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Normal Blood Sugar May Belie Diabetes Risk
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All Blood Sugar Levels Aren't Equal, Study Shows
".....This study revealed a progressively increased risk of incident diabetes with fasting plasma glucose levels at the high end of the normal range. Fasting glucose levels, body-mass index, and triglyceride levels may help to identify apparently healthy young men at increased risk for diabetes....NEJM"...triglycerides>150 & BMI >30 may be risk factors....
By Salynn Boyles
WebMD Medical News Reviewed By Brunilda Nazario, MD
Wednesday, October 05, 2005
Oct. 5, 2005 - When it comes to predicting type 2 diabetes risk, not all normal fasting blood sugar levels are equal, new research shows.
Fasting blood sugar levels that are currently considered in the normal range may actually be predictive of diabetes in otherwise healthy men. Higher yet normal-range blood sugar levels may predict diabetes risk, along with body weight, family history of the disease, or blood fat levels, according to the study published in the Oct. 6 issue of The New England Journal of Medicine.
The findings make it clear that what is normal for one person may not be normal for another when it comes to blood sugar testing, researcher Amir Tirosh, MD, of Israel's Sheba Medical Center, tells WebMD.
"Independently, this test doesn't tell the whole story," he says. "The thinking has been that there is a single cutoff point for what is normal, but this doesn't seem to be the case. It depends on the individual."
Soldiers Followed
Fasting blood sugar testing is widely used to diagnose type 2 diabetes and identify people at high risk for developing the disease. The test measures the amount of sugar in the blood, called glucose, after an overnight fast.
A blood sugar level of up to 100 mg/dL is considered normal, while people with levels between 100 and 125 mg/dL are considered to have impaired fasting glucose or prediabetes. Diabetes is typically diagnosed when the fasting blood glucose levels rise to 126 mg/dL or higher.
In the newly reported study, healthy, nondiabetic male Israeli soldiers were followed for 12 years. Blood samples were analyzed for fasting blood glucose levels. During that time, 208 of the approximately 13,000 men with initially normal blood sugar levels developed type 2 diabetes.
Despite normal blood sugar levels, those who were obese, had a family history of diabetes, and had high levels of blood fats (triglycerides) were nine times as likely as men with none of these risk factors to develop diabetes.
The researchers also show that men with the highest normal-range blood sugar, even levels of 90 mg/dL, had a higher risk.
Implications for Treatment
The findings could have implications for determining when to treat people at risk with blood sugar-lowering medications.
And they note that a one-level-fits-all approach to blood sugar testing is too simplistic, says diabetes specialist Ronald Arky, MD, of Harvard Medical School.
"Blood glucose means very little if you don't considered obesity, sedentary lifestyle, smoking, family history, and other diabetes risk factors along with it," he tells WebMD.
In an editorial accompanying the study, Arky wrote that the lessons learned about cholesterol and cardiovascular disease can help guide doctors in better understanding blood sugar and diabetes.
Revised guidelines released just over a year ago lower target cholesterol levels, but only for patients with the greatest risk of having a heart attack or stroke.
The new research shows that the same individualized approach is called for when counseling patients about their diabetes risk, Arky and Tirosh tell WebMD.
"We know what the risks are," Tirosh says. "By better recognizing them we may be able to prevent or at least delay diabetes with lifestyle modification and drug therapy."
Better and earlier identification of young adults at risk for diabetes may be warranted, given the success of interventions aimed at delaying the onset of diabetes among high-risk individuals, write the researchers.
"Normal Fasting Plasma Glucose Levels and Type 2 Diabetes in Young Men"
NEJM
Oct 6, 2005
Amir Tirosh, M.D., Ph.D., Iris Shai, R.D., Ph.D., Dorit Tekes-Manova, M.D., Eran Israeli, M.D., David Pereg, M.D., Tzippora Shochat, M.Sc., Ilan Kochba, M.D., Assaf Rudich, M.D., Ph.D., for the Israeli Diabetes Research Group
ABSTRACT
Background: The normal fasting plasma glucose level was recently defined as less than 100 mg per deciliter (5.55 mmol per liter). Whether higher fasting plasma glucose levels within this range independently predict type 2 diabetes in young adults is unclear.
