Hormones and Aging: An Endocrine Society Scientific Statement.

Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals.

A Study of Physical Resilience and Aging (SPRING): Conceptual framework, rationale, and study design.

Understanding the physiological basis of physical resilience to clinical stressors is crucial for the well-being of older adults. This article presents a novel framework to discover the biological underpinnings of physical resilience in older adults as part of the "Characterizing Resiliencies to Physical Stressors in Older Adults: A Dynamical Physiological Systems Approach" study, also known as The Study of Physical Resilience and Aging (SPRING). Physical resilience, defined as the capacity of a person to withstand clinical stressors and quickly recover or improve upon a baseline functional level, is examined in adults aged 55 years and older by studying the dynamics of stress response systems. The hypothesis is that well-regulated stress response systems promote physical resilience. The study employs dynamic stimulation tests to assess energy metabolism, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the innate immune system. Baseline characteristics influencing resilience outcomes are identified through deep phenotyping of physical and cognitive function, as well as of biological, environmental, and psychosocial characteristics. SPRING aims to study participants undergoing knee replacement surgery (n = 100), bone and marrow transplantation (n = 100), or anticipating dialysis initiation (n = 60). Phenotypic and functional measures are collected pre-stressor and at multiple times after stressor for up to 12 months to examine resilience trajectories. By improving our understanding of physical resilience in older adults, SPRING has the potential to enhance resilient outcomes to major clinical stressors. The article provides an overview of the study's background, rationale, design, pilot phase, implementation, and implications for improving the health and well-being of older adults.

The role of aldosterone and ideal cardiovascular health in incident cardiovascular disease: The Jackson heart study.

Background: Higher levels of ideal cardiovascular health (ICH) are associated with lower levels of aldosterone and incidence of cardiovascular disease (CVD). However, the degree to which aldosterone mediates the association between ICH and CVD incidence has not been explored. Thus, we investigated the mediational role of aldosterone in the association of 5 components of ICH (cholesterol, body mass index (BMI), physical activity, diet and smoking) with incident CVD and the mediational role of blood pressure (BP) and glucose in the association of aldosterone with incident CVD in a cohort of African Americans (AA). Methods: The Jackson Heart Study is a prospective cohort of AAs adults with data on CVD outcomes. Aldosterone, ICH metrics and baseline characteristics were collected at exam 1 (2000-2004). ICH score was developed by summing 5 ICH metrics (smoking, dietary intake, physical activity, BMI, and total cholesterol) and grouped into two categories (0-2 and ≥3 metrics). Incident CVD was defined as stroke, coronary heart disease, or heart failure. Cox proportional hazard regression models were used to model the association of categorical ICH score with incident CVD. The R Package Mediation was utilized to examine: 1) The mediational role of aldosterone in the association of ICH with incident CVD and 2) The mediational role of blood pressure and glucose in the association of aldosterone with incident CVD. Results: Among 3,274 individuals (mean age: 54±12.4 years, 65% female), there were 368 cases of incident CVD over a median of 12.7 years. The risk of incident CVD was 46% lower (HR: 0.54; 95%CI 0.36, 0.80) in those with ≥3 ICH metrics at baseline compared to 0-2. Aldosterone mediated 5.4% (p = 0.006) of the effect of ICH on incident CVD. A 1-unit increase in log-aldosterone was associated with a 38% higher risk of incident CVD (HR 1.38, 95%CI: 1.19, 1.61) with BP and glucose mediating 25.6% (p<0.001) and 4.8% (p = 0.048), respectively. Conclusion: Aldosterone partially mediates the association of ICH with incident CVD and both blood pressure and glucose partially mediate the association of aldosterone with incident CVD, emphasizing the potential importance of aldosterone and ICH in risk of CVD among AAs.

The role of aldosterone and ideal cardiovascular health in incident diabetes: The Jackson Heart Study.

