Christine Darwin

Feasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes

An automated closed-loop insulin delivery system based on subcutaneous glucose sensing and subcutaneous insulin delivery was evaluated in 10 subjects with type 1 diabetes (2 men, 8 women, mean [±SD] age 43.4 ± 11.4 years, duration of diabetes 18.2 ± 13.5 years). Closed-loop control was assessed over ∼30 h and compared with open-loop control assessed over 3 days. Closed-loop insulin delivery was calculated using a model of the β-cell’s multiphasic insulin response to glucose. Plasma glucose was 160 ± 66 mg/dl at the start of closed loop and was thereafter reduced to 71 ± 19 by 1:00 p.m. (preprandial lunch). Fasting glucose the subsequent morning on closed loop was not different from target (124 ± 25 vs. 120 mg/dl, respectively; P > 0.05). Mean glucose levels were not different between the open and closed loop (133 ± 63 vs. 133 ± 52 mg/dl, respectively; P > 0.65). However, glucose was within the range 70–180 mg/dl 75% of the time under closed loop versus 63% for open loop. Incidence of biochemical hypoglycemia (blood glucose <60 mg/dl) was similar under the two treatments. There were no episodes of severe hypoglycemia. The data provide proof of concept that glycemic control can be achieved by a completely automated external closed-loop insulin delivery system.

Rituximab Treatment of Patients with Severe, Corticosteroid-Resistant Thyroid-Associated Ophthalmopathy

PURPOSE To study the effectiveness of anti-CD20 (rituximab [RTX]; Rituxan; Genentech, Inc., South San Francisco, CA) therapy in patients with severe, corticosteroid (CS)-resistant thyroid-associated ophthalmopathy (TAO). DESIGN Retrospective, interventional case series. PARTICIPANTS Six consecutive subjects with severe, progressive TAO unresponsive to CS. METHODS Electronic medical record review of consecutive patients receiving RTX during the previous 18 months. Responses to therapy were graded using standard clinical assessment and flow cytometric analysis of peripheral lymphocytes. MAIN OUTCOME MEASURES Clinical activity score (CAS), proptosis, strabismus, treatment side effects, and quantification of regulatory T cells. RESULTS Six patients were studied. Systemic CS failed to alter clinical activity in all patients (mean CAS+/-standard deviation, 5.3+/-1.0 before vs. 5.5+/-0.8 during therapy for 7.5+/-6.4 months; P = 1.0). However, after RTX treatment, CAS improved from 5.5+/-0.8 to 1.3+/-0.5 at 2 months after treatment (P<0.03) and remained quiescent in all patients (CAS, 0.7+/-0.8; P<0.0001) at a mean follow-up of 6.2+/-4.5 months. Vision improved bilaterally in all 4 patients with dysthyroid optic neuropathy (DON). None of the 6 patients experienced disease relapse after RTX infusion, and proptosis remained stable (Hertel measurement, 24+/-3.7 mm before therapy and 23.6+/-3.7 mm after therapy; P = 0.17). The abundance of T regulatory cells, assessed in 1 patient, increased within 1 week of RTX and remained elevated at 18 months of follow-up. CONCLUSIONS In progressive, CS-resistant TAO, rapid and sustained resolution of orbital inflammation and DON followed treatment with RTX. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy

Type 2 diabetes and major depression are disorders that are mutual risk factors and may share similar pathophysiological mechanisms. To further understand these shared mechanisms, the purpose of our study was to examine the biochemical basis of depression in patients with type 2 diabetes using proton MRS. Patients with type 2 diabetes and major depression (n=20) were scanned along with patients with diabetes alone (n=24) and healthy controls (n=21) on a 1.5 T MRI/MRS scanner. Voxels were placed bilaterally in dorsolateral white matter and the subcortical nuclei region, both areas important in the circuitry of late-life depression. Absolute values of myo-inositol, creatine, N-acetyl aspartate, glutamate, glutamine, and choline corrected for CSF were measured using the LC-Model algorithm. Glutamine and glutamate concentrations in depressed diabetic patients were significantly lower (p<0.001) in the subcortical regions as compared to healthy and diabetic control subjects. Myo-inositol concentrations were significantly increased (p<0.05) in diabetic control subjects and depressed diabetic patients in frontal white matter as compared to healthy controls. These findings have broad implications and suggest that alterations in glutamate and glutamine levels in subcortical regions along with white matter changes in myo-inositol provide important neurobiological substrates of mood disorders.

