#1

I have read conflicting information about “Pre-Diabetes.” Would appreciate your thoughts/pointers.

My recent Hemoglobin A1C is 5.8. Back in 2017, the last time it was measured before this March, it was 5.9. In between, fasting glucose was about 100. So glucose has been high consistently for years, though none of my doctors ever told me to do anything about it. I decided that I wanted to take Metformin.

Have been on 1000mg Metformin for about 2 years. Also on Repatha and Exetimibe --(major concern was Lp(a) of 50 mg/dl now down to 29) and blood lipids are now good except for HDL which is crazy high – about 120. All the other factors are good: weight, exercise, diet, cardio function, but CAC of 0.96.

Genetic Data suggests that I might have an inborn tendency to both the higher glucose and HDL but don’t know what to make of that.

Article in the NYT says that prediabetes in women my age (70’s) progresses to diabetes less than about 30% of the time, so watch but don’t worry (or take meds).

So: how worried should I be? And is it OK to start Rapamycin with blood glucose at current levels?

#2

Seems like a question that would be easy to monitor and answer. Try the Rapa and see what it does to your glucose.

#3

I won’t give an individual medical advice on this forum, but happy to communicate in generalities.
An optimal HbA1C is 4.7%. Generally good advice to get to that level - not necessarily for Rapamycin - but for general longevity reasons. Rapamycin could increase your current blood glucose levels.
A fasting insulin level is useful to understand if the issue is insulin resistance or lack of production. I see a lot of older patients who simply have a pancreas that is happy with watching and not responding to higher than ideal blood sugar levels. These patients may have some response to diet/wt loss - but generally that isn’t the winning strategy. Folks who have a high serum insulin level - are much more likely to have great response to lifestyle change.
In general a non-ideal HbA1C should be optimized - but doesn’t influence being on rapamycin - it is just one thing that should be monitored and managed in an optimal range.

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#4

So, what is a winning strategy if the pancreas does not produce enough insulin, but you are not yet diabetic. Exercise and diet, of course, but are there any specific medications in addition to insulin? Ozempic?

#5

There are so many nuances here - you need a specialist to advise. If I were seeing you … first, I’d have your fasting insulin, glucose, c-peptide, hba1c and calculate your HOMA-IR.

If insulin sensitive but hyperglycemic/hba1c up … then there are a range of strategies … if insulin resistance another set of strategies.

If you truly have a lack of insulin then imaging of the pancreas is indicated as well as an immune workup unless there is a clear cause (e.g. multiple episodes of pancreatitis and known atrophy of the pancreas). Need to make sure you don’t have other stuff like hemochromatosis causing this … need to know your amount of visceral fat if insulin resistant via body composition dexa.

Ultimately, if you are insulin sensitive and not producing adequate insulin and no structural issue with your pancreas that needs addressing, there are ways to increase insulin secretion with meds, sometimes exogenous insulin is needed - but the main issue is maintaining normal range glucose AND normal amounts of insulin.

High glucose is likely more harmful to vascular health than high serum insulin to control it (but that is an insulin sensitivity issue which engages other strategies). Restoring normal physiology is the best with minimum insulin (exogenous/endogenous) to yield a normal average glucose and minimize major deviations upward (e.g. >>200 mg/dL for any significant period of time).

Those would be my general principles – but there is a lot of nuance and detail in sorting out what to recommend for an individual here. I have a lot of patients in their 60’s and 70’s who have what I phrase as “Lazy Pancreas” where they are insulin sensitive, and have HbA1C in the 6’s … and their pancreas can bump out plenty of insulin, but it is as though the “set point” of the pancreas to release insulin has gone from reacting at 120 mg/dL to not reacting until 150 or 200 mg/dL. So pancreas totally capable but setpoint messed up. I find metformin seems to work well in the majority of these patients. I don’t like metformin due to increased risk of sarcopenia - but it often is a great drug in these patients.

Hopefully this explanation helps.

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#6

I appreciate the answer, thank you very much.

