Personalized Digital Health Information to Substantiate Human-Delivered Exercise Support for Adults With Type 1 Diabetes.

OBJECTIVE: Pilot-test personalized digital health information to substantiate human-delivered exercise support for adults with type 1 diabetes (T1D). DESIGN: Single-group, 2-week baseline observation, then 10-week intervention with follow-up observation. SETTING: Community-based sample participating remotely with physician oversight. PARTICIPANTS: Volunteers aged 18 to 65 years with T1D screened for medical readiness for exercise intervention offerings. N = 20 enrolled, and N = 17 completed all outcomes with 88% to 91% biosensor adherence. INTERVENTION: Feedback on personalized data from continuous glucose monitoring (CGM), its intersection with other ecological data sets (exercise, mood, and sleep), and other informational and motivational elements (exercise videos, text-based exercise coach, and self-monitoring diary). MAIN OUTCOME MEASURES: Feasibility (use metrics and assessment completion), safety (mild and severe hypoglycemia, and diabetic ketoacidosis), acceptability (system usability scale, single items, and interview themes), and standard clinical and psychosocial assessments. RESULTS: Participants increased exercise from a median of 0 (Interquartile range, 0-21) to 64 (20-129) minutes per week ( P = 0.001, d = 0.71) with no severe hypoglycemia or ketoacidosis. Body mass index increased (29.5 ± 5.1 to 29.8 ± 5.4 kg/m 2 , P = 0.02, d = 0.57). Highest satisfaction ratings were for CGM use (89%) and data on exercise and its intersection with CGM and sleep (94%). Satisfaction was primarily because of improved exercise management behavioral skills, although derived motivation was transient. CONCLUSIONS: The intervention was feasible, safe, and acceptable. However, there is a need for more intensive, sustained support. Future interventions should perform analytics upon the digital health information and molecular biomarkers (eg, genomics) to make exercise support tools that are more personalized, automated, and intensive than our present offerings.

Compromised endothelial function in transgender men taking testosterone.

CONTEXT: Transgender men (TGM) are persons assigned female gender at birth with a male gender identity and are routinely treated with testosterone. Androgen excess is associated with endothelial dysfunction among cisgender females (CGF) and is an early sign of atherosclerosis and hypertension. OBJECTIVE: To determine the effect of testosterone treatment on endothelial function in TGM. SETTING: The John B. Pierce Laboratory and Yale School of Medicine. SUBJECTS: Eleven TGM (age 27 ± 5 years; BMI 24.4 ± 3.7 kg/m2 ) receiving testosterone (T) and 20 CGF (28 ± 5 years; BMI 26.0 ± 5.1 kg/m2 ) during the early follicular phase of their menstrual cycle. DESIGN AND OUTCOME MEASURES: We evaluated brachial vasodilatory responses following stimuli designed to elicit shear stress using 5-minute occlusion to determine endothelial function (flow-mediated vasodilation, FMD). RESULTS: Total T was greater in the TGM compared to CGF (484.6 ± 122.5 vs 1.5 ± 0.7 ng/dL), as was free T (83.9 ± 32.4 vs 1.9 ± 0.8 pg/dL). FMD was markedly lower in the TGM (4.5 ± 2.7%) compared to the CGF (8.1 ± 2.9%, P = .002) indicating significantly diminished endothelial function in TGM. CONCLUSIONS: We have shown for the first time that in TGM the androgen-dominant hormonal milieu was associated with impaired endothelial function. Endothelial dysfunction precedes clinically detectable atherosclerotic plaque in the coronary arteries, so is an important marker for clinical cardiovascular risk. Therefore, attention to cardiovascular risk factors should be integral to the care of transgender men.

Association of Race and Ethnicity with Prescriptions for Continuous Glucose Monitoring Systems Among a National Sample of Veterans with Diabetes on Insulin Therapy.

