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.