Methods: We obtained blood measurements, data from physical examinations, and medical and lifestyle information from men in the Israel Defense Forces who were 26 to 45 years of age.
Results:
A total of 208 incident cases of type 2 diabetes occurred during 74,309 person-years of follow-up (from 1992 through 2004) among 13,163 subjects who had baseline fasting plasma glucose levels of less than 100 mg per deciliter.
A multivariate model, adjusted for age, family history of diabetes, body-mass index, physical-activity level, smoking status, and serum triglyceride levels, revealed a progressively increased risk of type 2 diabetes in men with fasting plasma glucose levels of 87 mg per deciliter (4.83 mmol per liter) or more, as compared with those whose levels were in the bottom quintile (less than 81 mg per deciliter [4.5 mmol per liter], P for trend <0.001).
In multivariate models, men with serum triglyceride levels of 150 mg per deciliter (1.69 mmol per liter) or more, combined with fasting plasma glucose levels of 91 to 99 mg per deciliter (5.05 to 5.50 mmol per liter), had a hazard ratio of 8.23 (95 percent confidence interval, 3.6 to 19.0) for diabetes, as compared with men with a combined triglyceride level of less than 150 mg per deciliter and fasting glucose levels of less than 86 mg per deciliter (4.77 mmol per liter). The joint effect of a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more and a fasting plasma glucose level of 91 to 99 mg per deciliter resulted in a hazard ratio of 8.29 (95 percent confidence interval, 3.8 to 17.8), as compared with a body-mass index of less than 25 and a fasting plasma glucose level of less than 86 mg per deciliter.
Conclusions: Higher fasting plasma glucose levels within the normoglycemic range constitute an independent risk factor for type 2 diabetes among young men, and such levels may help, along with body-mass index and triglyceride levels, to identify apparently healthy men at increased risk for diabetes.
STUDY ARTICLE
BACKGROUND
The definition of a normal fasting plasma glucose level has recently been revised by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association. An impaired fasting plasma glucose level is now considered to include the range of 100 to 109 mg per deciliter (5.55 to 6.05 mmol per liter).1 Although it raises considerable controversy regarding the implications for health care policy,2,3,4,5,6 the concept that persons with fasting plasma glucose levels of 100 to 109 mg per deciliter are at increased risk for the development of type 2 diabetes, as compared with those with fasting plasma glucose levels of less than 100 mg per deciliter, is substantiated by data.5,7,8 Nonetheless, the question of whether there is an association between elevated fasting plasma glucose levels within the newly defined normal range and an increased risk of diabetes, and whether this association acts as an independent risk factor for the disease, has not been answered. This issue is particularly important for young adults, in whom the association between fasting plasma glucose levels and diabetes may have been masked in earlier studies that analyzed populations with a wide age range.8,9 In young adults, the absolute incidence of type 2 diabetes is low, but a marked surge in diabetes-associated morbidity has recently been reported.10 Better and earlier identification of young adults at risk for the development of diabetes may be warranted, given the success of interventions aimed at delaying the onset of diabetes among high-risk groups.11,12,13,14,15
Our investigation, which involved the use of data from the Metabolic, Lifestyle, and Nutrition Assessment in Young Adults (MELANY) study, assessed whether fasting plasma glucose levels can help to identify young, healthy, normoglycemic persons at increased risk for type 2 diabetes.
DISCUSSION
Discussion
In this follow-up study of 13,163 apparently healthy young adult men, we found an increased risk of type 2 diabetes across quintiles of fasting plasma glucose levels within the newly defined normal range; this increase was independent of other traditional risk factors for diabetes. Our findings suggest that among young adults, who generally have a relatively low incidence of diabetes, elevated normal fasting plasma glucose levels may predict type 2 diabetes.
