Diabetes “Lite”: GCK (Glucokinase) MODY

I have posted here about my lack of understanding of what’s going on with me.

Have had somewhat elevated FBG, PP glucose and Ha1C (5.9). The glucose has been about the same level for over ten years – maybe longer but I don’t have any test results going further back than about 2015. Insulin and C-peptide were/are low: that’s what really alarmed me. Is this some kind of incipient Type 1 DM? But I didn’t test positive for the antibodies. Have been on Metformin but it does not seem to have made any difference. I even tried (very low dose) Rybelsus and Harmine which made me feel awful and drop weight, which was not my objective. So quit those.

I finally saw an endocrinologist who seemed spectacularly unconcerned about my numbers. He sent me for an OGTT and said that if the numbers came back high he would test for mongenic diabetes. The numbers came back at prediabetic levels: not, he felt, at all concerning. And he said no treatment needed.

But since he had mentioned monogenic diabetes, I started reading about that. Came across this syndrome called Glucokinase MODY. In brief, it is a genetically caused lack-of-function mutation of the glucokinase sensing of glucose in the pancreas which causes inadequate detection of glucose in the blood, which then causes too-low insulin for the glucose you have, and thus too high glucose. But it does not seem to progress in most people, and there are none of the risks/negatives of diabetes. It does not respond to diet or meds. They aren’t even sure whether to call it diabetes, though it causes chronic mildly (pre diabetic level) elevated glucose.

It seems to fit with what’s been going on: the chronic elevated glucose of longstanding, low insulin, no or little response to metformin. The only way to confirm is through (expensive) genetic testing which the endocrinologist has not offered given the results of the OGTT. I am relieved to have learned about this weird and quite rare syndrome, and have just stopped worrying about it, and testing my FBG every day.

I have been going back and forth over whether to start rapamycin, given the already high-ish blood glucose. Finally just packed up my stash of rapamycin and sent it all off to my son. (But I could always get more . . .)

Would welcome hearing thoughts about all this.

My experience as a type 1 diabetic is that rapamycin has no noticeable effect on blood glucose in general and probably has a stabilizing effect during the first day or two after a dose. That said, it may be that my highly variable fasting glucose numbers (60-130) simply have too much noise to see the effect of rapamycin (current dose: 4mg/2weeks, with grapefruit 3 hours before).

I will soon be ordering an oral GLP-1 agonist as you have suggested.

Also, I am ordering it to approximate the Levicure Triple Therapy for increasing beta cell replication. One effect of the DPP4-i in the therapy is to increase GLP-1.
See:

I started this 11/10/24 and I am giving it a 5 month trial, but I am only using dihydroberberine (100mg x 3/day) as a weak DPP4-i. I’d like to get a pharmaceutical-grade DPP4-i. I measured my fasting c-peptide before starting, and am measuring at 1, 3, and 5 months. It went from baseline 0.1 to 0.21 at 1 month, but that increase might be noise. I’ll measure a second time in mid-Feb 2025.

If the problem is high glucose because of low insulin, why not simply get rid of the glucose? Low insulin is generally good – less cancer etc. So keep your low insulin and get rid of the glucose by other means. Best candidate is a SGLT2i. Pick one that you’re most compatible with. Empagliflozin is great, but it has slightly higher odds of UTI which is a bigger concern for women. I believe dapagliflozin is slightly better in this respect. But look at all of them, and pick one for your special situation. In general, if you can tolerate these inhibitors, they seem like great drugs overall, with many pleiotropic benefits. I’d take one regardless, like with lipid lowering drugs – if you find one that’s compatible with you they seem a pretty good intervention overall.

I have been prediabetic (A1c 5.7-5.9; FBG 105-115) for over a decade. But, I also have high insulin (so I’m insulin resistant), which is different from your situation. I started on empagliflozin 12.5mg/day December, so it’s been a little more than a month. No negative side effects that I can see, and my morning fasting blood sugar is consistently below 100 (measured by fingerprick monitor), I take measurements daily. I’ve also initiated rapamycin this month, so far one dose 3mg, one 4mg (I’m on a once a week schedule. I intend to have a complete blood panel in three months and I’ll see if it has any impact on A1c.

