Dexamethasone, Glycemic Control, and Outcomes in Patients With Type 2 Diabetes Mellitus Undergoing Elective, Primary Total Joint Arthroplasty.

Background: Dexamethasone (DEX) has been shown to reduce pain and postoperative nausea and vomiting for patients undergoing elective total joint arthroplasty (TJA). We investigated the impact of DEX on glycemic control and outcomes in patients with type 2 diabetes mellitus undergoing elective primary TJA. Methods: All patients with type 2 diabetes mellitus undergoing primary elective TJA between January 2016 and December 2021 at 4 sites within 1 hospital system were identified. Propensity scores were calculated to match patients receiving or not receiving DEX. Primary outcomes were perioperative blood glucose levels and the incidence of hyperglycemia. Secondary outcomes were the amount of insulin administered, the occurrence of 30-day postoperative surgical site infections, hospital readmission, and mortality. Results: After matching, we identified 1372 patients. DEX administration was associated with a significant increase in mean blood glucose levels in mg/dL on postoperative days (PODs) 0 to 2: POD 0 (28.4, 95% confidence interval [CI]: 24.6-32.1), POD 1 (14.4, 95% CI: 10.1-18.8), POD 2 (12.4, 95% CI: 7.5-17.2) when comparing patients who did or did not receive DEX. Additionally, patients receiving DEX, compared to patients who did not receive DEX, had increased odds of experiencing hyperglycemia on POD 0 (odds ratio: 4.0, 95% CI: 3.1-5.2). DEX was not associated with a significant difference in insulin administration, surgical site infections, hospital readmission, or mortality. Conclusions: In our review of 1372 patients with propensity-matched type 2 diabetes mellitus undergoing elective, primary TJA, we found that DEX administration was associated with an increased risk of elevated mean glucose on POD 0-2, hyperglycemia on POD 0, but was not associated with an increase in total insulin dose administered nor occurrence of surgical site infections, hospital readmission, or mortality within 30 days of surgery in patients who received DEX compared to patients who did not receive DEX. Level of Evidence: IV.

Iron-Catalyzed C-H Oxygenation Using Perchlorate Enabled by Secondary Sphere Hydrogen Bonds.

Perchlorate (ClO4-) is a groundwater pollutant that is challenging to remediate. We report a strategy to use Fe(II) tris(2-pyridylmethyl)amine (TPA) complexes featuring appended aniline hydrogen bonds (H-bonds) to promote ClO4- reduction. These complexes facilitate oxygen atom transfer from ClO4- to PPh3 and C-H oxygenation reactions of organic substrates. Catalytic reactions using 15 mol % afforded excellent yields for oxygenation of anthracene and cyclic alkyl aromatics, and this methodology tolerates aryl halides as well as heterocycles containing either O, S, or N.

Links between Thyroid Disorders and Glucose Homeostasis.

Thyroid disorders and diabetes mellitus often coexist and are closely related. Several studies have shown a higher prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. Thyroid hormone affects glucose homeostasis by impacting pancreatic ß-cell development and glucose metabolism through several organs such as the liver, gastrointestinal tract, pancreas, adipose tissue, skeletal muscles, and the central nervous system. The present review discusses the effect of thyroid hormone on glucose homeostasis. We also review the relationship between thyroid disease and diabetes mellitus: type 1, type 2, and gestational diabetes, as well as guidelines for screening thyroid function with each disorder. Finally, we provide an overview of the effects of antidiabetic drugs on thyroid hormone and thyroid disorders.

DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment.

BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. METHODS: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. RESULTS: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. CONCLUSIONS: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.

Late-stage ligand functionalization via the Staudinger reaction using phosphine-appended 2,2'-bipyridine.

The ability of a phosphine-appended-2,2'-bipyridine ligand ((Ph2P)2bpy) to serve as a platform for late-stage ligand modifications was evaluated using tetrahedral (Ph2P)2bpyFeCl2. We employed a post-metalation Staudinger reaction to install a series of functionalized arenes, including those containing Brønsted and Lewis acidic groups. This reaction sequence represents a versatile strategy to both tune the ligand donor properties as well as directly incorporate appended functionality.

Hydrogen-bonded nickel(I) complexes.

