Glycation & AGEs Inhibition (Carnosine, Benfotiamine) — References

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• Parent Topic: Glycation & AGEs Inhibition (Carnosine, Benfotiamine)
• Reference Hub: 04 - Longevity & Environment References MOC

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Primary Literature Dossier

1. Stirban et al. (2006) — Benfotiamine Prevents Dietary AGE-Induced Endothelial Dysfunction and Methylglyoxal Surges in Humans

• Citation: Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Götting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 2006 Sep;29(9):2064-2071.
• Identifiers: PMID: 16936154 (PubMed · Europe PMC) | DOI: 10.2337/dc06-0531 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, crossover human clinical intervention ($n=13$ patients with type 2 diabetes challenged with a heat-processed high-AGE test meal before and after 3 days of oral Benfotiamine $1,050\text{ mg/day}$).
• Key Quantitative Outcomes:
  • Without benfotiamine, the high-AGE meal caused a 60% drop in brachial artery Flow-Mediated Dilation (FMD) and a 35% drop in reactive hyperemia microvascular blood flow.
  • Three days of benfotiamine completely abolished both macro- and microvascular endothelial dysfunction ($p<0.001$) and blunted the postprandial surge in serum methylglyoxal ($\text{MGO}$, $-55\%$), $N^{ϵ}$-(carboxymethyl)lysine ($\text{CML}$, $-42\%$), and TBARS oxidative stress.

2. Hammes et al. (2003) — Benfotiamine Blocks Three Major Pathways of Hyperglycemic Damage via Transketolase Activation

• Citation: Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglcemic damage and prevents experimental diabetic retinopathy. Nature Medicine. 2003 Mar;9(3):294-299.
• Identifiers: PMID: 12592403 (PubMed · Europe PMC) | DOI: 10.1038/nm834 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Preclinical mechanistic and vascular pathology investigation in endothelial cells and diabetic retinas.
• Key Quantitative Outcomes:
  • Demonstrated that lipid-soluble benfotiamine activates transketolase ($\text{TKT}$) activity by 250–300%, converting excess glycolytic glyceraldehyde-3-phosphate ($\text{GA3P}$) and fructose-6-phosphate into pentose-5-phosphates.
  • Simultaneously normalized intracellular AGE formation ($-78\%$), hexosamine pathway activity, diacylglycerol-PKC activation, and $\text{NF-}\kappa \text{B}$ activation, completely preventing acellular capillary formation in the retina.

3. de Courten et al. (2016) — L-Carnosine Supplementation Improves Glucose Metabolism and Carbonyl Scavenging in Overweight Humans

• Citation: de Courten B, Jakubova M, de Courten MP, Kukurova IJ, Vallova S, Krumpolec P, Valkovic L, Pavlikova T, Sedivy P, Chmelik M, Ukropec J, Aldini G, Ukropcova B. Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial. Obesity (Silver Spring). 2016 May;24(5):1027-1034.
• Identifiers: PMID: 27040154 (PubMed · Europe PMC) | DOI: 10.1002/oby.21434 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled trial ($n=30$ overweight/obese non-diabetic adults; $2\text{ g/day}$ oral L-Carnosine [$1\text{ g}$ BID] vs. placebo for 12 weeks).
• Key Quantitative Outcomes:
  • Oral L-Carnosine significantly attenuated the rise in fasting insulin, $\text{HOMA-IR}$ ($p=0.04$), and 2-hour post-OGTT glucose ($-1.3\text{ mmol/L}$, $p=0.02$) and insulin ($p=0.01$) compared to placebo.
  • Companion LC-MS/MS urinary profiling confirmed a significant increase in urinary carnosine-propanal and carnosine-acrolein adducts, proving in vivo scavenging of reactive carbonyls and lipid-peroxidation products in humans.

4. Gibson et al. (2020) — Phase IIa Clinical Trial of Benfotiamine in Cognitive Decline and Serum AGE Reduction

• Citation: Gibson GE, Luchsinger JA, Cirio R, Chen H, Franchino-Elder J, Hirsch JA, Bettendorff L, Chen Z, Flowers SA, Gerber LM, Grandville T, Schupf N, Xu H, Stern Y, Habeck C,brickman AM, Feldman HH. Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. Journal of Alzheimer’s Disease. 2020;78(3):989-1010.
• Identifiers: PMID: 33074237 (PubMed · Europe PMC) | DOI: 10.3233/JAD-200896 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled 12-month Phase IIa clinical trial ($n=70$ patients with amnestic mild cognitive impairment or mild Alzheimer’s disease; $600\text{ mg/day}$ Benfotiamine [$300\text{ mg}$ BID] vs. placebo).
• Key Quantitative Outcomes:
  • Benfotiamine elevated whole-blood thiamine and thiamine diphosphate ($\text{TDP}$) by $>160\text{-fold}$ ($p<0.0001$), slowed cognitive decline on the ADAS-Cog by 43% ($p=0.125$), slowed Clinical Dementia Rating (CDR) worsening by 77% ($p=0.034$ in $\text{APOE }\epsilon 4$ non-carriers), and significantly suppressed the 12-month rise in serum Advanced Glycation End-products (AGEs) ($p=0.044$).