Great find. I am going to replace my 1.5 gms of Metformin with this. I will order it at the earliest. I have been worried about my kidneys as albumin excretion seems to have increased per my last test. This will be another leg of mitochondrial support along with SS31, MOTSc and NAD+ injections.
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The fact that this new drug is available from India inexpensively makes it much more interesting. If I were taking metformin on a regular basis I would definitely look into the idea of switching to this drug. I also think the ITP should probably look at this drug as a potential longevity drug.
My key area of interest was related to exercise effects, and thus this prompt:
Given the mechanisms of action for Imeglimin compared to metformin, is it likely to have the same exercise hypertrophy blunting effect that metformin has, as outlined in this paper: Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial - PMC
Gemini Pro response:
Based on recent clinical and mechanistic data (including studies from 2024–2025), Imeglimin is unlikely to blunt exercise adaptations to the same degree as Metformin.
In fact, emerging human evidence suggests Imeglimin may enhance muscle strength and mitochondrial function when combined with resistance training, marking a critical divergence from Metformin.
1. The Clinical Verdict: Imeglimin vs. Resistance Training
While the Walton et al. (MASTERS trial) paper you referenced confirmed that Metformin blunts muscle hypertrophy in older adults, a prospective cohort study published in late 2024/early 2025 (Shimada et al., Journal of Diabetes and its Complications) found the opposite functional outcome for Imeglimin:
- The Finding: T2D patients taking Imeglimin who engaged in resistance training showed significantly greater improvements in knee extension strength (+13%) compared to controls (+2.1%).
- The Nuance: Like Metformin, Imeglimin did not significantly increase Lean Body Mass (hypertrophy) in this short window. However, unlike Metformin, it did not prevent strength gains; it amplified them. This suggests Imeglimin improves muscle quality (efficiency) rather than just bulk.
2. Mechanistic Explanation: Why the Difference?
Metformin and Imeglimin both target mitochondrial Complex I, but their downstream effects on the hypertrophy signaling pathway (mTORC1) appear to differ.
| Feature | Metformin Effect | Imeglimin Effect | Impact on Muscle |
|---|---|---|---|
| AMPK Activation | Strong Activation. AMPK directly inhibits mTORC1 (the “muscle growth switch”). | Activation. Also activates AMPK (via AMP/ATP ratio shift). | Both: Theoretically brakes growth. |
| Akt Signaling | Inhibition/Neutral. Metformin often fails to phosphorylate Akt in muscle during exercise. | Activation. Studies (Ishiguro et al.) show Imeglimin increases Akt phosphorylation. | Imeglimin Advantage: Akt activates mTORC1, potentially counteracting the AMPK “brake.” |
| Mitochondria | Inhibition. Can limit ATP availability during high-demand exercise. | Optimization. Corrects Complex III, maintaining better ATP flux while reducing oxidative stress. | Imeglimin Advantage: Better fuel efficiency for contracting muscle. |
| ROS Hormesis | Blunting. Scavenges ROS “blindly,” potentially killing the signal for adaptation. | Targeted Reduction. Prevents Complex III superoxide leakage but increases PGC-1α (biogenesis). | Imeglimin Advantage: Enhances mitochondrial density without killing the exercise signal. |
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3. The “Hormesis” Factor
The primary fear with antioxidants (and Metformin) is that they blunt hormesis—the beneficial stress response where Exercise-Induced ROS signals the body to get stronger.
- Metformin tends to blunt this signal, leading to the “sub-optimal” training response seen in the MASTERS trial.
- Imeglimin appears to bypass this via the NAMPT/NAD+ pathway. By increasing intracellular NAD+, Imeglimin activates Sirtuins (SIRT1/SIRT3) and PGC-1α. This mimics the benefits of exercise (mitochondrial biogenesis) rather than just suppressing the signal.
Conclusion
Scientific evidence suggests Imeglimin is superior to Metformin for the active individual. While Metformin acts as a “metabolic brake” that can compromise the anabolic response to exercise, Imeglimin acts more like a “mitochondrial tuner.” It likely will not blunt strength gains and may synergize with exercise to improve sarcopenia risks, even if it doesn’t strictly act as a hypertrophy agent (muscle builder).
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Not medical advice. ChatGPT 5.2
Approved Japanese Prescribing Information (Summary)
Standard dose (normal renal function)
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1,000 mg twice daily (total 2,000 mg/day)
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Taken after meals (usually breakfast and dinner)
This is the only fully approved dose in the Japanese package insert.
Renal Impairment: What Is Known vs What Is Approved
Japan’s labeling is conservative. Dose reductions below are not formally approved indications, but are commonly cited in PK analyses, expert reviews, and post-marketing discussions.
| eGFR (mL/min/1.73 m²) | Dose Used / Suggested | Regulatory Status in Japan | Notes |
|---|---|---|---|
| ≥45 | 1,000 mg twice daily |
 Approved |
Standard dosing |
| 30–<45 | 500 mg twice daily |
 Not formally approved |
Based on PK modeling; monitor closely |
| 15–<30 | 500 mg twice daily |
Off-label / modeling only |
Very limited clinical data |
| <15 or dialysis | 500 mg once daily |
 Not recommended |
Not approved; insufficient safety data |
Key Regulatory Nuances (Important)
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Japanese labeling does NOT officially endorse dose adjustment for moderate or severe renal impairment.
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Instead, it states that use should be avoided or approached with extreme caution in advanced CKD.
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The reduced-dose schemes (500 mg BID or QD) come from:
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Pharmacokinetic simulations
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Small exposure studies
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Expert consensus (not large outcome trials)
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Safety Observations Relevant to Older Adults
Given your interest in glucose-lowering alternatives with mitochondrial relevance:
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Low hypoglycemia risk (no insulin stimulation)
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No lactic acidosis signal (unlike metformin)
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GI effects are usually mild and transient
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Long-term renal outcome data remain limited
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The price is affordable, Zydus is trustful.
