The Insulin Connection & How to Treat It
What is the connection between insulin resistance and PCOS?
At least 30 percent of women with PCOS are insulin resistant, although some investigators
claim a much stronger association exists. Hyperinsulinemia produces hyperandrogenism by
stimulating ovarian androgen production and by reducing serum sex-hormone binding globulin
(SHBG). This can heighten PCOS symptoms. Reducing insulin resistance through the use of
insulin-sensitizing medications can restore ovulatory function in many women with PCOS. It
appears that even some patients who do not test as being insulin resistant may benefit
from these medications.
How are insulin resistance and diabetes diagnosed?
Insulin resistance should be diagnosed by measuring insulin levels fasting levels alone,
or with a glucose tolerance test plus insulin (sometimes called an IGTT). Diabetes may be
diagnosed based on blood glucose levels alone.
What is the glucose tolerance test (GTT) and what are normal values?
An oral glucose tolerance test is done to check the body's ability to process sugar. The test
begins with blood being drawn in the morning after fasting overnight (usually more than 8
hours, but less than 16). The patient then drinks a bottle of "glucola" a special drink
prepared with 75 grams of glucose (sugar). There is some variation in how many blood draws are
made. Some will only check the 2-hour level, though most commonly blood draws are made at 1
hour, 2 hours, and 3 hours. Some labs will also draw at 30 minutes, and/or at 4 hours. Normal
values are:
Glucose Tolerance Test Glucose and Insulin Values
Time Normal Glucose Values Normal Insulin Values What the Results Mean
Fasting < 126 mg/dl < 10 mIU/ml Normal glucose results are 70-90, 111 or over is impaired, 126
or over is diabetic. Insulin levels above 10 show insulin resistance.
½ hour < 200 mg/dl 40-70 mIU/ml A truly normal glucose response will not exceed 150.
1 hour < 200 mg/dl 50-90 mIU/ml Some want to lower the threshold on glucose to < 180 to identify
early stages of diabetes. Insulin > 80 shows insulin resistance, or a level 5 times that of the
fasting level (i.e., a fasting of 11 followed by a 1 hour > 55)
2 hours < 140 mg/dl 6-50 mIU/ml A truly normal glucose response is 110 or lower.
Insulin > 60 is IR.
3 hours < 120 mg/dl
4 hours < 120 mg/dl
To get a reliable result, a patient should be in good health (not even a cold), and fasting
level should be done without taking anything but water by mouth no smoking, no medications,
no coffee, no gum, no toothpaste, etc. for 8-16 hours before the test.
Will following a low-carbohydrate diet affect the results of a fasting insulin test?
Because following a low-carbohydrate diet may lower fasting insulin test results, it is usually
recommended that one adhere to a diet that is not carbohydrate restricted for two to three days
prior to testing in order to ensure accuracy. Some doctors and labs have specific diet
requirements, so patients should request specific instructions if none are given.
What is a glycohemoglobin/glycosylated hemoglobin (HbA1c) test and what do the results mean?
This test is done to monitor a person's average blood glucose level over the past 3 months or
so. Unlike fasting and postprandial (after meal) tests that only give a value for a slice of
time, this test gives an average over time. It is not usually used to diagnose impaired glucose
tolerance or diabetes, but rather to assess glucose control. Glucose attaches itself to
hemoglobin, the protein in red blood cells that carries oxygen. Since blood cells remain in
circulation for 2-3 months, the HbA1c level is a good measure of average glucose level during
this time period.
A healthy level is less than 6 percent. When a level gets above 6 percent, it indicates some
high blood sugar levels. Higher levels may indicate risk for organ and nerve damage. In someone
who is trying to get pregnant, it is important to have blood sugar under control as elevated
levels increase the risk of serious birth defects.
Can lean women be insulin resistant or type II diabetic?
