Edward J. Boyko

Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function

To determine the relationship between insulin sensitivity and β-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18–44 yr of age; body mass index 19.5–52.2 kg/m2) and with fasting glucose levels <6.4 mM. SI was compared with measures of body adiposity and β-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the β-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and β-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the β-cell measures could not be distinguished from a hyperbola, i.e., SI × β-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, β-cell function varies quantitatively with differences in insulin sensitivity. Because the function governing this relationship is a hyperbola, when insulin sensitivity is high, large changes in insulin sensitivity produce relatively small changes in insulin levels and responses, whereas when insulin sensitivity is low, small changes in insulin sensitivity produce relatively large changes in insulin levels and responses. Percentile plots based on knowledge of this interaction are presented for evaluating β-cell function in populations and over time.

Alcohol Use and Alcohol-Related Problems Before and After Military Combat Deployment

CONTEXT High rates of alcohol misuse after deployment have been reported among personnel returning from past conflicts, yet investigations of alcohol misuse after return from the current wars in Iraq and Afghanistan are lacking. OBJECTIVES To determine whether deployment with combat exposures was associated with new-onset or continued alcohol consumption, binge drinking, and alcohol-related problems. DESIGN, SETTING, AND PARTICIPANTS Data were from Millennium Cohort Study participants who completed both a baseline (July 2001 to June 2003; n=77,047) and follow-up (June 2004 to February 2006; n=55,021) questionnaire (follow-up response rate = 71.4%). After we applied exclusion criteria, our analyses included 48,481 participants (active duty, n = 26,613; Reserve or National Guard, n = 21,868). Of these, 5510 deployed with combat exposures, 5661 deployed without combat exposures, and 37 310 did not deploy. MAIN OUTCOME MEASURES New-onset and continued heavy weekly drinking, binge drinking, and alcohol-related problems at follow-up. RESULTS Baseline prevalence of heavy weekly drinking, binge drinking, and alcohol-related problems among Reserve or National Guard personnel who deployed with combat exposures was 9.0%, 53.6%, and 15.2%, respectively; follow-up prevalence was 12.5%, 53.0%, and 11.9%, respectively; and new-onset rates were 8.8%, 25.6%, and 7.1%, respectively. Among active-duty personnel, new-onset rates were 6.0%, 26.6%, and 4.8%, respectively. Reserve and National Guard personnel who deployed and reported combat exposures were significantly more likely to experience new-onset heavy weekly drinking (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.36-1.96), binge drinking (OR, 1.46; 95% CI, 1.24-1.71), and alcohol-related problems (OR, 1.63; 95% CI, 1.33-2.01) compared with nondeployed personnel. The youngest members of the cohort were at highest risk for all alcohol-related outcomes. CONCLUSION Reserve and National Guard personnel and younger service members who deploy with reported combat exposures are at increased risk of new-onset heavy weekly drinking, binge drinking, and alcohol-related problems.

The Independent Contributions of Diabetic Neuropathy and Vasculopathy in Foot Ulceration: How Great Are the Risks?

OBJECTIVE To describe the relative contributions of neurological and vascular abnormalities to the overall risk of diabetic foot ulceration. RESEARCH DESIGN AND METHODS A case-control study of diabetic veterans from the Seattle Veterans Affairs Medical Center was conducted using data collected from 46 patients with diabetic foot ulcers and 322 control subjects. Neuropathy was determined by vibratory, monofilament, and tendon reflex testing. Macro-vascular disease was measured by ankle-arm blood pressure index, and cutaneous perfusion was measured by transcutaneous oxygen tension (TcPO2) on the dorsal foot. A multi variate logistic regression model was used to adjust for confounding variables and to calculate the odds ratios (ORs) for each independent risk factor. RESULTS Three variables were significant independent predictors of foot ulceration: absence of Achilles tendon reflexes (adjusted OR 6.48, 95% confidence interval [CI] 2.37–18.06), insensate to the 5.07 monofilament (adjusted OR 18.42, 95% CI 3.83–88.47), and TcPO2 <30 mmHg (adjusted OR 57.87, 95% CI 5.08–658.96). Absent vibratory sensation and low ankle-arm blood pressure index were not significant independent risk factors. CONCLUSIONS Both neuropathy and vasculopathy are strong independent risk factors for the development of diabetic foot ulcers. In our model, the strongest risk factor is impaired cutaneous oxygenation. However, in the clinical setting, sensory examination with a 5.07 monofilament probably remains the single most practical measure of risk assessment.

