have been repeatedly rebuffed at getting testing. There is basically little agreement on exactly how MODY-2 manifests or what the best treatment actually is. As Jenny says the are big missing pieces and it is very likely that what most medical professionals consider "mildly elevated blood sugars" of 140 are actually quite damaging. I became quite angry at my constantly elevated blood sugars despite not have a "bad" A1c. So I actually moved to insulin. My current endo has decided I cannot be MODY-2 because I am on insulin.
I have to tell you, you should absolutely not feel like you don't belong. You have diabetes, you belong. There are probably 10-20% of people diagnosed with diabetes who are actually MODY. We may actually find that the vast majority of diabetes is genetic in some form. You belong.
I also have had less than useful interactions with Kovler. For many years they were only interested in neonatal cases and research and had now clinical interest. I've talked with a number of people that have found more help from Exeter. Basically I gave up on the issue after deciding that the research was insufficient to suggest any particular treatment for MODY-2 that was any different than "type 2." And whether I was MODY-2 or "Type 2" didn't make any difference, the treatment was basically the same. All that really matters is normalizing blood sugars. And following a low carb high fat diet and finding a treatment regime that achieves that seems to be the most logical thing to do. So these days I continue to follow a low carb high fat diet with an insulin regime and have made significant progress in normalizing my blood sugars. The most recent addition of Invokana has finally done something to allow my fasting blood sugars into the 80-100 mg/dl range.
Facts are stubborn things. It *may* be true that controlling MODY2 BGs minimizes complications, and is therefore worth the effort, risk, and the complications that medications, especially exogenous insulin, themselves entail.
But whether that's the case is something to be studied. And note that when you are able to compare families where some have the GCK mutation and some don't, to see if having the mutation increases people's risk over decades and decades of being undiagnosed and untreated, you don't have to set arbitrary thresholds like 140, you just have to see who has what complications.
Many of us have strong intuitions, but if the past few days have taught me anything, it's to be very humble about my own intuitions. First I met two doctors, one a T1D, who helped me understand the way in which IV insulin interacts with the body better, and why my own simplistic understanding of insulin metabolism left me ill equipped to analyze that issue. And then I've had some very rich conversations with University of Chicago researcher-clinicians whose motivations and capabilities left me very impressed. And I've been a difficult audience for them, because I share many of the concerns you and others have.
I'm struck that a number of others have reported less-than-positive interactions with Kovler. All I can say is my experience has been the polar opposite.
We each have to find our own approaches. One question on yours--with intensive management, how much have you been able to reduce your A1c? That's not a perfect metric--as one of the Kovler people put it to me today, you can have your head in the oven and your butt in the freezer and have a healthy average temperature--but it's still a pretty decent indicator of whether your efforts are making a difference.
And I really appreciate the opportunity to engage here, because it helps me process all of this. And you guys are only a few hours behind me, which is to say that a few hours ago, I was raising many of the points you are with the Kovler folks.