While insulin resistance is frequently accompanied by excess weight, there are thin women who
are insulin resistant or type II diabetic. Unfortunately, lean women may not have as much
success reducing insulin resistance through lifestyle changes as their overweight counterparts,
but diet modifications and increased exercise often provide some benefit.
How do insulin-sensitizing medications work?
Metformin/Glucophage works primarily by suppressing hepatic glucose production, increasing
glucose utilization in peripheral tissues. It may also reduce intestinal glucose absorption.
Since it does not stimulate production of insulin, it does not cause hypoglycemia if used alone
(though hypoglycemia may result if used with insulin, a sulfonylurea, or with consumption of
an excessive amount of alcohol). Metformin is metabolized by the kidneys.
The thiazolidinediones (glitazones or TZDs) troglitazone (Rezulin, which was taken off the
market on March 21, 2000), rosiglitazone maleate (Avandia) and pioglitazone hydrochloride (Actos)
work primarily by improving sensitivity to insulin in muscle and adipose (fat) tissue and also
by inhibiting hepatic glucose production. They are metabolized by the liver and excreted into
the bile.
If hypoglycemia is experienced on either type of medication, it is most likely due to
insufficient caloric intake, rather than a direct result of the medication. These medications
may also help improve cholesterol and triglycerides levels, and may restore ovulation in
premenopausal women with PCOS or diabetes.
What are the side effects of insulin-sensitizing medications?
Metformin hydrochloride (Glucophage) Gastrointestinal problems such as diarrhea, nausea,
vomiting, abdominal bloating, flatulence, and anorexia are the most common reactions. Usually
the side effects are dose dependant and diminish over time. Starting with a low dose and building
up to the desired maintenance level may help. The biggest risk, though very rare (1 in 33,000),
of metformin is the possibility of lactic acidosis (a buildup of lactic acid in the blood).
Symptoms of lactic acidosis include feeling weak, muscle aches, trouble breathing, lightheaded
or dizziness, or suddenly developing slow or irregular heartbeat.
Rosiglitazone maleate (Avandia) The most commonly reported side effects include upper
respiratory tract infection, injury, and headache. Use of this medication may contribute to
weight gain. Because Avandia is in the same class of medications as Rezulin, it may reduce
effectiveness of oral contraceptives. (Clinical trials indicated that administration of Rezulin
and birth control pills containing ethinyl estradiol and norethindrone may lower the plasma
concentrations of both hormones by approximately 30 percent, which could result in loss of
contraception. Therefore, a higher dose of oral contraceptive or an alternative method should be
considered if pregnancy is not desired.) Avandia is generally considered safer than Rezulin and
less likely to cause liver damage, but it also has not been on the market as long. Liver testing
is recommended ever two months the first year of use, and quarterly thereafter.
Pioglitazone hydrochloride (Actos) The most commonly reported side effects include upper
respiratory tract infection, headache, sinus infection, muscle soreness, tooth disorder, and
sore throat. It may cause mild to moderate swelling (edema) and decrease in blood count (anemia)
in some patients. The prescribing information indicates that the effect of Actos on oral
contraceptives has not been studied, but because of its relation to Rezulin it is recommended
that patients not wishing to become pregnant exercise additional caution regarding contraception.
Like Avandia, Actos is generally considered safer than Rezulin as far as liver toxicity is
concerned, but it is also newer on the market and not used by as many people. Liver testing is
recommended ever two months the first year of use, and quarterly thereafter.
What testing should be done before prescribing insulin-sensitizing medications?
A comprehensive biochemical panel that includes liver enzymes and alanine transaminase (ALT)
should be performed before metformin or one of the thiazolidinediones (Avandia, Actos) are taken.
If there are liver or kidney abnormalities, caution should be used and the benefits weighed
before choosing to use these medications.
What is the maximum dosage of metformin?
The maximum recommended dose of metformin is 2550 mg per day (3 x 850 mg pills). The usual dose
in diabetics is 1000 mg twice daily. Studies with metformin for patients with PCOS usually use
500 mg three times a day or 850 mg twice daily.