Introduction and Objective: Continuous glucose monitoring (CGM) can improve glycemic control in people with diabetes on insulin therapy. We assessed rates of prescriptions for CGM in a national sample of Veterans across subgroups defined by race and ethnicity. Methods: This cross-sectional analysis of data from the U.S. Veterans Health Administration included adults with type 1 or type 2 diabetes on insulin therapy. Main exposures included self-reported race and ethnicity, and primary outcome was the percentage of patients with at least one CGM prescription between January 1, 2020, and December 31, 2021. Association of race and ethnicity categories with CGM prescription was examined using multilevel, multivariable mixed-effects models. Results: Among 368,794 patients on insulin (mean age, 68.5 years; 96% male; 96.8% type 2 diabetes; 0.8% American Indian or Alaska Native, 0.7% Asian, 18.9% Black or African American, 0.9% Native Hawaiian or other Pacific Islander, 70.2% White, 2.8% multiracial, 5.7% with unknown race, and 7.0% Hispanic or Latino ethnicity), 11.2% were prescribed CGM. CGM was prescribed for 10.4% American Indian or Alaska Native, 9.7% Asian, 9.2% Black or African American, 9.3% Native Hawaiian or other Pacific Islander, 11.8% White, 11.8% multiracial, and 10.1% patients with unknown race. CGM was prescribed for 8.3% Hispanic or Latino, 11.4% non-Hispanic, and 11.5% of patients with unknown ethnicity. After accounting for patient-, clinical-, and system-level factors, Black or African American patients had significantly lower odds of CGM prescription compared with White patients (adjusted odds ratio [aOR] 0.62, 95% confidence interval [CI] 0.59-0.64), whereas Hispanic or Latino patients had significantly lower odds compared with non-Hispanic patients (aOR 0.79, 95% CI 0.74-0.84). Findings were consistent across subgroups with clinical indications for CGM use. Conclusions: Among Veterans with diabetes on insulin therapy, there were significant disparities in prescribing of CGM technology by race and ethnicity, which require further study and intervention.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM.

Physiologic frailty and fragility fracture in HIV-infected male veterans.

BACKGROUND: The Veterans Aging Cohort Study (VACS) Index is associated with all-cause mortality in individuals infected with human immunodeficiency virus (HIV). It is also associated with markers of inflammation and may thus reflect physiologic frailty. This analysis explores the association between physiologic frailty, as assessed by the VACS Index, and fragility fracture. METHODS: HIV-infected men from VACS were included. We identified hip, vertebral, and upper arm fractures using ICD-9-CM codes. We used Cox regression models to assess fragility fracture risk factors including the VACS Index, its components (age, hepatitis C status, FIB-4 score, estimated glomerular filtration rate, hemoglobin, HIV RNA, CD4 count), and previously identified risk factors for fragility fractures. RESULTS: We included 40 115 HIV-infected male Veterans. They experienced 588 first fragility fractures over 6.0 ± 3.9 years. The VACS Index score (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.11-1.19), white race (HR, 1.92; 95% CI, 1.63-2.28), body mass index (HR, 0.94; 95% CI, .92-.96), alcohol-related diagnoses (HR, 1.65; 95% CI, 1.26-2.17), cerebrovascular disease (HR, 1.95; 95% CI, 1.14-3.33), proton pump inhibitor use (HR, 1.87; 95% CI, 1.54-2.27), and protease inhibitor use (HR, 1.25; 95% CI, 1.04-1.50) were associated with fracture risk. Components of the VACS Index score most strongly associated with fracture risk were age (HR, 1.40; 95% CI, 1.27-1.54), log HIV RNA (HR, 0.91; 95% CI, .88-.94), and hemoglobin level (HR, 0.82; 95% CI, .78-.86). CONCLUSIONS: Frailty, as measured by the VACS Index, is an important predictor of fragility fractures among HIV-infected male Veterans.

Use of a computerized order set to increase prescription of calcium and vitamin D supplementation in patients receiving glucocorticoids.

BACKGROUND: American College of Rheumatology guidelines recommend that patients taking glucocorticoids also take calcium and vitamin D supplements, regardless of the dose or intended duration of glucocorticoid use, to decrease their risk of glucocorticoid-induced osteopenia or osteoporosis (GIOP). OBJECTIVE: To increase the number of prescriptions made for calcium and vitamin D in patients who receive a prescription for glucocorticoids using an automated, computerized order set. DESIGN: Pre-post test design. PATIENTS: A total of 1,041 outpatients receiving care at a single VA medical center. INTERVENTION/MAIN MEASURES: We developed an automated order set in which calcium and vitamin D were automatically co-ordered with glucocorticoid prescriptions of at least 2-week duration. We tested the impact of the order set by comparing the number of calcium and vitamin D prescriptions in patients taking glucocorticoids during a 12-month period before (T1) and after (T2) implementation. The automated order set could be modified by the treating physician, and it was not generated for patients with hypercalcemia. KEY RESULTS: A total of 535 patients during T1 and 506 patients during T2 had a glucocorticoid prescription of at least 2-week duration. The percent of co-prescriptions for calcium increased from 37 to 49% and vitamin D from 38 to 53% (both p < 0.0001) after the new automated order set was implemented. CONCLUSIONS: Implementation of an automatic prescription for calcium and vitamin D supplementation modestly increases the number of patients on glucocorticoids who are prescribed calcium and vitamin D supplementation.