Background: Greater attainment of ideal cardiovascular health (ICH) and lower serum aldosterone are associated with lower diabetes risk. Higher levels of ICH are associated with lower aldosterone. The mediational role of aldosterone in the association of ICH with incident diabetes remains unexplored. Thus, we examined the mediational role of aldosterone in the association of 5 ICH components (smoking, diet, physical activity, body mass index [BMI], and cholesterol) with incident diabetes. Additionally, we investigated the mediational role of glucose and blood pressure (BP) in the association of aldosterone with incident diabetes in an African American (AA) cohort. Methods: We conducted a prospective cohort analysis among AA adults, aged 21-94 years, in the Jackson Heart Study. Data on ICH, aldosterone, and cardiometabolic risk factors were collected at exam 1 (2000-2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at exams 1 through 3 (2009-2012). ICH metrics were defined by American Heart Association 2020 goals for smoking, dietary intake, physical activity, BMI, total cholesterol, BP and glucose. The number of ICH metrics attained at exam 1, excluding BP and fasting glucose, were summed (0-2, vs. 3+). R Package Mediation was used to examine: 1) The mediational role of aldosterone in the association of ICH with incident diabetes; and 2) the mediational role of BP and glucose in the association of aldosterone with incident diabetes. Results: Among 2,791 participants (mean age: 53±12, 65% female) over a median of 7.5 years, there were 497 incident diabetes cases. Risk of incident diabetes was 37% (HR: 0.63, 95%CI: 0.47, 0.84) lower in 3+ ICH category compared to 0-2 ICH category. Aldosterone mediated 6.98% (95% CI: 1.8%, 18.0%) of the direct effect of ICH on incident diabetes. A 1-unit increase in log-aldosterone was associated with a 44% higher risk of diabetes (HR 1.44, 95%CI 1.25-1.64). BP and glucose mediated 16.3% (95% CI: 7.0%, 31.0%) and 19.7% (95% CI: 6.5%, 34.0%) of the association of aldosterone with incident diabetes, respectively. Conclusion: Aldosterone is a mediator of the association of ICH with incident diabetes, whereas BP and glucose are mediators of the association of aldosterone with incident diabetes, emphasizing the importance of the renin-angiotensin-aldosterone system and ICH in lowering risk of diabetes in AA populations.

Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

OBJECTIVES: The metabolic abnormalities that lead to diabetes mellitus (DM) after an episode of acute pancreatitis (AP) have not been extensively studied. This article describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) Study. METHODS: Three months after an index episode of AP, participants without preexisting DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three subcohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in ß-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure ß-cell function and insulin sensitivity. CONCLUSIONS: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.

Aspirin for Primary Prevention of Cardiovascular Disease in Diabetes: a Review of the Evidence.

PURPOSE OF REVIEW: People with diabetes are at a higher risk of atherosclerotic cardiovascular disease (ASCVD) compared with those without diabetes. Though aspirin has been shown to have an overall net clinical benefit when used for secondary prevention of ASCVD in people with and without diabetes, the evidence for primary prevention, especially in those with diabetes, remains inconsistent. In this article, we review the latest studies examining the risks and benefits of aspirin use for primary prevention of ASCVD in adults with diabetes, discuss key aspects in assessing the risk-benefit ratio of aspirin use for primary prevention of ASCVD, and summarize current guidelines from professional societies on aspirin use for primary prevention in adults with diabetes. RECENT FINDINGS: In the general population, past studies have shown no difference in the beneficial effect of aspirin for primary cardiovascular disease prevention by diabetes status. However, several randomized controlled studies and meta-analyses in adults with diabetes have shown lack of net clinical benefit of aspirin use for primary prevention of ASCVD. The recent ASCEND trial documented cardiovascular benefit of aspirin for primary prevention in adults with diabetes but suggested that the increased risk of bleeding may outweigh the cardiovascular benefit. The decision to initiate aspirin for primary prevention of ASCVD must be considered carefully on an individual basis to balance the cardiovascular benefit and bleeding risk in all patients, especially those with diabetes. A multifactorial approach that focuses on managing ASCVD risk factors such as hypertension, dyslipidemia, dysglycemia, and smoking is recommended in all patients. More research is needed to identify subgroups of people with diabetes who are more likely to benefit from aspirin use for primary prevention of ASCVD and develop better antithrombotic strategies that shift the risk-benefit balance toward an overall net clinical benefit.

The Association of Life's Simple 7 with Aldosterone among African Americans in the Jackson Heart Study.

