The new england journal of medicine original article Normal Fasting Plasma Glucose Levels and Type 2 Diabetes in Young Men 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., and Assaf Rudich, M.D., Ph.D., for the Israeli Diabetes Research Group abstract background From the Medical Corps Headquarters The normal fasting plasma glucose level was recently defined as less than 100 mg per (A.T., E.I., T.S., I.K.) and the Center for deciliter (5.55 mmol per liter). Whether higher fasting plasma glucose levels within this Medical Services (D.T.-M.), Israel Defense Forces Medical Corps; the Department of range independently predict type 2 diabetes in young adults is unclear. Internal Medicine A, Sheba Medical Cen- ter, Tel-Hashomer (A.T.); the S. Daniel Abra- methods ham International Center for Health and Nutrition (I.S., A.R.), the Department of We obtained blood measurements, data from physical examinations, and medical and Epidemiology (I.S.), and the Department lifestyle information from men in the Israel Defense Forces who were 26 to 45 years of Clinical Biochemistry (A.R.), Faculty of of age. Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva; and the Depart- ment of Internal Medicine A, Meir Hospital, results Sapir Medical Center, Kfar-Sava (D.P.) — A total of 208 incident cases of type 2 diabetes occurred during 74,309 person-years of all in Israel. Address reprint requests to Dr. Tirosh at the Department of Internal Medi- follow-up (from 1992 through 2004) among 13,163 subjects who had baseline fasting cine A, Sheba Medical Center, Tel-Hashom- plasma glucose levels of less than 100 mg per deciliter. A multivariate model, adjusted er, Israel, or at [email protected]. for age, family history of diabetes, body-mass index, physical-activity level, smoking Drs. Tirosh and Shai contributed equally to status, and serum triglyceride levels, revealed a progressively increased risk of type 2 the study. 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 N Engl J Med 2005;353:1454-62. Copyright © 2005 Massachusetts Medical Society. (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 di- vided 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 in- dependent 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. 1454 n engl j med 353;14 www.nejm.org october 6, 2005 The New England Journal of Medicine Downloaded from nejm.org on February 17, 2018. For personal use only. No other uses without permission. Copyright © 2005 Massachusetts Medical Society. All rights reserved. normal fasting plasma glucose levels and diabetes in young men he definition of a normal fasting questionnaire assessing demographic, nutritional, t plasma glucose level has recently been re- lifestyle, and medical factors. Thereafter, blood sam- vised by the Expert Committee on the Di- ples were drawn after a 14-hour fast and analyzed. agnosis and Classification of Diabetes Mellitus of A trained medical technician measured height and the American Diabetes Association. An impaired weight, and a physician at the center performed a fasting plasma glucose level is now considered to complete physical examination. Primary care for all include the range of 100 to 109 mg per deciliter Israel Defense Forces personnel between scheduled (5.55 to 6.05 mmol per liter).1 Although it raises visits to the center is obtained at designated military considerable controversy regarding the implica- clinics, and all medical information was recorded tions for health care policy,2-6 the concept that per- in the same central database, thereby facilitating sons with fasting plasma glucose levels of 100 to ongoing, tight, and uniform follow-up. 109 mg per deciliter are at increased risk for the de- The institutional review board of the Israel De- velopment of type 2 diabetes, as compared with fense Forces Medical Corps approved this study on those with fasting plasma glucose levels of less than the basis of strict maintenance of participants’ an- 100 mg per deciliter, is substantiated by data.5,7,8 onymity during database analyses. Data from sub- Nonetheless, the question of whether there is an jects were recorded anonymously, and no individu- association between elevated fasting plasma glu- al consent was obtained. The authors are solely cose levels within the newly defined normal range responsible for the design of the study, analysis and and an increased risk of diabetes, and whether this interpretation of the data, and writing of the manu- association acts as an independent risk factor for script, without any form of censorship or limita- the disease, has not been answered. This issue is tion by the Israel Defense Forces. particularly important for young adults, in whom the association between fasting plasma glucose lev- inclusion and exclusion criteria els and diabetes may have been masked in earlier Included in the study have been 13,163 men with studies that analyzed populations with a wide age fasting plasma glucose levels of less than 100 mg range.8,9 In young adults, the absolute incidence of per deciliter at their initial Staff Periodic Examina- type 2 diabetes is low, but a marked surge in diabe- tion Center visit, for whom follow-up data have tes-associated morbidity has recently been report- been available through either a subsequent sched- ed.10 Better and earlier identification of young uled visit or visits (average number of visits per per- adults at risk for the development of diabetes may son, 2.5; range, 2 to 6) or from the primary physi- be warranted, given the success of interventions cian for men who have received a diagnosis of aimed at delaying the onset of diabetes among high- diabetes. The ongoing cohort of the MELANY risk groups.11-15 study currently includes 9538 additional men for Our investigation, which involved the use of data whom follow-up data are not yet available. Patients from the Metabolic, Lifestyle, and Nutrition Assess- were excluded from the study if they had con- ment in Young Adults (MELANY) study, assessed firmed type 1 or type 2 diabetes at the time of en- whether fasting plasma glucose levels can help to rollment. Women were not included, since only identify young, healthy, normoglycemic persons at 11 new cases of diabetes were diagnosed among increased risk for type 2 diabetes. 1961 normoglycemic women, an insufficient number of incident cases to facilitate meaningful methods analysis. Glucose-tolerance tests, shown rarely to be impaired in people with fasting glucose levels the melany study of less than 100 mg per deciliter,16 were not per- The MELANY study has been conducted at the Is- formed, a decision consistent with current clinical rael Defense Forces Staff Periodic Examination Cen- guidelines for the diagnosis of diabetes in young, ter, to which all career service personnel older than asymptomatic, normoglycemic persons.17 25 years of age are referred every three to five years. A computerized database established in 1992 is the outcome definitions source of data for MELANY, which was designed The diagnosis of type 2 diabetes was defined as the to investigate risk factors for common diseases in primary end point of the study. All cases of diabetes young adults. At each visit to the Staff Periodic Ex- were diagnosed according to the criteria published amination Center, participants completed a detailed by the American Diabetes Association expert com- n engl j med 353;14 www.nejm.org october 6, 2005 1455 The New England Journal of Medicine Downloaded from nejm.org on February 17, 2018. For personal use only. No other uses without permission. Copyright © 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine mittee.18 The diagnoses of all 208 new cases of di- deciliter. A general linear model was used to assess abetes in the MELANY study were made on the ba- the age-adjusted means and proportions of the pop- sis of two fasting plasma glucose levels of 126 mg ulation’s characteristics across quintiles of fasting per deciliter (7.00 mmol per liter) or more. Since the glucose levels and to fit the median of the quintiles diagnostic criteria for diabetes were changed dur- as a continuous variable to estimate the trend of ing the follow-up period, all fasting glucose values variables across quintiles.