Elevated Blood Pressure and Aldosterone Dysregulation in Young Black Women Versus White Women on Controlled Sodium Diets.

CONTEXT: Black women have a higher prevalence of hypertension as compared to White women. Differences in dietary sodium intake have been implicated as a contributing factor for the disparities in hypertension. OBJECTIVE: Our objective was to understand whether young Black women would have higher systolic blood pressure (SBP) than White women even on controlled sodium diets and to determine whether SBP differences were due to differences in dietary sodium intake and/or aldosterone regulation. DESIGN: The analyses included 525 hypertensive and normotensive women (ages 18-71) from the International Hypertensive Pathotype consortium, who were maintained on liberal sodium (LIB; >200 mEq sodium/day) and restricted sodium (RES; 10 mEq sodium/day) diets. RESULTS: Multivariate regression analyses (adjusted for age, race, study site, body mass index) found that Black women (ages 18-50) had significantly higher SBP than White women on both sodium diets: +8.7 ± 2.7 mmHg (P-value = .002) on a LIB diet and +8.5 ± 2.5 mmHg (P-value = .001) on a RES diet. Even among 18- to 35-year-olds-who were normotensive and nonobese-Black women had higher SBP: +7.9 ± 2.4 mmHg (P-value = .001) on a LIB diet and +7.6 ± 2.7 mmHg (P-value = .005) on a RES diet. Younger Black women also had higher plasma aldosterone concentration to plasma renin activity ratio (ARR) on both LIB and RES diets as well as a higher sodium-modulated aldosterone suppression-stimulation index-an indicator of aldosterone dysregulation. In younger Black women-but not in White women-there was a significant association between SBP and ARR on both LIB and RES diets. CONCLUSION: Young Black women had increased SBP and ARR as compared to White women on LIB and RES diets, which offers insights into the possible mechanisms for the increased hypertension and cardiovascular disease risk in an at-risk and understudied population.

Effect of hypoglycemia on baroreflex sensitivity in individuals with type 2 diabetes: implications for autonomic control of cardiovascular function in diabetes.

PURPOSE: Hypoglycemia is associated with increased mortality, though the mechanisms underlying this association are not established. Hypoglycemia impairs the counterregulatory hormonal and autonomic responses to subsequent hypoglycemia. It is unknown whether hypoglycemia elicits a generalized impairment in autonomic control of cardiovascular function in individuals with type 2 diabetes. We tested the hypothesis that in individuals with type 2 diabetes, hypoglycemia impairs a key measure of cardiovascular autonomic homeostasis, baroreflex sensitivity. METHODS: Sixteen individuals with well-controlled type 2 diabetes and without known cardiovascular disease were exposed to two 90-min episodes of experimental hypoglycemia (2.8 mmol/L, 50 mg/dL) on the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). Baroreflex sensitivity was assessed using the modified Oxford method before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 min of hypoglycemia, and the following morning. A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on baroreflex sensitivity. The study is registered at ClinicalTrials.gov (NCT03422471). RESULTS: Baroreflex sensitivity during PM hypoglycemia was reduced compared to baseline, during AM hypoglycemia, and the next day. Insulin levels positively correlated with baroreflex sensitivity at baseline and during AM hypoglycemia. CONCLUSION: Exposure to hypoglycemia impairs a key measure of autonomic control of cardiovascular function and, thus, may increase the risk of cardiac arrhythmias and blood pressure lability in individuals with type 2 diabetes. This effect is attenuated in part by increased insulin levels.

Association Between Life's Simple 7 and Biomarkers of Cardiovascular Disease: Aldosterone, Interleukin-6, C-Reactive Protein.

Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)-achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C-reactive protein), and IL-6 (interleukin-6). Methods and Results We analyzed 379 individuals (age 18-66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14-point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3-14), we classified participants as "inadequate" (3-6), "average" (7-10), and "optimal" (11-14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone (Ptrend<0.001 and Ptrend=0.001, respectively), lower plasma renin activity (Ptrend<0.001), and a blunted increase in serum aldosterone with angiotensin II infusion (Ptrend=0.023). Being in the "optimal" LS7 score group was associated with lower serum CRP (Ptrend=0.001) and IL-6 (Ptrend=0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.

A Patent Foramen Ovale Grants Cardiac Output Over an Obstructive Primary Cardiac Lymphoma.

Primary cardiac lymphomas are extremely rare and involve mainly the pericardium. We present the case of a 77-year-old man with a germinal center diffuse large B-cell lymphoma causing severe right ventricular inflow obstruction. Clinical presentation of isolated dyspnea and severe desaturation and cyanosis were, otherwise, unexpected. (Level of Difficulty: Beginner.).