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30). RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Risk factors associated with suicide in current and former US military personnel.

IMPORTANCE Beginning in 2005, the incidence of suicide deaths in the US military began to sharply increase. Unique stressors, such as combat deployments, have been assumed to underlie the increasing incidence. Previous military suicide studies, however, have relied on case series and cross-sectional investigations and have not linked data during service with postservice periods. OBJECTIVE To prospectively identify and quantify risk factors associated with suicide in current and former US military personnel including demographic, military, mental health, behavioral, and deployment characteristics. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal study with accrual and assessment of participants in 2001, 2004, and 2007. Questionnaire data were linked with the National Death Index and the Department of Defense Medical Mortality Registry through December 31, 2008. Participants were current and former US military personnel from all service branches, including active and Reserve/National Guard, who were included in the Millennium Cohort Study (N = 151,560). MAIN OUTCOMES AND MEASURES Death by suicide captured by the National Death Index and the Department of Defense Medical Mortality Registry. RESULTS Through the end of 2008, findings were 83 suicides in 707,493 person-years of follow-up (11.73/100,000 person-years [95% CI, 9.21-14.26]). In Cox models adjusted for age and sex, factors significantly associated with increased risk of suicide included male sex, depression, manic-depressive disorder, heavy or binge drinking, and alcohol-related problems. None of the deployment-related factors (combat experience, cumulative days deployed, or number of deployments) were associated with increased suicide risk in any of the models. In multivariable Cox models, individuals with increased risk for suicide were men (hazard ratio [HR], 2.14; 95% CI, 1.17-3.92; P = .01; attributable risk [AR], 3.5 cases/10,000 persons), and those with depression (HR, 1.96; 95% CI, 1.05-3.64; P = .03; AR, 6.9/10,000 persons), manic-depressive disorder (HR, 4.35; 95% CI, 1.56-12.09; P = .005; AR, 35.6/10,000 persons), or alcohol-related problems (HR, 2.56; 95% CI, 1.56-4.18; P <.001; AR, 7.7/10,000 persons). A nested, matched case-control analysis using 20:1 control participants per case confirmed these findings. CONCLUSIONS AND RELEVANCE In this sample of current and former military personnel observed July 1, 2001-December 31, 2008, suicide risk was independently associated with male sex and mental disorders but not with military-specific variables. These findings may inform approaches to mitigating suicide risk in this population.

The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002.

OBJECTIVES:The presence of elevated serum aminotransferase activity is a sign of possible underlying liver disease. We aimed to describe the prevalence and associations of elevated serum aminotransferase activity in a recent, nationally representative U.S. survey.METHODS:We described the prevalence and predictors of elevated alanine aminotransferase (ALT >43 IU/L) or elevated aspartate aminotransferase (AST >40 IU/L) activity among 6,823 participants of the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2002. We compared our findings to the results already published based on the NHANES conducted between 1988 and 1994.RESULTS:In NHANES 1999–2002, the prevalences of elevated ALT, AST, or either ALT or AST were 8.9%, 4.9%, and 9.8%, respectively, in the entire population and 7.3%, 3.6%, and 8.1%, respectively, after excluding participants who tested positive for hepatitis C virus (HCV) antibody or reported excessive alcohol consumption. Strong predictors of elevated ALT activity included increasing waist circumference and body mass index, alcohol consumption, male sex, Mexican American ethnicity, decreasing age, and presence of HCV antibody. In NHANES 1988–1994, which employed a different assay methodology, the prevalences of elevated aminotransferases were approximately half of the prevalences we describe in NHANES 1999–2002, but the predictors of elevated ALT activity were similar.CONCLUSIONS:The current prevalence of elevated ALT activity in the United States (8.9%) is more than double that of previously available estimates. This prevalence is very high (7.3%) even among persons without viral hepatitis C or excessive alcohol consumption and is strongly associated with risk factors for nonalcoholic fatty liver disease.