I’ve been following my blood glucose via CGM and lately the problem has been more surprisingly high overnight fasting glucose and also morning fasting glucose (about 100mg/dl or 5.6 mmol/l). I exercise a lot and eat relatively clean and my fat percentage is really low. I need to order a measurement of morning insulin and glucose.

I stopped the statins, but it had no effect. I need to test for a while without ezetimibe.

#7

If I were evaluating someone with this limited information - the data needed to make decisions from a lab perspective will be:

  1. Fasting insulin paired with glucose and calculate HOMA-IR
  2. HbA1C
  3. C peptide

If HOMA-IR >2 then DEXA for whole body composition specifically for % body fat and most importantly visceral fat. If not insulin resistant (e.g. HOMA IR <2) then can pass on the DEXA.

If C peptide low, also need to consider imaging of the pancreas and assessment of exocrine function of pancreas (e.g. digestive enzymes) and check fecal elastase.

I know there is a lot of self management by individuals - but I do suggest seeing a physician who is a specialist, as getting this evaluated and managed properly is often missed in routine primary care.

Also, don’t sacrifice lipid control thinking that this will help your glucose. Yes, don’t push high dose statins, in general, but modest doses e.g. 10-20 mg of Atorvastatin or 5-10 mg of Rosuvastatin don’t make big differences. As an aside for anyone doing GFJ with their Rapa, be aware that Atorvastatin is impacted by GFJ, but Rosuvastatin isn’t.

The trifecta of vascular disease risk is insulin sensitivity/glycemic control, blood pressure and lipids. As vascular disease is the #1 killer and disabler, managing this is critical with all components needing optimization. There are more factors than these 3, such as diet, exercise, sleep, stress ….

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#8

Lipoic acid improved my fasting glucose to a normal level. I also changed rapamycin dosing to every 2 weeks which seems to be better for overall glucose levels.

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#9

Dr. Fraser, thank you for taking the time to write a very helpful response. I noted especially your statement : “restoring normal physiology is the best with minimum insulin . . .”

Since I started this thread I asked for testing and learned that my C-peptide is low (1.4), my insulin is low (4 ulU/mL and 3 ulU/mL – two separate test dates). Tested negative for LADA antibodies (at least two of them --not sure about the others). Fasting Blood Glucose varies a lot but usually in range of about 110- 130.

I take 2000 metformin, added 1200 Berberine, and many supplements: gymnema sylvestre, cinnamon, turmeric, Jinlada tea, et al. Daily exercise, careful diet. BMI of 18.3

Referred to an endocrinologist in March and appointment was cancelled three times – now waiting for September 25.

In the meantime, decided to not just wait.

Read about the work of Andrew Stewart at Mount Sinai. He and his team have demonstrated that Harmine can disenable the kinase DYRK1A, and in so doing, enable the pancreatic Beta cells to replicate at a higher rate. Further, when a GLP1 agonist is added, it greatly catalyzes the effect and can restore insulin to a normal level in 30 days. The amount of Harmine required to achieve this is far below the amount that is harmful – this has already been demonstrated as Harmine at varying increasing levels in human subjects has been tested in their phase 1 trials. The reaction works with any GLP1 agonist. They used Exanitide, with lab synthesized Harmine.
Independently, work at Buffalo by Dr. Paresh Dandona in a small group of human patients shows that GLP1 agonists improved the level of insulin secretion in Type 1 diabetics to the extent that they were all either able to reduce or stop insulin.

The GLP1 agonist increases insulin but it is the Harmine that stops the DYRK1A from inhibiting the Beta Cells. The two independent research projects indicate that GLP1 agonists should be approved for Type1 Diabetes. At present GLP1 agonists are not officially approved for Type 1 – only for Type2.

Given my insulin and C-peptide, (and genetics) I am pretty certain I have some form of Type 1. Not full blown yet but glucose has been high for many years and now going higher. I am doubtful that I will get the optimum treatment even if I am eventually successful in getting in to see the endocrinologist since GLP1agonists are not going to be “approved” by insurance for Type 1. So I have just started on the entire protocol on my own. For me personally it feels like the risk/reward justifies going ahead and not just sitting on my hands at this point.

I would so appreciate any guidance or suggestions about all this.

