If you've been diagnosed with pre-diabetes or impaired glucose tolerance, or if your fasting blood sugar is higher than normal, or if you have a family history of diabetes, you may wonder what your real risk is of developing full-fledged diabetes. Several recent medical studies give us some answers.

Diabetes Development in a Large Population Over Time

A team of epidemiologists led by J. B. Meigs of Harvard Medical School analyzed the results of oral glucose tolerance tests (OGTT) that given every two years to participants in the Baltimore Longitudinal Study of Aging. (1)

This is an ongoing study that was begun by the National Institutes of Health in 1958. It's goal is to track the health experience of volunteers from Baltimore and the Washington, DC area through time. Participants are primarily Caucasian, middle- and upper-middle socioeconomic class volunteers who return to the Gerontology Research Center in Baltimore every two years for an exam.

The study is what is called an "open cohort" design study, which means that any people who drop out of the study replaced to maintain equal numbers of subjects in each 10-year age group. About 1,000 volunteers have been examined at each study cycle.

Researchers Tested Glucose Tolerance and Fasting Glucose over at Least Eight Years

For their analysis of what happens to blood sugars over time, Meigs and his team included only subjects who had attended at least three examination and had had an OGTT within an 8 year period. Participants were excluded if they had less than 2 OGTTs or if more than four years had elapsed between two OGTTs.

The methodology used to administer the OGTT in this study was a bit different from usual, in that the amount of glucose administered was adjusted to match the participant's body size. The average dose given men was 78 g and for women 68 g.

52% of Normals Developed Abnormal Blood Sugar and 11% Developed Diabetes

When the study of their blood sugar began, the participants' average age was 57. At that point, 60% of them had normal glucose tolerance as measured by the OGTT. Normal was defined using the American Diabetes Association definition which calls normal OGTT blood sugar values under 140 mg/dl at two hours.

The researchers found that of the 437 people who started out with normal glucose tolerance whom they were able to track for roughly a decade, 48% remained normal. Of the rest, 52% developed abnormal blood sugars during the course of the study.

Breaking down exactly what kind of dysfunction the participants who had begun as normal and developed abnormal blood sugars showed, the researchers found that by the end roughly a decade:

31% of the original group of 437 participants had impaired glucose tolerance (OGTT > 140 mg/dl) though they still had normal fasting blood glucose levels under 110 mg/dl

3% had developed both impaired glucose tolerance and impaired fasting glucose.

5% had developed impaired fasting glucose but still had normal 2-h glucose tolerance.

11% had developed diabetes as diagnosed either by a 2-h OGTT result greater than 200 mg/dl or a FPG > 126 mg/dl.

Please Scroll Down to See Table

Outcome for 437 Originally Normal Subjects over a Decade of Observation Baltimore Longitudinal Study of Aging Data
Normal	IGT only	IGT and IFG	IFG only	Diabetes
209 (48%)	137 (31%)	15 (3%)	21 (5%)	55 (11%)

IGT = Impaired Glucose Tolerance

IFG = Impaired Fasting Glucose

Abnormal Post-Challenge Blood Sugar with Normal Fasting Glucose is The Most Common Pattern for Those Developing Type 2 Diabetes

If you wonder which is more common a manifestation of early blood sugar abnormality, high post-meal numbers or high fasting glucose, The Baltimore Longitudinal Study of Aging data answers that clearly.

In the group that went on to develop diabetes, 225 people initially developed abnormal 2 hour glucose tolerance test results (Impaired Glucose Tolerance) while maintaining normal Fasting Plasma Glucose.

Of those who eventually developed diabetes, only 30 participants developed abnormal Fasting Plasma Glucose without showing abnormal results on the glucose tolerance test.

When these groups of participants were followed over time, it was found that 37% of those with abnormal fasting glucose went on to develop abnormal glucose tolerance test results while only 15% of
those originally diagnosed with Impaired Glucose Tolerance went on to develop Impaired Fasting Glucose.

This should make it very clear how little help an abnormal fasting plasma glucose test result can be when doctors try to identify the people at risk for becoming diabetic in this population, since 67% of the people who progressed to diabetes as measured by the glucose tolerance test did so without ever developing impaired fasting glucose.