Several limitations of this study warrant consideration. First, the MELANY cohort may be considered representative of a unique group of healthy young men. However, the characteristics of the population are strikingly similar to those of cohorts in published studies of young men from various industrialized countries,20,21,22,23,24 and the relatively homogeneous environment to which participants in our study were exposed might reduce the effect of unknown confounders. Second, although they did not compromise the outcome definition, measurements of circulating insulin, C-peptide, or both were not obtained in this study, limiting our ability to assess the role of insulin resistance in the association between normal fasting plasma glucose levels and diabetes. Finally, we did not measure glycosylated hemoglobin levels or perform glucose-tolerance tests. Although the current definition of normal fasting plasma glucose levels resulted in a substantial increase in the overlap with normal glucose tolerance, as defined by glucose-tolerance testing,8 we may have missed men with normal fasting plasma glucose levels who were already glucose intolerant at enrollment. To limit this possibility, we confirmed our results by performing a secondary analysis in which a two-year lag between enrollment and outcome was used. The strengths of the MELANY study include the detailed, uniform, and systematic follow-up and outcome definition; the use of measured (rather than reported) values for the body-mass index; the availability of reliable determinations of glucose levels in fresh venous blood; and the direct measurements of lipids.
The identification of a high-normal fasting plasma glucose level as a risk factor for type 2 diabetes may help to identify young, healthy men for whom preventive interventions might be considered. Indeed, a number of strategies, including lifestyle modification14 and medications such as metformin,14 thiazolidinediones,13 acarbose,11,12 and orlistat15 have been reported as efficient interventions that may delay the onset of diabetes in selected groups that have classic risk factors for the disease. If such strategies are also found to be efficacious in preventing diabetes in young men with high-normal fasting plasma glucose levels, the findings of our study may facilitate efforts to halt the diabetes pandemic that is increasingly affecting people in the third to fifth decades of life.10
An impaired fasting plasma glucose level is a known risk factor for diabetes, along with other traditional risk factors such as a family history, sedentary lifestyle, central adiposity, dyslipidemia, and hypertension.25 However, the definition of a normal fasting plasma glucose level was recently revised to be less than 100 mg per deciliter.2 It is interesting to note that a few studies have reported the absence of a threshold in the association between fasting plasma glucose levels and the risk of diabetes in cohorts with a wide age range. Furthermore, a fasting plasma glucose level of 94 mg per deciliter (5.22 mmol per liter) was suggested as an optimal point of specificity and sensitivity for predicting type 2 diabetes.8,9 Our results suggest that in young men, fasting plasma glucose levels within the normoglycemic range can predict type 2 diabetes. Consistent with our findings is the observation that elevated fasting plasma glucose levels within the normoglycemic range can predict cardiovascular, cerebrovascular, and overall mortality risks in persons 45 years of age or older.26,27 Thus, subcategories within the range defined as normal for fasting plasma glucose levels contain information relevant for the assessment of the risk of various diseases,28,29 as indicated here for type 2 diabetes.
More than half of the entire study population had fasting plasma glucose levels exceeding 90 mg per deciliter (5.00 mmol per liter), which were associated with a significantly increased risk of diabetes during the mean follow-up of nearly six years. The absolute incident risk of type 2 diabetes among men who had fasting plasma glucose levels of 91 to 99 mg per deciliter was 2.3 percent during this follow-up period. Therefore, designating a fasting plasma glucose level of more than 90 mg per deciliter as the sole marker of imminent diabetes is unlikely to be useful. Alternatively, the use of an individualized definition of a normal fasting plasma glucose level, which incorporates the compound effect observed with body-mass index and triglyceride levels (Figure 1), may prove to be of greater clinical value. Indeed, among normoglycemic obese subjects with fasting plasma glucose levels of more than 90 mg per deciliter, the incidence of diabetes was 5.7 percent, as compared with 0.4 percent in lean men with glucose levels of 86 mg per deciliter or less. On the basis of population attributable risk, 60.5 percent of the cases might be preventable by a joint reduction in the risks associated with obesity and high-normal fasting plasma glucose levels. Risk stratification for the definition of normoglycemia is reminiscent of the current guidelines for antidyslipidemic and antihypertensive interventions.30
Our study raises potential testable hypotheses with regard to mechanisms. The fasting plasma glucose level is largely determined by hepatic glucose production.31 Thus, the observation that a high-normal fasting plasma glucose level predicts type 2 diabetes suggests that a relative overproduction of hepatic glucose already exists early in the natural history of diabetes and is exaggerated by obesity (Figure 1B). Obese persons who do not have diabetes consistently exhibit an enhanced rate of glucose production.32 This enhanced rate may emanate from elevated levels of free fatty acids that directly accelerate the rate of hepatic gluconeogenesis,33 combined with desensitization of the hepatic regulatory loop involving hypothalamic sensing of fatty acids.34 Obesity-associated altered secretion of adipocytokines from adipocytes, macrophages in fat tissue, or both has been suggested as the mechanism involved in mediating such dysregulated "crosstalk" between fatty tissue and the liver.35,36,37,38 Understanding the operative mechanisms that regulate fasting plasma glucose levels may bring us closer to finding new and effective measures to prevent type 2 diabetes in young adults.