Differing effects of oral conjugated equine estrogen and transdermal estradiol on vitamin D metabolism in postmenopausal women: a 4-year longitudinal study.

OBJECTIVE: The aim of this study was to examine the effect of either conjugated equine estrogen or transdermal estradiol on vitamin D metabolism in postmenopausal women. METHODS: Twenty-five women from the Kronos Early Estrogen Prevention Study who were randomized to conjugated equine estrogen 0.45 mg/d and 20 women who were treated with transdermal estradiol 50 mg/d (patch replaced weekly) were analyzed in the present study. All participants received micronized progesterone for 12 days per month. RESULTS: There was no significant treatment effect on serum total 25-hydroxyvitamin D over 48 months in either study group, and there were no significant differences between treatment arms. In contrast, at 12 months, directly measured free 25-hydroxyvitamin D was significantly higher in the transdermal estradiol group than in the conjugated equine estrogen group. Directly measured free 25-hydroxyvitamin D subsequently increased significantly from 12 to 48 months in both treatment arms. Calculated free 25-hydroxyvitamin D was also significantly higher in the transdermal estradiol group at 36 months. Vitamin D-binding protein decreased significantly in both treatment groups from 12 to 48 months, but at 48 months, least square mean values were no different based on treatment assignment. CONCLUSIONS: Directly measured free 25-hydroxyvitamin D levels, but not serum total 25-hydroxyvitamin D levels, are different within the first 12 months of estrogen replacement depending on the preparation. However, this difference is transient, in that there were no differences at 36 or 48 months. These findings suggest that there may be a short-term benefit to prescribing transdermal estradiol for women who are either vitamin D deficient or vitamin D insufficient.

Stress, hypoglycemia, and the autonomic nervous system.

Stress can be classified as either psychosocial or physiologic. Physiologic stress refers to stresses due to acute illness, trauma, pain, hypoglycemia, and sleep deprivation-much less is known regarding its health consequences. This review focuses on hypoglycemia as a model to further investigate physiological stress. Experimental mild to moderate hypoglycemia is a paradigmatic physiological stress that evokes autonomic, neuroendocrine, and immune responses. Hypoglycemic stress is an ideal model to examine the interactions and consequences of physiological stress on the autonomic nervous system. Acute hypoglycemia has been demonstrated to increase inflammatory markers, prolong QTc, and impair cardiac-vagal baroreflex sensitivity. Some of these consequences may not reverse completely when euglycemia is restored. For example, there is attenuation of the cardiac-vagal baroreflex, attenuation of the vascular sympathetic baroreflex (muscle sympathetic nerve activity response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure that is present the next day after hypoglycemia has resolved.

Bloodstream Infections Caused by Magnusiomyces capitatus and Magnusiomyces clavatus: Epidemiological, Clinical, and Microbiological Features of Two Emerging Yeast Species.

Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. Our objectives were to determine the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. In seven institutions, a total of 34 Magnusiomyces BSI were identified. Identification was done by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/L), followed by posaconazole (MIC50, 0.125/0.25 mg/L). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, low essential agreement between gradient test and microdilution was recorded for all antifungals (0 to 70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.

Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway.

[Figure: see text].

Improvement of the froth flotation of LiAlO2 and melilite solid solution via pre-functionalization.

In this work froth flotation studies with LiAlO2 (lithium-containing phase) and Melilite solid solution (gangue phase) are presented. The system was optimized with standard collectors and with compounds so far not applied as collectors. Furthermore, the principle of self-assembled monolayers was introduced to a froth flotation process for the first time resulting in excellent yields and selectivities.

The crux of C1-INH testing in everyday lab work.

BACKGROUND: The determination of functional C1-INH is complex and depends on methodology, sample transport, and storage conditions. In clinical practice, we encounter individuals with pathological values which then cannot be proved true, and HAE patients in whom the values were wrongly found to be normal under non-optimum conditions. We aimed to test realistic real-life sample processing conditions for accurate C1-INH determination. METHODS: We conducted two national inter-laboratory comparisons with optimal sample preparation but different dispatch conditions. We also investigated variations of temperature and time, and their influence on C1-INH. RESULTS: C1-INH levels showed a significantly wider dispersion under suboptimal transport conditions than under optimal conditions (p < 0.00001). Two putatively healthy patient samples turned out to be pathological. Contrary to our expectations, we found no significant trend in a specific direction when the variables of temperature, time and sample material were combined and varied under realistic conditions. However, the range of variation in [%] functionality was markedly greater in supposedly healthy volunteers. Thus, under experimental conditions we obtained false pathological results that were not far from reality. CONCLUSION: C1- INH determination is crucial for the diagnosis of HAE. Time, temperature, and sample handling have a significant impact on this laboratory value, sometimes leading to incorrect values, inaccurate diagnoses, and inappropriate therapies. This underlines the importance of proper handling of samples. If a patient has ambiguous C1-INH values despite optimized conditions, thus hindering a conclusive diagnosis of HAE, we recommend genetic testing.