Please Scroll Down to See Table

Outcome for 245 Subjects with IGT over a Decade of Observation Baltimore Longitudinal Study of Aging Data
Remained IGT	Developed Diabetes
149 (61%)	96 (39%)

Outcome for 47 Subjects Originally IFG over a Decade of Observation Baltimore Longitudinal Study of Aging Data
Remained IFG	Diabetes
24 (51%)	23 (49%)

The Real Risk of Diabetes from the Baltimore Longitudinal Study of Aging Statistics

These data suggest that a person in their fifties who has a normal blood sugar test result has roughly a 1 in 8 chance of becoming diabetic over the next decade. Of those already impaired, a person who has impaired glucose tolerance has a 4 in 10 chance of progressing to diabetes over a decade while a person with impaired fasting glucose has almost a 1 in 2 chance of progressing to diabetes.

Who Progresses?

People over 56 Years Old, Males, Overweight People

When looking at exactly who the unlucky people were who progressed to diabetes, Meigs' team found that people older than 56 years, "had substantially accelerated rates of progression to abnormal 2hPG compared with younger subjects" but that older and younger subjects had a similar rate of progression to abnormal FPG.

They also found that "Men progressed to abnormal FPG or 2hPG more rapidly than women, as did subjects with overall or central obesity compared with lean subjects."

Contrary to expectations (and the findings of other studies), the researchers found that a family history of diabetes did not modify the rates of progression to abnormal glucose tolerance.

How Many Reverted Back to Normal after an Abnormal Test?

The researchers also examined how many subjects who tested abnormally on one test occasion reverted back to normal on a subsequent test. They found that 30% of those showing impaired fasting plasma glucose values testing on a single test remained abnormal on a test given 2 years later. Of those testing as having impaired glucose tolerance with a 2-h OGTT on a single test, 48% remained abnormal on a subsequent test. (Remember, however that all those who were eventually classed as progressing from normal to impaired or impaired to diabetic remained impaired on subsequent tests.)

A More Recent Study Shows That Progression to Diabetes is Not Gradual

Another study which looked more closely at the way in which diabetes develops looked not at the statistics for the group as a whole as did the study discussed above, but instead looked at how the blood sugar of individuals changed over time. (2)

Sampling Fasting Plasma Glucose, Fasting Insulin, and Glucose Tolerance Every Three Years

This team, led by Dr. Ele Ferrannini of The University of Pisa School of Medicine in Pisa, Italy, examined a population of 2,279 low-income people aged 35 to 64 in Mexico City who were known to have a high risk of developing diabetes. The subjects were tested three times over a seven year period beginning in 1990. The researchers measured fasting plasma glucose and the fasting insulin level, and then sampled the participants' blood glucose and insulin levels at 2 hours after the administration of a 75 gram dose of glucose.

Ferrannini's team found that of 1074 subjects followed over the whole seven years, 90 subjects (8% of the total) converted from normal glucose tolerance to diabetes in the 3 years between one examination and the next, and 73 (7%) converted from impaired glucose tolerance to diabetes over the same 3 year period between exams.

Finding: A Swift and Unexpected Deterioration in Blood Sugar Control Precedes Diabetes

Rather than being a gradual process, they found that the transition to diabetes appeared to occur very quickly within a 3 year period, and was characterized by a swift increase in fasting plasma glucose values. While the fasting plasma glucose of those who did not become diabetic increased "slightly and in an apparently linear manner" that of the people who became diabetic took a sudden step up, showing an average gain in fasting plasma glucose of 50 mg/dl between one examination and another about 3 years later.

The two hour glucose tolerance test results showed a similar pattern. The people who did not become diabetic showed a "slight increase" while those who became diabetic saw an average surge of 108 mg/dl between one exam and another 3 years later.

That this change was not gradual was highlighted by the finding that when they looked at the test results of the people who went from normal to diabetic between the 3 year and 7 year exams, they found that the changes in their blood sugar test results between the exams at years 1 and 3 of the study were the same as those of people who remained normal throughout the whole study.

Who Deteriorated

The two factors that the researchers found correlated to a likelihood of going from normal to diabetic was Body Mass Index and high fasting insulin levels.

Twenty-five percent of the subjects whose BMI was above the median of the group became diabetic compared to 8% of those whose BMI was below the median.

The other factor that increased the likelihood of becoming diabetic was having a high fasting insulin level--a sign of insulin resistance. Twenty-five percent of those with high fasting insulin progressed to diabetes vs 9% of those with normal insulin levels.

The "Normal" People who Deteriorated Started with Significantly Higher Blood Sugars.