BACKGROUND: Among African Americans (AAs), attaining higher levels of American Heart Association (AHA) ideal cardiovascular health (Life's Simple 7 [LS7]) is associated with lower risk of diabetes and cardiovascular disease (CVD). We previously showed that aldosterone is associated with higher risk of diabetes and CVD in AAs. Thus, we investigated the association of LS7 metrics with aldosterone in the Jackson Heart Study (JHS). METHODS: Ideal metrics were defined by AHA 2020 goals for health behaviors (smoking, dietary intake, physical activity, and body mass index) and health factors (total cholesterol, blood pressure, and fasting glucose). The number of ideal LS7 metrics attained at baseline were summed into a continuous score (0-7) and categorical groups (Poor: 0-1, Intermediate: 2-3, and Ideal: ≥4 ideal LS7 metrics). Multivariable linear regression was used. RESULTS: Among 4,095 JHS participants (mean age 55 ± 13 years, 65% female), median serum aldosterone was 4.90, 4.30, and 3.70 ng/dL in the poor (n = 1132), intermediate (n = 2288) and ideal (n = 675) categories respectively. Aldosterone was 15% [0.85 (0.80, 0.90)] and 33% [0.67 (0.61, 0.75)] lower in the intermediate and ideal LS7 categories compared to the poor LS7 category. Each additional LS7 metric attained on continuous LS7 score (0-7) was associated with an 11% [0.89 (0.86, 0.91)] lower aldosterone level with variation by sex with women having a 15% lower aldosterone vs. 5% in men. CONCLUSIONS: Higher attainment of ideal LS7 metrics was associated with lower serum aldosterone among AAs with a greater magnitude of association among women compared to men.

The association of morning serum cortisol with glucose metabolism and diabetes: The Jackson Heart Study.

BACKGROUND: Serum cortisol levels have been associated with type 2 diabetes (T2D). However, the role of cortisol in glycemia and T2D is not fully elucidated among African Americans (AAs). We hypothesized that among AAs morning serum cortisol would be positively associated with glycemic measures and prevalent T2D. METHODS: We examined the cross-sectional association of baseline morning serum cortisol with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), ß-cell function (HOMA-ß), and prevalent T2D in the Jackson Heart Study. Linear regression models were used to examine the association of log-transformed cortisol with glycemic traits, stratified by T2D status. Logistic regression was used to examine the association of log-transformed cortisol with prevalent T2D. Models were adjusted for age, sex, education, occupation, systolic blood pressure, waist circumference, physical activity, smoking, beta-blocker/hormone replacement medications and cortisol collection time. RESULTS: Among 4,206 AAs (mean age 55 ± 13 years, 64% female), 19% had prevalent T2D. A 100% increase in cortisol among participants without diabetes was associated with 2.7 mg/dL (95% CI: 2.0, 3.3) higher FPG and a 10.0% (95% CI: -14.0, -6.0) lower HOMA-ß with no significant association with HbA1c or HOMA-IR. In participants with diabetes, a 100% increase in cortisol was associated with a 23.6 mg/dL (95% CI: 13.6, 33.7) higher FPG and a 0.6% (95% CI: 0.3, 0.9) higher HbA1c. Among all participants, quartile 4 vs. 1 of cortisol was associated with a 1.26-fold (95% CI: 1.75, 2.91) higher odds of prevalent T2D. CONCLUSION: Higher morning serum cortisol was associated with higher FPG and lower ß-cell function among participants without T2D and higher FPG and HbA1c in participants with diabetes. Among all participants, higher cortisol was associated with higher odds of T2D. These findings support a role for morning serum cortisol in glucose metabolism among AAs.

Sex Hormones and Measures of Kidney Function in the Diabetes Prevention Program Outcomes Study.

CONTEXT: Despite sex differences in chronic kidney disease (CKD) onset and progression, it is unclear whether endogenous sex hormones are associated with kidney function in persons without CKD. DESIGN AND METHODS: We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and its follow-up observational study, the DPP Outcomes Study, over 11 years. Participants included overweight and glucose-intolerant men (n = 889) and pre- and postmenopausal women (n = 1281) not using exogenous sex hormones and whose urine albumin-to-creatinine ratio (ACR) was <30 mg/g and normal estimated glomerular filtration ratio (eGFR) was ≥60 mL/min/1.73 m2 at randomization. We examined the association between sex hormone levels and incidence of low eGFR and/or ACR ≥30 mg/g on at least one measurement. RESULTS: At randomization, the mean (SD) eGFR was 94 (15) mL/min/1.73 m2; the median ACR (interquartile range) was 4.5 (3.3 to 7.6) mg/g. During follow-up, 187 men (24.6%) and 263 women (24.2%) had incident albuminuria and 136 men (17.9%) and 123 women (11.3%) had incident low eGFR. Among men, higher baseline sex hormone-binding globulin (SHBG) level was associated with reduced low eGFR risk (hazard ratio per SD, 0.80; 95% CI, 0.57 to 0.90) in adjusted analyses. No significant associations were observed among women. There were significant interactions between sex steroid levels and low eGFR by randomization arm. CONCLUSION: Sex steroids were not associated with development of low eGFR or albuminuria. Among men, higher SHBG level was associated with reduced risk of low eGFR on at least one measurement.

