Association of Metformin With the Development of Age-Related Macular Degeneration.

Importance: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD. Objective: To investigate the association between metformin use and age-related macular degeneration (AMD). Design, Setting, and Participants: The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Interventions: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Main Outcomes and Measures: Prevalence of AMD in the treatment arms. Results: Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02). Conclusions and Relevance: These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.

Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience.

OBJECTIVE: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS: By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20-0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46-1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS: DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Noninvasive assessment of abdominal adipose tissues and quantification of hepatic and pancreatic fat fractions in type 2 diabetes mellitus.

The purpose of this study was to evaluate adipose tissue distributions and hepatic and pancreatic fat contents using a 6-point Dixon MRI technique in type 2 diabetes mellitus (T2DM), and to assess associations between fat distributions and biochemical markers of insulin resistance. Intra-abdominal MRI was investigated in 14 T2DM patients, 13 age- and sex-matched healthy controls (HC) and 11 young HC using a 3 T Prisma MRI scanner. All T2DM subjects completed a fasting comprehensive metabolic panel, and demographic measurements were taken according to standardized methodologies. We observed excellent correlation (R2 = 0.94) between hepatic fat fraction quantified using 6-point Dixon MRI and gold standard MRS, establishing the accuracy and reliability of the Dixon technique. Significantly increased visceral adipose tissue (VAT) volumes were found in T2DM patients compared to age-matched HC (1569.81 ± 670.62 cm3 vs. 1106.60 ± 566.85 cm3, p = .04). We also observed a trend of increasing subcutaneous adipose tissues (SAT), and total abdominal fat (TAT) volumes in T2DM compared to age-matched HC. Hepatic fat fraction percentage (HFF%) was 44.6% higher in T2DM compared to age-matched HC and 64.4% higher compared to young HC. Pancreatic fat fractions in the head and body/tail were higher in T2DM patients compared to both healthy cohorts. We also observed correlations between fat contents of the liver and pancreas in T2DM patients, and association between biochemical markers of T2DM with HFF, indicating a risk for non-alcoholic fatty liver disease among T2DM. In summary, this study provides evidence of T2DM patients having increased liver and pancreatic fat, as well as increased adipose tissues.

Infertility, Gravidity, and Risk Of Diabetes among High-Risk Women in the Diabetes Prevention Program Outcomes Study.

OBJECTIVE: The extent to which infertility and pregnancy independently increase risk of diabetes and subclinical atherosclerosis is not known. RESEARCH DESIGN AND METHODS: We conducted a secondary analysis of Diabetes Prevention Program (DPP) and the DPP Outcomes Study over a 15-year period. We included women who answered questions about gravidity and infertility at baseline (n = 2085). Infertility was defined as > 1 year of unsuccessful attempts to conceive; thus, women could have histories of infertility as well as pregnancy. Risk of diabetes associated with gravidity and infertility was calculated using Cox proportional hazards models adjusting for age, race/ethnicity, treatment arm, body mass index, and pregnancy during the study. Among women who underwent assessment of coronary artery calcification (CAC) (n = 1337), odds of CAC were calculated using logistic regression models with similar covariates. RESULTS: Among premenopausal women (n = 1075), women with histories of pregnancy and infertility (n = 147; hazard ratio [HR] 1.80; 95% confidence interval [CI] 1.30, 2.49) and women with histories of pregnancy without infertility (n = 736; HR 1.49; 95% CI 1.15, 1.93) had greater diabetes risk than nulligravid women without infertility (n = 173). Premenopausal nulligravid women with histories of infertility had a non-significant elevation in risk, although the number of these women was small (n = 19; HR 1.63; 95% CI 0.88, 3.03). Associations were not observed among postmenopausal women (n = 1010). No associations were observed between infertility or pregnancy with CAC. CONCLUSIONS: Pregnancy, particularly combined with a history of infertility, confers increased risk of diabetes but not CAC among glucose-intolerant premenopausal women.

Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study.

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00038727 and NCT00004992.

Changes in Visceral Adiposity, Subcutaneous Adiposity, and Sex Hormones in the Diabetes Prevention Program.