What makes this study even more interesting is that it includes some vital information that Dr. Meigs and his team left out when reporting their findings with the Baltimore data. Rather than just telling us that the study subjects fell into the various ADA classifications like "normal,"IGT" or "IFG" this study gives us more detailed information about the actual fasting and 2-h test result values of the group of people who became diabetic and of those who did not.

And the difference between the "normal" blood sugar test results of these two groups of "normals" is striking.

At the outset of the study the average fasting plasma glucose of the people who remained normal was 82 mg/dl with a narrow standard deviation reaching up to 92 mg/dl. But the average fasting plasma glucose of the "normal" people who went on to develop diabetes was 10% higher--at 90 mg/dl but the standard deviation extended all the way up to 139 mg/dl, the pre-1998 ADA cut off for "normal." (The standard deviation is a measure of how tightly values in a range cluster around the mean.)

So, in fact, these "normal people" as a group already had significantly higher fasting blood sugars than the people who remained normal.

In a similar manner at the outset of the study, the 2-h OGTT values of the people who remained normal averaged 93 mg/dl and one standard deviation ranged up to 116 mg/dl. But the average 2-h OGTT result of the people who went from normal to diabetic was 22% higher than the people who remained normal, at 113 mg/dl, and again, but the standard deviation was much wider reaching up slightly above to the top ADA cutoff for normal at 143 mg/dl.

Many People Who Developed Diabetes Started with Normal Fasting Blood Glucose Tests

At the start of the study, the fasting blood sugars of the patients classified as "IGT" who also became diabetic were not significantly higher than those of the "normals". Their average fasting plasma glucose was 96 mg/dl, only 7% higher than that of the normals who became diabetic, though their average 2-h OGTT value was 153 mg/dl.

A 2007 Study Confirms Progression Within 3 Years to Diabetes with Fasting Bg over 100 mg/dl (5.6 mmol/L)

This study of 5,452 members of an HMO with no prior history of diabetes and published in Diabetes Care. 2007; 30(2):228-33 found that, as reported in Diabetes in Control overall, 8.1% of subjects whose initial abnormal fasting glucose was 100-109 mg/dl (added IFG subjects) and 24.3% of subjects whose initial abnormal fasting glucose was 110-125 mg/dl (original IFG subjects) developed diabetes (P < 0.0001). Added IFG subjects who progressed to diabetes did so within a mean of 41.4 months, a rate of 1.34% per year. Original IFG subjects converted at a rate of 5.56% per year after an average of 29.0 months. A steeper rate of increasing fasting glucose; higher BMI, blood pressure, and triglycerides; and lower HDL cholesterol predicted diabetes development."

What this means is that if your blood sugar tests over 100 mg/dl fasting more than once, your fasting blood sugar will be over the 125 mg/dl (7.0 mmol/L) level used to diagnose full diabetes within 3 years.

More importantly, and not addressed in this article, if your blood sugar is at 100 mg/dl fasting, it is very likely that your post-meal blood sugar is already in the diabetic range, which is over 200 mg/dl (11.1 mmol/L) which is why your fasting blood sugar is deteriorating. High post-meal blood sugars kill beta cells. If you can bring down those post-meal highs, you may be able to prevent the beta cell death that is destroying your fasting control!

Truly Normal is Clearly Lower than American Diabetes Association "Normal"

The data here suggest strongly that truly normal people--people whose fasting blood sugar is close to 82 mg/dl and whose 2-h result on an OGTT is closer to 90 than 140 probably don't become diabetic. Those whose blood sugars are higher than this true "normal" do even though the current diagnostic standard embraced by the American Diabetes Association tells them they are normal. They may go on for many years showing only slight changes from year to year, but eventually they suddenly hit a critical point where their blood sugar control suddenly deteriorates very swiftly.

Does This Mean YOU Will Deteriorate?

By now you're probably wondering how you can tell whether any mild blood sugar abnormality you have is something to worry about. Were you one of the lucky ones who will "revert" back to normal, or are you on the way to developing diabetes?

The answer has a lot to do with how close to abnormal your "normal" results might be. The study subject who is considered by researchers as having "reverted" from abnormal glucose tolerance to normal glucose tolerance may have tested into the "impaired" category with a value of 141 mg/dl on the first glucose tolerance test and tested "normal" with a value of 139 mg/dl on the second. But as far as that person's health is concerned, the difference is insignificant. Unfortunately, if dozens of study subjects make that kind of change, it makes for a big difference in the researchers' charts and graphs. This is the problem with all-or-nothing cutoffs.