Modeling β-Cell Insulin Secretion - Implications for Closed-Loop Glucose Homeostasis

Glucose sensing and insulin delivery technology can potentially be linked to form a closed-loop insulin delivery system. Ideally, such a system would establish normal physiologic glucose profiles. To this end, a model of beta-cell secretion can potentially provide insight into the preferred structure of the insulin delivery algorithm. Two secretion models were evaluated for their ability to describe plasma insulin dynamics during hyperglycemic clamps (humans; n=7), and for their ability to establish and maintain fasting euglycemia under conditions simulated by the minimal model. The first beta-cell model (SD) characterized insulin secretion as a static component that had a delayed response to glucose, and a dynamic component that responded to the rate of increase of glucose. The second model (PID) described the response in terms of a proportional component without delay, an integral component that adjusted basal delivery in proportion to hyper/hypoglycemia, and a derivative component that responded to the rate of glucose change. Both models fit the beta-cell response during the clamp, and established fasting euglycemia under simulated closed-loop conditions; however, the SD model did not maintain euglycemia following simulated changes in insulin sensitivity or glucose appearance, whereas the PID model did. The PID model was more stable under the simulated closed-loop conditions. Both the SD and PID models described beta-cell secretion in response to a rapid increase in glucose. However, the PID model could maintain fasting euglycemia and was more stable under closed-loop conditions, and thus is more suited for such conditions.

Gray matter prefrontal changes in type 2 diabetes detected using MRI

To examine the volumes of the gray and white matter both globally and regionally in patients diagnosed with type 2 diabetes and controls.

Decreased Polymorphonuclear Leukocyte Deformability in NIDDM

OBJECTIVE To determine the rheological properties of polymorphonuclear leukocytes (PMN) from non-insulin-dependent diabetes mellitus (NIDDM) patients. RESEARCH DESIGN AND METHODS The deformability of PMN from 33 NIDDM subjects, 13 with impaired glucose tolerance (IGT), and 22 with normal glucose tolerance (NGT) was studied. A Cell Transit Analyzer that measures the transit time of PMN through 8-(xm pores was used. Studies were performed under three different conditions: J) basal state; 2) after incubation with cytochalasin B (20 μM) to dissociate f-actin from the cytoskeleton; and 3) following activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP, 1 nM). RESULTS PMN from diabetic patients were more rigid (i.e., had longer transit time) than those from subjects with NGT or IGT under basal conditions and after cytochalasin B, but not after stimulation with fMLP. The deformability of PMN from subjects with IGT was similar to those of the NGT group. In the pooled data, basal transit time correlated with age; systolic and diastolic blood pressure; HbA1c; and serum creatinine, cholesterol, and triglyceride concentrations (r = 0.29, 0.34, 0.37, 0.48, 0.25, 0.36, 0.29, respectively, P < 0.05 for each). Hypertensive diabetic patients had less deformable PMN than normotensive ones. No relation was found between PMN deformability and the duration of diabetes, type of treatment, or the presence of retinopathy. CONCLUSIONS These data indicate increased rigidity of PMN in NIDDM that may contribute to development of microcirculatory disturbances and microangiopathy.

N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis

Background—Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population. Methods and Results—A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001). Conclusions—Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487.

Genome-Wide Linkage of Plasma Adiponectin Reveals a Major Locus on Chromosome 3q Distinct From the Adiponectin Structural Gene The IRAS Family Study

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polyporphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.

Proximal aortic distensibility is an independent predictor of all-cause mortality and incident CV events: the MESA study.

BACKGROUND The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events has not been fully established. OBJECTIVES This study sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indexes of subclinical atherosclerosis, and Framingham risk score. RESULTS There were 246 deaths, 171 hard CVD events (myocardial infarction, resuscitated cardiac arrest, stroke and CV death), and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first versus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indexes of subclinical atherosclerosis. Overall, patients with the lowest AAD had an independent 2-fold higher risk of hard CVD events. Decreased AAD was associated with CV events in low to intermediate- CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. CONCLUSIONS Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals.

Geographic variation in hypertension prevalence among blacks and whites: the multi-ethnic study of atherosclerosis

BACKGROUND Many studies have examined differences in hypertension across race/ethnic groups but few have evaluated differences within groups. METHODS We investigated within-group geographic variations in hypertension prevalence among 3,322 black and white participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Place of birth and place of residence were included in multivariate Poisson regression analyses. RESULTS Blacks born in southern states were 1.11 (95% confidence interval (CI): 1.02, 1.23) times more likely to be hypertensive than non-southern states after adjusting for age and sex. Findings were similar, though not statistically significant, for whites (prevalence ratio (PR): 1.15, 95% CI: 0.98, 1.35). Blacks and whites living in Forsyth (blacks, PR: 1.23, 95% CI: 1.07, 1.42; whites, PR: 1.32, 95% CI: 1.09, 1.60) and Baltimore (blacks, PR: 1.14, 95% CI: 1.00, 1.31; whites, PR: 1.24, 95% CI: 1.05, 1.47) were also significantly more likely to be hypertensive than those living in Chicago after adjusting for age and sex. Among blacks, those living in New York were also significantly more likely to be hypertensive. Geographic heterogeneity was partially explained by socioeconomic indicators, neighborhood characteristics or hypertension risk factors. There was also evidence of substantial heterogeneity in black-white differences depending on which geographic groups were compared (ranging from 82 to 13% higher prevalence in blacks compared with whites). CONCLUSIONS A better understanding of geographic heterogeneity may inform interventions to reduce racial/ethnic disparities.