Arterial Input Functions and Tissue Response Curves in Dynamic Glucose-Enhanced (DGE) Imaging: Comparison Between glucoCEST and Blood Glucose Sampling in Humans.

Dynamic glucose-enhanced (DGE) imaging uses chemical exchange saturation transfer magnetic resonance imaging to retrieve information about the microcirculation using infusion of a natural sugar (D-glucose). However, this new approach is not yet well understood with respect to the dynamic tissue response. DGE time curves for arteries, normal brain tissue, and cerebrospinal fluid (CSF) were analyzed in healthy volunteers and compared with the time dependence of sampled venous plasma blood glucose levels. The arterial response curves (arterial input function [AIF]) compared reasonably well in shape with the time curves of the sampled glucose levels but could also differ substantially. The brain tissue response curves showed mainly negative responses with a peak intensity that was of the order of 10 times smaller than the AIF peak and a shape that was susceptible to both noise and partial volume effects with CSF, attributed to the low contrast-to-noise ratio. The CSF response curves showed a rather large and steady increase of the glucose uptake during the scan, due to the rapid uptake of D-glucose in CSF. Importantly, and contrary to gadolinium studies, the curves differed substantially among volunteers, which was interpreted to be caused by variations in insulin response. In conclusion, while AIFs and tissue response curves can be measured in DGE experiments, partial volume effects, low concentration of D-glucose in tissue, and osmolality effects between tissue and blood may prohibit quantification of normal tissue perfusion parameters. However, separation of tumor responses from normal tissue responses would most likely be feasible.

Diabetes and Platelet Response to Low-Dose Aspirin.

Context: Previous studies have suggested less cardioprotective benefit of aspirin in adults with diabetes, raising concerns about "aspirin resistance" and potentially reduced effectiveness for prevention of cardiovascular disease (CVD). Objective: To examine differences in platelet response to aspirin by diabetes status. Design, Setting, Participants: We examined platelet response before and after aspirin (81 mg/day for 14 days) in 2113 adults (175 with diabetes, 1,938 without diabetes), in the Genetic Study of Aspirin Responsiveness cohort, who had family history of early-onset CVD. Main Outcome Measures: In vivo platelet activation (urinary thromboxane B2), in vitro platelet aggregation to agonists (arachidonic acid, adenosine diphosphate, collagen), and platelet function analyzer-100 closure time. Results: Although adults with diabetes had higher in vivo platelet activation before aspirin, the reduction in in vivo platelet activation after aspirin was similar in those with vs without diabetes. Likewise, the reduction in multiple in vitro platelet measures was similar after aspirin by diabetes status. In regression analyses adjusted for age, sex, race, BMI, smoking, platelet counts, and fibrinogen levels, in vivo platelet activation remained higher in adults with vs without diabetes after aspirin (P = 0.04), but this difference was attenuated after additional adjustment for preaspirin levels (P = 0.10). No differences by diabetes status were noted for any of the in vitro platelet measures after aspirin in fully adjusted models that also accounted for preaspirin levels. Conclusions: In vitro platelet response to aspirin does not differ by diabetes status, suggesting no intrinsic differences in platelet response to aspirin. Instead, factors extrinsic to platelet function should be investigated to give further insights into aspirin use for primary prevention in diabetes.

The relationship of health literacy to diabetes status differs by sex in older adults.