Factors that Cause Temporary Rises in Blood Glucose Test Results

And there are a lot of factors that the researchers don't check for that can push your blood sugar up or down 10 or 20 mg/dl. For example, if your body is fighting off a cold, long before you start to sniffle, your blood sugar will rise perhaps by 20 mg/dl or more. This additional glucose is used by the immune system as it tools up to fight the invader.

Another factor that researchers miss is that women often see a significant boost in their blood sugars during certain parts of the menstrual cycle. Birth control pills and hormone replacement can also push their blood sugars up or down. And these hormonal changes may cause blood sugars to rise or fall by a significant amount--10 mg/dl for fasting blood sugar and 20 or 30 mg/dl in a post-meal value. So it is possible that some of the subjects in population studies who revert to normal from impaired may have been tested during a high blood sugar phase of their menstrual cycle. Remember, a rise of only 5 to 10 mg/dl could push you from the normal category into the impaired category if you are already near the cutoff point.

Another factor that can push your blood sugars up or down, particularly if you are closer to impaired than to truly normal, is what you've been eating over the week before your test. Paradoxically, eating a very low carbohydrate diet or a very high carbohydrate diet can skew your results higher.

Medications can also push your blood sugars up and down enough to push you from one category to another. Sulfa antibiotics like Septra, for example, lower blood sugars, while cortisones and some mood-changing drugs can push it up.

But in all these situations, we're talking about a small difference, the difference between a post meal test blood sugar concentration of 145 and 125 mg/dl, not the difference between 145 and 87. And though this small difference doesn't really mean that much has changed in your health, it will move you from one category to the next when researchers use hard cutoffs.

So Who is Truly Normal?

So although it is possible to move back into the "normal" category based on a relatively small fluctuation from test to test, if your numbers are significantly elevated above 82 mg/dl for fasting and 100 mg/dl two hours after a meal tolerance test you would do well to assume that you may very well have a significant exposure to developing diabetes within the next decade--if not the next 3 years.

Diabetes: The Serious Health Risk Most People Ignore

The next time your doctor tells you not to worry about your slightly elevated blood sugar, while writing you an expensive prescription to control your only slightly abnormal cholesterol, consider this:

White the chances are very good that you have spent a lot more time worrying about your cholesterol than you have ever given to your blood sugar status, your actual risk of heart attack may be far lower than your risk of diabetes. Consider this, the chance of a 55 year old woman with very high cholesterol having a heart attack over the next ten years is actually only one in a hundred--even if she is taking medication for high blood pressure. (3)

The same statistic analysis shows that the chances of a 55 year old man with very high cholesterol having a heart attack over the next decade is only six in a hundred.

And though every 55-year old woman is warned to have a mammogram every year, the chance of that 55-year old woman developing breast cancer in the next 5 years is again only slightly over one in a hundred. (4)

The Table below uses the data from the Baltimore Longitudinal Study, cited above.

A 55-Year Old "Normal" Woman's Risk For Developing Major Diseases
Heart Disease (10 yr)	Breast Cancer (5 yr)	Diabetes (10 yr)
1%	1.5%	13%

How strange it is that people with "normal" blood sugars in the upper half of the "normal" category are told they have "nothing" to worry about when their risk can be 13 times higher of developing diabetes than it is of developing heart disease or cancer!

CITATIONS

1 James B. Meigs, Denis C. Muller, David M. Nathan, Deirdre R. Blake, and Reubin Andres;
The Natural History of Progression From Normal Glucose Tolerance to Type 2 Diabetes in the Baltimore Longitudinal Study of Aging Diabetes 52: 1475-1484. 2003


http://diabetes.diabetesjournals.org/cgi/content/abstract/52/6/1475

2 Ele Ferrannini, Monica Nannipieri, Ken Williams, Clicerio Gonzales, Steve M. Haffner, Michael P. Stern.

Mode of onset of type 2 diabetes from normal or impaired glucose tolerance. Diabetes 53:160-165, 2004


http://diabetes.diabetesjournals.org/cgi/content/full/53/1/160

3 10 Year CVD Risk


http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=pub

4 Breast Cancer Risk Assessment Tool National Cancer Institute.


http://bcra.nci.nih.gov/brc/questions.htm