Visceral Adiposity Is an Independent Predictor of Incident Hypertension in Japanese Americans

Context Central obesity and hypertension are well-established components of the metabolic syndrome, but what exactly is the relationship between visceral adiposity and hypertension? Contribution This prospective study used computed tomography to measure multiple body fat areas of 300 middle-aged, normotensive Japanese Americans. Ninety-two participants developed hypertension within 10 to 11 years. Greater visceral adiposity, independent of other measures of body fat and other risk factors, such as plasma insulin and glucose levels, was associated with increased risk for hypertension. Cautions Relationships between visceral adiposity and the development of hypertension may vary in different ethnic groups. The Editors A central pattern of body fat distribution is now generally considered to play an important role in the metabolic syndrome, which involves obesity, insulin resistance, hyperinsulinemia, dyslipidemia, glucose intolerance, and hypertension (1, 2). In particular, visceral adiposity rather than regional or generalized obesity appears to play a key role in these diseases (3-7). Several cross-sectional and prospective studies have examined associations between hypertension and greater central obesity, as measured by waist circumference, the ratio of waist-to-hip circumference, or the ratio of subscapular-to-triceps skinfold thickness (8-15). The cross-sectional studies have reported a positive association (8, 9), but the prospective studies have been inconclusive (10-15). These studies have posited that visceral adiposity and insulin resistance are the most important factors linking greater abdominal obesity (as assessed by surface measurements) and hypertension. Although visceral fat is thought to affect the prevalence of hypertension, only 3 cross-sectional studies have suggested a possible association between visceral adiposity (measured by using computed tomography [CT]) and blood pressure (3, 4, 16); however, the results of these studies were inconclusive. No prospective studies have examined whether directly measured visceral fat is associated with an increased risk for incident hypertension. Therefore, we prospectively examined the relationship between directly measured visceral adiposity and the risk for incident hypertension, independent of other measurements of total and regional adiposity and fasting plasma insulin. Methods Study Sample Between 1983 and 1988, we enrolled 658 second- and third-generation Japanese Americans who were between 34 and 76 years of age (mean age, 54.2 years) into the Japanese American Community Diabetes Study (17, 18). Participants were chosen from volunteers through community-wide recruitment and were representative of Japanese-American residents of King County, Washington, in age distribution, residential distribution, and parental immigration pattern. A comprehensive mailing list and telephone directory that included almost 95% of the Japanese-American population of King County, Washington, was used. All participants were of 100% Japanese ancestry. Participants returned for follow-up examinations 5 to 6 and 10 to 11 years after a baseline evaluation. For the current analysis, eligible participants had systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg and were not taking antihypertensive or oral hypoglycemic medications or insulin. We excluded 277 of the 658 participants in the original cohort because they did not meet the inclusion criteria. We excluded an additional 67 persons because of death, loss to follow-up, or withdrawal from the study. Another 14 persons who completed follow-up but had missing covariate information were also excluded. The analytic cohort consisted of 300 persons (Figure). The follow-up rate in the present study was 91% (345 of 381) at the 5- to 6-year examination and 80% (304 of 381) at the 10- to 11-year examination (Figure). Figure. Flow of participants through the study. Data Collection All measurements were made in the General Clinical Research Center at the University of Washington, Seattle, Washington. The Human Subjects Review Committee at the University of Washington approved the protocol for this research, and we obtained signed informed consent from all participants. At all examinations, blood pressure was measured to the nearest 2 mm Hg with a mercury sphygmomanometer while the participant was in a recumbent position. Systolic blood pressure was determined by the first perception of sound, and diastolic blood pressure was determined at the disappearance of sounds (fifth-phase Korotkoff). Average blood pressure was calculated from the second and third of 3 consecutive measurements. We diagnosed hypertension at baseline or follow-up if the average systolic blood pressure was 140 mm Hg or greater, the average diastolic blood pressure was 90 mm Hg or greater, or the participant was