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Cardiovascular and Metabolic Risk ORIGINAL ARTICLE

Insulin Resistance, the , and Risk in Type 1 “Double diabetes” in the Diabetes Control and Complications Trial

1 ERIC S. KILPATRICK, MD, FRCPATH with (11–13). When 2 ALAN S. RIGBY, MSC present in type 1 diabetes, the phrase 3 STEPHEN L. ATKIN, PHD, FRCP “double diabetes” has been coined (14), with the assumption that these are likely to be at especially high risk of OBJECTIVE — The presence of resistance and the metabolic syndrome are known developing cardiovascular . risk markers for macrovascular disease in patients with and without . This study Beyond the use of labor-intensive and has examined whether these also were predictors of micro- and macrovascular complications in invasive euglycemic-hyperinsulinemic type 1 diabetic patients participating in the Diabetes Control and Complications Trial (DCCT). clamp techniques, estimation of in type 1 diabetes is difficult RESEARCH DESIGN AND METHODS — International Diabetes Federation (IDF) cri- teria were used to identify the metabolic syndrome in 1,337 Caucasian DCCT patients at base- because simpler tools such as the ho- line. Insulin resistance was calculated using their estimated disposal rate (eGDR). Insulin meostasis model are not applicable for dose (units/kg) was also used as a separate marker of insulin resistance. this group of patients (15). Clinically, in- sulin resistance in type 1 diabetic patients RESULTS — The eGDR (but not insulin dose or metabolic syndrome) at baseline strongly is often recognized by their larger require- predicted the development of retinopathy, nephropathy, and (hazard ments for insulin, but more recently a val- ratios 0.75, 0.88, and 0.70, respectively, per mg kgϪ1 minϪ1 change; P Ͻ 0.001, P ϭ 0.005, ϭ idated method for estimated glucose and P 0.002, respectively). Through mainly , the prevalence of the metabolic disposal rate (eGDR) has been developed syndrome increased steadily from baseline to year 9 in conventionally treated (from 15.5 to 27.2%) and especially in the intensively treated (from 13.7 to 45.4%) patients. (16). This calculates a score based on clin- ical factors of the , which shows a CONCLUSIONS — Higher insulin resistance at baseline in the DCCT (as estimated by close relationship to insulin resistance eGDR) was associated with increased subsequent risk of both micro- and macrovascular com- when formally measured by the clamp plications. Insulin dose and the presence of IDF-defined metabolic syndrome were poor predic- method. Using this technique, data from tors by comparison. Although intensive treatment was associated with a higher subsequent the Pittsburgh Epidemiology of Diabetes prevalence of metabolic syndrome, the benefits of improved glycemia appear to outweigh the Complications Study has found low risks related to development of the metabolic syndrome. eGDR (and therefore high insulin resis- tance) to be associated with an increased Diabetes Care 30:707–712, 2007 risk of nephropathy (17), peripheral vas- cular disease (18), and coronary artery he metabolic syndrome is a cluster tions for the metabolic syndrome (7–9), disease (19). By comparison, few studies of metabolically related cardiovas- with the most recent being the consensus have looked at the metabolic syndrome T cular risk factors, the core compo- from the International Diabetes Federa- itself in type 1 diabetes using current cri- nents of which comprise of central tion (IDF) (10). teria. Data to date has shown that in a , insulin resistance, , Central to the development of the cross-section of type 1 diabetic patients and (1). The presence of the metabolic syndrome appears to be the there was an association between the metabolic syndrome predicts the risk of presence of increased insulin resistance. presence of the metabolic syndrome and cardiovascular disease in nondiabetic Although this is a characteristic usually that of nephropathy and poor glycemic subjects as well as in those with type 2 associated with the development of type 2 control (20). diabetes (2–6). There are multiple defini- diabetes, it can also be a feature of patients ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● The Diabetes Control and Complica-