But can it be counteractive with Rapamycin?
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Have you tried an SGLT2 inhibitor instead of metformin?
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I’ve tried Jardiance. It’s not nearly as effective as metformin.
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You wrote that Jardiance was ok for you, just takes time to start working at full strength. Whats happened?
Imeglimin: A Comprehensive Bioenergetic Analysis of Mechanisms, Comparative Pharmacodynamics, and Geroprotective Potential
Executive Summary
The pharmacological management of metabolic disease and the emerging field of geroprotection—therapies designed to extend healthspan and lifespan—are currently converging on the mitochondrion as a central therapeutic target. For decades, the biguanide metformin has stood as the vanguard of this class, modulating energy metabolism through mechanisms that, while clinically effective, impose specific bioenergetic taxes on cellular respiration. The emergence of Imeglimin (IMEG), a novel tetrahydrotriazine-containing entity, represents a significant evolution in this domain. This report provides an exhaustive analysis of Imeglimin’s molecular mechanisms of action (MOA), contrasting them with the established pharmacodynamics of metformin, and rigorously evaluates the scientific evidence supporting Imeglimin’s potential as a healthspan-extending agent in mammals.
The core thesis of this analysis posits that Imeglimin functions as a “mitochondrial optimizer” rather than a metabolic stressor. Unlike metformin, which exerts uncompetitive inhibition on Complex I and suppresses mitochondrial respiration, Imeglimin induces a specific kinetic constraint that preserves oxidative capacity while reducing Reactive Oxygen Species (ROS) generation via Reverse Electron Transport (RET). Furthermore, Imeglimin exhibits a unique tripartite mechanism: the competitive modulation of Complex I, the amplification of the NAD+ salvage pathway through Nicotinamide Phosphoribosyltransferase (NAMPT) induction, and the direct inhibition of the Mitochondrial Permeability Transition Pore (mPTP) via Cyclophilin D interaction.
Full Gemini Pro Deep Search Analysis: https://gemini.google.com/share/0718a4c876e9
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I have been taking it for 2 years (with jardiance). So far so good.
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What can you share with us about it. Overall performance compared to Metformin. Standard 2 gm dosage? What prompted you to try this. Your physician recommend this? Are you in Japan or someplace this is available?
Thanks
Cheers
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last visit
DrFraser
I think this review is pretty balanced … it’s something one might substitute for metformin for presumed mitochondrial effects and reduction of ROS … looks inferior to higher dose metformin on the glucose side of things.
Imeglimin vs Metformin: Efficacy, Mechanisms, Dosing, and “Longevity” Considerations
Summary of Findings (SoF)
- Glycemic efficacy:
- Imeglimin monotherapy or add‑on lowers HbA1c by approximately 0.6–0.9% vs placebo at approved doses (1,000 mg twice daily), with consistent reductions in fasting plasma glucose (FPG) and favorable tolerability (Level I: meta‑analyses, RCTs) 19, 7, 2, 4.
- Metformin monotherapy typically lowers HbA1c by ~1.0–1.2% vs placebo, with dose–response up to ~2,000 mg/day (Level I: meta‑analyses) 4, 3.
- Head‑to‑head:
- A 24‑week randomized study found similar HbA1c lowering with imeglimin 2,000 mg/day vs metformin 1,000 mg/day; imeglimin increased insulin levels and GIP (and GLP‑1), whereas metformin did not increase insulin (Level I: RCT) 7.
- Mechanisms:
- Imeglimin is a mitochondrial modulator that amplifies glucose‑stimulated insulin secretion (GSIS) via NAD+ salvage and cADPR/CD38‑mediated Ca2+ signaling, preserves β‑cell mass, reduces hepatic gluconeogenesis, and improves insulin sensitivity; it increases GLP‑1 and uniquely increases GIP (Level I/II) 8, 8, 7, 1.
- Metformin primarily suppresses hepatic gluconeogenesis via mitochondrial complex I/AMPK and mGPDH, with important gut‑mediated effects and increased GLP‑1 (Level I/II) 4, 1.
- Dose “equivalency” (HbA1c‑equivalent):
- Practical clinical inference: Imeglimin 1,000 mg BID ≈ metformin ~1,000 mg/day for HbA1c lowering (based on the single head‑to‑head RCT); at full metformin dose (2,000 mg/day), metformin generally achieves greater HbA1c reduction (≈0.3–0.5% more) than imeglimin 1,000 mg BID (Level I/II) 7, 4, 11, 3.
- Safety:
- Imeglimin shows a favorable GI profile and very low hypoglycemia risk; preclinical comparative work suggests a lower lactic acidosis liability vs metformin (distinct mitochondrial effects, less complex I inhibition, no mGPDH inhibition) (Level II/III) 20; human TIMES studies show good tolerability (Level I) 19.
- Metformin—rare lactic acidosis; robust long‑term clinical experience and strong cardio‑metabolic safety data (Level I) 4, 13.
- “Longevity”:
- No randomized cardiovascular outcomes or mortality data exist for imeglimin; therefore, there is no evidence it is a “longevity drug” at present (Level I/II for absence of outcomes data) 7, 2.
- Metformin is associated with long‑term micro/macrovascular and mortality benefits in select populations (e.g., UKPDS post‑trial follow‑up in overweight T2D; multiple observational/meta‑analytic signals), but randomized mortality evidence is mixed and population‑dependent (e.g., no mortality benefit in DPPOS for prediabetes) (Level I/II) 14, 21, 12, 17, 18.
