AMPK & Glycemic Agents (Metformin, Berberine, Acarbose) — References

Mirrored Reference Dossier

Parent Topic: AMPK & Glycemic Agents (Metformin, Berberine, Acarbose) | References Hub: 02 - Compounds & Molecules References MOC

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Landmark Peer-Reviewed Studies

1. Harrison et al. (2014) — Aging Cell (NIA Interventions Testing Program)

• Citation: Harrison, D. E., Strong, R., Allison, D. B., Ames, B. N., Astle, C. M., Atamna, H., Fernandez, E., Flurkey, K., Javors, M. A., Nadon, N. L., Nelson, J. F., Pletcher, S., Simpkins, J. W., Smith, D., Wilkinson, J. E., & Miller, R. A. (2014). Acarbose, 17-$\alpha$-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell, 13(2), 273–282.
• Identifiers: PMID: 24245565 (PubMed · Europe PMC) | PMCID: PMC3954939 (PMC Full Text) | DOI: 10.1111/acel.12170 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Three-center randomized longevity trial in genetically heterogeneous UM-HET3 mice ($N=1,752$) fed Acarbose ($1,000\text{ ppm}$) starting at 4 months of age.
• Key Quantitative Outcomes: Acarbose increased median lifespan by $+22\%$ in males ($p<0.0001$) and $+5\%$ in females ($p=0.01$), and increased 90th-percentile maximal lifespan by $+11\%$ in males and $+9\%$ in females ($p<0.001$). Acarbose significantly blunted postprandial glucose excursions without lowering HbA1c excessively and increased circulating FGF21 while reducing IGF-1.

2. Konopka et al. (2019) — Aging Cell

• Citation: Konopka, A. R., Laurin, J. L., Schoenberg, H. M., Reid, J. J., Castor, W. M., Wolff, C. A., Musci, R. V., Safairad, O. D., Linden, M. A., Biela, L. M., Hamilton, K. L., & Miller, B. F. (2019). Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell, 18(1), e12880.
• Identifiers: PMID: 30548390 (PubMed · Europe PMC) | PMCID: PMC6351883 (PMC Full Text) | DOI: 10.1111/acel.12880 (DOI · SciDB · Scholar)
• Study Design & Sample Size: 12-week randomized, double-blind, placebo-controlled trial in older adults (mean age $62\text{ years}$, $N=53$) undergoing supervised high-intensity aerobic exercise training ($45\text{ min}$ at $85\%{\text{ HR}}_{\max }$, $3\times /\text{week}$) combined with $1,500\text{–}2,000\text{ mg/day}$ Metformin vs. placebo, including vastus lateralis muscle biopsies and hyperinsulinemic-euglycemic clamps.
• Key Quantitative Outcomes: While exercise + placebo increased cardiorespiratory fitness (${\text{VO}}_2\max$) by $+20\%$, Metformin attenuated the ${\text{VO}}_2\max$ gain by nearly $-50\%$ ($p<0.05$), completely abolished the exercise-induced $+25\%$ increase in skeletal muscle Complex I-linked mitochondrial respiration ($p<0.05$), and blunted the exercise-induced improvement in whole-body insulin sensitivity on clamps.

3. Yin et al. (2008) — Metabolism

• Citation: Yin, J., Xing, H., & Ye, J. (2008). Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, 57(5), 712–717.
• Identifiers: PMID: 18442638 (PubMed · Europe PMC) | PMCID: PMC2410097 (PMC Full Text) | DOI: 10.1016/j.metabol.2008.01.013 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Two-part 13-week randomized clinical trial ($N=84$) comparing Berberine HCl ($500\text{ mg}$ three times daily) head-to-head against Metformin ($500\text{ mg}$ three times daily) in newly diagnosed Type 2 Diabetes Mellitus, plus add-on efficacy in poorly controlled patients.
• Key Quantitative Outcomes: Berberine demonstrated equipotent glycemic control to Metformin: reducing HbA1c from $9.5\%$ to $7.5\%$ ($-2.0\%,p<0.01$), fasting blood glucose from $10.6$ to $6.9\text{ mmol/L}$ ($-3.8\text{ mmol/L},p<0.01$), postprandial blood glucose from $19.8$ to $11.1\text{ mmol/L}$ ($-8.8\text{ mmol/L},p<0.01$), and HOMA-IR by $-44.7\%$ ($p<0.001$). Unlike Metformin, Berberine also significantly lowered total cholesterol by $-18\%$ ($p<0.001$) and LDL-C by $-21\%$ ($p<0.001$).

4. Bannister et al. (2014) — Diabetes, Obesity and Metabolism

• Citation: Bannister, C. A., Holden, S. E., Jenkins-Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., Mukherjee, J., & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity and Metabolism, 16(11), 1165–1173.
• Identifiers: PMID: 25041462 (PubMed · Europe PMC) | DOI: 10.1111/dom.12354 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Retrospective observational cohort study utilizing the UK Clinical Practice Research Datalink ($N=180,284$), comparing 78,241 T2D patients initiated on metformin monotherapy, 12,222 on sulfonylureas, and 90,463 matched non-diabetic controls.
• Key Quantitative Outcomes: Patients with Type 2 Diabetes treated with metformin monotherapy exhibited a $15\%$ higher adjusted survival rate (Survival Ratio $=1.15,95\%\text{ CI }1.09\text{–}1.22,p<0.001$) than matched non-diabetic control subjects without diabetes, whereas sulfonylurea-treated patients had a $38\%$ lower survival rate than controls—catalyzing the TAME (Targeting Aging with Metformin) clinical trial design.