Supported by the Israel Defense Forces Medical Corps.
We are indebted to Drs. Ilana Harman-Boehm and Shimon Weitzman of the Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel, for their valuable discussions and careful reading of the manuscript; to Dr. Itamar Raz, Hadassah Medical Center, Jerusalem, for his support and encouragement; and to Ms. Yehudit Mish for her valuable assistance with data collection.
Results
Data from 13,163 apparently healthy men (mean age, 32 years; range, 26 to 45) with fasting plasma glucose levels of less than 100 mg per deciliter at baseline were analyzed. Age-adjusted values for body-mass index, triglyceride levels, and the proportion of men with a family history of diabetes were more likely to increase across quintiles of fasting glucose levels.
During 74,309 person-years (mean follow-up, 5.7 years), there were 208 documented incident cases of type 2 diabetes. Age-adjusted hazard ratios for type 2 diabetes increased across quintiles of fasting plasma glucose levels, reaching 3.05 (95 percent confidence interval, 1.78 to 5.18) for the top quintile as compared with the bottom quintile (P for trend <0.001). Further adjustments for body-mass index and triglyceride levels only mildly attenuated the risk values. In a multivariate model adjusted for age, family history of diabetes, body-mass index, serum triglyceride levels, physical activity, and smoking status, we observed a significant and progressive increase in the risk of diabetes in men with fasting plasma glucose levels in the third, fourth, and fifth quintiles as compared with the bottom quintile (P for trend <0.001). This association remained unchanged after further adjustment for blood pressure and for the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, as well as after a secondary analysis that excluded 27 subjects who had received a diagnosis of diabetes within the first two years of follow-up (data not shown).
The addition of fasting plasma glucose levels to a model adjusted for age, body-mass index, family history of diabetes, smoking status, the presence or absence of hypertension, physical-activity level, triglyceride levels, and ratio of total cholesterol to HDL cholesterol further improved the prediction model (P<0.001 on the basis of the likelihood-ratio test).
In the multivariate model, serum triglyceride levels and family history of diabetes, in addition to fasting plasma glucose levels and body-mass index, remained independent risk factors for the development of diabetes (data not shown). Thus, we further assessed the association between fasting plasma glucose levels and the occurrence of type 2 diabetes among strata of these independent risk factors. In the multivariate models, increased levels of normal fasting plasma glucose were more strongly associated with diabetes among overweight and obese men (those with a body-mass index of 25 or more) than among leaner men (P for interaction, 0.03). The trend of increased risk of type 2 diabetes across increasing quintiles of normal fasting plasma glucose levels appeared to be similar among subgroups classified according to triglyceride levels and family-history status (P for interaction >0.05).