A series of nickel(ii) tris(2-pyridylmethyl)amine (TPA) complexes featuring appended hydrogen bonds (H-bonds) to halides (F, Cl, Br) was synthesized and charcterized. Reduction to the nickel(i) state provided access to an unusual nickel(i) fluoride complex stabilized by H-bonds, enabling structural and spectroscopic characterization.

Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal.

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous glucagon-like peptide-1 (GLP-1). We hypothesized that genetic variation in the gene encoding the GLP-1 receptor (GLP1R) could affect the metabolic response to DPP-4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G-to-A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7-day treatment with placebo and the DPP-4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP-1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP-1 signalling merits study in large populations.

Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition.

CONTEXT: Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. OBJECTIVE: This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. PARTICIPANTS AND DESIGN: Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. RESULTS: Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. CONCLUSION: DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor-dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.

DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition.

DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P≤0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women.

BACKGROUND: Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity. METHODS AND RESULTS: Healthy adults participated in a 2-part double-blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (rs=-0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA. CONCLUSIONS: Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.

Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin.

CONTEXT: Patients with diabetes often have comorbidities such as hypertension. It is not known how individual characteristics influence response to dipeptidyl peptidase-4 (DPP4) inhibitors. OBJECTIVE: We tested the hypothesis that individual characteristics, sitagliptin dose, and genetic variability in DPP4 influence DPP4 activity during sitagliptin. DESIGN AND SETTING: Post hoc analysis of clinical and laboratory data from individuals randomized to sitagliptin versus placebo in crossover studies. PATIENTS AND INTERVENTIONS: Sixty-five subjects [27 with type 2 diabetes mellitus (T2DM) and hypertension, 38 healthy controls] were randomized to 100 mg/d sitagliptin or 200 mg sitagliptin and matching placebo in double-blind, crossover fashion. Fasting blood was obtained at baseline and 60 to 180 minutes after sitagliptin or placebo. MAIN OUTCOME MEASURES: DPP4 activity and antigen during placebo and sitagliptin and DPP4 inhibition during sitagliptin. RESULTS: Sitagliptin 100 mg/d was less effective at inhibiting DPP4 activity in individuals with T2DM and hypertension than in healthy controls (P = 0.001, percent inhibition). In healthy controls, 100 mg/d sitagliptin was not as effective as single-dose 200 mg sitagliptin (P = 0.001, percent inhibition). DPP4 genotypes rs2909451 TT (P = 0.02) and rs759717 CC (P = 0.02) were associated with DPP4 activity during sitagliptin. In multivariable analyses, T2DM with hypertension, sitagliptin dose, age, systolic blood pressure, DPP4 activity during placebo, and rs2909451 genotype were significantly associated with DPP4 activity during sitagliptin. CONCLUSIONS: Sitagliptin is less effective in inhibiting DPP4 in individuals with T2DM and hypertension than in healthy controls. Higher doses of DPP4 inhibitors may be required in patients with the metabolic syndrome.

Ectopic ACTH Production Leading to Diagnosis of Underlying Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) has been described as a source of ectopic ACTH secretion in patients with Cushing's syndrome. This is an infrequent association, occurring in less than 1% of MTC cases. Among these, it is even more unusual for an initial diagnosis of hypercortisolism to lead to the discovery of underlying MTC. Here we present a case of a patient with weakness, diarrhea, and hypokalemia who was found first to have Cushing's syndrome and later diagnosed with metastatic MTC. The patient was treated initially with oral agents to control his hypercortisolism, then with an etomidate infusion after experiencing intestinal perforation. He also received vandetanib therapy targeting his underlying malignancy, as this has been shown to reverse clinical signs of Cushing's syndrome in patients with MTC and subsequent ectopic ACTH secretion. Bilateral adrenalectomy was ultimately required. Medullary thyroid carcinoma should be considered in patients presenting with Cushing's syndrome due to ectopic ACTH secretion, and a multimodality treatment approach is often required.

Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease.