receiving antihypertensive medications. We classified participants as hypertensive if they met these criteria at the follow-up examination at 5 to 6 years or 10 to 11 years (Figure). All patients received a 75-g oral glucose tolerance test after a 10-hour fast. We then used the American Diabetes Association criteria (19) to classify patients as having normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes mellitus. Blood samples were drawn after an overnight 10-hour fast and during an oral glucose tolerance test for measurement of plasma glucose and insulin levels. We used an automated glucose oxidase method to assay plasma glucose. Fasting plasma insulin was measured by radioimmunoassay, as reported previously (5, 7). We measured triglyceride and high-density lipoprotein cholesterol levels in the Northwest Lipid Research Laboratory, according to modified procedures of the Lipid Research Clinics (20). We calculated body mass index (BMI) as the weight in kilograms divided by height in meters squared. For CT scans, we used single slices of the thorax, abdomen (at the umbilicus), and mid-thigh to measure cross-sectional subcutaneous thoracic, abdominal, and right thigh and intra-abdominal fat areas (measured in cm2), as described elsewhere (21). We directly estimated visceral adiposity from the intra-abdominal fat area. This measurement has been reported to have a high correlation with directly ascertained total visceral fat volume measured by using CT or magnetic resonance imaging (22, 23). We calculated total subcutaneous fat area as the sum of subcutaneous thoracic and abdominal fat areas and twice the right thigh subcutaneous fat area. We defined total fat area as total subcutaneous fat area plus intra-abdominal fat area. Among Japanese Americans, total fat area correlates highly with fat mass, as measured by hydrodensitometry (r= 0.89 to 0.94) (24). Waist circumference was measured at the level of the umbilicus to the nearest tenth of a centimeter. Participants were questioned about current use of cigarettes and daily consumption of alcoholic beverages, which was converted into grams of alcohol consumed per day. Usual weekly energy expenditure in kilocalories was estimated from questionnaire data on work and recreational activities, strenuous exercise, distance walked, and stairs climbed, as described elsewhere (25). Statistical Analysis We used multiple logistic regression analysis to estimate the odds ratio for incident hypertension in relation to an increase of 1 SD in baseline variables. For rare outcomes, the odds ratio will approximately equal the relative risk. For more frequent outcomes, such as hypertension, the odds ratio will overestimate the relative risk (26). We evaluated nonlinear effects of continuous independent variables by using quadratic and log transformations (27). The linear trends in odds were evaluated by using the median value for each quartile category of continuous variables. To assess departure from linearity, we included linear and quadratic terms (the median and the value squared) in the model (28). To determine whether interaction was present (that is, the relationship between the risk factor and the outcome varied depending on the value of a third variable) (27, 29, 30), we inserted first-order interaction terms into appropriate regression models. We assessed interaction to determine whether the relationship between hypertension status at follow-up and baseline adipose variables, such as intra-abdominal fat area, subcutaneous abdominal fat area, total subcutaneous fat area, BMI, or waist circumference, differed according to the level of an additional variable (for example, sex) in the model. We used the likelihood ratio test to determine the statistical significance of nonlinear effects of continuous independent variables and interaction terms in the logistic regression models. Multicollinearity was assessed by using the variance inflation factor (31). A variance inflation factor exceeding 10 is regarded as indicating serious multicollinearity, and values greater than 4.0 may be a cause for concern (31). We calculated the 95% CI for each odds ratio. P values were 2-tailed. We performed statistical analyses using Stata SE, version 8.0 (Stata Corp., College Station, Texas). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Among the 300 eligible men and women followed for 10 to 11 years, there were 92 incident cases of hypertension. In univariate logistic regression analysis, intra-abdominal fat area, abdominal subcutaneous fat area, total subcutaneous fat area, total fat area, BMI, and waist circumference were associated with a higher incidence of hypertension. Fasting plasma insulin level, fasting plasma glucose level, 2-hour plasma glucose level, and high-density lipoprotein cholesterol level were also associated with incidence of hypertension (Table 1). Wealso compared the baseline characteristics of participants included in