We assessed the joint effect of fasting plasma glucose levels and either triglyceride levels or body-mass index on the risk of type 2 diabetes. In multivariate models, serum triglyceride levels of 150 mg per deciliter or more were associated with an increased risk of diabetes in each category of fasting plasma glucose levels, as compared with the risk in the respective low-serum-triglyceride group. Men with fasting plasma glucose levels at the high end of the normal range (91 to 99 mg per deciliter [5.05 to 5.50 mmol per liter]) and serum triglyceride levels of 150 mg per deciliter or more had a risk of 8.23 (95 percent confidence interval, 3.6 to 19.0) for the development of diabetes, as compared with those with fasting glucose levels of 86 mg per deciliter (4.77 mmol per liter) or less and triglyceride levels of less than 150 mg per deciliter. When we cross-classified body-mass index with fasting plasma glucose levels, we observed that each risk factor enhanced the association of the other factor with type 2 diabetes. Obese men (those with a body-mass index of 30 or more) with fasting plasma glucose levels in the high-normal range had a hazard ratio of 8.29 (95 percent confidence interval, 3.8 to 17.8) for the development of diabetes, as compared with the reference group, whereas those with fasting plasma glucose levels between 87 and 90 mg per deciliter had a risk of 7.78 (95 percent confidence interval, 3.2 to 18.7). The joint effect of obesity and fasting plasma glucose levels was also apparent in the population attributable risk. Among lean men, 27.5 percent of cases of diabetes could be prevented by modifying the risk attributable to elevated fasting plasma glucose levels, and in men with the lowest range of fasting plasma glucose levels, 29.1 percent of cases could be attributed to obesity. The combined, population attributable risk increased to 60.5 percent among men with the highest values for both body-mass index and fasting plasma glucose levels, as compared with the reference group.
EDITORIAL
NEJM OCT 6, 2005
"Doctor, Is My Sugar Normal?"
Ronald A. Arky, M.D.
We live in an era in which the public interest in medical matters is high. When so much information and misinformation are available on the Internet, many patients devote a fair share of time to matching their most recent laboratory results with the "normal" values cited in health-related Web sites or even in the advertisements for their medication. It seems reasonable for patients to strive to achieve the best possible results from medication or other treatments, and patients' requests for information about the desired goals of treatment are to be commended.
Frequently, as physicians, we are asked, "Are my laboratory results normal?" On the surface, this seems to be a benign, straightforward question that should lend itself to a simple answer. But, in fact, over the past several decades, the complexity of this question has been compounded by the increased number of epidemiologic studies that point out how differences in sex, ethnic background, age, and a multiplicity of other factors may determine what is "normal." In addition, outcome studies permit a retrospective analysis of the meaning of laboratory results of the past. Thus, if after 20 years of follow-up of a large cohort of subjects who had an original laboratory value of x milligrams per deciliter, lesion y is detected in a significant number of these subjects, it becomes useful to cite x milligrams per deciliter as a marker of the future appearance of that lesion. As a result of such outcome studies, there has been a redefinition of what is normal and what should be the desired level or goal of therapeutic interventions.
Moreover, advances in technology that allow for more precise measurements of common substances in tissues, blood, and other body fluids have altered our conceptions of the values that are considered normal or in the normal range. As a consequence, the accepted normal values for fasting plasma glucose and low-density lipoprotein (LDL) cholesterol levels have been lowered over the past two decades. For patients and their families, explanations of these complexities and the variables that affect normalcy are not always easy to comprehend; understanding requires time and clarity from the health care provider who explains the results.