Context: The degree to which changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) relate to corresponding changes in plasma sex steroids is not known. Objective: We examined whether changes in VAT and SAT areas assessed by computed tomography were associated with changes in sex hormones [dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG)] among Diabetes Prevention Program participants. Design: Secondary analysis of a randomized trial. Participants: Overweight and glucose-intolerant men (n = 246) and women (n = 309). Interventions: Intensive lifestyle change with goals of weight reduction and 150 min/wk of moderate intensity exercise or metformin administered 850 mg twice a day or placebo. Main Outcome Measures: Associations between changes in VAT, SAT, and sex hormone changes over 1 year. Results: Among men, reductions in VAT and SAT were both independently associated with significant increases in total testosterone and SHBG in fully adjusted models. Among women, reductions in VAT and SAT were both independently associated with increases in SHBG and associations with estrone differed by menopausal status. Associations were similar by race/ethnicity and by randomization arm. No significant associations were observed between change in fat depot with change in estradiol or DHEAS. Conclusions: Among overweight adults with impaired glucose intolerance, reductions in either VAT and SAT were associated with increased total testosterone in men and higher SHBG in men and women. Weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat.

Acculturation is associated with left ventricular mass in a multiethnic sample: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Acculturation involves stress-related processes and health behavioral changes, which may have an effect on left ventricular (LV) mass, a risk factor for cardiovascular disease (CVD). We examined the relationship between acculturation and LV mass in a multiethnic cohort of White, African-American, Hispanic and Chinese subjects. METHODS: Cardiac magnetic resonance assessment was available for 5004 men and women, free of clinical CVD at baseline. Left ventricular mass index was evaluated as LV mass indexed by body surface area. Acculturation was characterized based on language spoken at home, place of birth and length of stay in the United States (U.S.), and a summary acculturation score ranging from 0 = least acculturated to 5 = most acculturated. Mean LV mass index adjusted for traditional CVD risk factors was compared across acculturation levels. RESULTS: Unadjusted mean LV mass index was 78.0 ± 16.3 g/m(2). In adjusted analyses, speaking exclusively English at home compared to non-English language was associated with higher LV mass index (81.3 ± 0.4 g/m(2) vs 79.9 ± 0.5 g/m(2), p = 0.02). Among foreign-born participants, having lived in the U.S. for ≥ 20 years compared to < 10 years was associated with greater LV mass index (81.6 ± 0.7 g/m(2) vs 79.5 ± 1.1 g/m(2), p = 0.02). Compared to those with the lowest acculturation score, those with the highest score had greater LV mass index (78.9 ± 1.1 g/m(2) vs 81.1 ± 0.4 g/m(2), p = 0.002). There was heterogeneity in which measure of acculturation was associated with LV mass index across ethnic groups. CONCLUSIONS: Greater acculturation is associated with increased LV mass index in this multiethnic cohort. Acculturation may involve stress-related processes as well as behavioral changes with a negative effect on cardiovascular health.

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.

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.

Association of carotid intima-media thickness with progression of urine albumin-creatinine ratios in The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: The association between measures of subclinical cardiovascular disease and progression of urine albumin-creatinine ratios (UACRs) over time is uncertain. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45-84 years without baseline clinical cardiovascular disease. Examinations were completed approximately every 1.5 years, and UACR was measured during the first 3 examinations. Analysis was limited to 4,878 participants without baseline micro- or macroalbuminuria. PREDICTOR: 1-standard deviation (SD) unit difference in baseline maximum common and internal carotid intima-media thickness (CIMT) measured using ultrasonography. OUTCOMES & MEASUREMENTS: Baseline UACR was categorized as normal or high-normal. UACR progression was categorized as no progression (consistent UACR category across all 3 examinations or regression to a lower category) and definite progression (higher UACR category at examination 2 compared with baseline, then stabilizing or progressing at examination 3). UACR changes not consistent with definite or no UACR progression were classified as intermediate UACR progression. Change in log UACR also was examined. RESULTS: In the 4,878 participants, median baseline UACR was 4.6 mg/g (range, 0.4-24.6 mg/g). Definite and intermediate UACR progression was noted in 279 and 807, respectively. Every 1-SD unit difference in common CIMT was associated with a 22% increased adjusted odds of definite compared with no UACR progression (95% CI, 1.07-1.41). No significant association was noted between 1-SD unit difference in maximum internal CIMT and definite UACR progression after adjusting for covariates (OR, 1.08; 95% CI, 0.96-1.21). In the mixed-effects model, changes in log UACR were 0.029 (95% CI, 0.012-0.046) and 0.019 mg/g (95% CI, 0.001-0.037) per 1-SD difference in maximum common and internal CIMT after adjustment for covariates, respectively. LIMITATIONS: UACR was measured in a single spot urine specimen at each exam. CONCLUSION: Higher common CIMT is associated with UACR progression.

Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression.

The purpose of this study was to examine the effect of type 2 diabetes with major depression on cortical gray matter using magnetic resonance imaging and cortical pattern matching techniques. We hypothesized that diabetic subjects and depressed diabetic subjects would demonstrate decreased cortical gray matter thickness in prefrontal areas as compared to healthy control subjects. Patients with type 2 diabetes (n=26) and patients with diabetes and major depression (n=26) were compared with healthy controls (n=20). Gray matter thickness across the entire cortex was measured using cortical pattern matching methods. All subjects with diabetes demonstrated decreased cortical gray matter thickness in the left anterior cingulate region. Additionally, depressed diabetic subjects showed significant cortical gray matter decreases in bilateral prefrontal areas compared with healthy controls. Correlations between clinical variables and cortical gray matter thickness revealed a significant negative relationship with cerebrovascular risk factors across all three groups, most consistently in the left dorsomedial prefrontal cortex. A significant positive relationship between performance on attention and executive function tasks and cortical gray matter thickness predominantly in left hemisphere regions was also seen across all subjects. Depression and diabetes are associated with significant cortical gray matter thinning in medial prefrontal areas.

Evidence of early retinal microvascular changes in patients with type 2 diabetes and depression.

OBJECTIVE: To examine retinal vascular caliber, an indicator of early microvascular disease and depression in patients with Type 2 diabetes. METHODS: We conducted a clinic-based study, comparing participants with Type 2 diabetes with major depression (n = 43), without depression (n = 49), and healthy controls without diabetes or depression (n = 54). Retinal vascular caliber was measured from digital photographs. Depression status was determined, using standardized clinical assessment. RESULTS: After adjusting for age and gender, participants with diabetes and depression had larger arteriolar and venular calibers (147.7 microm for arteriolar and 215.7 microm for venular calibers) than participants with diabetes but without depression (143.3 microm and 213.9 microm) and healthy controls (135.8 microm and 202.5 microm, p for trend = .002 for arteriolar and p = .02 for venular caliber). In multivariate models adjusting for duration of diabetes, systolic blood pressure, cigarette smoking, serum glucose, Cerebrovascular Risk Factor Scale, Cumulative Illness Rating Scale, and retinopathy levels, this relationship remained significant for retinal arterioles (p = .02) but not for retinal venules (p = .10). CONCLUSIONS: These data show that patients with Type 2 diabetes with major depression have wider retinal arterioles, supporting the concept that depression is associated with early microvascular changes in Type 2 diabetes.

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.

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.

Prefrontal myo-inositol concentration and visuospatial functioning among diabetic depressed patients.

Patients with diabetes mellitus are reported to be at higher risk for developing neuropsychiatric disorders such as dementia and depression. Myo-inositol (mI), a neuronal/glial metabolite associated with multiple functions in the brain, has been shown to be increased in cognitive disorders, depression and diabetes. This study examined whether elevations in dorsolateral (DL) mI of diabetic patients with depression were associated with visuospatial deficits. Diabetic and depressed patients (n=18) were matched with patients with diabetes but without depression (n=20) and control subjects (n=19). Subjects were scored on both the recall and recognition tasks of the Rey-Osterreith Complex Figure (ROCF). Proton magnetic spectroscopy spectra from bilateral prefrontal white matter voxels were used to obtain concentrations of mI. Controls showed negative correlations between mI in right DL white matter and recall and recognition subtests. No correlation was observed for depressed diabetic patients. Correlations for diabetic controls fell midway between the comparison and depressed diabetic groups. The expected pattern of association between mI and visuospatial impairment in the right DL prefrontal region was seen among healthy controls. Progressive weakening of this association across both diabetic groups might be related to progressive changes in neural activity that underlies visuospatial function.

Neuroanatomical correlates of executive functioning in depressed adults with type 2 diabetes.

Depression is often comorbid with type 2 diabetes. Depression may increase vulnerability to and/or exacerbate existing cognitive deficits. Little is known about the brain pathophysiology underlying depression and cognitive abnormalities in diabetes. The aim of this study was to examine the relationship of orbitofrontal and anterior cingulate volumes with executive functioning and attention/processing speed in type 2 diabetic participants with and without major depression. A total of 21 diabetic participants with major depression, 23 diabetic participants with no depression, and 22 healthy controls were compared. Using brain magnetic resonance imaging, volumetric measures of the prefrontal cortex were examined in relation to executive functioning and attention/processing speed. Partial correlations suggested a significant positive relationship between right orbitofrontal regions and executive functioning in the group with diabetes and depression only, indicating that neurobiological changes in the orbitofrontal region may contribute to observed cognitive dysfunction.