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

Dietary sodium intake and cortisol measurements.

OBJECTIVES: To assess the influence of a dietary sodium intake intervention on cortisol measurements within the general population. DESIGN: Cross-over intervention. PATIENTS: Six hundred thirty adults without known Cushing syndrome, cardiovascular or renal disease completed a restricted dietary sodium diet (10 mmol/d, 230 mg/d) followed by cross-over to a liberalized dietary sodium diet (200 mmol/d, 4600 mg/d). Twenty-four-hour urine collection and biochemical investigations were performed at the end of each dietary intervention. RESULTS: Mean 24-hour urinary free cortisol increased with liberalized sodium intake when compared with restricted sodium intake (178.0 ± 89.7 vs 121.3 ± 65.6 nmol/d, P < .001). Nearly all participants (84%) had an increase in the urinary free cortisol following liberalized sodium intake. This translated to a substantial difference in the proportion of participants exceeding categorical thresholds of urinary cortisol on liberalized vs restricted sodium intake: 62% vs 27% for 138 nmol/d (50 mcg/d), 46% vs 17% for 166 nmol/d (60 mcg/d), 32% vs 10% for 193 nmol/d (70 mcg/d), 23% vs 6% for 221 nmol/d (80 mcg/d), 17% vs 4% for 248 nmol/d (90 mcg/d). In parallel, there was a small decrease in morning total serum cortisol with liberalized sodium intake (303.0 ± 117.3 vs 326.4 ± 162.5 nmol/L, P < .001). CONCLUSIONS: Increased dietary sodium intake increases urinary free cortisol excretion and may increase the risk for false-positive results. Variations in dietary sodium intake may influence the interpretations of cortisol measurements performed to evaluate for hypercortisolism.

Continuous spinal anaesthesia for partial gastrectomy in an adult patient with unrepaired tetralogy of Fallot.

Correction of tetralogy of Fallot during infancy usually eliminates the risks associated with general anaesthesia. In rare cases of uncorrected defects persisting into adulthood, anaesthetic management during non-cardiac surgery may therefore be challenging. We describe the use of continuous spinal anaesthesia to successfully circumvent the operative risk of major abdominal surgery in an adult patient with uncorrected tetralogy of Fallot.

Higher urinary cortisol levels associate with increased cardiovascular risk.

There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P < 0.001. Framingham risk score was also statistically higher in the caveolin-1 risk allele carriers (8.91 ± 0.37) compared to caveolin-1 non-risk allele carriers (7.59 ± 0.48), P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.

Sex Differences in Coronary Microvascular Function in Individuals With Type 2 Diabetes.

Cardiovascular (CV) disease fatality rates are higher for women compared with men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post hoc analysis to determine whether there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled type 2 diabetes and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared with men. In addition, rest MBF was positively correlated with worse diastolic function in women. We previously showed that mineralocorticoid blockade improved CFR in men and women with type 2 diabetes, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with type 2 diabetes and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared with men. The greater aldosterone responsivity in women may be a mechanism for this sex effect.

Osteoanabolic Agents for Osteoporosis.

Medications for osteoporosis are classified as either antiresorptive or anabolic. Whereas antiresorptive agents prevent bone resorption, anabolic agents promote new bone formation. Anabolics should be considered in individuals with severe osteoporosis, failure of alternative osteoporosis agents, intolerability or contraindications to other osteoporosis agents, and glucocorticoid-induced osteoporosis. There are currently two approved anabolic therapies, teriparatide and abaloparatide, and a third anabolic agent, romozosumab, is under review by the US Food and Drug Administration. Teriparatide and abaloparatide are administered as daily subcutaneous injections and have been shown to reduce vertebral and nonvertebral fractures significantly. The most common side effects are headache and nausea, but teriparatide and abaloparatide are generally well tolerated. The sequence of administration of anabolic therapy is important. Benefits of anabolics are attenuated in individuals with prior antiresorptive exposure; however, antiresorptive agents administered after anabolics consolidate bone mineral density gains.

Global Corner Spotlight: Perspectives on Diabetes Care in Cambodia as Seen Through an Ngo-Run Healthcare System.

ABBREVIATIONS: CMC = Community Medical Center; SGLT2 = sodium-glucose cotransporter 2; SHCH = Sihanouk Hospital Center of Hope.