Bottom line for clinical decision-making:
- For HbA1c lowering, metformin at full therapeutic dose (2,000 mg/day) is generally more potent than imeglimin 1,000 mg BID. Imeglimin can be roughly “equivalent” to lower‑dose metformin (~1,000 mg/day) on HbA1c. Mechanistically, imeglimin’s insulinotropic and incretin (including GIP) effects differentiate it from metformin and can be advantageous where β‑cell dysfunction is prominent. As a “longevity drug,” imeglimin lacks outcomes evidence; metformin has the stronger long‑term cardiovascular/mortality data, though not uniform across settings.
Evidence Synthesis
- Magnitude of HbA1c reduction:
- Imeglimin (TIMES 1) monotherapy vs placebo reduced HbA1c by −0.87% at 24 weeks in Japanese T2D patients on diet/exercise (1,000 mg BID) 19. Meta‑analyses across broader RCTs show mean placebo‑adjusted HbA1c reductions of ~−0.6 to −0.7% at typical doses (1,000–1,500 mg BID) 7, 2, 4, 19.
- Metformin monotherapy meta‑analysis: HbA1c −1.12% (95% CI 0.92–1.32) vs placebo, with dose–response favoring higher doses up to ~2,000 mg/day; add‑on reductions ~0.6–1.0% (Level I) 4; similar magnitude in older pooled RCTs 3.
- Head‑to‑head HbA1c:
- A randomized open‑label trial (24 weeks) in drug‑naïve or single‑OHA patients (after washout) showed similar HbA1c reductions with imeglimin 2,000 mg/day vs metformin 1,000 mg/day. Imeglimin increased insulin levels and selectively increased GIP (and GLP‑1), whereas metformin increased GLP‑1 without raising insulin, underscoring distinct mechanisms (Level I) 7.
- Mechanisms: why might imeglimin feel “stronger” in some patients?
- Imeglimin enhances GSIS via mitochondrial NAD+ salvage (NAMPT), increasing cADPR/CD38‑mediated Ca2+ mobilization and ATP generation; it reduces ROS and stabilizes the mitochondrial permeability transition pore; it preserves β‑cell mass and improves insulin sensitivity in liver and muscle (partial rebalance of respiratory chain, reduced complex I activity, correction of complex III deficiency) (Level I/II) 8, 8.
- In an exploratory RCT, imeglimin increased active/total GIP and GLP‑1; metformin increased GLP‑1 but not GIP; only imeglimin raised insulin during OGTT, consistent with its insulinotropic mechanism (Level I) 7.
- In hepatocytes, imeglimin and metformin show some shared mitochondrial/AMPK effects but differ significantly in gene expression signatures and in mGPDH/complex I inhibition, helping explain differing lactic acidosis risk and insulinotropic profiles (Level II) 1.
- Safety and lactic acidosis:
- Longevity and outcomes:
- Imeglimin: No cardiovascular or mortality outcomes trials to date; emerging real‑world signals are small and uncontrolled; no evidence for lifespan extension (Level I/II) 7, 2.
- Metformin: UKPDS post‑trial follow‑up in overweight T2D showed persistent risk reductions in MI (−33%) and all‑cause mortality (−27%) years after randomization (legacy effect) (Level I) 14. Subsequent analyses/meta‑analyses and large cohorts associate metformin with lower MACE and mortality vs sulfonylureas and in CKD/CHF (Level II), though randomized mortality benefits are not uniform across all populations (e.g., DPPOS in prediabetes showed no mortality advantage) 21, 12, 10, 17, 23, 18.
Evidence Table
Table 1: Comparative glycemic efficacy and mechanisms
| Domain | Imeglimin | Metformin | Evidence level |
|---|---|---|---|
| Typical dose | 1,000 mg BID (approved in Japan) | 1,500–2,000 mg/day (titrated to GI tolerance) | — |
| HbA1c reduction vs placebo | ≈ −0.6 to −0.9% at 24 weeks (dose‑dependent; TIMES 1 −0.87%) | ≈ −1.0 to −1.2% (dose‑response up to ~2,000 mg/day) | Level I: 19, 7, 2, 4; 4, 3 |
| Head‑to‑head A1c | Similar at imeglimin 2,000 mg/day vs metformin 1,000 mg/day (24 weeks) | Same as previous cell | Level I: 7 |
| FPG reduction vs placebo | ~ −0.5 mmol/L | ~ −2.0 mmol/L (meta‑analysis) | Level I: 19; 3 |
| Mechanism — β‑cell/GSIS | Amplifies GSIS via NAD+ salvage (NAMPT) → cADPR/CD38‑Ca2+; ↑ ATP; preserves β‑cell mass | No direct insulinotropic effect; primary is hepatic glucose output suppression; gut GLP‑1 effects | Level I/II: 8, 8, 1; 7 |
| Mechanism — liver/muscle | Improves insulin sensitivity; corrects complex III deficiency; reduces complex I activity and ROS; reduces gluconeogenesis | Inhibits hepatic gluconeogenesis (complex I, AMPK, mGPDH), gut actions; ↑ GLP‑1 | Level I/II: 8, 1 |
| Incretins | ↑ GLP‑1 and uniquely ↑ GIP | ↑ GLP‑1; no GIP increase | Level I: 7 |
| Hypoglycemia | Low (monotherapy) | Low (monotherapy) | Level I: 19, 4 |
| Lactic acidosis biology | Lower preclinical propensity vs metformin (less complex I and no mGPDH inhibition) | Rare clinical risk; mGPDH and complex I inhibition observed | Level II/III: 20 |
Caption: Imeglimin’s dual pancreatic and extra‑pancreatic actions contrast with metformin’s dominant hepatic mechanism and gut incretin effects. Head‑to‑head evidence at 24 weeks suggests equivalence between imeglimin 2,000 mg/day and metformin 1,000 mg/day for HbA1c, but full‑dose metformin typically achieves greater A1c reduction.