Higher burden of cardiometabolic and socioeconomic risk factors in women with type 2 diabetes: an analysis of the Glycemic Reduction Approaches in Diabetes (GRADE) baseline cohort.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017. RESULTS: Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes. CONCLUSIONS: This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01794143).

Performance of a modified fracture risk assessment tool for fragility fracture prediction among older veterans living with HIV.

OBJECTIVE: Fragility fractures (fractures) are a critical outcome for persons aging with HIV (PAH). Research suggests that the fracture risk assessment tool (FRAX) only modestly estimates fracture risk among PAH. We provide an updated evaluation of how well a 'modified FRAX' identifies PAH at risk for fractures in a contemporary HIV cohort. DESIGN: Cohort study. METHODS: We used data from the Veterans Aging Cohort Study to evaluate veterans living with HIV, aged 50+ years, for the occurrence of fractures from 1 January 2010 through 31 December 2019. Data from 2009 were used to evaluate the eight FRAX predictors available to us: age, sex, BMI, history of previous fracture, glucocorticoid use, rheumatoid arthritis, alcohol use, and smoking status. These predictor values were then used to estimate participant risk for each of two types of fractures (major osteoporotic and hip) over the subsequent 10 years in strata defined by race/ethnicity using multivariable logistic regression. RESULTS: Discrimination for major osteoporotic fracture was modest [Blacks: area under the curve (AUC) 0.62; 95% confidence interval (CI) 0.62, 0.63; Whites: AUC 0.61; 95% CI 0.60, 0.61; Hispanic: AUC 0.63; 95% CI 0.62, 0.65]. For hip fractures, discrimination was modest to good (Blacks: AUC 0.70; 95% CI 0.69, 0.71; Whites: AUC 0.68; 95% CI 0.67, 0.69]. Calibration was good in all models across all racial/ethnic groups. CONCLUSION: Our 'modified FRAX' exhibited modest discrimination for predicting major osteoporotic fracture and slightly better discrimination for hip fracture. Future studies should explore whether augmentation of this subset of FRAX predictors results in enhanced prediction of fractures among PAH.

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03). Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

Evaluation of Web-Based and In-Person Methods to Recruit Adults With Type 1 Diabetes for a Mobile Exercise Intervention: Prospective Observational Study.