1 2 tion Trial (DCCT) was performed at a From the Department of Clinical Biochemistry, Hull Royal Infirmary, Hull, U.K.; the Academic Depart- time before patients with diabetes were ment of Cardiology, University of Hull, Hull, U.K.; and the 3Department of Diabetes, Hull York Medical School, Hull, U.K. routinely prescribed lipid-lowering and Address correspondence and reprint requests to Prof. Eric S. Kilpatrick, Department of Clinical Biochem- antihypertensive treatment (21). This istry, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ. E-mail: [email protected]. means that it is a dataset that can investi- Received for publication 22 September 2006 and accepted in revised form 9 December 2006. gate factors that influence the risk of de- Abbreviations: DCCT, Diabetes Control and Complications Trial; eGDR, estimated glucose disposal rate; IDF, International Diabetes Federation; NCEP, National Cholesterol Education Program. veloping diabetes complications while A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion being free from many of the confounding factors for many substances. factors found in contemporary studies. DOI: 10.2337/dc06-1982 This current study has analyzed the © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby DCCT data to establish how the metabolic marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. syndrome, insulin resistance, and insulin

DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 707 Insulin resistance in type 1 diabetes

Table 1—Demographic and other baseline features change from baseline of three or more units on the Early IDF metabolic syndrome Treatment Study score on any two succes- sive annual evaluations. During the 9 Variable Yes No years of follow-up, 242 people developed n 291 1,046 sustained retinopathy, 67 of whom were Age (years) 26.5 Ϯ 7.5 27.0 Ϯ 6.9 in the intensive treatment group. Ne- circumference (cm) 96.1 Ϯ 13.4 87.8 Ϯ 10.2 phropathy was defined as an increase in 2 Ϯ Ϯ albumin excretion rate Ն40 mg/24 h (28 BMI (kg/m ) 24.7 2.9 23.1 2.7 ␮ HDL cholesterol (mmol/l) 1.08 Ϯ 0.19 1.37 Ϯ 0.32 g/min) on any annual evaluation pro- Ϯ Ϯ viding that the baseline albumin excretion (mmol/l) 1.13 0.69 0.87 0.48 Ͻ ␮ Systolic blood pressure (mmHg) 115.3 Ϯ 12.2 114.1 Ϯ 11.4 rate was 40 mg/dl (28 g/min) (22). Diastolic blood pressure (mmHg) 73.7 Ϯ 9.4 72.5 Ϯ 8.6 Cardiovascular events during the trial eGDR (mg kgϪ1 minϪ1) 7.4 Ϯ 1.7 8.3 Ϯ 1.3 were those as defined as by the DCCT A1C (%) 9.2 Ϯ 1.6 8.8 Ϯ 1.5 group and included angina, fatal and Blood glucose (mmol/l) 12.7 Ϯ 5.3 12.0 Ϯ 4.9 nonfatal , coronary revascularization, and major electrocar- Data are means Ϯ SD. A total of 54 subjects did not have waist circumference measured. A further 50 non-Caucasians were excluded. diogram events (23). Analysis was per- formed on a time-to-first-event basis. In addition to these 31 initial events, there dosage at trial baseline related to the sub- cose management on the development of were another 73 macrovascular events in- sequent risk of developing micro- and the microvascular complications of diabe- cluding those affecting cerebrovascular macrovascular complications in this tes. The study participants were random- and peripheral arteries. group of patients with type 1 diabetes. ized into intensive (n ϭ 711) and conventional (n ϭ 730) treatment groups. The study did not include individuals at Metabolic syndrome RESEARCH DESIGN AND especially high cardiovascular risk, as Metabolic syndrome was defined accord- METHODS both hypertension and severe dyslipide- ing to the recent IDF consensus criteria mia were exclusion criteria. (10). These criteria make central obesity The datasets essential for the diagnosis. Central obesity We used the publicly accessible datasets was defined as a waist circumference Ն94 collected by the DCCT, which was stored Definition of events cm (in male subjects), Ն80 cm (in female in SAS format (available at www.gcrc. Severity of retinopathy was determined subjects), and/or a BMI Ն30 kg/m2. Since umn.edu). The DCCT was a 9-year fol- by the 25-point Early Diabetic Retinopa- we used the Europid definition for waist low-up study of 1,441 participants with thy Treatment Study interim score (21). circumference, races other than Cauca- type 1 diabetes comparing the effect of The development and progression of sus- sians were excluded (n ϭ 50). In addition intensive versus conventional blood glu- tained retinopathy was defined as a to central obesity, the metabolic syn- drome required the presence of any two additional criteria, namely raised triglyc- erides (Ͼ1.7 mmol/l), reduced HDL cho- lesterol (Ͻ1.03 mmol/l in male subjects and Ͻ1.29 mmol/l in female subjects), raised blood pressure (systolic Ն130 mmHg, diastolic Ն85 mmHg), or raised plasma glucose (Ͼ5.6 mmol/l). All DCCT patients were assumed to fulfill the latter criterion. Although many of these risk factors are known to track with age (and many of the individuals in the DCCT were adolescents), none of the currently recommended definitions of metabolic syndrome (10) vary their thresholds ac- cording to subject age. Waist circumference was only re- corded at baseline, whereas BMI data were collected annually. To determine the prevalence of metabolic syndrome throughout the DCCT study period, we used a BMI threshold of Ն25 kg/m2 in- stead (10). Indeed, the waist circumfer- Figure 1—Criteria in addition to raised waist circumference defining study patients at baseline as ence cutoffs described above were having the metabolic syndrome. originally chosen because they were felt,