Regarding rapamycin, be aware that increased lipids and BG are not universal. In fact it’s a minority. My thinking is that with empagliflozin I’m not worried about rapa raising my BG. I also have the option of increasing the empa dose to 25mg/day. YMMV.

but caution on SGLT2i if you are type 1 diabetic or otherwise very low insulin:

SGLT2 inhibitor therapy induces serious adverse events: a 5- to 10-fold increase in the risk of ketoacidosis.

Note, that this study was evaluating exclusively Type 1 diabetics on insulin therapy, NOT subjects with “very low insulin levels”.

Insulin lowers glucose levels, that is a key function of this hormone. The addition of exogenous insulin will obviously lower glucose. If you add SGLT2i agents on top of injected insulin, yes you can create the conditions for excessive glucose lowering including severe hypoglycemia and keto acidosis. Absolutely.

I am not aware of any studies showing SGLT2i used by themselves, without concurrent use of additional glucose lowering agents causing excessive cases (compared to placebo) of hypoglycemia or keto acidosis at prescribed doses.

Now, perhaps a non-Type 1 diabetic who doesn’t use insulin or any other blood glucose lowering medications concurrently, might still experience hypoglycemia or keto acidosis just from taking a prescribed dose of an SGLT2i – I don’t know – but this study does not show that.

To show that SGLT2i by itself can cause hypoglycemia in patients with low insulin levels, we would need to see a study. This is not that study. The study cited here is in patients with completely different conditions and medications regiments. YMMV.

Caution should always be exercised before taking any new medication and that caution should have rational grounds.

You are quite right, I’ve seen no study on SGLT2i’s with people whose endogenous insulin production is in the type 1 range (which can be non-zero for many with T1D). And if you are not on glucose lowering agents, there are no DKA worries with SGLT2i’s.

However, many type 2 diabetics (and perhaps some MODY conditions?) eventually have their insulin production decline to the point where they need to exogenous insulin. For them, I’d caution against using an SLGT2i.

Yes, and that can be broadened to: if you take any medication which might lower your blood glucose, you should exercise caution with concurrent SGLT2i use. In fact, this should be understood in a wider context, meaning not just medications which are indicated specifically for lowering blood glucose, but medications whose side effect, or secondary outcome results in the lowering of blood glucose. In other words, don’t blindly stack glucose lowering interventions.

The dangers of polypharmacy are real. This doesn’t mean – as some would have it – that you should avoid concurrent use of multiple medications. What it does mean, is that you have to carefully vet DDI (Drug Drug Interactions) interactions before taking any of them. I myself am an example of this. I both am a great fan of polypharmacy, multiple drugs are the most rational and efficatious path forward in life extension – with current levels of medical science (can’t wait for genetic interventions!). And at the same time, extremely cautious in selecting drug combos – it’s like having a very powerful tool, it’s both dangerous and at the same time highly productive. I have taken months – in some cases years – before I have settled on my current regimen. I trawled pubmed for papers showing any interactions between empagliflozin and pitavastatin – as I take them both. I first took pita for a time, then added empa. I then did a ton of research on possible interactions between these and rapamycin. Now I’m easing slowly into rapa.

Bottom line: don’t just gobble up meds and supps willy nilly because you saw some positive press, or a recommendation from x, y, or z. Look at your specific situation very carefully and do a ton of research before selecting a course of action. Posts like mine, highlighting a possible intervention – SGLT2is for the OP’s situation, is simply alerting the OP to a candidate to look at, in case she has not explored this option. That’s how I read this site. If someone gives a personal testimony, or cites a paper or video etc., to me, this highlights a candidate for me to research to see if it fits into my situation. The vast majority of time, it does not, but I don’t regret the research as more knowledge is… more knowledge, and helps me make future decisions. Thank you for bringing further context to SGLT2i’s and blood glucose.