Insurance just approved MODY genetic testing!

Type 1 and LADA
1

My insurance just approved the full MODY panel of genetic testing for me, I think the list price is $6K, performed by Athena Diagnostics. I'm posting here to solicit feedback on any readings I should do or questions/issues I should raise with my endo when I go in to talk with him about the results.

I was diagnosed in 2002 with a fasting BG of 124, OGTT peaking in the mid-200s, A1c of 5.6. An OGTT with insulin levels suggested I had substantially impaired Phase 1 post-prandial endogenous insulin response, but decent Phase 2 response. My c-peptides have consistently been modestly below reference range, but just a little below, e.g. 0.4 ng/mL-ish or even a bit higher.

I tested negative for the antibodies for which I've been tested (and I was just tested recently, a dozen years post-diagnosis, my prior docs didn't seem too concerned about doing the tests, though I might have had one antibody tested way back when, not sure), but my endo only ordered two tests, ISLET CELL AB SCREEN W/RFX TO TITER and GLUTAMIC ACID DECARBOXYLASE-65 AB. My impression is there's another antibody test that only works if you haven't been taking exogenous insulin, and maybe yet another one that's not widely available?

I was initially briefly put on a sulphonylurea, within months on basal insulin (Lantus), within a few more months also bolus insulin (Humalog, these days Novolog). I used MDI until two months ago when I started my first pump. My doses have always been modest, e.g. I was using 12 units/day of Lantus on MDI, 9/day on the pump.

Over the years things have declined a little, but not much, my highest A1c ever was 6.2, normally I'm 5.8ish these days. I still make enough endogenous insulin that I can (and must, to avoid hypos) go without basal and bolus insulin during periods of intense physical activity, like alpine climbing or intense trekking trips (I still take some basal with dinner in camp, but otherwise no exogenous insulin at all).

But during my day-to-day life, I need both basal and bolus to keep things in check. During morning runs I keep the basal flowing, and BGs actually rise a bit, during other times of the day I kill the basal a few hours in advance of a workout and BGs stay relatively stable. My I:C ratio seems to be between 1:15 and 1:20, my correction factor, which I still need to dial in more precisely, about 1:75. I'm pretty lean, but not severely so, and less so than I was in my 20s, have both more muscle mass and a little more fat, too.

I think that about covers it, are there any other key parts of the history/presentation that I'm missing?

2

I'd be surprised if you were not MODY.
Knowing is better than not knowing.
Since you have tried Sulphonylureas, and it is clear from your insulin/carb ratio that you are not dealing with insulin resistance, it seems unlikely that a Dx of MODY would change your treatment.

You are doing great on the pump.
Way to go!

-Lloyd

3

Agreed, which is why I think past physicians were reluctant to order the tests. But the diagnosis does change my prognosis, e.g. whether we expect my condition to worsen over time. It might suggest some interesting tweaks in my care going forward (one radical change would be to put me back on sulphonylureas paired with a very low-carb diet). A non-immune mechanism also makes me a great candidate for a future beta cell transplant. And it has huge implications for any kids I might have. The pump is indeed great, but MDI was great before that for a decade, too.

And thank you!

4

Sulphonylureas tend to shorten the period of time where you have significant beta cells. Been there, done that. Also, you don't have much dosage control with sulphonylureas. I had lows in the 40's for years on them. Nothing below 60 for at least a year on a pump. I have significant IR, so I am on the max metformin dosage - and still need about 80 U a day even with limiting my carbs to 80 a day.

Best wishes,

-Lloyd

5

Yep, beta cell preservation was a key argument I made to my doctors for my getting off sulphonylureas. Do you know whether we actually have empirics to back up the plausible argument that they stress, and ultimately shorten the life of, beta cells?

I don't have meaningful IR, as my I:C ratio suggests, and the OGTT with insulin levels I had confirmed. I use what little insulin I make, and inject, extremely efficiently.

My insulin production is clearly impaired, so the MODY subtype that just involves a broken "thermostat," i.e. the body's ability to accurately gauge glucose levels and appropriately respond with insulin, doesn't seem to apply. Unless that defect led to elevated BGs that themselves damaged the beta cells, which I suppose is plausible.

6

Well, it's only anecdotal, but I pushed my beta cells into overdrive with sulfonylureas for more than 15 years and now I have very few working ones left. I can't prove it but I am convinced that if I had demanded insulin ten years earlier than I did, I'd have many more left than I do.

7

It's certainly plausible. It seems like a pretty easy question to study empirically, there must be some stuff on it out there. I've noticed doctors seem to think it's plausible, but they never seem to be very confident one way or another on whether it's actually the case. Even doctors who seem like they should be informed. Which suggests that maybe the literature is conflicting, or for some odd reason there is little relevant literature?

8

To clarify this potentially confusing sentence, "My doses have always been modest, e.g. I was using 12 units/day of Lantus on MDI, 9/day on the pump," that only refers to my basals, i.e. I currently use 9 units of Novolog per day of basal insulin, plus a bit more than that of bolus insulin, i.e. my daily total Novolog use is probably around 25 units on a low end of moderate carb diet.

