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ForumsPharmacology & MechanismsIncretin effect in healthy vs T2DM — why GLP-1 response is blunted in diabetes

Incretin effect in healthy vs T2DM — why GLP-1 response is blunted in diabetes

Dr.MetabolicMD Mon, May 25, 2026 at 12:30 AM 13 replies 471 viewsPage 1 of 3
Dr.MetabolicMD
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May 25, 2026 at 12:30 AM#1

Collecting this in one place because it comes up every few weeks and the answer is always assembled from scratch. It is about glycaemic control, and it is deliberately narrow — everything I am not confident about is marked as such.

What is actually established

HbA1c reflects roughly three months of average glycaemia weighted toward the most recent weeks, which is why repeating it at six weeks tells you very little. The improvement on this class comes from two directions — direct glucose-dependent insulin secretion and glucagon suppression, plus the indirect effect of weight loss on insulin sensitivity — and the second continues after the first has plateaued.

The condition it depends on

The caveat that HbA1c is unreliable in anaemia, haemoglobinopathies and recent blood loss, all of which are commoner than people assume. If it disagrees with fasting glucose or a CGM, that is worth chasing.

The practical version

Because it is glucose-dependent, this class carries a low intrinsic hypoglycaemia risk on its own — the risk arrives when it is combined with insulin or a sulfonylurea, which usually need reducing.

What I am not sure about

What would genuinely help is knowing why A1C lags the way it does, and what to look at in the meantime if you want to know sooner. I have searched first, so if this is covered somewhere point me at it and I will read it.

— Dr.MetabolicMD · corrections welcome and will be edited into this post with credit
27 22SleepDoc_PDX, RegAffairsDC, BiostatsBrad and 24 others
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Dr.SleepRoch
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May 25, 2026 at 1:34 AM#2
Dr.MetabolicMD said:
HbA1c reflects roughly three months of average glycaemia weighted toward the most recent weeks, which is why repeating it at six weeks tells you very…

Insulin sensitivity test (HOMA-IR) on glycaemic control — arguably the most important metabolic marker most people aren't tracking:

HOMA-IR = (fasting insulin × fasting glucose) ÷ 405

My numbers: Baseline HOMA-IR = 5.8 (insulin resistant) → Current = 1.2 (insulin sensitive)

Anything above 2.0 indicates insulin resistance. The goal is below 1.5. GLP-1 agonists address the root metabolic dysfunction, not just the symptoms. This is why they work so much better than calorie restriction alone.

Last edited: May 25, 2026 at 5:34 AM
26 21kim_atl_prep, sarah_TO, wendy_avl and 23 others
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TrialTracker_MD
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May 25, 2026 at 2:37 AM#3
Dr.MetabolicMD said:
HbA1c reflects roughly three months of average glycaemia weighted toward the most recent weeks, which is why repeating it at six weeks tells you very…

My labs after 9 months on glycaemic control: A1C 5.1%, fasting glucose 81 mg/dL, fasting insulin 8 uIU/mL. My endo says these are "textbook perfect."

For context, my baseline A1C was 7.7% and fasting glucose was 126 mg/dL. The improvement has been dramatic and consistent.

25 20maya_sedona, stefan_berlin, Dr.EM_Chicago and 22 others
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GenomicsKate
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May 25, 2026 at 3:41 AM#4
TrialTracker_MD said:
My labs after 9 months on glycaemic control: A1C 5.1%, fasting glucose 81 mg/dL, fasting insulin 8 uIU/mL.

Complete metabolic panel trending on glycaemic control — sharing because comprehensive data helps everyone:

TestBaselineMonth 3Month 6Month 12
Glucose (fasting)1251078985
Insulin (fasting)211595
HOMA-IR5.53.11.71.4
Uric Acid7.86.55.65.1

The insulin resistance improvement (HOMA-IR) is what my endo focuses on most. Going from 5.5 to near 1.0 is a metabolic transformation.

24 19Dr.PeteFamMed, claudia_zurich, nancy_portland and 21 others
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SaraMom3
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May 25, 2026 at 9:50 AM#5
Dr.SleepRoch said:
Insulin sensitivity test (HOMA-IR) on glycaemic control — arguably the most important metabolic marker most people aren't tracking: HOMA-IR = (fasting…

Same experience, arrived at from the opposite direction. Posting only so the count is not one.

23 18ZaraB_AL, JakeSmashed95, NauseaFreeNow and 20 others
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