Effect of the Duodenal-Jejunal Bypass Liner on Glycemic Control in Patients With Type 2 Diabetes With Obesity: A Meta-analysis With Secondary Analysis on Weight Loss and Hormonal Changes.

OBJECTIVE: Duodenal-jejunal bypass liner (DJBL) is an endoscopic device that may mimic small bowel mechanisms of Roux-en-Y gastric bypass (RYGB). Previous studies have demonstrated the efficacy of DJBL at inducing weight loss. We assessed the effect of DJBL on glycemic control in patients with type 2 diabetes (T2D) with obesity. RESEARCH DESIGN AND METHODS: Data sources included MEDLINE, EMBASE, and Web of Science through 1 July 2017. Included were published studies that assessed DJBL outcomes in obese T2D patients. RESULTS: Primary outcomes were change in HbA1c and HOMA of insulin resistance (HOMA-IR). Secondary outcomes were change in weight and gut hormones glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin. Seventeen studies were included. At explant, HbA1c decreased by 1.3% [95% CI 1.0, 1.6] and HOMA-IR decreased by 4.6 [2.9, 6.3]. Compared with control subjects, DJBL subjects had greater HbA1c reduction by 0.9% [0.5, 1.3]. Six months after explant, HbA1c remained lower than baseline by 0.9% [0.6, 1.2]. At explant, patients lost 11.3 kg [10.3, 12.2], corresponding to a BMI reduction of 4.1 kg/m2 [3.4, 4.9], total weight loss of 18.9% [7.2, 30.6], and excess weight loss of 36.9% [29.2, 44.6]. The amount of weight loss remained significant at 1 year postexplantation. After DJBL, GIP decreased, whereas GLP-1, PYY, and ghrelin increased. CONCLUSIONS: DJBL improves glycemic control and insulin resistance in T2D patients with obesity. DJBL also appears to induce significant weight loss in this population. Additionally, changes in gut hormones suggest mechanisms similar to RYGB. Study limitations included heterogeneity among studies.

POSITIVE THYROTROPIN RECEPTOR ANTIBODIES IN PATIENTS WITH TRANSIENT THYROTOXICOSIS.

OBJECTIVE: Thyrotropin (TSH) receptor antibody (TRAb) testing is considered accurate for the diagnosis of Graves disease (GD) and has been identified rarely in thyrotoxic patients without GD. We describe 4 patients with transient thyrotoxicosis and positive TRAb to highlight this clinical possibility. METHODS: Patient demographics, symptoms, laboratory findings, and time to resolution of thyrotoxicosis are summarized. TRAb testing was performed by either a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) competitive-binding assay or a thyroid-stimulating immunoglobulin (TSI) bioassay from either Mayo Clinic Laboratory or Quest Diagnostics. RESULTS: Four patients with transient thyrotoxicosis and positive TRAb testing were identified. Of these, three were female, and the median age was 44 years (range, 25 to 49 years). Median symptom duration at evaluation was 6.5 weeks (range, 3 to 12 weeks). No patient had any clinical manifestations unique to GD or exposure to biotin, thyroid hormone, supplements, iodine, or relevant medications. The TSH was <0.1 mIU/L in all patients. Three patients had a positive TSI, which was elevated less than twice the upper limit of the reference range in all cases, and 1 patient had a strongly positive TBII. None of the patients were treated with thionamides or radioactive iodine. Spontaneous resolution occurred in all patients at a median of 5.5 weeks (range, 2 to 14.4 weeks). CONCLUSION: These cases demonstrate that TSI or TBII may be present in thyrotoxic patients with transient thyrotoxicosis. For clinically stable patients presenting without pathognomonic evidence of GD, mildly elevated TRAb results may require cautious interpretation, and alterative diagnostic testing or close monitoring should be considered. ABBREVIATIONS: cAMP = cyclic adenosine monophosphate; FT4 = free thyroxine; GD = Graves disease; TBII = thyrotropin-binding inhibitory immunoglobulin (also known as TBI); TRAb = thyrotropin receptor antibody; TSH = thyrotropin; TSHR = thyrotropin receptor; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine.

Pathogenesis of Cardiovascular Disease in Diabetes.

The most common cause of death among adults with diabetes is cardiovascular disease (CVD). In this concise review on pathogenesis of CVD in diabetes, the 4 common conditions, atherosclerosis, microangiopathy, diabetic cardiomyopathy, and cardiac autonomic neuropathy, are explored and illustrated to be caused by interrelated pathogenetic factors. Each of these diagnoses can present alone or, commonly, along with others due to overlapping pathophysiology. Although the spectrum of physiologic abnormalities that characterize the diabetes milieu is broad and go beyond hyperglycemia, the authors highlight the most relevant evidence supporting the current knowledge of potent factors that contribute to CVD in diabetes.