OBJECTIVE: Body weight blunts the growth hormone (GH) response to provocative stimuli. The appropriate GH cut-off to confirm GH deficiency in obese and overweight patients undergoing the glucagon stimulation test (GST) has recently been questioned. We hypothesized that the peak GH would be inversely related to the nadir blood glucose (BG) after glucagon and that this may be a mechanism influencing peak GH in overweight patients. This retrospective study examined effects of gender, body weight, and BG dynamics on GH response to GST in patients evaluated in our Pituitary Center. DESIGN: Adult patients who underwent GST from September 2009-2014 were included. Continuous variable comparisons were analyzed using the Mann-Whitney U-test and categorical data by Fisher's Exact Test. Spearman correlation was used to determine associations between continuous variables. RESULTS: 42 patients (N=28, 66.7% female) had sufficient data for analysis. Obese patients (N=26) had a reduced GH response, summarized as GH area under the curve (AUC) (p=0.03 vs. non-obese patients) and higher BG during GST, summarized as AUC (p<0.01 vs. non-obese patients). Obese women (N=19), in particular, stimulated lower (p=0.03 vs. non-obese women) and had a higher nadir BG (p=0.03 vs. non-obese women). While weight correlated with extent (rs=0.35; p=0.02) and timing (rs=0.31; p=0.05) of nadir BG reached, there was no significant correlation between BG dynamics and the GH response in the total population (N=42). Ten patients (7 with pan anterior hypopituitarism, defined as 3 anterior pituitary deficiencies) had a peak GH≤0.1ng/mL during GST. When these subjects with a negligible peak GH response were excluded from the analysis, weight was associated with GH AUC (rs=-0.45; p=0.01), peak GH response (rs=-0.42; p=0.02) and nadir BG (rs=0.48; p<0.01). Furthermore, the nadir BG achieved during GST was inversely related to GH AUC (rs=-0.38; p=0.03) and peak GH (rs=-0.37; p=0.04) such that patients (N=32) with higher nadir BG had lower peak GH in response to glucagon. CONCLUSIONS: Obese patients, particularly women, do not respond as robustly to glucagon stimulation. These data suggest that there exists an altered BG profile during GST in obese individuals, and that a less robust hypoglycemic stimulus may contribute to an impaired GH response. We suggest measuring BG levels during glucagon stimulation testing to assist with clinical interpretation of GH dynamics. The diagnostic accuracy of the GST in patients with known disorders in glucose metabolism and those taking anti-diabetic medications deserves further study.

Treatment outcomes of a crisis intervention program for dementia with severe psychiatric complications: the Kansas bridge project.

PURPOSE: Although declines in memory and attention are hallmark symptoms of Alzheimer's disease (AD), noncognitive symptoms are prevalent. Over 80% of individuals will experience neuropsychiatric symptoms, which complicates symptom profiles. Research indicates a community-integrated response to dementia crisis can reduce negative consequences attributed to crisis including increased caregiver burden, increased health care costs, and premature institutionalizations. DESIGN AND METHODS: The Kansas Dementia Crisis Bridge Project is a multidisciplinary collaboration to provide direct support in critical situations to reduce psychiatric rehospitalizations. Coordinators provided counsel and dementia education to families throughout critical period of acute neuropsychiatric symptoms, facilitated professional involvement, and provided crisis prevention planning through crisis review. The Neuropsychiatric Inventory Questionnaire and Geriatric Depression Scale were used to measure the impact of neuropsychiatric symptoms and Bridge interventions on patient and caregivers. RESULTS: The Bridge project significantly reduced patient anxiety, depression, resistance to care, impulsive behavior, verbal outbursts, and wandering. Caregivers reported significantly reduced anxiety, apathy, resistance to care, and less distress over patient neuropsychiatric symptoms. Caregivers also reported increased confidence in managing difficult behaviors, and the project effectively reduced or resolved neuropsychiatric crisis. The project delayed nursing home placement for community-dwelling patients. IMPLICATIONS: Crisis support models like the Bridge project reduce strain on care-delivery systems by incorporating nonpharmacological interventions, assisting families with communication, and reducing family distress during symptom crises. Although much of AD research focuses on disease-modifying medical interventions, aging and care systems in the state must simultaneously move towards dependency-modifying care interventions.

The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*.

OBJECTIVES: Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients. DESIGN, SETTING, AND PATIENTS: This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients. MEASUREMENTS AND MAIN RESULTS: Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6-3.1) and 2.1 (95% confidence interval 1.0-3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively). CONCLUSIONS: Increased kynurenine pathway activation, assessed by plasma kynurenine and kynurenine/tryptophan ratio, was associated with fewer days alive and without acute brain dysfunction in intensive care unit patients. Future studies are warranted to clarify this relationship and investigate potential therapeutic interventions.