OBJECTIVE: Lower health literacy is associated with higher rates of mortality and chronic disease. It remains unclear whether health literacy is associated with diabetes and/or hyperglycemia in older adults, and if this relationship differs by sex. RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis of 2510 older adults in the Health, Aging and Body Composition (Health ABC) Study who had both a Rapid Estimate of Adult Literacy in Medicine (REALM) measurement and diabetes status available. Sex-stratified logistic regression models were used to analyze the relationship of health literacy categories (low, medium, and high) to diabetes status, adjusting for key covariates. Secondary analyses examined the relationship of health literacy to glycemic markers (A1C, fasting blood glucose). RESULTS: Among participants in the Health ABC cohort, 429 had diabetes. Mean age was 76years old and 45% were female. Men with diabetes more commonly had low health literacy levels than men without diabetes (10.1% versus 9.3%, p=0.02). Similar results were seen among women (14.7% versus 6.1%, p<0.01). In a model adjusting for age, race, income, education, BMI, smoking, and alcohol use, women with low versus high health literacy had a two-fold higher likelihood of diabetes (OR=2.2; 95% CI 1.1-4.3). No significant relationship was observed in men. Progressively lower categories of health literacy were associated with higher age-adjusted mean A1C and fasting blood glucose levels in women (both p for trend <0.01) but not men. CONCLUSIONS: In this large, ethnically diverse sample of community-dwelling older adults, lower health literacy level is related to a greater likelihood of diabetes and higher A1C and fasting blood glucose levels in women-but not in men-after adjusting for age, race, and other demographic and lifestyle factors. Future studies are needed to assess mechanisms underlying this relationship and if interventions to improve health literacy are effective in reducing the burden of diabetes, particularly in women.

Aldosterone, Renin, Cardiovascular Events, and All-Cause Mortality Among African Americans: The Jackson Heart Study.

OBJECTIVES: This study examined the association of aldosterone and plasma renin activity (PRA) with incident cardiovascular disease (CVD), using a composite endpoint of coronary heart disease, stroke, and/or heart failure and mortality among African Americans in the Jackson Heart Study. BACKGROUND: There is a paucity of data for the association of aldosterone and PRA with incident CVD or all-cause mortality among community-dwelling African Americans. METHODS: A total of 4,985 African American adults, 21 to 94 years of age, were followed for 12 years. Aldosterone, PRA, and cardiovascular risk factors were collected at baseline (from 2000 to 2004). Incident events included coronary heart disease and stroke (assessed from 2000 to 2011) and heart failure (assessed from 2005 to 2011). Cox models were used to estimate hazard ratios (HRs) for incident CVD and mortality, adjusting for age, sex, education, occupation, current smoking, physical activity, dietary intake, and body mass index. RESULTS: Among 4,160 participants without prevalent CVD over a median follow-up of 7 years, there were 322 incident CVD cases. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HR of 1.26 (95% confidence intervals [CI]: 1.14 to 1.40) and 1.16 (95% CI: 1.02 to 1.33) for incident CVD, respectively. Over a median of 8 years, 513 deaths occurred among 4,985 participants. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HRs of 1.13 (95% CI: 1.04 to 1.23) and 1.12 (95% CI: 1.01 to 1.24) for mortality, respectively. CONCLUSIONS: Elevated aldosterone and PRA may play a significant role in the development of CVD and all-cause mortality among African Americans.

Prevalence and predictors of pain and opioid analgesic use following total pancreatectomy with islet autotransplantation for pancreatitis.

BACKGROUND & OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is employed for the management of refractory pain in chronic pancreatitis (CP) with the prospect of partial beta cell preservation. The primary aim of this study is to evaluate the prevalence and predictors of abdominal pain and opioid use following TPIAT. METHODS: A single center cohort study of all adult patients who underwent TPIAT from 2011 to 2015 for CP. Postoperative pain outcomes included: opioid use, ongoing abdominal pain and new characteristic abdominal pain. Multiple logistic regression analysis was used to evaluate known and potential predictors of postoperative pain outcomes. RESULTS: During the study period, 46 patients underwent TPIAT. Following surgery, 89% of patients had resolution of their pre-operative abdominal pain; however, 83% of patients developed a new characteristic abdominal pain. Opioid independence was achieved in 46% of patients. Acute recurrent pancreatitis (ARP) (OR: 11.66; 95%CI: 1.47-92.39; p = 0.02) but not pain duration >3 years or ≥ 5 ERCPs was independently associated with resolution of pre-operative abdominal pain on multiple logistic regression. None of these factors were associated with cessation of opioid use. CONCLUSION: While the majority of patients have resolution of their initial abdominal pain following TPIAT, many will also develop a new characteristic abdominal pain and only half of all patients achieve opioid independence. ARP is the only independent factor associated with positive postoperative pain outcomes and should be considered a standard criterion for patient selection.