Table 2: Practical dose “equivalency” on HbA1c (approximate, based on available data)
| Regimen | Expected HbA1c change vs placebo | Notes |
|---|---|---|
| Imeglimin 1,000 mg BID | ≈ −0.6 to −0.9% | TIMES 1 −0.87% at 24 weeks 19; meta‑analyses consistent 7, 2 |
| Metformin 1,000 mg/day | ≈ −0.6 to −0.9% | Head‑to‑head: similar to imeglimin 2,000 mg/day at 24 weeks 7 |
| Metformin 1,500–2,000 mg/day | ≈ −1.0 to −1.2% | Dose–response; optimization to 2,000 mg/day improves HbA1c further 4, 11 |
Caption: Based on one head‑to‑head RCT (imeglimin 2,000 mg/day ≈ metformin 1,000 mg/day), imeglimin 1,000 mg BID is roughly “equivalent” to lower‑dose metformin on HbA1c. Full‑dose metformin (2,000 mg/day) typically lowers HbA1c more than imeglimin 1,000 mg BID.
Table 3: Outcomes and “longevity” signals
| Agent | Cardiovascular/mortality outcomes | Summary |
|---|---|---|
| Imeglimin | No completed CV or mortality outcomes trials | No evidence for reduced MACE or mortality to date (needs CVOT). Glycemic efficacy and safety established over 24–52 weeks 7, 20, 21 |
| Metformin | UKPDS legacy effect: ↓ MI (33%), ↓ all‑cause mortality (27%) in overweight T2D; multiple cohort/meta‑analytic signals favor lower MACE/mortality vs sulfonylureas; mixed across settings (e.g., no mortality benefit in DPPOS prediabetes) | Strongest long‑term data among “older” agents but heterogeneous; not a dedicated mortality drug; benefits are context‑dependent 14, 21, 12, 10, 17, 23, 18 |
Caption: Only metformin has randomized and large‑scale observational evidence suggesting long‑term macrovascular and mortality benefits in specific T2D populations; imeglimin lacks outcomes data at present.
Results
- HbA1c lowering:
- Imeglimin: TIMES 1 (Japanese phase 3, N=~213) achieved −0.87% (95% CI −1.04 to −0.69) vs placebo at 24 weeks with 1,000 mg BID and placebo‑like safety 19. Pooled RCTs demonstrate HbA1c reductions of ~−0.6 to −0.7% and FPG ~−0.5 mmol/L vs placebo 7, 2, 4, 19.
- Metformin: Meta‑analysis of 35 trials quantified HbA1c lowering of −1.12% for monotherapy vs placebo, with additional reductions as add‑on and a dose–response up to ~2,000 mg/day (without higher GI intolerance) 4. Older NEJM RCTs confirm comparable efficacy to sulfonylureas, favorable lipid effects, and neutrality on fasting lactate 13.
- Direct comparison:
- 24‑week open‑label RCT: imeglimin 2,000 mg/day vs metformin 1,000 mg/day yielded similar HbA1c reductions; imeglimin uniquely increased insulin and GIP (+GLP‑1), while metformin increased GLP‑1 without raising insulin—supporting different primary mechanisms (insulinotropic vs hepatic/gut) 7.
- Mechanistic data:
- Imeglimin augments GSIS via NAD+ salvage (NAMPT) → cADPR/CD38 and enhanced Ca2+ mobilization and ATP generation; restores mitochondrial function (rebalances respiratory chain; reduces ROS; prevents mPTP opening) and preserves β‑cell mass (rodent/islet and clinical translational evidence) 8, 8.
- Comparative hepatocyte profiling shows some shared mitochondrial/AMPK effects with metformin but differential gene expression and lack of mGPDH inhibition by imeglimin 1.
- Glycemic variability/acute add‑on effects:
- Adding imeglimin 2,000 mg/day to background metformin acutely improved 24‑h mean glucose (−22.7 mg/dL) and increased time‑in‑range over 72 hours in CGM analyses (nonrandomized) 24.
- Safety:
- Imeglimin: tolerability similar to placebo over 24–52 weeks; low hypoglycemia risk; preclinical models show lower lactic acidosis propensity than metformin under stress/renal impairment; less complex I inhibition and no mGPDH inhibition vs metformin 20, 19, 20, 21.
- Metformin: long‑standing safety with rare lactic acidosis and favorable weight and lipid effects; dose optimization to 2,000 mg/day in GRADE run‑in lowered HbA1c by ~−0.65% (dose‑increase subgroup), with ~0.9 kg weight loss 11; meta‑analysis supports ~−1.12% HbA1c at effective dosing 4.
Discussion
- Could imeglimin be better at blood sugar control?
- In a direct, albeit small and open‑label randomized comparison, imeglimin 2,000 mg/day was non‑inferior to metformin 1,000 mg/day at 24 weeks for HbA1c lowering, with mechanistic advantages in insulin secretion (↑ insulin) and incretin biology (↑ GIP + GLP‑1) 7.
- However, at standard full therapeutic doses, metformin (1,500–2,000 mg/day) generally achieves ~0.3–0.5% greater HbA1c reduction than imeglimin 1,000 mg BID based on high‑quality dose‑response meta‑analytic evidence for metformin and the pooled imeglimin effect sizes 4, 7, 3.
- Clinically, imeglimin may “feel” more effective in phenotypes where β‑cell dysfunction limits metformin’s effect, because imeglimin directly amplifies GSIS, preserves β‑cell mass, and enhances both GLP‑1 and GIP signaling 8, 8, 7.