708 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 Kilpatrick, Rigby, and Atkin

Table 2—IDF-defined metabolic syndrome by randomization group (102 cm for male subjects and 88 cm for female subjects). Metabolic Assessment Intervention group Total syndrome (n) Relative risk (95% CI) Insulin resistance and insulin dose Baseline Conventional 722 112 1.0 Insulin resistance was calculated using Intensive 705 97 0.9 (0.7–1.1) the eGDR according to the following 1 year Conventional 715 122 1.0 equation: 24.31 Ϫ (12.22 ϫ WH) Ϫ Intensive 694 141 1.2 (1.0–1.5) (3.29 ϫ HT) Ϫ (0.57 ϫ A1C), where the Ϫ Ϫ 2 years Conventional 715 124 1.0 units are mg kg 1 min 1, the WH ϭ Intensive 673 166 1.4 (1.2–1.8) waist-to-hip ratio, and HT ϭ hyperten- 3 years Conventional 708 128 1.0 sion (16). This formula has been adapted Intensive 654 176 1.5 (1.2–1.8) for the use of A1C rather than HbA (20). 4 years Conventional 701 146 1.0 1 Insulin dose was measured in units per Intensive 643 184 1.4 (1.1–1.7) 5 years Conventional 616 124 1.0 kilogram body weight at baseline. Intensive 549 196 1.8 (1.5–2.2) 6 years Conventional 422 80 1.0 Intensive 397 135 1.8 (1.4–2.3) Statistical methods 7 years Conventional 265 70 1.0 The relationship between the baseline co- Intensive 246 98 1.5 (1.2–1.9) variates and the time-to-event data (e.g., 8 years Conventional 159 41 1.0 retinopathy development) was carried Intensive 147 55 1.5 (1.0–2.0) out by Cox proportional hazards model- 9 years Conventional 125 34 1.0 ing. Statistical modeling of time-to-event Intensive 119 54 1.7 (1.2–2.4) data are known in general terms as “sur- Metabolic syndrome by IDF criteria, but using BMI Ն25 kg/m2 to replace waist circumference, which was vival analysis.” A distinguishing feature of not measured annually. survival data is that the end of the fol- low-up period will not have occurred in all patients. In such patients, the survival based on Europid data, to be the best val- requirement using the NCEP definition, 2 time is said to be “censored.” This censor- ues for identifying a BMI Ն25 kg/m but at least three risk factors are required ing makes survival models difficult to an- (10,24). The other IDF criteria remained from a possible five. Four of these five alyze statistically (25) but was made unchanged. factors comprise raised triglycerides, re- possible by the theoretical development While concentrating analysis on the duced HDL cholesterol, raised blood of the Cox proportional hazards model IDF definition of metabolic syndrome, we pressure, and raised fasting plasma glu- (26). also established which patients met the cose using the same criteria as the IDF In the DCCT data the Cox model al- previous National Cholesterol Education definition, but the fifth—waist circumfer- lows for the prediction of retinopathy Program (NCEP) Adult Treatment Panel ence—uses thresholds that are greater III criteria (8). Obesity is not an absolute from a given set of baseline covariates, such as eGDR and metabolic syndrome. The covariates may be continuous, bi- nary, or categorical. The relationship be- tween the covariates and retinopathy is expressed by the hazard ratio (HR) (es- sentially the risk of, say, retinopathy for a given covariate). A key statistical assump- tion is that the HR is constant over time (known as proportionality of hazards). This “proportionality” assumption can be tested by residual plotting (27). The pre- cision of the HR is determined from the 95% CI; the narrower the CI the more precise the HR and vice versa. The P value, which represents the probability of a false-positive result, was calculated by the likelihood ratio test statistic, the cal- culation of which determines whether an association between a baseline covariate and retinopathy is random or not (albeit at an arbitrary level of 5%). The GLIM4 Figure 2—Prevalence of IDF-defined metabolic syndrome by randomization group throughout and SPSS statistical computer packages the study period. f, intensively treated group; , conventionally treated group. were used to analyze the data (28).

DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 709 Insulin resistance in type 1 diabetes

Table 3—Cox regression models relating metabolic syndrome and measures of insulin resis- diovascular for which there were tance to microvascular risk too few events). The relationship between eGDR and complication outcome was Variable Retinopathy P value Nephropathy P value stronger in the conventionally treated group. The HR for any macrovascular dis- Metabolic syndrome 0.85 (061–1.18) 0.33 0.98 (0.71–1.35) 0.91 ease in the conventionally treated group eGDR 0.75 (0.69–0.81) Ͻ0.001 0.88 (0.80–0.96) 0.005 was 0.81 (0.70–1.00; P ϭ 0.05) per unit Insulin dose 0.77 (0.41–1.45) 0.42 1.61 (0.93–2.82) 0.09 change, with the HR in the intensive Data are HR (95% CI). Units for eGDR are mg kgϪ1 minϪ1 and for insulin dose are units per kilogram body group 0.85 (0.70–1.04; P ϭ 0.11). The weight. Models adjusted for the following baseline covariates: age, sex, disease duration, randomization HR for retinopathy in the conventionally treatment (conventional/intensive), and prevention cohort (primary/secondary). treated group was 0.69 (0.62–0.76; P Ͻ 0.001), while in the intensive group was Ϫ RESULTS mean (median) eGDR was 8.11 mg kg 1 0.83 (0.72–0.96; P ϭ 0.013). The HR for Ϫ min 1 (8.21) (SD 1.49). One quarter nephropathy in the conventionally Metabolic syndrome (n ϭ 344) had an eGDR Ͼ9.03. The mean treated group was 0.84 (0.74–0.95; P ϭ Using the IDF criteria, 291 patients (22% (median) dose of insulin at baseline was 0.005), while in the intensive group was of those with complete data and after ex- 0.67 units/kg (0.63) (range 0.08–2.06). 0.92 (0.80–1.06; P ϭ 0.24). There were cluding non-Caucasians) had metabolic fewer micro- and macrovascular events in syndrome at baseline; 1,046 did not have Cox regression both groups separately (especially in the metabolic syndrome; 61 did not have Multivariable Cox regression models for intensively treated patients), so any differ- their waist circumference recorded, 7 of both microvascular and macrovascular ences in statistical significance could be a whom had a BMIՆ30 kg/m2. Thirty-two risks are presented in Tables 3 and 4, re- function of reduced power. percent (n ϭ 93) of patients with meta- spectively. After adjusting for insulin dose bolic syndrome were male compared with and the presence of metabolic syndrome, CONCLUSIONS — This study has 59% (n ϭ 620) without metabolic syn- there was still a significant inverse associ- shown that DCCT patients with the high- drome. Other demographic features are ation between lower eGDR at baseline and est insulin resistance at their baseline visit presented in Table 1. Those without waist a subsequent increased risk of retinopa- (as assessed by a low eGDR) were at the circumference recorded were younger thy and nephropathy progression (Table highest subsequent risk of developing the (mean age 24.9 years) and had lower BMI 2), cardiovascular events, and macrovas- microvascular and macrovascular com- on average (22.6 kg/m2) than the rest, and cular disease (Table 3). By comparison, plications of type 1 diabetes, indepen- 24 (44%) were male. there were no significant relationships dently of their assigned treatment group. The Venn diagram (Fig. 1) shows between baseline metabolic syndrome or In comparison, the presence of the meta- which factors (raised blood pressure, high insulin dose on microvascular or macro- bolic syndrome at the start of the study, triglycerides, and low HDL cholesterol) vascular disease risk. In addition, models defined using IDF criteria, showed little classified patients as having the metabolic that did not adjust eGDR, metabolic syn- predictive value. Furthermore, a clinical syndrome. Most patients had low HDL drome, and insulin dose for one another estimate of insulin resistance—the insulin cholesterol (n ϭ 247); a further 47 had yielded similar results, as did further ad- dose required by a patient in units per high triglycerides, while 28 had raised justment for smoking. Substituting the kilogram body weight—was also a poor blood pressure. Only one patient had all NCEP in