David K. McCulloch

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.

Collaborative Care for Patients with Depression and Chronic Illnesses

BACKGROUND Patients with depression and poorly controlled diabetes, coronary heart disease, or both have an increased risk of adverse outcomes and high health care costs. We conducted a study to determine whether coordinated care management of multiple conditions improves disease control in these patients. METHODS We conducted a single-blind, randomized, controlled trial in 14 primary care clinics in an integrated health care system in Washington State, involving 214 participants with poorly controlled diabetes, coronary heart disease, or both and coexisting depression. Patients were randomly assigned to the usual-care group or to the intervention group, in which a medically supervised nurse, working with each patients primary care physician, provided guideline-based, collaborative care management, with the goal of controlling risk factors associated with multiple diseases. The primary outcome was based on simultaneous modeling of glycated hemoglobin, low-density lipoprotein (LDL) cholesterol, and systolic blood-pressure levels and Symptom Checklist-20 (SCL-20) depression outcomes at 12 months; this modeling allowed estimation of a single overall treatment effect. RESULTS As compared with controls, patients in the intervention group had greater overall 12-month improvement across glycated hemoglobin levels (difference, 0.58%), LDL cholesterol levels (difference, 6.9 mg per deciliter [0.2 mmol per liter]), systolic blood pressure (difference, 5.1 mm Hg), and SCL-20 depression scores (difference, 0.40 points) (P<0.001). Patients in the intervention group also were more likely to have one or more adjustments of insulin (P=0.006), antihypertensive medications (P<0.001), and antidepressant medications (P<0.001), and they had better quality of life (P<0.001) and greater satisfaction with care for diabetes, coronary heart disease, or both (P<0.001) and with care for depression (P<0.001). CONCLUSIONS As compared with usual care, an intervention involving nurses who provided guideline-based, patient-centered management of depression and chronic disease significantly improved control of medical disease and depression. (Funded by the National Institute of Mental Health; ClinicalTrials.gov number, NCT00468676.).

The effectiveness of disease and case management for people with diabetes: A systematic review

This report presents the results of a systematic review of the effectiveness and economic efficiency of disease management and case management for people with diabetes and forms the basis for recommendations by the Task Force on Community Preventive Services on the use of these two interventions. Evidence supports the effectiveness of disease management on glycemic control; on screening for diabetic retinopathy, foot lesions and peripheral neuropathy, and proteinuria; and on the monitoring of lipid concentrations. This evidence is applicable to adults with diabetes in managed care organizations and community clinics in the United States and Europe. Case management is effective in improving both glycemic control and provider monitoring of glycemic control. This evidence is applicable primarily in the U.S. managed care setting for adults with type 2 diabetes. Case management is effective both when delivered in conjunction with disease management and when delivered with one or more additional educational, reminder, or support interventions.

Depression and Advanced Complications of Diabetes A prospective cohort study

OBJECTIVE To prospectively examine the association of depression with risks for advanced macrovascular and microvascular complications among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A longitudinal cohort of 4,623 primary care patients with type 2 diabetes was enrolled in 2000–2002 and followed through 2005–2007. Advanced microvascular complications included blindness, end-stage renal disease, amputations, and renal failure deaths. Advanced macrovascular complications included myocardial infarction, stroke, cardiovascular procedures, and deaths. Medical record review, ICD-9 diagnostic and procedural codes, and death certificate data were used to ascertain outcomes in the 5-year follow-up. Proportional hazard models analyzed the association between baseline depression and risks of adverse outcomes. RESULTS After adjustment for prior complications and demographic, clinical, and diabetes self-care variables, major depression was associated with significantly higher risks of adverse microvascular outcomes (hazard ratio 1.36 [95% CI 1.05–1.75]) and adverse macrovascular outcomes (1.24 [1.0–1.54]). CONCLUSIONS Among people with type 2 diabetes, major depression is associated with an increased risk of clinically significant microvascular and macrovascular complications over the ensuing 5 years, even after adjusting for diabetes severity and self-care activities. Clinical and public health significance of these findings rises as the incidence of type 2 diabetes soars. Further research is needed to clarify the underlying mechanisms for this association and to test interventions to reduce the risk of diabetes complications among patients with comorbid depression.

Increasing diabetes self-management education in community settings: A systematic review.

This report presents the results of a systematic review of the effectiveness and economic efficiency of self-management education interventions for people with diabetes and forms the basis for recommendations by the Task Force on Community Preventive Services. Data on glycemic control provide sufficient evidence that self-management education is effective in community gathering places for adults with type 2 diabetes and in the home for adolescents with type 1 diabetes. Evidence is insufficient to assess the effectiveness of self-management education interventions at the worksite or in summer camps for either type 1 or type 2 diabetes or in the home for type 2 diabetes. Evidence is also insufficient to assess the effectiveness of educating coworkers and school personnel about diabetes.