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.

Hemoglobin A1c and Mortality in Older Adults With and Without Diabetes: Results From the National Health and Nutrition Examination Surveys (1988-2011).

OBJECTIVE: Hemoglobin A1c (HbA1c) level has been associated with increased mortality in middle-aged populations. The optimal intensity of glucose control in older adults with diabetes remains uncertain. We sought to estimate the risk of mortality by HbA1c levels among older adults with and without diabetes. RESEARCH DESIGN AND METHODS: We analyzed data from adults aged ≥65 years (n = 7,333) from the Third National Health and Nutrition Examination Survey (NHANES III) (1998-1994) and Continuous NHANES (1999-2004) and their linked mortality data (through December 2011). Cox proportional hazards models were used to examine the relationship of HbA1c with the risk of all-cause and cause-specific (cardiovascular disease [CVD], cancer, and non-CVD/noncancer) mortality, separately for adults with diabetes and without diabetes. RESULTS: Over a median follow-up of 8.9 years, 4,729 participants died (1,262 from CVD, 850 from cancer, and 2,617 from non-CVD/noncancer causes). Compared with those with diagnosed diabetes and an HbA1c <6.5%, the hazard ratio (HR) for all-cause mortality was significantly greater for adults with diabetes with an HbA1c >8.0%. HRs were 1.6 (95% CI 1.02, 2.6) and 1.8 (95% CI 1.3, 2.6) for HbA1c 8.0-8.9% and ≥9.0%, respectively (P for trend <0.001). Participants with undiagnosed diabetes and HbA1c >6.5% had a 1.3 (95% CI 1.03, 1.8) times greater risk of all-cause mortality compared with participants without diabetes and HbA1c 5.0-5.6%. CONCLUSIONS: An HbA1c >8.0% was associated with increased risk of all-cause and cause-specific mortality in older adults with diabetes. Our results support the idea that better glycemic control is important for reducing mortality; however, in light of the conflicting evidence base, there is also a need for individualized glycemic targets for older adults with diabetes depending on their demographics, duration of diabetes, and existing comorbidities.

Laparoscopic Total Pancreatectomy With Islet Autotransplantation and Intraoperative Islet Separation as a Treatment for Patients With Chronic Pancreatitis.

Importance: Pain management of patients with chronic pancreatitis (CP) can be challenging. Laparoscopy has been associated with markedly reduced postoperative pain but has not been widely applied to total pancreatectomy with islet autotransplantation (TPIAT). Objective: To examine the feasibility of using laparoscopic TPIAT (L-TPIAT) in the treatment of CP. Design, Setting, and Participants: Thirty-two patients with CP presented for TPIAT at a tertiary hospital from January 1, 2013, through December 31, 2015. Of the 22 patients who underwent L-TPIAT, 2 patients converted to an open procedure because of difficult anatomy and prior surgery. Pain and glycemic outcomes were recorded at follow-up visits every 3 to 6 months postoperatively. Main Outcomes and Measures: Operative outcomes included operative time, islet isolation time, warm ischemia time, islet equivalent (IE) counts, estimated blood loss, fluid resuscitation, and blood transfusions. Postoperative outcomes included length of stay, all-cause 30-day readmission rate, postoperative complications, mortality rate, subjective pain measurements, opioid use, random C-peptide levels, insulin requirements, and glycated hemoglobin level. Results: Of the 32 patients who presented for TPIAT, 20 underwent L-TPIAT (8 men and 12 women; mean [SD] age, 39 [13] years; age range, 21-58 years). Indication for surgery was CP attributable to genetic mutation (n = 9), idiopathic pancreatitis (n = 6), idiopathic pancreatitis with pancreas divisum (n = 3), and alcohol abuse (n = 2). Mean (SD) operative time was 493 (78) minutes, islet isolation time was 185 (37) minutes, and warm ischemia time was 51 (62) minutes. The mean (SD) IE count was 1325 (1093) IE/kg. The mean (SD) length of stay was 11 (5) days, and the all-cause 30-day readmission rate was 35% (7 of 20 patients). None of the patients experienced postoperative surgical site infection, hernia, or small-bowel obstruction, and none died. Eighteen patients (90%) had a decrease or complete resolution of pain, and 12 patients (60%) no longer required opioid therapy at a median follow-up period of 6 months. Postoperative random insulin C-peptide levels were detectable in 19 patients (95%) at a median follow-up of 10.4 months. At a median follow-up of 12.5 months, 5 patients (25%) were insulin independent, whereas 9 patients (45%) required 1 to 10 U/d, 5 patients (25%) required 11 to 20 U/d, and 1 patient (5%) required greater than 20 U/d of basal insulin. The mean (SD) glycated hemoglobin level was 7.4% (0.5%). Conclusions and Relevance: This study represents the first series of L-TPIAT, demonstrating its safety and feasibility. Our approach enables patients to experience shorter operative times and the benefits of laparoscopy, including reduced length of stay and quicker opioid independence.