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#10

Deborah,

I think you are in a limited evidence zone without a huge reason at this point to act in regard to blood sugar. The problem as you note is that you may have a progressive issue where you will end up symptomatically short of insulin.

It sounds more like you might have Type 1.5 Diabetes (Latent autoimmune diabetes in adults) or less likely Type IIIC Diabetes.

Have you had your exocrine aspect of your pancreas tested and have you had imaging done?

Luckily you are just a month from being seen by endocrine … if they don’t cancel you again. Please update us on what their impression is, and what they plan.

Interesting information on the GLPs … that is new information to me with GLPs increasing insulin secretion in Type I DM

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#11

Thank you Dr. Fraser. If I don’t get in to see endocrine I will ask my PCP for pancreatic imaging and the test of the exocrine aspect. I did test negative for GADA and the islet cell antibody but I think there are two other possible antibodies that may be in play (?). Interestingly, I had seen a flag in Promethease saying that I had a tendency toward obesity. I could not reckon this as I am thin. But now, after reading more about Type 1, what I think Promethease may be pointing to is a genetic imbalance – a shortfall of glucagon production. There were also mentions of diabetes risks in some of the areas associated with cardiovascular risk. Thank you again!

#12

I can’t give specific advice to you … but general information yes.
So neurocognitive decline highly linked to total use of anticholinergics, and antipsychotics. Promethazine is both.
Obesity highly linked to H1 antihistamines that cross the blood brain barrier (which is all of them except loratidine and desloratidine … this includes all the newer ones except those two). Note that promethazine is an H1 antihistamine.
Duration of action is important - so promethazine isn’t rapidly metabolized - it has a half life of almost 10 hours. Thus when you take this medication, it’s around for most of 24 hours, which is also the risk on neurocognitive decline is dose - time of activity.
Interesting Article that Discusses Some of this
Another summary
Discussion of Anticholinergics and Cognitive Impairment

I however don’t see anything relating to a risk to someone’s pancreas due to that medication … it’s one I stay away from, especially as a chronic medication.

#13

Wouldn’t that cause low blood sugar? Glucagon tells the liver to put glucose in the blood. I recall protein stimulates glucagon and insulin production from the pancreas…the insulin tells cells to take in amino acids but will also cause glucose to be take from the blood causing low blood sugar unless the liver add more glucose to the supply. Glucagon tells the liver to add glucose.

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#14

Thank you Joseph Lavelle. Clearly I need to be worked up by a doctor who understands this better than I do! At the moment though, the primary two signals that have me focused on Type 1 are the low C-Peptide and the low insulin, and secondarily, knowing that whatever this is, it is not caused by weight, diet, or lack of exercise.

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#15

Casual internet searches reveal that only something like 5% of the population has an HbA1C this low. Of course, we don’t want to be the average (obese, diabetic or prediabetic) person. Yet I wonder how many people in this forum have an HbA1C that is usually this low. I think 4.9 was my lowest recent tested value.

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#16

I have the same problem.

Same for me.
I have been to several endocrinologists. I’ve done some autoantibody tests, all negative, everything normal. The doctors say everything is fine so I don’t worry, but my glucose is always between 100 and 120. That’s not normal, but don’t know what to do.

#17

Do you think choline supplementation with something like CDP choline or Alpha GPC choline would offset some of the negative effects of anticholinergics?

#18

It certainly could … but I don’t think we have proof - so I’d try to avoid to extent possible -it is a dose response - so minimizing it. About the only anticholinergic I rx is oxybutynin and in 5 mg immediate release at bedtime for nocturia in men. Apart from that I stay away from them. My logic there, is I think disrupted sleep is a big risk factor for dementia/MCI also … and quality of life is important - so probably a win on balance.

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#19

My doctor has also said it is probably “normal for me” but I don’t think so-- not with the low c peptide and low insulin.

#20

If you suspect you have a funky variant of Diabetes, you should try enrolling in this study: https://rally.massgeneralbrigham.org/study/radiant

They will first screen you to see if you are a likely match for them. Then maybe they figure out what is up with you.