BACKGROUND: Our clinical trial of a mobile exercise intervention for adults 18 to 65 years old with type 1 diabetes (T1D) occurred during COVID-19 social distancing restrictions, prompting us to test web-based recruitment methods previously underexplored for this demographic. OBJECTIVE: Our objectives for this study were to (1) evaluate the effectiveness and cost of using social media news feed advertisements, a clinic-based approach method, and web-based snowball sampling to reach inadequately active adults with T1D and (2) compare characteristics of enrollees against normative data. METHODS: Participants were recruited between November 2019 and August 2020. In method #1, Facebook and Instagram news feed advertisements ran for five 1-to-8-day windows targeting adults (18 to 64 years old) in the greater New Haven and Hartford, Connecticut, areas with one or more diabetes-related profile interest. If interested, participants completed a webform so that the research team could contact them for eligibility screening. In method #2, patients 18 to 24 years old with T1D were approached in person at clinical visits in November and December 2019. Those who were interested immediately completed eligibility screening. Older patients could not be approached due to clinic restrictions. In method #3, snowball sampling was conducted by physically active individuals with T1D contacting their peers on Facebook and via email for 48 days, with details to contact the research staff to express interest and complete eligibility screening. Other methods referred participants to the study similarly to snowball sampling. RESULTS: In method #1, advertisements were displayed to 11,738 unique viewers and attracted 274 clickers (2.33%); 20 participants from this group (7.3%) volunteered, of whom 8 (40%) were eligible. Costs averaged US $1.20 per click and US $95.88 per eligible volunteer. Men had lower click rates than women (1.71% vs 3.17%; P<.001), but their responsiveness and eligibility rates did not differ. In method #2, we approached 40 patients; 32 of these patients (80%) inquired about the study, of whom 20 (63%) volunteered, and 2 of these volunteers (10%) were eligible. Costs including personnel for in-person approaches averaged US $21.01 per inquirer and US $479.79 per eligible volunteer. In method #3, snowball sampling generated 13 inquirers; 12 of these inquirers (92%) volunteered, of whom 8 (67%) were eligible. Incremental costs to attract inquirers were negligible, and total costs averaged US $20.59 per eligible volunteer. Other methods yielded 7 inquirers; 5 of these inquirers (71%) volunteered, of whom 2 (40%) were eligible. Incremental costs to attract inquirers were negligible, and total costs averaged US $34.94 per eligible volunteer. Demographic overrepresentations emerged in the overall cohort (ie, optimal glycemic control, obesity, and low exercise), among those recruited by news feed advertisements (ie, obesity and older age), and among those recruited by snowball sampling (ie, optimal glycemic control and low exercise). CONCLUSIONS: Web-based advertising and recruitment strategies are a promising means to attract adults with T1D to clinical trials and exercise interventions, with costs comparing favorably to prior trials despite targeting an uncommon condition (ie, T1D) and commitment to an intervention. These strategies should be tailored in future studies to increase access to higher-risk participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04204733; https://clinicaltrials.gov/ct2/show/NCT04204733.

Medicare Prescription Drug Plan Coverage of Hormone Therapies Used by Transgender Individuals.

Purpose: Although pharmacologic hormone therapy represents one of the mainstays of gender-affirming therapy for transgender individuals, there are many access barriers for these therapies, including insurance coverage of these drugs. The purpose of this study was to examine Medicare coverage of hormone therapies used by transgender individuals. Methods: Using Centers for Medicare and Medicaid Services prescription drug plan formulary files, we determined plan coverage, coverage restrictions, and out-of-pocket (OOP) costs for all 10 drugs recommended in the 2009 and 2017 Endocrine Society treatment guidelines for transgender patients. Results: For masculinizing therapies, the proportion of plans providing unrestricted coverage ranged from 22% to 79% in 2010 and from 5% to 75% in 2018. For feminizing therapies, the proportion providing unrestricted coverage ranged from 24% to 100% in 2010 and from 13% to 100% in 2018. Median annual OOP costs for masculinizing therapies ranged from $232 to $1112 in 2010 and from $180 to $2176 in 2018. For feminizing therapies, OOP costs ranged from $84 to $2716 in 2010 and from $72 to $3792 in 2018. Conclusion: Our findings highlight the variability in access to guideline-recommended hormone therapies for individuals insured through Medicare.

Patient willingness to take teriparatide.

OBJECTIVE: Teriparatide [rhPTH (1-34)] is an effective treatment for osteoporosis administered by daily subcutaneous injection. The objective of this study was to determine how much benefit women expect teriparatide to confer before agreeing to perform daily injections. METHODS: We recruited postmenopausal women who had recently undergone bone densitometry and were found to have either a T-score less than -2.5 at the hip or spine and/or had a fracture index (FI) of > or =6. Participants completed an adaptive conjoint analysis questionnaire to determine their treatment preferences. RESULTS: The study sample included 185 women, mean age 71 (range 46-90). An increasing number of subjects preferred rhPTH (1-34) as the efficacy of teriparatide increased, but most women demanded efficacy advantages greater than those demonstrated in clinical studies. We found no association between absolute fracture risk and preference for rhPTH (1-34); however, subjects with an excessively high perceived risk of future fracture were more likely to accept daily subcutaneous injections compared to subjects with a lower perceived risk of future fracture (40% versus 15%, p = 0.001). CONCLUSION: Our results suggest that most women demand benefits far greater than those conferred by rhPTH (1-34) in order to administer daily subcutaneous injections to decrease their future risk of fractures. PRACTICE IMPLICATIONS: Given the poor adherence for treatment of osteoporosis, and the choices older adults must make when paying for medications, development of novel treatment approaches should be based on older adults' treatment preferences.