place of the IDF definition of predictor of future complications. three of these criteria together. metabolic syndrome did not alter the Our findings in relation to the value The changing prevalence of the met- findings either. The waist-to-hip ratio was of the eGDR in predicting those patients abolic syndrome, using BMI rather than measured at the iliac crest. Replacing this at highest risk of small- and large-vessel waist circumference criteria, are pre- by the “natural” waist-to-hip ratio made disease are consistent with those from the sented in Table 2 and Fig. 2. The preva- little difference to the HRs. The eGDR did Pittsburgh Epidemiology of Diabetes lence of metabolic syndrome increases in not seem to be superior to baseline A1C Complications Study. This prospective both conventionally and intensively (itself a component of eGDR) for predict- cohort study found low eGDR to be asso- treated groups but at a statistically higher ing any of the complications studied. ciated with the risk of nephropathy (17), rate in the latter group from year 1 on- peripheral vascular disease (18), and cor- wards. The baseline prevalence of BMI Subgroup analyses onary artery disease (19). An analysis of Ն25 kg/m2 was 25.6% in the intensively We carried out Cox modeling stratifying the cross-sectional FinnDiane study also treated group and 27.9% in the conven- by randomization group (excepting car- showed that type 1 diabetic patients with tionally treated patients. This rose to 61.0 and 45.0%, respectively, by year 9 of the study. Mainly as a consequence of the Table 4—Cox regression models relating metabolic syndrome and measures of insulin resis- higher waist circumference thresholds, tance to macrovascular risk fewer patients (n ϭ 114) had metabolic syndrome at baseline when defined by Variable Cardiovascular P value Any macrovascular P value NCEP criteria. Metabolic syndrome 1.15 (0.41–3.20) 0.79 1.15 (0.69–1.92) 0.60 Insulin resistance and insulin dose eGDR 0.70 (0.56–0.88) 0.002 0.83 (0.73–0.96) 0.009 All subjects with a waist measurement Insulin dose 3.35 (0.58–19.5) 0.18 1.45 (0.55–3.87) 0.45 also had a waist-to-hip ratio (20). The Data are HR (95% CI). Notes: Models adjusted as in Table 3.

710 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 Kilpatrick, Rigby, and Atkin had lower eGDR than likely to develop the metabolic syndrome 2716, 2002 those without but, in contrast to our find- during the course of the study were those 4. Sattar N, Gaw A, Scherbakova O, Ford I, ings, found the metabolic syndrome (de- least likely to have subsequent long-term O’Reilly DSJ, Haffner SM, Isles C, Macfar- fined using NCEP criteria [8]) to be more microvascular and cardiovascular se- lane PW, Packard CJ, Cobbe SM, Shep- common in microalbuminuric patients as quelae (35,38). herd J: Metabolic syndrome with and without c-reactive protein as a predictor well (20). In its defense, the metabolic syn- of coronary disease and diabetes in The same study showed that the met- drome definition was never primarily in- the west of scotland coronary prevention abolic syndrome is a frequent finding in tended for patients with type 1 diabetes, study. Circulation 108:414–419, 2003 type 1 diabetes. We have confirmed this although there continues to be debate 5. Dekker JM, Girman C, Rhodes T, Nijpels to be the case in the DCCT but have also surrounding its value in other clinical sit- G, Stehouwer CDA, Bouter LM, Heine RJ: found that as the study progressed the uations for which it is proposed (39,40). Metabolic syndrome and 10-year cardio- prevalence of the metabolic syndrome, Consideration also has to be given to the vascular disease risk in the Hoorn Study. using BMI rather than waist circumfer- fact that the IDF definition of the meta- Circulation 112:666–673, 2005 ence criteria, increased markedly in both bolic syndrome may not be as specific as 6. Saely CH, Aczel S, Marte T, Langer P, treatment groups. This was especially so other criteria in identifying patients at Hoefle G, Drexel H: The metabolic syn- drome, insulin resistance, and cardiovas- in those treated intensively, which meant