- Dose equivalency:
- The only randomized head‑to‑head comparison suggests HbA1c equivalence between imeglimin 2,000 mg/day and metformin 1,000 mg/day at 24 weeks 7.
- Given the robust metformin dose–response to 2,000 mg/day, a pragmatic approach is:
- Safety and renal/surgical contexts:
- Preclinical comparative data indicate imeglimin’s lactic acidosis liability is lower than metformin under conditions of renal impairment or major surgery (less complex I inhibition; no mGPDH inhibition) 20. Human data are limited but clinical trials show good tolerability.
- Longevity:
- Imeglimin lacks CV outcomes and mortality RCTs; thus, it cannot be considered a longevity agent at this time.
- Metformin has the most extensive long‑term data among traditional oral agents, including the UKPDS legacy effect showing durable reductions in MI and all‑cause mortality in overweight newly diagnosed T2D randomized to metformin vs conventional care or vs other agents (with late emergence of benefits) 14, 21. Observational/meta‑analytic data also suggest lower MACE and mortality vs sulfonylureas and in CKD/CHF subsets 10, 23, 17, though randomized mortality benefits are not universal (e.g., DPPOS in prediabetes showed no mortality difference) 12.
- For patients prioritizing disease‑modifying, outcome‑proven therapies with mortality benefits, GLP‑1 RAs and SGLT2 inhibitors have robust contemporary CV/renal outcome evidence beyond glycemia; this does not diminish metformin’s foundational role but contextualizes “longevity” options in 2026 care 9, 26, 27.
Conclusion
- HbA1c control:
- At therapeutic doses, metformin (1,500–2,000 mg/day) generally produces greater HbA1c reduction than imeglimin 1,000 mg BID. Imeglimin 2,000 mg/day appears roughly equivalent to lower‑dose metformin (~1,000 mg/day) based on one 24‑week RCT. Expect imeglimin −0.6 to −0.9% vs placebo; metformin −1.0 to −1.2% vs placebo. Mechanistically, imeglimin’s insulinotropic and dual incretin (GLP‑1 + GIP) actions differentiate it and may be advantageous in β‑cell‑limited phenotypes.
- Dose “equivalency” (approximate, HbA1c‑based):
- Imeglimin 1,000 mg BID ≈ Metformin ~1,000 mg/day for HbA1c; Metformin 2,000 mg/day > Imeglimin 1,000 mg BID by ~0.3–0.5% HbA1c on average.
- Longevity:
- No evidence that imeglimin prolongs life or reduces hard outcomes; metformin has the stronger, albeit heterogeneous, long‑term cardiovascular/mortality evidence among traditional orals, but is not a dedicated “longevity drug.” For outcome‑driven longevity goals, prioritize agents with proven CV/renal benefits (SGLT2i, GLP‑1 RA) in appropriate patients.
References (inline citations only)
- Imeglimin efficacy/safety (TIMES program and meta-analyses): 19, 20, 21, 7, 2, 4, 19.
- Imeglimin vs metformin RCT and incretin/insulin effects: 7.
- Imeglimin mechanisms (mitochondria, NAD+, cADPR/CD38, β‑cell mass): 8, 8.
- Comparative hepatocyte/AMPK/respiration/mGPDH signals: 1.
- Lactic acidosis biology (preclinical imeglimin vs metformin): 20.
- Metformin HbA1c magnitude and dose–response: 4, 3, 11.
- Metformin outcomes and “longevity” signals: UKPDS and legacy analyses 14, 21; comparative cohorts and meta‑analyses 10, 17, 23, 18; null mortality in DPPOS (prediabetes) 12.
- Acute add‑on imeglimin CGM: 24.
References:
- Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial Diabetes Care. 2021. DOI: 10.2337/dc20-0763
- Efficacy and safety of imeglimin in type 2 diabetes: A systematic review and meta-analysis of randomized placebo-controlled trials. Diabetes & metabolic syndrome. 2023. DOI: 10.1016/j.dsx.2023.102710
- Efficacy, safety and tolerability of imeglimin in patients with type 2 diabetes mellitus: A meta‐analysis of randomized controlled trials Journal of Diabetes Investigation. 2023. DOI: 10.1111/jdi.14070
- Efficacy and safety of imeglimin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized clinical trials. Diabetes & metabolic syndrome. 2021. DOI: 10.1016/j.dsx.2021.102323
- Quantifying the Effect of Metformin Treatment and Dose on Glycemic Control Diabetes Care. 2012. DOI: 10.2337/dc11-1465
- Efficacy of metformin in the treatment of NIDDM. Meta-analysis. Diabetes care. 1999. DOI: 10.2337/DIACARE.22.1.33
- Differential effects of imeglimin and metformin on insulin and incretin secretion—An exploratory randomized controlled trial Diabetes, Obesity & Metabolism. 2024. DOI: 10.1111/dom.16086
- Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes Diabetes, Obesity & Metabolism. 2020. DOI: 10.1111/dom.14277
- Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action PLoS ONE. 2020. DOI: 10.1101/2020.10.20.346841
- Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes Scientific Reports. 2023. DOI: 10.1038/s41598-023-27689-y
- Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight Diabetes Care. 2020. DOI: 10.2337/dc19-1769
- Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin Physiological Reports. 2022. DOI: 10.14814/phy2.15151
- Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. The New England journal of medicine. 1995. DOI: 10.1056/NEJM199508313330902
- 10-year follow-up of intensive glucose control in type 2 diabetes. The New England journal of medicine. 2008. DOI: 10.1056/NEJMoa0806470
- Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study Diabetes Care. 2019. DOI: 10.2337/dc18-1970
- Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study Diabetes Care. 2021. DOI: 10.2337/dc21-1046
- Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis Cardiovascular Diabetology. 2019. DOI: 10.1186/s12933-019-0900-7
- Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials. Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020. DOI: 10.1016/j.numecd.2020.11.031
- Imeglimin, a novel, first in-class, blood glucose-lowering agent: a systematic review and meta-analysis of clinical evidence British Journal of Diabetes. 2020. DOI: 10.15277/bjd.2020.247
- Long‐term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52‐week, open‐label, multicentre phase 3 trial Diabetes, Obesity & Metabolism. 2021. DOI: 10.1111/dom.14613
- Efficacy and safety of imeglimin add‐on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): A randomized, double‐blind, placebo‐controlled phase 3 trial with a 36‐week open‐label extension period Diabetes, Obesity & Metabolism. 2021. DOI: 10.1111/dom.14642
- Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function. JAMA. 2019. DOI: 10.1001/jama.2019.13206
- Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis Frontiers in Endocrinology. 2020. DOI: 10.3389/fendo.2020.559446
- Acute Effect of Imeglimin Add-on Therapy on 24-h Glucose Profile and Glycemic Variability in Patients with Type 2 Diabetes Receiving Metformin Medical Principles and Practice. 2024. DOI: 10.1159/000540852
- Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2016. DOI: 10.1056/NEJMoa1603827
- Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015. DOI: 10.1056/NEJMoa1504720
- The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials. Diabetologia. 2021. DOI: 10.1007/s00125-021-05529-w
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Jardiance isn’t working for me. I’m still taking it, but it’s not as effective as metformin at lowering my fasting glucose levels. I took metformin for ~20 years, but in the last year of taking it, it started to affect my gut, mainly in the form of diarrhea. When I was young I had an iron gut, and it wasn’t affected by foods or medications. But, at 85, it is now a weakling, and I have to watch what I take. I am hoping that Imeglin with Jardiance will be as effective as metformin alone.
ChatGPT 5.2
Average glucose-lowering effect (monotherapy)
| Drug (typical dose) | HbA1c reduction (vs placebo) | Fasting glucose reduction (vs placebo) |
|---|---|---|
| Metformin (often 1500–2000 mg/day) | ~−1.1% HbA1c | ~−2.0 mmol/L (≈ −36 mg/dL) |
| Empagliflozin (Jardiance 10–25 mg/day) | ~−0.74% to −0.85% at 24 weeks | Across SGLT2 inhibitors: ~−0.78 to −2.02 mmol/L (≈ −14 to −36 mg/dL) |
Bottom line on “effectiveness” for A1c and fasting glucose:
- Metformin usually lowers A1c more than Jardiance when each is used alone (roughly ~1.1% vs ~0.7–0.9% in typical trials).
- For fasting glucose, they can overlap, but metformin often lands toward the stronger end of the range on average in older meta-analyses.
A key nuance for your situation (mild elevations)
If someone starts with an A1c near-normal (e.g., ~5.4%) and fasting glucose ~110 mg/dL, the absolute drop you’ll see from any drug is typically much smaller than the averages above, because those trial averages are mostly in people starting around A1c ≥7%.
Why Jardiance is still often chosen (even if metformin lowers A1c more)
Guidelines emphasize that in people with heart failure, chronic kidney disease, established ASCVD, or high CV risk, an SGLT2 inhibitor like empagliflozin may be selected for organ protection regardless of baseline A1c or metformin use.
Combination tends to beat either alone
When used together early, empagliflozin + metformin reduces A1c more than either drug alone (as you’d expect from additive mechanisms).
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Ordered some from India.
For me it’s more a replacement for Plioglitazone which works well but has some safety issues.
Also my DEXA fat % went from 14% to 16% with Plioglitazone.
Metformin did not do anything at all for me.
I did a Gemini Pro deep research: Bioenergetic Pharmacotherapy in Type 2 Diabetes: A Comprehensive Analysis of Imeglimin Interactions, Comparative Safety, and Physiological Adaptations
That includes interaction with rapamycin, empagliflozin, exercise, etc.
