Type 2 diabetes mellitus (T2DM) is a chronic condition characterized by insulin resistance and an inability to properly regulate blood sugar levels. The two most important risk factors for T2DM are a family history of diabetes and obesity, though age, race, diet, and exercise level also impact risk. Common symptoms include frequent urination, nerve damage, and dark skin patches. Treatment involves lifestyle changes like diet and exercise as well as medications like metformin, which improves insulin sensitivity and decreases glucose production in the liver. Patients are counseled on managing diabetes-related risks and provided support through organizations and groups.

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T2DM is an asymptomatic disease. It usually
worsens over the years.
Symptoms include but are not limited to:
• Polyuria: When the kidneys are unable to
keep up with the high glucose levels
leading to frequent urination.
• Diabetic neuropathy: Nerve damage that
results in tingling or numbness of the
hands, fingers, feet and toes.
• Acanthosis nigricans: Dark discoloration in
the folds of the skin usually found in the
armpits, neck, and groin.
Treatment:. Metformin is usually the first medication of choice that is prescribed for patients with
T2DM. It improves the body’s sensitivity to insulin and decreases hepatic glucose production. Other
treatment options include: exercise, dietary management, bariatric surgery, and vaccination.
Counseling: Patients should be provided with information about the increased risk of morbidity and
premature death associated with T2DM. Some other counselling points for T2DM related diseases
include:
• Stroke: Patients should be advised that aggressive glycemic control can improve clinical results,
especially, with respect to the cardiovascular system.
• Blindness: T2DM patients are advised to have a yearly IOP check-up by an
optometrist/ophthalmologist. Early detection of glaucoma and treatment with eye drops can keep
the IOP levels within an acceptable range and help avoid further damage to the optic nerve.
• Depression: Motivating and encouraging a T2DM patient to take control of their diabetes can help
reduce the level of depression experienced by the patient.
Support: The American Diabetes Association and The National Kidney Foundation(NKF) provide support.
Seeing a specialist and joining a diabetes support group is also recommended.
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[cited 2016 Feb 1]. Available from: http://www.healthline.com/health-
slideshow/history-type-2-diabetes#1
2. Graham G, Punt J, Arora M, Day R, Doogue M, Duong J, et al. Clinical
pharmacokinetics of Metformin. Clin pharmacokinet. 2011; 50 (2): 81-98
3. James G Boyle, Miles Fisher, Gerard A McKay. Drugs for Diabetes: Part 1
Metformin. Br J Cardiol. 2010;17(5):231-234.
4. World Health Organization. Screening for type 2 diabetes [Internet]. 2003
[cited 2016 Feb 10]. Available from:
http://www.who.int/diabetes/publications/en/screening_mnc03.pdf
The two most important risk factors of type 2
diabetes mellitus are: a positive family history
and obesity.
Other risk factors include but are not limited
to: age (45 years and older), race, poor diet
and exercise, etc.
Chigozirim Amaechi, Odochi Daniel, Samuel Kwarteng, Adelaida Mrombo, Larique Wallace-Dessejour
Type II Diabetes Mellitus (T2DM)
Type II diabetes mellitus is a chronic condition that affects the way the body processes blood sugar
(glucose). Persons diagnosed with type II diabetes mellitus are unable to use insulin properly; a
phenomenon called insulin resistance. T2DM dates back to ancient times in Egyptian manuscripts
around 1500 BCE. Ancient Indians around 600 BCE called it sweet urine disease.
Edward Albert Sharpey-Shafer concluded that the pancreas of a diabetic patient was unable to
produce what he termed “insulin”. In 1921, two Canadian research scientists extracted insulin from
dogs and then injected it into diabetic dogs to improve their condition. Insulin treatment became
successful in treating diabetes but did not work in all patients.
Metformin is one of oldest treatments used to reduce high blood sugar in people with
T2DM and is considered to be the first-line medication for the treatment of T2DM.
Brand names: Glucophage, Glucophage XR, Fortamet, Riomet
Available dosage forms: 500, 850, and 1000 mg.