high cardiovascular risk because of the cular risk in diabetic and nondiabetic that by year 9 of the study three times as lower waist circumference thresholds patients. J Clin Endocrinol Metab 90: many intensively treated patients remain- used (41). In respect of this current anal- 5698–5703, 2005 ing had the metabolic syndrome than at ysis, the NCEP definition of the metabolic 7. World Organization: Definition, baseline, resulting in nearly half the pa- syndrome at study baseline did not pre- Diagnosis, and Classification of Diabetes tients meeting the IDF criteria. dict complication risk either, although Mellitus and Its Complications. Part 1: Diag- The bulk of this rise was due to the this may be partly related to the fact that nosis and Classification of Diabetes Mellitus: weight gain experienced during the far fewer patients were identified when Report of a WHO Consultation. Alwan study. Since it is known that patients with using these criteria. AKH, Ed. Geneva, World Health Org., type 1 diabetes are at particularly high In summary, this study has shown 1999, p. 1–59 risk of cardiovascular disease already that the IDF definition of the metabolic 8. Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults: Ex- (29–31), there has been concern that this syndrome appears to have little clinical ecutive summary of the Third Report of increase in body weight may only add to utility in distinguishing type 1 diabetic the National Cholesterol Education Pro- this likelihood, with intensively treated patients most likely to develop micro- and gram (NCEP) Expert Panel on Detection, patients being placed at especial risk. In- macrovascular disease. Indeed, some pa- Evaluation, and Treatment of High Blood deed, in the DCCT itself the excess weight tients who acquire this label might have Cholesterol in Adults (Adult Treatment gain with intensive was associ- done so through the pursuit of glycemic Panel III). JAMA 285:2486–2497, 2001 ated with increases in visceral adiposity goals that may ultimately reduce their risk 9. Balkau B, Charles MA: Comment on the (32), which had consequent deleterious of complications. Assessing insulin resis- provisional report from the WHO consul- effects on lipids, blood pressure (33), and tance through the dosage of insulin taken tation: European Group for the Study of inflammatory markers (34). However, de- by an individual was equally poor at pre- Insulin Resistance (EGIR). Diabet Med 16: 442–443, 1999 spite these concerns, the long-term fol- dicting outcome. By contrast, assessing 10. Alberti KGMM, Zimmet P, Shaw J: Meta- low-up study of the DCCT cohort (the insulin resistance by calculating the eGDR bolic syndrome: a new world-wide defi- Epidemiology of Diabetes Interventions identified type 1 diabetic patients who nition: a consensus statement from the and Complications) has found that inten- were at highest risk of subsequent small International Diabetes Federation. Diabet sive treatment during just the period of and large vessel disease. Med 23:469–480, 2006 the DCCT greatly reduced, rather than in- 11. DeFronzo RA, Simonson D, Ferrannini E: creased, the long-term risk of cardiovas- Hepatic and peripheral insulin resistance: cular disease by 42% (35). Differences in Acknowledgments— We thank the DCCT a common feature of type 2 (non-insulin- A1C during the DCCT (rather than sim- investigators for making their trial dataset dependent) and type 1 (insulin-depen- ply changes in known cardiovascular risk public and therefore allowing independent in- dent) diabetes mellitus. Diabetologia 23: vestigators to analyze their work for the benefit 313–319, 1982 factors) seemed to account for much of of patients with type 1 diabetes. 12. DeFronzo RA, Hendler R, Simonson D: the benefit. Thus, together with the find- Insulin resistance is a prominent feature ings from other studies (36,37), it indi- of insulin-dependent diabetes. Diabetes cates that there is likely to be a net benefit References 31:795–801, 1982 to improving glycemic control in type 1 1. Reaven G: Banting Lecture 1988: Role of 13. 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