An often-asked question is, "Doctor, how is my cholesterol count?" The textbooks of the 1940s and early 1950s, which were written before the discovery that an elevated cholesterol level was a risk factor for coronary artery disease, cited only the value of total cholesterol. However, as knowledge about lipoprotein metabolism accumulated and the important relationship of LDL cholesterol to atherosclerosis became clear, the emphasis on LDL, or "bad," cholesterol caught the public's eye. The messages of the successive reports1,2,3,4 of the National Cholesterol Education Program are noteworthy examples of the trend of translating clinical and epidemiologic studies to define normal values and, by implication, desired goals for treatment. As the number of therapeutic trials and epidemiologic studies and the understanding of the molecular biology and physical chemistry of lipoprotein metabolism progressed, the desired goal of treatment became a lowering of LDL cholesterol in both men and women, to prevent coronary heart disease and other macrovascular consequences of atherosclerosis. Similarly, over the past 12 years, the expert panel responsible for the National Cholesterol Education Program has suggested that therapeutic intervention begin at lower levels of LDL cholesterol than previously defined. This recommendation is particularly applicable to persons with risk factors other than elevated cholesterol levels, especially persons with diabetes.4
The LDL cholesterol story of the past two decades is analogous in a number of ways to the recent history of diabetes. In 1979, the National Diabetes Data Group5 recommended criteria for the diagnosis of diabetes: a fasting plasma glucose level of 140 mg per deciliter (7.77 mmol per liter) or less was considered to be within the normal range and not indicative of diabetes. Over the next several years, the World Health Organization and numerous national diabetes associations reaffirmed this criterion and also included among the categories of abnormalities impaired glucose tolerance. Once more, as the numbers of reported epidemiologic and therapeutic studies increased and it became apparent that certain end points in this case, diabetic retinopathy might serve as markers of diabetes and an indicator of the border between normal and abnormal fasting glucose levels, an international expert committee6 convened in 1997 and recommended that the upper limit of normal fasting plasma glucose levels be 126 mg per deciliter (7.00 mmol per liter) and that the diagnosis of diabetes be made when the fasting plasma glucose level exceeded that value. That group of experts also defined the normal fasting plasma glucose level as being no higher than 110 mg per deciliter (6.10 mmol per liter) and introduced the concept of impaired fasting glucose levels, thus identifying persons whose fasting plasma glucose levels ranged from 110 to 125 mg per deciliter as having impaired fasting glucose levels.
Neither the 1979 nor the 1997 recommendation won universal approval from the physician community. Especially questioned were the discrepancies that exist when fasting plasma glucose values are used as criteria for diagnosis, as compared with postprandial values or the levels noted after a standard glucose load (i.e., an oral glucose-tolerance test). In addition, since the publication of the recommendations of the National Diabetes Data Group, the use of glycosylated hemoglobin levels as means to assess the glycemic control of patients with diabetes has become an accepted standard. Why, some argue, should this measurement not serve as a diagnostic tool, too?
Although these debates continue to simmer, many new data related to the diagnosis of diabetes have appeared, and recently the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus issued a follow-up report.7 That group analyzed data from four diverse populations to determine what level of fasting plasma glucose predicted the future outcome of diabetes and, by applying a statistical analysis, concluded that a level of 110 mg per deciliter was "inappropriately high as a lower limit" of impaired fasting glucose and recommended changing the cutoff point for impaired fasting glucose to 100 mg per deciliter (5.60 mmol per liter). The Expert Committee accepts that the criteria for fasting plasma glucose and for 2-h post-prandial evaluate "different metabolic states" and that the impaired fasting glucose level identifies a lesser portion of the population than will the criterion for impaired glucose tolerance. Once again, the recommended upper level of the normal range for fasting plasma glucose levels has been lowered. But the pot continues to boil.
In this issue of the Journal, Tirosh and colleagues demonstrate that among a large cohort of healthy young Israeli military men who were followed for periods of up to 12 years, higher initial fasting plasma glucose levels within the normoglycemic range can foretell the onset of diabetes.8 The absolute incidence of diabetes among persons with fasting plasma glucose levels of 91 to 99 mg per deciliter (5.05 to 5.50 mmol per liter) over the follow-up period was 2.3 percent. Not unexpectedly, men with a high body-mass index or an increased fasting level of triglycerides were at greater risk for diabetes even though their fasting plasma glucose levels were within the normal range. When it is appreciated that fasting plasma glucose levels represent a continuum, as do the other circulating fuels, and that the border between "normal" and "abnormal" is a shady zone influenced by weight, age, other metabolic substrates, sex, and other factors, the complexity of the answer to the question of whether one's blood sugar is normal becomes apparent.
Although the study reported by Tirosh et al. deals only with men, there is no reason to believe that the lessons from the study are sex specific. Fasting plasma glucose levels in the high-normal range (91 to 99 mg per deciliter) in young men and women warrant counseling with regard to weight and lifestyle, as well as an assessment of the lipid profile. Markers of future disease are always very useful when prevention is possible.9 There is ample evidence that this situation is true in the case of diabetes. "Yes, your glucose level is normal, but let's do something about that weight and your sedentary lifestyle" is too frequently the most appropriate response to the question, "Doctor, is my sugar normal?"
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