Recommended course: Start with a 500 mg dose with a weekly increment of 14g/week
until the maximum tolerated dose is achieved.
● It should be taken with food, to reduce the potential for GI side effects.
● The main side effect of concern is lactic acidosis.
● Modest weight loss may be seen as a result of drug-induced anorexia.
Metformin decreases plasma VLDL triglycerides. This causes a modest decrease in plasma
triglycerides and total cholesterol. Patients using metformin show significant improvement
in their hemoglobin A1c, which may lead to improvements in their lipid profile.
Mechanism of Action: Metformin is an antihyperglycemic agent that improves glucose
tolerance. It lowers the basal and postprandial plasma glucose using mechanisms different
from other classes of oral antidiabetic agents:
• It acts by countering insulin resistance, mainly in the liver and skeletal muscle
• It suppresses the production of glucose in the liver
• In tissues sensitive to insulin, metformin increases peripheral insulin sensitivity
• It enhances peripheral glucose utilization
• It causes a 10-20% decrease in fatty-acid oxidation and a slight increase in glucose
oxidation
• Hypoglycemia is not typically seen with metformin use
Chemical Structure: C4H11N5
Half-life: 6.2 hours (plasma) and 17.6
hours (blood) Excretion: urine (90%)
Metabolism: none; CYP450: none
T2DM is a multifactorial disorder. The chances of
reappearance for the immediate relative of a person with
T2DM is higher than for an individual suffering from type 1
diabetes. With identical twins, the probability of the other
twin suffering from T2DM if the first one has it ranges from
60-90%.
• A gene has been characterized that codes for a transcription
factor involved in secreting insulin, called TCF7L2 and a
modification of this gene has been linked with a 50%
increased likelihood of getting T2DM.
• PPAR-y, is an allele that codes for the receptor involved in
glucose metabolism. They are targeted by drugs known as
thiazolidinediones, which are utilized to increase an
individual’s sensitivity to insulin.
• Other alleles adding increased risks include: PPARG, which is
found in more than 75% of individuals of European descent,
and KCNJ11.
Screening tests for T2DM include questionnaires checking
for potential risk, lab testing, and combinations of both. It is
diagnosed using lab tests which should be considered in all
people 45 years of age and above. However, if you have
other risk factors, then you should consider getting tested at
a younger age.
Testing for T2DM can be done through blood tests and
urine tests.
Blood tests include fasting blood glucose and casual blood
glucose tests. Urine tests include checking urine ketone and
urine glucose levels.
●The peak plasma concentration of metformin ranges from
1.0 to 1.6mg/L after a 0.5g dose is 3 hours.
●Absorption occurs mainly in the small intestine and it stops
about 6-10 hours after administration.
●To minimize gastrointestinal side effects such as bloating,
flatus and diarrhea, metformin should be taken with food.
Transporters, Absorption and Distribution
●Plasma membrane monoamine transporter (PMAT) is the
main transporter involved in metformin uptake in the
gastrointestinal tract.
●The OCT1 (SLC22A1 gene) and OCT3 (SLC22A3 gene)
transporters are localized on the basolateral side of
hepatocytes. About 50% of the drug is absorbed.
●Multidrug and toxin extrusion transporter (MATE) -1 is
located in the bile and it facilitates metformin transport into
bile canaliculus.
Clearance/Elimination
The main mode of elimination is through renal clearance
(CLR) where there is excretion of unchanged drug in urine.
Genetic polymorphisms in organic transporters
The noncoding polymorphism rs2289669G>A in SLC47A1 has
been linked to an enhanced glucose-lowering effect of
metformin. Patients with genotype AA have been found to
have better response to metformin as compared to patients
with genotype AG or GG. Homozygous genetic variants of
SLC22A1 and SLC22A3 have been seen to have high plasma
concentration of the drug and reduced absorption.
Edward Albert Sharpey-Shafer
Background
Treatment, Counseling and Support
Pharmacology of Metformin
Symptoms
Risk Factors
Inheritance
Screening and Diagnostic Testing
Pharmacogenomics of Metformin
References