Chronic Gastrointestinal Dysmotility and Pain Following Total Pancreatectomy with Islet Autotransplantation for Chronic Pancreatitis.

BACKGROUND: The prevalence and impact of chronic gastrointestinal dysmotility following total pancreactectomy with islet autotransplantation (TP-IAT) for chronic pancreatitis is not known. METHODS: A cross-sectional study of all patients who underwent TP-IAT at our institution from August 2011 to November 2015 was undertaken. The GCSI (Gastroparesis Cardinal Symptom Index), PAGI-SYM (Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index), PAC-SYM (Patient Assessment of Constipation Symptoms), Bristol stool chart, 12-item Short Form Health Survey (SF-12), and visual analog scale for pain were administered ≥4 weeks following TP-IAT. KEY RESULTS: The prevalence of any dysmotility symptoms in patients who completed the survey (33/45, 73%) post-TP-IAT was 45%. Post-TP-IAT, the mean reduction in opioid dosing was 77.6 oral morphine equivalents (OMEs) (95% CI 32.1-123.0, p = 0.002) with 42% of patients requiring no opioids. There was significant negative correlation between dysmotility scores and SF-12 physical scores (r = -0.46, p = 0.008, 95% CI -0.70 to -0.13). Self-reported abdominal pain had significant negative correlation with both physical and mental SF-12 scores (r = -0.67, p < 0.001, 95% CI -0.83 to -0.41 and r = -0.39, p = 0.03, 95% CI -0.65 to -0.04). There was no correlation between gastrointestinal dysmotility and self-reported pain. CONCLUSIONS AND INFERENCES: Symptoms of chronic gastrointestinal dysmotility and chronic abdominal pain are common post-TP-IAT and will need to be better recognized and differentiated to improve the management of these patients.

Serum vitamin D and sex hormones levels in men and women: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: 25-hydroxyvitamin D [25(OH)D] deficiency has been associated with low testosterone levels in men, but there are conflicting reports of its associations with sex hormones in women. Less is known about whether these associations are independent of adiposity and lifestyle factors, and whether they differ by race/ethnicity. AIM: To examine associations of 25(OH)D concentrations with sex hormone levels. METHODS: Cross-sectional analysis of 3017 men and 2929 women in a multi-ethnic cohort. MAIN OUTCOME MEASURES: Testosterone, estradiol, dehydroepiandrosterone (DHEA), sex hormone binding globulin (SHBG), and free testosterone. RESULTS: The mean (SD) levels of 25(OH)D in men and women were 25.7(10.4) and 26.1(12.0)ng/ml, respectively. In men, after adjusting for demographic and lifestyle variables, a 10ng/ml [25nmol/L] decrease in 25(OH)D was associated with an average difference of -0.70nmol/L (95%CI -1.36, -0.05) in SHBG and 0.02 percent (0.01, 0.04) in free testosterone, but was not associated with low total testosterone level (<10.41nmol/L). In women, a 10ng/ml decrease in 25(OH)D levels was associated with an average difference of -0.01nmol/L (-0.01, -0.00) for estradiol, -8.29nmol/L (-10.13, -6.45) for SHBG, 0.06 percent (0.04, 0.07) for free testosterone, and 0.40nmol/L (0.19, 0.62) for DHEA. There was no significant interaction by race/ethnicity. CONCLUSIONS: Lower 25(OH)D concentrations were associated with lower SHBG levels and higher free testosterone levels in both men and women, and lower estradiol and higher DHEA levels in women, independent of adiposity and lifestyle. We observed no significant association of 25(OH)D with total testosterone in men. Future studies are needed to determine whether vitamin D supplementation influences sex hormone levels.