8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models.
The clinical use of the natural alkaloid berberine (BBR) as an antidiabetic reagent is limited by its poor bioavailability. Our previous work demonstrated that dihydroberberine (dhBBR) has enhanced bioavailability and in vivo efficacy compared with berberine. Here we synthesized the 8,8-dimethyldihydroberberine (Di-Me) with improved stability, and bioavailability over dhBBR. Similar to BBR and dhBBR, Di-Me inhibited mitochondria respiration, increased AMP:ATP ratio, activated AMPK and stimulated glucose uptake in L6 myotubes. In diet-induced obese (DIO) mice, Di-Me counteracted the increased adiposity, tissue triglyceride accumulation and insulin resistance, and improved glucose tolerance at a dosage of 15mg/kg. Administered to db/db mice with a dosage of 50mg/kg, Di-Me effectively reduced random fed and fasting blood glucose, improved glucose tolerance, alleviated insulin resistance and reduced plasma triglycerides, with better efficacy than dhBBR at the same dosage. Our work highlights the importance of dihydroberberine analogs as potential therapeutic reagents for type 2 diabetes treatment.
Cheng
Zhe
Z
National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, PR China.
Chen
An-Feng
AF
Wu
Fang
F
Sheng
Li
L
Zhang
Han-Kun
HK
Gu
Min
M
Li
Yuan-Yuan
YY
Zhang
Li-Na
LN
Hu
Li-Hong
LH
Li
Jing-Ya
JY
Li
Jia
J
D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D007004:Hypoglycemic Agents; D001599:Berberine; C039639:dihydroberberine; D005947:Glucose