What kind of monitoring should be done while on insulin-sensitizing medications, and how often?
Fasting blood sugar, insulin and HbA1c measurements should be performed periodically to monitor
glycemic control and the therapeutic response to medication.
With metformin, it is recommended that kidney function tests be repeated periodically.
For those using Avandia or Actos, ALT levels should be checked every two months for the first
year of therapy, and quarterly thereafter.
Liver function tests should also be obtained if one has symptoms suggestive of hepatic
dysfunction, such as jaundice (yellowing of skin and whites of eyes), nausea, vomiting, abdominal
pain, fatigue, anorexia, or dark urine.
Can metformin be used along with one of the glitazones?
Because metformin and glitazones work in different ways to improve insulin utilization, they may
have a synergistic effect when used together. Treatment with more than one medication often
increases side effects, costs, and necessary monitoring, so should only be considered after use
of a single medication fails to get the desired result (lowering of insulin and androgen levels,
and restoration of cycles).
How do doctors decide which medications, or which combination of medications to use?
For the treatment of PCOS, especially among women trying to conceive, most doctors would start
with the older and safer metformin therapy and only switch to or add one of the glitazones if
metformin alone is not working, or if the side effects are intolerable. In patients with kidney
problems, one of the glitazones may be the first course of treatment. Other considerations
include the fact that the safety of Rezulin is currently being questioned in the U.S., and ACTOS
and Avandia are Pregnancy Category C medications that should be stopped when pregnancy is
achieved.
How long do the nausea and diarrhea last after starting metformin?
Usually symptoms lessen over time and go away with long-term use (usually after 3-4 weeks at the
same dose). If diarrhea and nausea continue, one should make sure to take the medication in the
middle of a meal. Also consider diet the uncomfortable side effects may be prolonged by a diet
that is high in carbohydrates and/or high in fat. Reducing both may lessen symptoms.
Is diet modification needed in addition to taking insulin-sensitizing medications?
The medications themselves may help, but lifestyle changes are beneficial. It is generally
recommended that patients taking metformin or one of the glitazones reduce carbohydrate intake
and increase exercise to aid in glucose metabolism and possible weight loss in those who are
overweight. Seeking a consult with a registered dietician and beginning a structured exercise
program are central to an effective therapeutic plan.
Is there any benefit to using insulin-sensitizing medications to treat lean PCOS patients or
those who do not test as being insulin resistant?
Some doctors do give insulin-sensitizing medications to patients with PCOS, including lean women,
whether or not they test as clearly being insulin resistant. Though studies are needed to firmly
establish the benefit, many patients appear to experience improvements in symptoms and cycling.
The cause of this improvement is unclear.
Is it safe to consume alcoholic beverages while on metformin?
Drinking alcohol while on metformin is not recommended, though not completely banned either. One
may feel the effects of the liquor sooner and become intoxicated more easily. It also increases
the risks of hypoglycemia. Alcohol may work with metformin to increase blood lactate levels,
increasing the risk of lactic acidosis.
What is Syndrome X or Metabolic Syndrome?
Syndrome X, also called Metabolic Syndrome or Insulin Resistance Syndrome, is a combination of
insulin resistance or diabetes, dyslipidemia, hypertension, and central obesity.
What is the difference between Syndrome X and PCOS?
One of the biggest differences is that both men and women can have Syndrome X, while men cannot
have PCOS. Syndrome X involves a cluster of symptoms found within the larger scope of PCOS
symptoms it is this metabolic disorder that contributes most to heart disease.
Is everyone with PCOS also considered to have Syndrome X?
No. To be diagnosed with Syndrome X, one must have insulin resistance, hypertension, obesity and
dyslipidemia. It is possible to have PCOS without having all of these symptoms, and some women
with PCOS may not appear to have any of them.