Racial disparities in stroke risk factors: the impact of socioeconomic status.

BACKGROUND AND PURPOSE: In the US, blacks have a higher incidence of stroke and more severe strokes than whites. Our objective was to determine if differences in income, education, and insurance, as well as differences in the prevalence of stroke risk factors, accounted for the association between ethnicity and stroke. METHODS: We used data from the Third National Health and Nutrition Survey (NHANES III), a cross-sectional sample of the noninstitutionalized US population (1988-1994), and included blacks and whites aged 40 years or older with a self-reported stroke history. Income was assessed using a ratio of income to US Census Bureau annual poverty threshold. RESULTS: Among 11 163 participants, 2752 (25%) were black and 619 (6%) had a stroke history (blacks: 160/2752 [6%]; whites: 459/8411 [6%]; P=0.48). Blacks had a higher prevalence of 5 risk factors independently associated with stroke: hypertension, treated diabetes, claudication, higher C-reactive protein, and inactivity; whites had a higher prevalence of 3 risk factors: older age, myocardial infarction, and lower high-density lipoprotein cholesterol. Ethnicity was independently associated with stroke after adjusting for the 8 risk factors (adjusted odds ratio, 1.32; 95% CI, 1.04 to 1.67). Ethnicity was not independently associated with stroke after adjustment for income and income was independently associated with stroke (adjusted odds ratios for: ethnicity, 1.15; 95% CI, 0.88 to 1.49; income, 0.89; 95% CI, 0.82 to 0.95). Adjustment for neither education nor insurance altered the ethnicity-stroke association. CONCLUSIONS: In this study of community-dwelling stroke survivors, ethnic differences exist in the prevalence of stroke risk factors and income may explain the association between ethnicity and stroke.

Undiagnosed hyperglycemia in patients treated with atypical antipsychotics.

BACKGROUND: The use of atypical antipsychotics has been associated with abnormalities of glucose metabolism in patients with schizophrenia. This study was designed to determine the proportion of undiagnosed hyperglycemia in patients receiving a broad range of atypical antipsychotics. METHOD: All outpatients treated at an urban Veterans Affairs medical center who received a prescription for clozapine, risperidone, olanzapine, quetiapine, or ziprasidone were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. Testing took place October 2000 to November 2002. Patients previously diagnosed as diabetic were excluded. RESULTS: Of the 647 patients who received antipsychotic prescriptions and were not diagnosed as diabetic, 494 (76.4%) had a random glucose result, while 153 (23.6%) had an FPG result. Within the FPG group, 107 (69.9%) had a normal FPG level, while 46 (30.1%) had an abnormally elevated FPG. There were no differences between these 2 groups in terms of race/ethnicity, age, body mass index, or comorbid diagnoses. However, significantly more patients receiving clozapine were found to have occult hyperglycemia (p = .001); no significant differences in the percentage of patients with FPG levels > or = 100 mg/dL and those with FPG levels < 100 mg/dL were observed for any of the other medications. CONCLUSION: Hyperglycemia is common in patients treated with atypical antipsychotics and thought to be euglycemic. Screening for elevated FPG is indicated for patients receiving atypical antipsychotics.

Evidence that the IL-6/IL-6 soluble receptor cytokine system plays a role in the increased skeletal sensitivity to PTH in estrogen-deficient women.

Estrogen-deficient women show increased skeletal sensitivity to the resorbing actions of PTH. The basis for this effect is not known. To examine the influence of estrogen deficiency on PTH-induced proresorptive cytokine production in humans, the response of five young women to a 36-h infusion of (1-34)human PTH (hPTH) was studied. PTH induced significant increases in circulating levels of IL-6 (mean values, T(0)-->T(36 h); 2.2-->19.2 pg/ml), IL-6 soluble receptor (IL-6sR; 29.8-->67.2 ng/ml), urine N-telopeptide of type I collagen (NTX) (38.6-->148 nM bone collagen equivalent/mM creatinine) and serum calcium (2.12-->2.62 mmol/liter). To examine the impact of hormonal status on this response, PTH infusions were next undertaken in seven estrogen-deficient and seven estrogen-treated postmenopausal women. When compared with estrogen-treated women, and correcting for differences in baseline values, estrogen-deficient women demonstrated an exaggerated increase in circulating levels of IL-6 (5.0-->31.7 vs. 3.2-->14.4 pg/ml; P = 0.0001) and IL-6sR (49.2-->102.1 vs. 37.7-->66.7; P = 0.0001). This was accompanied by greater increases in NTX excretion in the estrogen-deficient women (61.2-->201.6 vs. 44.8-->114.8, E(-) vs. E(+), P = 0.0001). Estrogen deficiency was not associated with augmented PTH-induced increases in colony-stimulating factor-1, IL-1beta, IL-11, or TNF-alpha. In a multiple regression model controlling for group, age, years since menopause both IL-6 and IL-6sR were strong predictors of NTX. These data, along with previous animal studies, support the conclusion that the IL-6/IL-6SR cytokine system plays a role in the increased skeletal sensitivity to PTH seen in estrogen-deficient women.

