Goat's Rue or French Lilac (Galega
officinalis) is a flowering plant that has been used to treat diabetes
since the early 1900's.1,2 The active ingredient is known to be guanidine
and initially marketed under the trade name Synthalin.2,3,4,5 It was
guanidine from which the most widely used and cost-effective prescription
medication for the treatment of type 2 diabetes mellitus, metformin
(Glucophage), was derived.2
is well known that patients with type 2 diabetes mellitus (T2DM) are
characterized as having insulin resistance, a decrease in insulin mediated
glucose uptake by peripheral tissues and excessive basal rates of hepatic
gluconeogenesis.6 An impairment in peripheral glucose uptake and
suppression of gluconeogenesis both contribute to worsening postprandial
(post-meal) hyperglycemia, whereas excessive basal rates of hepatic
gluconeogenesis primarily contributes to the worsening of fasting glucose
levels. Since the guanidine found in Galega officinalis was
the precursor to metformin, guanidine may in part exert its glucose lowering
properties through an inhibition of the excessive basal rates of hepatic
gluconeogenesis.3,4,5,7 In addition, it is plausible, that guanidine
slows down this process by decreasing the ability of glucose 6-phosphate
generated from glycogen breakdown to be converted to glucose through an
inhibition of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase as
seen with its derivative, metformin.4,5,8,9
guanidine compounds have been associated with significant toxicities limiting
their further use in clinical practice. The reported toxicities include
kidney and liver damage, hypotension, ataxia, and seizures.3,4,5,10
Unfortunately the limited science on guanidine in the early 1900's and its
toxicity profile preventing its further use did not allow for a clear
determination of reasons for the toxicities. However, many of these
toxicities can also be seen with lactic acidosis.10 In fact, very early
studies indicated increases in lactic acid production with guanidine.5
Interestingly, the derivatives of guanidine (metformin and phenformin) have
been shown to inhibit complex I of the mitochondrial electron transport chain,
thereby causing a back up in the TCA cycle (Kreb's Cycle) that forces the
pyruvate generated from glycolysis to accumulate and thus be converted to
lactate (lactic acid). This preferential conversion of pyruvate to lactic
acid is done to oxidize NADH back to NAD+ so that glycolysis can continue to
generate at least 2 ATP to be used for energy. Unfortunately, phenformin
is more likely to do this compared to metformin and was the reason it was
withdrawn from the U.S. and European markets.
is likely that guanidine containing supplements are likely to increase the risk
for lactic acidosis, as well as other toxicities not adequately characterized
given drug class' history. Clinicians should discourage the use of
guanidine containing herbal medicinals for the above reasons. If however,
the patient does take them, it may be prudent to monitor blood glucose levels,
chemistries for the presence of an anion gap or changes in renal function,
liver enzymes, and signs/symptoms of lactic acidosis.
- Yeh GY, Eisenberg DM, Kaptchuk TJ et al. Systematic review of herbs
and dietary supplements for glycemic control in diabetes. Diabetes Care
- Dey L, Attele AS, Yuan CS. Alternative therapies for type 2 diabetes. Altern Med Rev 2002;7:45-58.
GS. An investigation of the toxicity and hypoglycemic effect of
several guanidine compounds. J Pharmacol Exp Ther 1935;51:17-24.
- Blatherwick NR, Sahyun M, Hill E. Some
effects of synthalin on metabolism. J Biol Chem 1927;75:671-82.
- Bodo R, Marks HP. The relation of synthalin to carbohydrate metabolism. J Physiol. 1928;65:83-99.
L, Colette C, Owens DR. Type 2 diabetes: a well-characterised but
suboptimally controlled disease. Can we bridge the divide? Diabetes
K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose
and lactate metabolism in noninsulin-dependent diabetes mellitus. J
Clin Endocrinol Metab 1996;81:4059-67.
G, Guignot L, Bordet JC et al. Intrahepatic mechanisms underlying the
effect of metformin in decreasing basal glucose production in rats fed a
high fat diet. Diabetes 2002;51:139-43.
RJ, Lamia KA, Vasquez D et al. The kinase LKB1 mediates glucose
homeostasis in liver and therapeutics effects of metformin. Science
- Kwong SC, Brubacher J. Phenformin and lactic acidosis: a case report and review. J Emerg Med 1998;16:881-6.
A, Nugent K, Kalakunja A et al. Severe acidosis in a patient with type
2 diabetes mellitus, hypertension and renal failure. CHEST
D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-treated
diabetics: a review of 330 cases. Diabetologia 1978;14:75-87.