Table 1: Comparative Safety and Efficacy Profile: Imeglimin vs. Pioglitazone
| Feature | Pioglitazone (TZD) | Imeglimin (Glimin) | Clinical Consequence |
|---|---|---|---|
| Primary Target | Nuclear PPARγ Receptor | Mitochondrial Complex I/III | Imeglimin avoids nuclear transcription side effects. |
| Heart Failure Risk | Increased (Boxed Warning) | Neutral (Potential Benefit) | Imeglimin is safer for patients with cardiac history. |
| Edema | Frequent (Renal Na+ reabsorption) | Rare / Absent | Imeglimin preferred in patients prone to volume overload. |
| Bone Fracture Risk | Increased (Marrow adipogenesis) | Neutral | Imeglimin preferred in postmenopausal women/elderly. |
| Weight Effect | Weight Gain (Adipogenesis + Fluid) | Neutral | Imeglimin avoids exacerbating obesity. |
| Liver Fat | Reduces (Potent) | Reduces (Moderate) | Both benefit MASH, but Pioglitazone has more data. |
| Onset of Action | Slow (Weeks/Months) | Rapid | Imeglimin offers faster glycemic control. |
Table 2: Mechanism of Interaction: Imeglimin + Empagliflozin
| Component | Empagliflozin Contribution | Imeglimin Contribution | Synergistic Outcome |
|---|---|---|---|
| Glycemia | Urinary glucose excretion (Insulin Independent) | Insulin sensitization + GSIS (Insulin Dependent) | Potent HbA1c reduction covering all mechanisms. |
| Cardiac | Hemodynamic unloading + Ketone fuel | Mitochondrial efficiency + Endothelial function | Structural and metabolic cardiac remodeling. |
| Renal | Reduced glomerular pressure | Reduced oxidative stress | Preservation of nephron mass. |
| Liver | Reduced hepatic fat | Reduced lipogenesis + fibrosis | Mitigation of MASH progression. |
Table 3: Summary of Imeglimin Interactions and Effects
| Domain | Interaction / Comparison | Key Outcome / Mechanism |
|---|---|---|
| Pharmacology | vs. Metformin | Competitive vs. Non-competitive Complex I inhibition; Imeglimin rescues Complex III and amplifies GSIS. |
| Safety | vs. Pioglitazone | Imeglimin has NO heart failure, edema, or bone fracture risk. Weight neutral. |
| Synergy | w/ Tirzepatide | Complementary beta-cell effects: Tirzepatide stimulates, Imeglimin protects (mitochondrial buffering). |
| Synergy | w/ Empagliflozin | Full Cardio-Renal protection: SGLT2i (hemodynamic) + Imeglimin (metabolic/endothelial). |
| Longevity | w/ Rapamycin | Imeglimin (AMPK/SIRT1) rescues mitochondrial biogenesis inhibited by Rapamycin (mTORC1 blockade). |
| Muscle | Strength Training | Increases strength (~13%) without hypertrophy. Improves NMJ/Bioenergetics. |
| Muscle | Endurance | Enhances PGC-1α and mtDNA. Potentially additive to exercise adaptations. |
| Renal | TWINKLE Study | Safe in eGFR < 45 mL/min (unlike Metformin). No lactic acidosis signal. |
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Also cited in the post of Dr. Fraser (citation #7)
In the present study, only imeglimin enhanced insulin secretion and the effect on insulin sensitivity was similar between imeglimin and metformin; however, the reduction of HbA1c in both drugs was similar at 24 weeks. This may be explained by that metformin has the glucose‐lowering effect via mechanisms not involving insulin signal such as enhancing release of glucose into the intraluminal space of the intestine or influencing the gut microbiota.
Is that a desired result? Isn’t increased insulin age accelerating?
In humans, epidemiological studies suggest a pro-aging effect of insulin. Insulin resistance increases with aging, but centenarians usually preserve normal glucose tolerance, low levels of fasting insulin and higher insulin sensitivity, when compared with adults > 75 years of age (52–54). The higher longevity in shorter men is also associated with lower fasting insulin concentrations (55).
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again using AI to help: Imeglimin (brand name Twymeeg) is a first-in-class oral antidiabetic approved in Japan since 2021 for Type 2 diabetes. It shares some mechanisms with metformin but works differently at the mitochondrial level, which is why longevity enthusiasts are interested in it.
How It Differs from Metformin
| Feature | Metformin | Imeglimin |
|---|---|---|
| Complex I | Non-competitive inhibition (blunts respiration) | Competitive modulation (preserves oxidative capacity) |
| Complex III | No effect | Corrects dysfunction, reduces ROS |
| NAD+ effect | Indirect | Direct upregulation via NAMPT |
| Insulin secretion | None (works via liver) | Amplifies glucose-stimulated insulin secretion (GSIS) |
| GI tolerance | Often poor (diarrhea) | Generally better tolerated |
| Lactic acidosis risk | Rare but possible | Lower theoretical risk |
| HbA1c reduction | ~1.0–1.2% at full dose | ~0.6–0.9% (head-to-head similar to lower-dose metformin) |
| Cost | Very low (generic) | High (patented) |
Longevity Angle
The appeal for healthspan is its “mitochondrial optimizer” profile—it reduces ROS via reverse electron transport while preserving ATP production, and it boosts the NAD+ salvage pathway through NAMPT induction. However, no human clinical data currently support lifespan extension, and no large cardiovascular outcome trials (CVOTs) exist yet.
Exercise and Muscle
Unlike metformin, which can blunt muscle hypertrophy (per the MASTERS trial), emerging data suggest imeglimin may enhance muscle strength (~13% improvement in one cohort) without blocking exercise adaptations. It activates Akt signaling (which supports mTORC1/growth) rather than purely braking it through AMPK, and it enhances PGC-1α for mitochondrial biogenesis.
Practical Notes
- Dose: 1,000 mg twice daily (Japan-approved); dose reductions for CKD are off-label but used clinically.
- Availability: Not approved in the US/EU, but available from Indian generics (e.g., Zydus) at reasonable cost.
- Rapamycin interaction: Mechanistically, imeglimin’s AMPK/SIRT1 activation may actually rescue mitochondrial biogenesis that rapamycin’s mTORC1 blockade inhibits—potentially complementary rather than counteractive.
Bottom Line
Imeglimin is a promising “super-metformin” candidate for those who cannot tolerate metformin or want more targeted mitochondrial support, especially if they exercise regularly. The glycemic efficacy is slightly weaker than full-dose metformin, but the safety profile (no lactic acidosis signal, better GI tolerance, neutral on weight/heart failure/bone) and potential exercise compatibility make it attractive. That said, it remains speculative for longevity until human outcome trials are completed
Certainly a valid concern. However, it is super important to try to understand the MOA (mechanism of action) of any drug before making a decision about taking it. There are drugs that increase insulin output, such as sulfonylureas, meglitinides, glp-1ra etc. However, you have to ask about the MOA of any particular class of drugs. If the drugs force greater insulin output from beta cells leading to beta cell exhaution, that can be a long term negative. But what if your pancreas would release a “normal” amount of insulin in response to glucose levels, but it’s prevented by some kind of defect in some beta cell pathway, either production or release or whatever. Then, removing that defect simply restores insulin levels to “normal” - in that scenario increased insulin levels are not a negative.
