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Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes the Insulin Resistance Atherosclerosis Study (IRAS)

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Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes the Insulin Resistance Atherosclerosis Study (IRAS) Cardiovascular and Metabolic Risk ORIGINAL ARTICLE Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes The Insulin Resistance Atherosclerosis Study (IRAS) 1 5 CARLOS LORENZO, MD RICHARD N. BERGMAN, PHD ticipants or targeted persons from a single 2 6 LYNNE E. WAGENKNECHT, DRPH ANTHONY J.G. HANLEY, PHD ethnic group. Since direct methods have 3 7 MARIAN J. REWERS, MD STEVEN M. HAFFNER, MD 4 demanding technical requirements, the ANDREW J. KARTER, PHD product of measures of insulin sensitivity and insulin secretion derived from the oral glucose tolerance test has attracted OBJECTIVE — Disposition index (DI) and glucose effectiveness (SG) are risk factors for interest. This product has been shown to diabetes. However, the effect of DI and SG on future diabetes has not been examined in large have a modest correlation with minimal epidemiological studies using direct measures. model–derived DI, to decrease as glucose tolerance status deteriorates, and to pre- RESEARCH DESIGN AND METHODS — Insulin sensitivity index (S ), acute insulin I dict the development of diabetes inde- response (AIR), and SG were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance pendent of other risk factors including ϫ test. DI was expressed as SI AIR. At the 5-year follow-up examination, 128 individuals (15.5%) fasting and 2-h glucose concentrations had developed diabetes. (7,8). It includes the incretin effect and therefore may not always follow the hy- RESULTS — The area under the receiver operating characteristic curve of a model with SI and perbolic law (7–9). The hyperbolic para- AIR was similar to that of DI (0.767 vs. 0.774, P ϭ 0.543). In a multivariate logistic regression digm of the minimal model–derived DI model that included both DI and SG, conversion to diabetes was predicted by both SG (odds ϫ has also been criticized (10). Further- ratio 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic more, its predictive power has not been variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes tested for large epidemiological studies. In addition to the insulin-dependent did not have a significant modifying impact on the relation of SG and DI to incident diabetes. component of glucose tolerance (or DI), CONCLUSIONS — The predictive power of DI is comparable to that of its components, SI the insulin-independent component (glu- and AIR. SG and DI independently predict conversion to diabetes similarly across race/ethnic cose effectiveness [SG]) has already been groups, varying states of glucose tolerance, family history of diabetes, and obesity. explored in mice (11) and humans (12). SG is the capacity of glucose to enhance its Diabetes Care 33:2098–2103, 2010 own cellular uptake and to suppress en- dogenous glucose production. Although oth insulin sensitivity and first- tolerance test (FSIGTT) with minimal reduced in individuals with impaired glu- phase insulin secretion are indepen- model analysis, this relationship is hyper- cose tolerance (IGT) and diabetes (4,13), dent determinants of conversion to bolic (2) and similar across glucose toler- B SG contributes to glucose tolerance even diabetes in different ethnic groups and ance categories (3). Known as the in conditions of significant insulin resis- varying states of glucose tolerance, family disposition index (DI), the product of tance, including diabetes (13). Reduced history of diabetes, and obesity (1). First- measures of insulin sensitivity and first- SG has also been described in healthy in- phase insulin secretion compensates for phase insulin secretion, it has been shown dividuals following the infusion of corti- the worsening of insulin sensitivity (2). In to predict conversion to diabetes (4–6). sol or glucagon, individuals in states of studies using direct methods, such as the The evidence, however, comes from stud- very low caloric intake, women with poly- frequently sampled intravenous glucose ies that have enrolled relatively few par- cystic ovary syndrome, and the elderly ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● (13–15). Contrary to the insulin sensitiv- 1 From the Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio, ity index (SI), SG may not be influenced by Texas; the 2Division of Public Health Sciences, Wake Forest University School of Medicine, Winston- exercise (16) or weight loss interventions Salem, North Carolina; the 3Barbara Davis Center for Childhood Diabetes and Human Medical (17). In relatively small studies, S has Genetics Program, University of Colorado Health Sciences Center, Aurora, Colorado; the 