Association of endogenous sex hormones and insulin resistance among postmenopausal women: results from the Postmenopausal Estrogen/Progestin Intervention Trial.

Most studies of sex hormones and insulin resistance (IR) have focused on androgens; few have examined the association of endogenous estrogens and IR. We determined the cross-sectional association of endogenous levels of total and bioavailable testosterone and estradiol and SHBG with IR among 845 healthy, postmenopausal women aged 45-65 yr. Women were within 10 yr of menopause and not using hormone replacement therapy. Total adiposity was estimated by body mass index, visceral adiposity by waist to hip ratio (WHR), and IR by the homeostasis model assessment. We defined homeostasis model assessment-IR as the highest quartile (cutpoint, 2.1) of the distribution in this cohort. In logistic regression analyses, the odds for IR were significant and increased in a dose-response fashion across each quartile of total estradiol, bioavailable estradiol, and bioavailable testosterone (all P < 0.001 for linear trend). These associations remained significant after adjusting for WHR; adjusted odds ratios were 4.0, 6.1, and 2.7 for total estradiol, bioavailable estradiol, and bioavailable testosterone, respectively, comparing the highest to the lowest quartile (all P < 0.001). Adjusting for body mass index and WHR together eliminated the linear association of IR with total estradiol and bioavailable testosterone, but the association with bioavailable estradiol remained (adjusted odds ratio, 2.7; P < 0.001, comparing the highest to the lowest quartile). IR was not associated with total testosterone before or after adjusting for adiposity. Lower SHBG levels were associated with higher odds of IR, independent of adiposity. These results suggest that estrogen may be equally or more important than testosterone in the pathway to IR in healthy, young postmenopausal women, with differences not entirely explained by body size.

Undiagnosed hyperglycemia in clozapine-treated patients with schizophrenia.

BACKGROUND: Clozapine has been demonstrated to be superior to typical neuroleptics in reducing refractory symptoms in patients with schizophrenia, but it has also been associated with hyperglycemia and diabetes mellitus. This study was designed to investigate the proportion of undiagnosed impaired fasting glucose and diabetes mellitus in patients prescribed clozapine at 8 Department of Veterans Affairs (VA) medical centers. METHOD: All patients diagnosed by the VA in New England with ICD-9 schizophrenia from Oct. 1, 1999, to Sept. 30, 2000, who received a prescription for clozapine were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. All patients were also characterized as to whether they were diagnosed as diabetic prior to the screening FPG. Patients not previously diagnosed as diabetic were divided into 2 groups: normal FPG (< 110 mg/dL) and elevated FPG (>or= 110 mg/dL). Clinical and sociodemographic characteristics of the 2 groups were compared using chi-square and t tests. RESULTS: Overall, 121 patients were not previously diagnosed as diabetic and received an FPG. Ninety-three (77%) had a normal FPG, and 28 (23%) had an elevated plasma glucose-including 17% with impaired fasting glucose and 6% with diabetes. Patients with hyperglycemia were significantly older (p =.007) and more commonly codiagnosed with bipolar disorder (p =.04). CONCLUSION: Hyperglycemia was common in patients receiving clozapine who had not been previously diagnosed as diabetic. These patients should be considered a group at high risk to develop diabetes mellitus and deserve both close monitoring and early intervention at the first sign of the onset of either diabetes or impaired glucose tolerance.

Two measures of insulin sensitivity provided similar information in a U.S. population.

