Serotonin is to blame! Excessive release of 5HT(serotonin) from
intestinal mucosa cells can cause diarrhea and nausea. Metformin
stimulates these intestinal cells to produce increased levels of 5HT,
as soon as 10-15 minutes after taking metformin. The good news is that
most symptoms dissapear after taking metformin for 2-3 weeks.
?Our results indicate that metformin induces 5-HT3
receptor-independent release of 5-HT from human duodenal mucosa via
neuronal and non-neuronal mechanisms. Part of the gastrointestinal
side effects observed during treatment with metformin could, thus, be
produced by the release of 5-HT and other neurotransmitter substances
within the duodenal mucosa.?
?Visceral hypersensitivity implies increased nerve cell signals
traveling from the intestines up to the brain (afferent signals), and
increased signals going in the opposite direction (efferent signals).
These signals are transmitted with the aid of a chemical called
serotonin, or 5HT (short for 5-hydroxytryptamine).?
GLP-1 also stimulates production of insulin and prevents glucose from
being absorbed in the intestine. Too much glucose in the intestines
causes a form of osmotic diarrhea ? electrolytes become unbalanced,
from the unabsorbed glucose and the osmolarity of the stool is
changed, causing watery stools and diarrhea.
Scientifically put: ?GLP-1 is an incretin released from L cells in the
intestine after oral ingestion of nutrients. This incretin has
multiple actions, including stimulation of inhibition of glucagon
secretion, increase of glycogen synthase activity, and slowing of
gastric emptying, in addition to promotion of satiety and inhibition
of food intake (Drucker, 2001 , 2002 ). Mannucci et al. (2001 )
proposed that the reduced food intake and body weight gain in subjects
treated with metformin might be related to GLP-1 increase.
GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV or CD26,
EC 18.104.22.168 [EC] ), resulting in a circulating half-life of only 1 to
2 min. Thus, inhibition of DPPIV activity could be a useful strategy
to enhance the activity of GLP-1. Many studies have confirmed the
utility of DPPIV inhibitors not only in the treatment of diabetes with
obesity in animal models (Pederson et al., 1998 ; Balkan et al., 1999
; Pospisilik et al., 2002 ; Reimer et al., 2002 ; Sudre et al., 2002
), but also in humans (Ahrén et al., 2002 ). These data suggest that
DPPIV inhibitors would be of value in the treatment of obesity and
?Metformin quite frequently (5 to 20%) causes gastrointestinal
problems such as nausea, stomach pain, bloating, diarrhea and
malabsorption of vitamin B12 and folic acid. These side effects
usually go away soon after the metformin is started and occur less
often if metformin is taken with food. Another possible problem with
metformin is a rare but serious condition called lactic acidosis, when
your tissues do not get enough oxygen to survive. To avoid this
problem, metformin should not be given to people with kidney or liver
disease, severe heart failure, or a history of alcohol abuse.?
?Metformin is a biguanide derivative, which resembles 5-HT3-receptor
agonists in its structure. Activation of 5-HT3 receptors is known to
induce nausea, vomiting, and diarrhea.?
?However, its mechanism of action is not fully understood at the
molecular level. Recently, it was indicated that metformin increases
plasma active glucagon-like peptide-1 (GLP-1) in obese nondiabetic
subjects (Mannucci et al., 2001 )?
Metformin (Glucophage) is the only available member of the biguanide
class. Metformin decreases hepatic (liver) glucose production,
decreases intestinal absorption of glucose and increases peripheral
glucose uptake and use.
?Gastrointestinal adverse effects such as abdominal pain, nausea,
dyspepsia, anorexia, and diarrhea are common and widely accepted when
occurring at the start of metformin therapy. Diarrhea occurring long
after the dosage titration period is much less well recognized.?
?The most common side effect of Metformin HCl immediate-release is
diarrhea. In a clinical trial of 286 subjects, 53.2% of the 141 who
were given Metformin IR (as opposed to placebo) reported diarrhea, and
25.5% reported nausea/vomiting. (source: Drug Facts & Comparisons
?Metformin HCl is generally well tolerated, but can cause minor
transient gastrointestinal upsets. These can generally be avoided by
taking metformin with meals or, occasionally, by temporarily lowering
Approximately 3% of patients may have to discontinue treatment because
of this complication. In the majority of patients who show signs of
intolerance, gastrointestinal upsets disappear by the time the
diabetes is controlled and do not return. It is, therefore, important
not to discontinue therapy at the first signs of intolerance to
?METFORMIN ? Metformin has been used in Europe for over thirty years,
and has been available in the United States since March 1995. It is
effective only in the presence of insulin but, in contrast to
sulfonylureas, it does not directly stimulate insulin secretion. Its
major effect is to increase insulin action.
How metformin increases insulin action is not known but it is known to
affect many tissues. One important effect appears to be suppression of
glucose output from the liver.
Clinical use ? Metformin is most often used in patients with type 2
diabetes who are obese, because it promotes modest weight reduction or
at least weight stabilization. This is in contrast to the increased
appetite and weight gain often induced by insulin and sulfonylureas.
Metformin typically lowers fasting blood glucose concentrations by
approximately 20 percent, a response similar to that achieved with a
Metformin given in combination with a sulfonylurea lowers blood
glucose concentrations more than either drug alone.
In addition to causing modest weight loss, metformin has two other
advantages as compared with sulfonylureas. They are:
· It is less likely to cause hypoglycemia.
· It has prominent lipid-lowering activity, producing a significant
reduction in serum triglyceride and free fatty acid concentrations, a
small reduction in serum low-density lipoprotein (LDL) cholesterol
concentration, and an elevation in serum high-density lipoprotein
(HDL) cholesterol concentration.
There are, however, two disadvantages to metformin: the risk for
lactic acidosis described below and its prominent gastrointestinal
?Metformin interferes with several processes linked to HGP
(gluconeogenesis, glycogenolysis and their regulatory mechanisms),
lowering glucose production and resensitizing the liver to insulin.
The hepatic drug effect is largely favoured by prevailing glycemia. In
peripheral tissues, metformin potentiates the effects of both
hyperglycemia and hyperinsulinemia. Increase in glucose-mediated
glucose transport is mainly mediated by an improvement in the glucose
transporter's intrinsic activity. Potentiation of the hormone effect
relates to an increase in insulin receptor tyrosine kinase activity.?
?Metformin decreases hepatic glucose production, decreases intestinal
absorption of glucose, and improves insulin sen-sitivity by increasing
peripheral glucose uptake and utilization.?
?Food decreases the extent of and slightly delays the absorption of
metformin, as shown by approximately a 40% lower mean peak plasma
concentration (C max ), a 25% lower area under the plasma
concentration versus time curve (AUC), and a 35 minute prolongation of
time to peak plasma concentration (T max ) following adminis-tration
of a single 850-mg tablet of metformin with food, compared to the same
tablet strength administered fasting.?
?Once a patient is stabilized on any dose level of metformin, gastrointestinal
symptoms, which are common during initiation of therapy, are unlikely to be drug
related. Later occurrence of gastrointestinal symptoms could be due to
lactic acidosis or other serious disease.?
There is a newer form of metformin recently approved by the FDA.
Glumetza, is an extended-release form of metformin, available in
500-milligram and 1,000 tablets, and is intended not to cause
?Glumetza's extended-release system (a special coating that causes the
drug to be absorbed slowly) is designed to deliver high doses without
raising the risk of gastrointestinal side effects.?
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Mechanism metformin + gastrointestinal side effects
Metformin + cause + diarrhea
5HT + diarrhea
physiology + metformin
pharmacology + metformin