4Division G of Research, Northern California Region, Kaiser Permanente, Oakland, California; the 5Department been shown to predict future diabetes of Physiology and Biophysics, University of Southern California, Los Angeles, California; the 6De- (4,5,18), but its contribution to the devel- partments of Nutritional Sciences and Medicine, Mount Sinai Hospital and the University of Toronto, opment of diabetes remains largely Toronto, Ontario, Canada; and the 7Department of Medicine, Baylor College of Medicine, Houston, unknown. Texas. Since the hyperbolic paradigm has Corresponding author: Carlos Lorenzo, [email protected]. Received 26 January 2010 and accepted 9 June 2010. not been tested in large epidemiological DOI: 10.2337/dc10-0165 studies, our first objective was to analyze © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly the risk of future diabetes associated with cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. minimal model-derived DI relative to its org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby components, SI, and acute insulin re- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. sponse (AIR). The second objective was to 2098 DIABETES CARE, VOLUME 33, NUMBER 9, SEPTEMBER 2010 care.diabetesjournals.org Lorenzo and Associates assess the relative contribution of the in- sitivity across a broad range of glucose of extreme observations. Given that some sulin-independent component of glucose tolerance (20). Second, the reduced sam- individuals had SI and DI equal to zero, ϩ tolerance, SG, to the development of dia- pling protocol (12 samples) was used be- we used the natural logarithms of SI 1 ϩ betes. To meet these aims, we used data cause of the large number of subjects. SI and DI 1 as the transformation for SI from the Insulin Resistance Atherosclero- and SG were calculated using mathemati- and DI, respectively. Accuracy for the pre- sis Study (IRAS), a multicenter observa- cal modeling methods (MINMOD, ver- diction of diabetes was determined by the tional epidemiological study of different sion 3.0 [1994], Los Angeles, California, area under the receiver operating charac- ethnic groups and varying states of glu- courtesy of Richard Bergman, PhD) (21). teristic curve (AUC). cose tolerance (19). AIR was calculated as the mean of 2- and 4-min insulin concentrations after glu- RESULTS — During the 5-year fol- RESEARCH DESIGN AND cose administration and DI as the product low-up period, 128 (15.5%) of 826 IRAS METHODS — The design and meth- of SI and AIR. participants developed type 2 diabetes: ods of the IRAS have been described else- Race/ethnicity was assessed by self- 44 (7.9%) of 557 participants with nor- where (19). Briefly, the study was report. Family history of diabetes was de- mal glucose tolerance at baseline, and 84 conducted at four clinical centers. Cen- fined as diabetes in parents or siblings. (31.2%) of 269 participants with IGT at ters in Oakland and Los Angeles, Califor- Anthropometric variables and blood baseline. Those participants converting to nia, recruited non-Hispanic whites and pressure were obtained by trained per- type 2 diabetes did not differ from non- African Americans from Kaiser Perma- sonnel. Plasma glucose and insulin con- converters in terms of sex or ethnicity (Ta- nente, a nonprofit HMO. Two other cen- centrations were determined by the ble 1). However, older age and family ters in San Antonio, Texas, and San Luis glucose oxidase and dextran-charcoal ra- history of diabetes were more common Valley, Colorado, recruited non-Hispanic dioimmunoassay methods, respectively. among converters. Converters also had whites and Hispanics from two ongoing This last assay displays a high degree of higher BMI and waist circumference, population–based studies, the San Anto- cross-reactivity with proinsulin. The higher glucose and insulin levels, and nio Heart Study and the San Luis Valley 1999 World Health Organization criteria lower SI, AIR, DI, and SG. Diabetes Study. A total of 1,625 individ- were used to define diabetes (fasting glu- In linear regression models, SG was Ն uals were enrolled (56% women) be- cose concentration 7.0 mmol/l, 2-h directly related to SI (parameter esti- tween October 1992 and April 1994. A plasma glucose concentration Ն11.1 mate ϫ 1 SD, 0.11 Ϯ 0.02, P Ͻ 0.001), follow-up examination was performed 5 mmol/l, or treatment with hypoglycemic AIR (parameter estimate ϫ 1 SD, 0.22 Ϯ years after the baseline examination medications) and IGT (2-h plasma glu- 0.03, P Ͻ 0.001), and DI (parameter es- (range 4.5–6.6 years). The response rate cose level between Ն7.8 and Ͻ11.1 timate ϫ 1 SD, 0.29 Ϯ 0.05, P Ͻ 0.001) was 81%. Protocols were approved by lo- mmol/l). after accounting for the effects of age, sex, cal institutional review committees. All race/ethnicity, and research center.
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