That’s why it is so crucial to try to establish the MOA. But let us assume that imeglimin increases insulin production through repairing a defect along the beta cell pathway.
Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action
https://www.biorxiv.org/content/10.1101/2020.10.20.346841v1
Does that mean you should add imeglimin to your drug stack if you have elevated A1c? Not necessarily. Let us go back to a fundamental concept, frequently invoked by Ralph DeFronzo, that diabetes (and prediabetes is just along the spectrum of poor glucose control) is a multifactorial disease with many causes, as in the defect may be along any pathway of glucose control. If it so happens, that your poor glucose control is down to a specific defect in the beta cell pathway that imeglimin addresses, you are golden: go take this drug. But that may not be the case at all. For example, many prediabetics, or even people who are normoglycemic have very high insulin levels. Clearly their problem is not an inadequate production or release of insulin by the pancreas. In that scenario, trying to fix a non-existant defect in the pancreas with imeglimin as a way to normalize glucose metabolism might not yield the desired results. Addressing any disease starts with the correct diagnosis. You must establish - and the more precisely the better - where does the defect in glucose metabolism lie in your case. And once you’ve established that, you can try to address it with the appropriate drug.
Unfortunately, we face two problems. Problem one, is that we often are not sure where the problem lies, and problem two is that a given drug may have MOA that is not transparent to us, or has multiple pathways (a “dirty” drug, like metformin). Sure, you can say metformin/sglt2i/pio/glp-1ra “brings down A1c” - but if that’s all the study shows, you really can’t be sure that it will work for you or indeed that it is appropriate and not counterproductive.
Just as an example, I take myself. My A1c is consistently high (5.7-5.9). My morning fasting blood glucose is also high (~110mg/dL). However, my insulin levels are also high. It doesn’t seem like the problem for me is inadequate insulin release. For the amount of insulin I pump out, my glucose levels ought to be lower (HOMA-IR 1.7 in my case) as reflected by A1c. I therefore am going to hold off on imeglimin for the time being. It seems to me, the problem here is somewhere else - either insulin sensitivity or excessive hepatic neoglucogenesis. That would make pioglitazone more interesting to me (in my case). But the complication is of course that imeglimin also works along multiple pathways muddying the issue - is it worth hammering the pancreas with an unnecessary “fix” because the drug also suppresses hepatic neoglucogenesis? Maybe. Or maybe I’d prefer a more targeted intervention, a drug that addresses my defect and not anything else (maybe a luxury I don’t have!).
My point here is this: we often read that a given drug does something (lowers glucose, A1c, lipids, homocysteine whatnot) and we decide to spring for it, especially if we suffer from some issue (excessive glucose levels, lipid levels whatnot). But that may transpire to be a very unwise choice.
Instead you need to ask: given my problem (say, glucose control) - will drug X (say, imeglimin) help in my case? Unless you know, why take the drug? What is the MOA of that drug and what is your defect and etiology of your pathology, does that drug address it, or does it merely give you side effects without benefits or merely surface benefits which are disastrous longer term (insulin therapy for some T2DM cases). Perhaps imeglimin might work short term - but will it work for you long term, or be counterproductive?
And that’s why I’m interested in the MOA of this drug. And why it takes me a long time to research a drug before I even consider taking it. YMMV.
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Is there a trusted pharmacy that is typically used?
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See here:
- Buy Rapamycin Online - List of Reliable Pharmacies
- What Brands of Medications to buy: Generally Good Indian Pharma Companies
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Doing further research, I am wondering about drug interactions. For example, what if your version of poor glucose control does not result from any defect in beta cells GSIS, and since one way in which imeglimin works is that it “fixes” GSIS, you may surmise that imeglimin might not be for you. But what if you are also taking another drug, say, sirolimus, which longer term or with some protocols (daily dosing?) actually damages beta-cells GSIS? Now you might be adding this defect to your glucose control issues, and what if under those circumstances (i.e. you taking sirolimus) taking imeglimin might make sense, whereas without sirolimus it does not.
Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms
Quote:
“Overall, the majority of these studies demonstrate significant effects of rapamycin on glucose homeostasis, and the combined evidence strongly suggests that rapamycin adversely affects GSIS from β-cells.”
Of course, GSIS from beta-cells can be impacted through various mechanisms, so it remains to be shown whether imeglimin can “fix” the damage sirolimus does to beta-cells. Again we need to take a closer look at the MOA of both drugs to guess at any possible interaction, and then test it. The research continues.
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“suppresses hepatic neoglucogenesis” “fixes GSIS”
Aren’t these good things? GSIS declines with age.
(Gemini)
"Yes, Imeglimin suppresses hepatic gluconeogenesis (the production of new glucose by the liver). It is a core part of its “dual-benefit” mechanism of action, which targets the liver, skeletal muscle, and pancreatic beta cells.
Mechanism in the Liver
Imeglimin reduces excessive glucose production through several mitochondrial-dependent pathways:
Mitochondrial Rebalancing: It acts on the mitochondrial respiratory chain by partially and competitively inhibiting Complex I and restoring the activity of Complex III.
Energy Regulation: This rebalancing lowers the ATP/ADP ratio and increases mitochondrial redox potential in hepatocytes, which reduces the driving force for gluconeogenesis."
"Age-Related Decline in GSIS
In humans, beta cell function generally declines with age, estimated at a rate of approximately 1% per year. This decline is often independent of peripheral insulin resistance or body mass index.
Reduced Stimulated Secretion: Islets from younger donors (<40 years) typically exhibit significantly higher GSIS than those from older donors.
Elevated Basal Secretion: Aging is often associated with an increase in basal (fasting) insulin secretion, which may represent a compensatory state but also reduces the cell’s “dynamic range” when stimulated by high glucose.
Mechanisms of Dysfunction."
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