BACKGROUND AND OBJECTIVE: Two methods for measuring insulin sensitivity, fasting plasma insulin (FPI) and homeostasis model assessment (HOMA) have been proposed for use in large epidemiological research and clinical practice. This project describes the range of observed values of the HOMA and FPI in a large sample of the U.S. population. METHODS: We used fasting plasma glucose and insulin values from the Third National Health and Nutrition Survey (NHANES III) to identify the FPI and HOMA values. For both FPI and HOMA, higher values indicate lower insulin sensitivity. RESULTS: Among 6,511 participants without treated diabetes mellitus, FPI ranged from 1.8 to 175.8 microU/mL, with 25th percentile=6.7, median=9.3, 75th percentile=13.3, and mean+/-1 SD=11.2+/-7.5; HOMA ranged from 0.3 to 52.6 (mmol)(microU)/L(2), with 25th percentile=1.5, median=2.2, 75th percentile=3.3, and mean+/-SD=2.8+/-2.4. CONCLUSION: These findings describe the spectrum of insulin sensitivity and may be useful in helping physicians develop a clinical understanding of the dynamic range of both FPI and HOMA measures.

Increased brain transport and metabolism of acetate in hypoglycemia unawareness.

CONTEXT: Intensive insulin therapy reduces the risk for long-term complications in patients with type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia-associated autonomic failure (HAAF), a syndrome that includes hypoglycemia unawareness and defective glucose counterregulation (reduced epinephrine and glucagon responses to hypoglycemia). OBJECTIVE: The objective of the study was to address mechanisms underlying HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid (MCA), can support cerebral energetics during hypoglycemia in T1DM individuals with hypoglycemia unawareness. DESIGN: Magnetic resonance spectroscopy was used to measure brain transport and metabolism of [2-(13)C]acetate under hypoglycemic conditions. SETTING: The study was conducted at the Yale Center for Clinical Investigation Hospital Research Unit, Yale Magnetic Resonance Research Center. PATIENTS AND OTHER PARTICIPANTS: T1DM participants with moderate to severe hypoglycemia unawareness (n = 7), T1DM controls without hypoglycemia unawareness (n = 5), and healthy nondiabetic controls (n = 10) participated in the study. MAIN OUTCOME MEASURE(S): Brain acetate concentrations, (13)C percent enrichment of glutamine and glutamate, and absolute rates of acetate metabolism were measured. RESULTS: Absolute rates of acetate metabolism in the cerebral cortex were 1.5-fold higher among T1DM/unaware participants compared with both control groups during hypoglycemia (P = .001). Epinephrine levels of T1DM/unaware subjects were significantly lower than both control groups (P < .05). Epinephrine levels were inversely correlated with levels of cerebral acetate use across the entire study population (P < .01), suggesting a relationship between up-regulated brain MCA use and HAAF. CONCLUSION: Increased MCA transport and metabolism among T1DM individuals with hypoglycemia unawareness may be a mechanism to supply the brain with nonglucose fuels during episodes of acute hypoglycemia and may contribute to the syndrome of hypoglycemia unawareness, independent of diabetes.

Increased brain uptake and oxidation of acetate in heavy drinkers.

When a person consumes ethanol, the body quickly begins to convert it to acetic acid, which circulates in the blood and can serve as a source of energy for the brain and other organs. This study used 13C magnetic resonance spectroscopy to test whether chronic heavy drinking is associated with greater brain uptake and oxidation of acetic acid, providing a potential metabolic reward or adenosinergic effect as a consequence of drinking. Seven heavy drinkers, who regularly consumed at least 8 drinks per week and at least 4 drinks per day at least once per week, and 7 light drinkers, who consumed fewer than 2 drinks per week were recruited. The subjects were administered [2-13C]acetate for 2 hours and scanned throughout that time with magnetic resonance spectroscopy of the brain to observe natural 13C abundance of N-acetylaspartate (NAA) and the appearance of 13C-labeled glutamate, glutamine, and acetate. Heavy drinkers had approximately 2-fold more brain acetate relative to blood and twice as much labeled glutamate and glutamine. The results show that acetate transport and oxidation are faster in heavy drinkers compared with that in light drinkers. Our finding suggests that a new therapeutic approach to supply acetate during alcohol detoxification may be beneficial.