The Contribution of Insulin-Dependent and Insulin-Independent Glucose Uptake to Intravenous Glucose Tolerance in Healthy Human Subjects

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18–44 years of age; body mass index, 19.5–52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated β-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG [SI × basal insulin]). Insulin-dependent glucose uptake was estimated as SI × IIR0-19, because the relationship between SI and β-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI × IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08). By multiple regression, 72% of the variance in Kg could be explained by GEZI and S1 × IIR0-19 (r = 0.85; P < 0.0001). We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance and that the interaction of insulin sensitivity and insulin levels are more important than either factor alone as a determinant of intravenous glucose tolerance.

Depression and Increased Mortality in Diabetes: Unexpected Causes of Death

PURPOSE Recent evidence suggests that depression is linked to increased mortality among patients with diabetes. This study examines the association of depression with all-cause and cause-specific mortality in diabetes. METHODS We conducted a prospective cohort study of primary care patients with type 2 diabetes at Group Health Cooperative in Washington state. We used the Patient Health Questionnaire (PHQ-9) to assess depression at baseline and reviewed medical records supplemented by the Washington state mortality registry to ascertain the causes of death. RESULTS Among a cohort of 4,184 patients, 581 patients died during the follow-up period. Deaths occurred among 428 (12.9%) patients with no depression, among 88 (17.8%) patients with major depression, and among 65 (18.2%) patients with minor depression. Causes of death were grouped as cardiovascular disease, 42.7%; cancer, 26.9%; and deaths that were not due to cardiovascular disease or cancer, 30.5%. Infections, dementia, renal failure, and chronic obstructive pulmonary disease were the most frequent causes in the latter group. Adjusting for demographic characteristics, baseline major depression (relative to no depression) was significantly associated with all-cause mortality (hazard ratio [HR]=2.26, 95% confidence interval [CI], 1.79–2.85), with cardiovascular mortality (HR = 2.00; 95% CI, 1.37–2.94), and with noncardiovascular, noncancer mortality (HR = 3.35; 95% CI, 2.30–4.89). After additional adjustment for baseline clinical characteristics and health habits, major depression was significantly associated only with all-cause mortality (HR = 1.52; 95% CI, 1.19–1.95) and with death not caused by cancer or atherosclerotic cardiovascular disease (HR = 2.15; 95% CI, 1.43–3.24). Minor depression showed similar but nonsignificant associations. CONCLUSIONS Patients with diabetes and coexisting depression face substantially elevated mortality risks beyond cardiovascular deaths.

Chronic Disease Management: A Definition And Systematic Approach To Component Interventions

The burden of chronic diseases is tremendous, and traditional methods of healthcare delivery are unsuitable for addressing these needs. Chronic disease management has emerged as a new strategy for chronic disease care, but a consistent definition has not been utilized. Our objective is to present an operational definition of chronic disease management. Based on prior systematic reviews of chronic disease management programs, we propose a definition encompassing the main constructs noted in our reviews.We define chronic disease management in the clinical setting as an organized, proactive, multi-component, patient-centered approach to healthcare delivery that involves all members of a defined population who have a specific disease entity (or a subpopulation with specific risk factors). Care is focused on, and integrated across the entire spectrum of the disease and its complications, the prevention of comorbid conditions, and relevant aspects of the delivery system. Essential components include identification of the population, implementation of clinical practice guidelines or other decision-making tools, implementation of additional patient-, provider-, or healthcare system-focused interventions, the use of clinical information systems, and the measurement and management of outcomes.Consistent use of this definition and adequate documentation of the component interventions of chronic disease management will enable comparisons among programs and outcomes in evaluation research and clinical practice. Most importantly, it will assist in determining which specific interventions or combinations thereof, implemented as part of chronic disease management, are most effective.

The Use of Automated Data to Identify Complications and Comorbidities of Diabetes: A Validation Study

We evaluated the accuracy of administrative data for identifying complications and comorbidities of diabetes using International Classification of Diseases, 9th edition, Clinical Modification and Current Procedural Terminology codes. The records of 471 randomly selected diabetic patients were reviewed for complications from January 1, 1993 to December 31, 1995; chart data served to validate automated data. The complications with the highest sensitivity determined by a diagnosis in the medical records identified within +/-60 days of the database date were myocardial infarction (95.2%); amputation (94.4%); ischemic heart disease (90.3%); stroke (91.2%); osteomyelitis (79.2%); and retinal detachment, vitreous hemorrhage, and vitrectomy (73.5%). With the exception of amputation (82.9%), positive predictive value was low when based on a diagnosis identified within +/-60 days of the database date but increased with relaxation of the time constraints to include confirmation of the condition at any time during 1993-1995: ulcers (88.5%); amputation (85.4%); and retinal detachment, vitreous hemorrhage and vitrectomy (79.8%). Automated data are useful for ascertaining potential cases of some diabetic complications but require confirmatory evidence when they are to be used for research purposes.

Standardization of IVGTT to Predict IDDM

OBJECTIVE To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. RESEARCH DESIGN AND METHODS Postal questionnaires were delivered to 12 centers. RESULTS Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg; the dosage in adults was limited to a maximum of 25–50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 ± 10 s to 4 ± 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the + 1-min sample varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. CONCLUSIONS The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.