9

MODY 2, if I remember right.

-Lloyd

10

Hi Niccolo: I will tackle the sulfonylurea issue first. The study that I have quoted most often is Kobayashi 2002, which concluded that sulfonylureas hastened destruction of beta cells in people with LADA. The Diabetes Care article "β-Cell Protection and Therapy for Latent Autoimmune Diabetes in Adults" says:

Sulfonylureas are commonly used for the treatment of type 2 diabetes and act by stimulating insulin release from the pancreatic β-cells to lower blood glucose levels. Despite their initial efficacy, there is a progressive reduction in insulin-producing capacity of pancreatic β-cells and deterioration of glycemic control over time. The cause might be exhaustion or desensitization of β-cells by prolonged exposure to sulfonylureas and possibly acceleration of oxidative stress and apoptosis. It has also been suggested that stimulation of insulin release might be associated with increased autoantigen expression, which could be deleterious in LADA because it might accentuate the ongoing autoimmune process. These results suggest that therapy with sulfonylureas in LADA would actually expedite the progression toward β-cells depletion and the necessity of insulin initiation, and several studies have confirmed this hypothesis.

Even though it is difficult to generalize these data because the studies had different selection criteria and ethnicity as well as different outcome parameters and follow-up durations, taken together, they do suggest that sulfonylureas accelerate (or at least do not protect against) progressive β-cell failure and are similar to (or worse than) insulin in obtaining good metabolic control. Therefore, sulfonylureas should not be used as first-line therapy in patients with LADA.

11

Great, nice to have actual (larger n) empirics! Curious to hear your thoughts/recommendations on the broader MODY issue, too.

12

Hi Niccolo: CONGRATULATIONS on getting approval for the full panel of MODY testing. That is awesome! The things that make me think monogenic diabetes when I read of a person's situation are generation after generation of people with something that resembles Type 1 in some ways, but doesn't in others. Do you have lots of people in your family line with diabetes?

Yes, regarding autoantibody testing, IAA can't be tested for once a person has used insulin, and ZnT8 is not widely tested excepted in scientific studies. Idiopathic Type 1 is always a possibility--the detection rate of autoimmunity in new-onset Type 1 diabetes is about 94% with four autoantibodies (GAD, IAA, IA-2, and ZnT8) ("ZnT8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes" Diabetes Care January 2010). New autoantibodies are being discovered, some people are T-reactive cell positive but autoantibody negative (but the T-reactive cell positivity points to an autoimmune process), and researchers think that the overrepresentation of the HLA DQ2/DQ8 high-risk genotype in patients with idiopathic T1D suggests an immune-mediated disease process ("Contribution of Antibodies Against IA-2 and ZnT8 to Classification of Diabetes Diagnosed Under 40 Years of Age" Diabetes Care August 2011).

Doing all this testing may provide you with some answers, but in the end, you are using low doses of insulin via an insulin pump, so IMO you are getting the best treatment and you are doing well. But please don't go back to sulfonylureas (again, IMO)!

13

The TuD member that really delved in monogenic diabetes was April (http://www.tudiabetes.org/profile/April). She posted a lot in the monogenic diabetes group, but did most of her posting I think on the ADA pages. Perhaps of some help/interest?

14

Great! Yep, almost everyone on my dad’s side of the family, including aunt and cousins, and my sister, have some variant of T2 or prediabetes. But they all seem to manifest a bit more as classic T2s, whereas I have little to no insulin resistance. On top of this, my mom had gestational diabetes with me, but not at all now, in fact more hypo than hyper. We’re all fairly lean, to “normal,” this doesn’t appear to be an obesity issue, though some are a bit heavier than others.

15

I'm very impressed. I've always been dismissed when asking about MODY testing, I've never even gotten to the cost issue. I always thought I might be MODY-2 since I had chronic high fasting numbers and didn't respond to any T2 medications. My doctors alternate between identifying me as T2 and an "ideopathic T1." I hope these tests give you some answers, but they may not. Diabetes is really complex and everyone is different. We may never know all the answers of why this condition happened to us, but in the end if we can manage things and live a long, healthy happy life that is all that matters.

16

The Kovler diabetes center, U of Chicago is doing research into MODY. They will test for MODY free, IF YOU QUALIFY.

-Lloyd

17

That’s great, it will be interesting to see if any Mody genes turn up. My blood glucose issues are very much like yours niccolo as we’ve discussed in the past.

18

I emailed the principle investigators directly and they did not respond. I then called them and they actually informed me that MODY was a problem with babies and that I did not qualify. I got totally blown off by Kovler. Maybe others can get somebody useful but I didn't.

19

Better make that "some doctors". Bernstein is utterly convinced of it, and says so in clear unambiguous terms.

20

Despite their initial efficacy, there is a progressive reduction in insulin-producing capacity . . .

That is precisely what this T2 experienced over more than a decade. And I've got the numbers to prove it.