Prediction of Diabetic Foot Ulcer Occurrence Using Commonly Available Clinical Information: The Seattle Diabetic Foot Study

OBJECTIVE—The ability of readily available clinical information to predict the occurrence of diabetic foot ulcer has not been extensively studied. We conducted a prospective study of the individual and combined effects of commonly available clinical information in the prediction of diabetic foot ulcer occurrence. RESEARCH DESIGN AND METHODS—We followed 1,285 diabetic veterans without foot ulcer for this outcome with annual clinical evaluations and quarterly mailed questionnaires to identify foot problems. At baseline we assessed age; race; weight; current smoking; diabetes duration and treatment; HbA1c (A1C); visual acuity; history of laser photocoagulation treatment, foot ulcer, and amputation; foot shape; claudication; foot insensitivity to the 10-g monofilament; foot callus; pedal edema; hallux limitus; tinea pedis; and onychomycosis. Cox proportional hazards modeling was used with backwards stepwise elimination to develop a prediction model for the first foot ulcer occurrence after the baseline examination. RESULTS—At baseline, subjects were 62.4 years of age on average and 98% male. Mean follow-up duration was 3.38 years, during which time 216 foot ulcers occurred, for an incidence of 5.0/100 person-years. Significant predictors (P ≤ 0.05) of foot ulcer in the final model (hazard ratio, 95% CI) included A1C (1.10, 1.06–1.15), impaired vision (1.48, 1.00–2.18), prior foot ulcer (2.18, 1.61–2.95), prior amputation (2.57, 1.60–4.12), monofilament insensitivity (2.03, 1.50–2.76), tinea pedis (0.73, 0.54–0.98), and onychomycosis (1.58, 1.16–2.16). Area under the receiver operating characteristic curve was 0.81 at 1 year and 0.76 at 5 years. CONCLUSIONS—Readily available clinical information has substantial predictive power for the development of diabetic foot ulcer and may help in accurately targeting persons at high risk of this outcome for preventive interventions.

Risk Factors for Diabetic Peripheral Sensory Neuropathy Results of the Seattle Prospective Diabetic Foot Study

OBJECTIVE To identify risk factors for diabetic lower-extremity peripheral sensory neuropathy prospectively in a cohort of U.S. veterans with diabetes. RESEARCH DESIGN AND METHODS General medicine clinic outpatients with diabetes were followed prospectively for the development of insensitivity to the 5.07 monofilament on the foot. RESULTS Of 775 subjects, 388 (50%) had neuropathy at baseline. Of the 387 subjects without neuropathy at baseline, 288 were followed up, and of these, 58 (20%) developed neuropathy. Multivariate logistic regression modeling of prevalent neuropathy controlling for sex and race revealed independent and significant associations with age, duration of diabetes, glycohemoglobin level, height, history of lower-extremity ulceration, callus, and edema; an independent and inverse correlation was noted with ankle-arm index. Risk factors for incident neuropathy in multivariate logistic regression included age, baseline glycohemoglobin level, height, history of ulcer, and CAGE screening instrument alcohol score; current smoking and albumin level were inversely associated with risk. CONCLUSIONS Poorer glycemic control increases the risk of neuropathy and is amenable to intervention. Height and age directly increase risk of neuropathy and may help identify patients at risk. A proportion of neuropathy in diabetic veterans is probably due to or worsened by alcohol ingestion. Neuropathy was less common in current smokers than subjects not currently smoking.

Chronology and Determinants of Tissue Repair in Diabetic Lower-Extremity Ulcers

The natural history of tissue repair and the critical determinants of faulty healing of diabetic ulcers remain obscure despite recent advances in our knowledge of the cellular physiology of normal cutaneous healing. To characterize the chronology and identify important factors affecting healing, we applied an objective method to quantify the rate of wound healing of full-thickness lower-extremity ulcers in 46 diabetic outpatients who received local wound care under a standardized clinical protocol. The initial ulcer healing rate, eventual status of tissue repair, and definitive clinical outcome were not significantly associated with age; diabetes type, duration, or treatment; level or change in glycosylated hemoglobin; current smoking; presence of sensory neuropathy; ulcer location or class; initial infection; or frequency of recurrent infections. However, direct measures of local cutaneous perfusion, estimated by periwound measurements of transcutaneous O2 tension (TcPo2) and transcutaneous CO2 tension (TcPco2), were significantly associated with the initial rate of tissue repair (P = 0.003 and 0.005, respectively). The strong prediction of early healing by these parameters of local skin perfusion was independent from the effects of segmental Doppler arterial blood pressure at the dorsalis pedis, although eventual ulcer reepithelialization was significantly related to foot blood pressure and periwound TcPo2 and TcPco2. We conclude that periwound cutaneous perfusion is the critical physiological determinant of diabetic ulcer healing, indicating a 39-fold increased risk of early healing failure when the average periwound TcPo2 is <20 mmHg.