Gray matter prefrontal changes in type 2 diabetes detected using MRI.

PURPOSE: To examine the volumes of the gray and white matter both globally and regionally in patients diagnosed with type 2 diabetes and controls. MATERIALS AND METHODS: Our samples were comprised of 26 patients with type 2 diabetes, 26 patients with diabetes and major depressive disorder, and 25 nondiabetic, nondepressed control subjects. All subjects were studied cross-sectionally on a 1.5 T scanner and were recruited from medicine/diabetes clinics. Both gray and white matter volumes were estimated using an automated method, and the prefrontal areas studied included the anterior cingulate, the gyrus rectus, and the orbitofrontal regions. RESULTS: Patients with diabetes, both with and without depression, had smaller total brain gray matter volumes when compared with the control subjects after controlling for age, intracranial volume, and years of education. This group also had smaller gray matter volumes in the anterior cingulate and orbitofrontal regions when compared with the controls after additionally controlling for total gray matter volume. The depressed and nondepressed diabetic groups did not differ on any neuroimaging measure. Cerebrovascular risk factors correlated negatively with gray matter volumes. CONCLUSION: The findings indicate that type 2 diabetes is associated with specific neuroanatomical abnormalities in the prefrontal gray matter. Vascular disease might contribute to the findings observed in our sample. These observations have implications for the behavioral sequelae of diabetes.

Is depression associated with microvascular disease in patients with type 2 diabetes?

We hypothesize that late-life depression is a manifestation of microvascular disease in patients with type 2 diabetes. We conducted a clinic-based cross-sectional study, comparing retinal vascular caliber, a marker of microvascular disease, in participants with type 2 diabetes with major depression (n=34), without depression (n=27) and healthy non-diabetic controls (n=38). Retinal vascular caliber was measured from digital retinal photographs using a validated computer-assisted method. After adjusting for age and gender, there was a trend of increasing retinal arteriolar caliber from healthy controls (132.6 microm), to diabetic patients without depression (139.2 microm), and diabetic patients with major depression (145.3 microm, P=0.008). The trend in retinal arteriolar caliber remains significant after adjusting for duration of diabetes, but not after further adjusting for vascular risk factors. Our findings suggest that there is variation in the retinal vascular caliber between type 2 diabetic patients with and without major depression and non-diabetic controls. This variation was largely related to poorer diabetes control and a higher frequency of vascular risk factors in diabetic patients, particularly those with depression. Studies with larger sample size may provide further insights into this association.

Antihypertensive medications and C-reactive protein in the multi-ethnic study of atherosclerosis.

BACKGROUND: The effects of different antihypertensive medication classes on C-reactive protein (CRP) levels are still not well characterized, and might be of relevance to treatment choices. METHODS: We studied the association between antihypertensive medication class and CRP levels among participants with treated hypertension in the Multi-Ethnic Study of Atherosclerosis. We performed a cross-sectional study of hypertensive participants free of clinical cardiovascular disease who were taking one or more of the following medication classes: beta-blockers, calcium channel blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II type I receptor blockers (ARB). RESULTS: Among 2340 participants taking one or more antihypertensive medications, the mean serum CRP level was lower among participants taking a beta-blocker than among those not taking a beta-blocker (2.13 v 2.54 mg/L, P = .002). This difference persisted after multivariate adjustment (P = .021). There were no other statistically significant differences in multivariate models. Among 1314 participants receiving monotherapy, the multivariate adjusted mean CRP level among participants taking a beta-blocker was lower (1.97 mg/L) than those taking a diuretic (2.72 mg/L, P < .001). In this monotherapy group, participants taking an ACE inhibitor or ARB also had a lower adjusted mean CRP (2.25 mg/L) than those taking a diuretic (P = .046). African-American race/ethnicity did not modify any of those relationships. CONCLUSIONS: The beta-blocker use was associated with lower CRP levels overall and among participants on monotherapy, whereas ACE inhibitor and ARB use was associated with lower CRP levels among participants on monotherapy. These findings warrant further evaluation in randomized trials.

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.