Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic Regulation and Metabolic Control.

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism.

Glycemic Patterns Are Distinct in Post-Bariatric Hypoglycemia After Gastric Bypass (PBH-RYGB).

CONTEXT: Severe hypoglycemia with neuroglycopenia, termed post-bariatric hypoglycemia (PBH). typically occurs postprandially, but it is also reported after activity or mid-nocturnally. OBJECTIVE: To quantify glycemia, glycemic variability, and magnitude/duration of low sensor glucose (SG) values in patients with PBH after Roux-en-Y gastric bypass (PBH-RYGB). METHODS: This retrospective analysis of data from an academic medical center included individuals with PBH-RYGB (n = 40), reactive hypoglycemia without gastrointestinal surgery (Non-Surg Hypo, n = 20), prediabetes (Pre-DM, n = 14), newly diagnosed T2D (n = 5), and healthy controls (HC, n = 38). Masked continuous glucose monitoring (Dexcom G4) was used to assess patterns over 24 hours, daytime (6 am-midnight) and nighttime (midnight-6 am). Prespecified measures included mean and median SG, variability, and percent time at thresholds of sensor glucose. RESULTS: Mean and median SG were similar for PBH-RYGB and HC (mean: 99.8 ±â€…18.6 vs 96.9 ±â€…10.2 mg/dL; median: 93.0 ±â€…14.8 vs 94.5 ±â€…7.4 mg/dL). PBH-RYGB had a higher coefficient of variation (27.3 ±â€…6.8 vs 17.9 ±â€…2.4%, P < 0.0001) and range (154.5 ±â€…50.4 vs 112.0 ±â€…26.7 mg/dL, P < 0.0001). Nadir was lowest in PBH-RYGB (42.5 ±â€…3.7 vs HC 49.0 ±â€…11.9 mg/dL, P = 0.0046), with >2-fold greater time with SG < 70 mg/dL vs HC (7.7 ±â€…8.4 vs 3.2 ±â€…4.1%, P = 0.0013); these differences were greater at night (12.6 ±â€…16.9 vs 1.0 ±â€…1.5%, P < 0.0001). Non-Surg Hypo also had 4-fold greater time with SG < 70 at night vs HC (SG < 70: 4.0 ±â€…5.9% vs 1.0 ±â€…1.5%), but glycemic variability was not increased. CONCLUSION: Patients with PBH-RYGB experience higher glycemic variability and frequency of SG < 70 compared to HC, especially at night. These data suggest that additional pathophysiologic mechanisms beyond prandial changes contribute to PBH.

USE OF THE FREE THYROXINE INDEX TO REFINE THE LOWER LIMIT OF A FREE THYROXINE IMMUNOASSAY FOR DETECTION OF SECONDARY HYPOTHYROIDISM.

OBJECTIVE: To determine the utility of measuring free T4 index (FT4I) in patients with low free T4 (FT4) levels using immunoassay and normal thyroid-stimulating hormone for the evaluation of secondary hypothyroidism. METHODS: We performed a retrospective medical chart review of patients seen at a single institution as outpatients who had a simultaneously normal thyroid-stimulating hormone level, low FT4 level, and any FT4I measured between June 2014 and October 2016. Demographic, laboratory, and imaging data were collected. Using FT4I as the reference for diagnosis of hypothyroidism, the sensitivity and specificity of the FT4 immunoassay's lower-limit thresholds were determined. Within each threshold group, available brain imaging and biochemical evaluation were categorized according to the presence or absence of pituitary disease. RESULTS: A total of 155 sets of result pairs (FT4 and FT4I) performed on 118 subjects were analyzed. The lower limit of a normal FT4 level by immunoassay at this institution was 0.93 ng/dL, though all pairs with FT4 ≥0.89 ng/dL had a normal FT4I. All pairs with FT4 ≤0.67 ng/dL had a low FT4I. No pituitary macroadenomas were identified in any subject, though the rates of pituitary imaging in this patient sample were low. CONCLUSION: Patients with a borderline low FT4 level by immunoassay often have normal FT4I. In such patients at our center, significant structural and biochemical pituitary pathology was uncommon.

Influence of Cinnamon on Glycemic Control in Individuals With Prediabetes: A Randomized Controlled Trial.

CONTEXT: The identification of adjunct safe, durable, and cost-effective approaches to reduce the progression from prediabetes to type 2 diabetes (T2D) is a clinically relevant, unmet goal. It is unknown whether cinnamon's glucose-lowering properties can be leveraged in individuals with prediabetes. OBJECTIVE: The objective of this work is to investigate the effects of cinnamon on measures of glucose homeostasis in prediabetes. DESIGN SETTING PARTICIPANTS AND INTERVENTION: This double-blind, placebo-controlled, clinical trial randomly assigned adult individuals meeting any criteria for prediabetes to receive cinnamon 500 mg or placebo thrice daily (n = 27/group). Participants were enrolled and followed at 2 academic centers for 12 weeks. MAIN OUTCOME MEASURES: Primary outcome was the between-group difference in fasting plasma glucose (FPG) at 12 weeks from baseline. Secondary end points included the change in 2-hour PG of the oral glucose tolerance test (OGTT), and the change in the PG area under the curve (AUC) derived from the OGTT. RESULTS: From a similar baseline, FPG rose after 12 weeks with placebo but remained stable with cinnamon, leading to a mean between-group difference of 5 mg/dL (P < .05). When compared to the respective baseline, cinnamon, but not placebo, resulted in a significant decrease of the AUC PG (P < .001) and of the 2-hour PG of the OGTT (P < .05). There were no serious adverse events in either study group. CONCLUSIONS: In individuals with prediabetes, 12 weeks of cinnamon supplementation improved FPG and glucose tolerance, with a favorable safety profile. Longer and larger studies should address cinnamon's effects on the rate of progression from prediabetes to T2D.

A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. METHODS: Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 µg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. RESULTS: Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. CONCLUSION: A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. CLINICAL TRIALS REGISTRATION: NCT03255629.

Management of Diabetes in Patients Undergoing Bariatric Surgery.

PURPOSE OF REVIEW: The number of bariatric surgeries for patients with type 1 or type 2 diabetes continues to grow. Clinicians are challenged to choose therapies that reach glycemic targets without inducing adverse effects in post-bariatric patients without published guidelines. This review evaluates data supporting the best strategies for diabetes management in patients undergoing bariatric surgery. RECENT FINDINGS: Though few clinical trials have evaluated the safety and effectiveness of different glucose-lowering therapies following bariatric surgery, remission of diabetes or reduced medications is an established benefit of bariatric surgery. Adverse events including diabetic ketoacidosis in post-bariatric patients on sodium-glucose co-transporter 2 (SGLT2) inhibitors or inadequate insulin have been reported in patient's with both type 1 and type 2 diabetes. Metformin, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors, insulin, and sulfonylureas have been used successfully in the perioperative period for other surgeries and guidelines recommend adjusting the doses of these medications especially in the perioperative period. Clinicians should favor weight-neutral or weight-loss promoting therapies in post-bariatric surgery patients such as medical nutrition therapy, metformin, GLP-1 agonists, SGLT2 inhibitors, and DPP-4 inhibitors.

Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia.

BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH. CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.

Variations in glucose/C-peptide ratio in patients with type 2 diabetes associated with renal function.

INTRODUCTION: Accurate dosing of medications for glycemic control is a challenge for clinicians in diabetic patients with kidney disease. Diminishing glomerular filtration rates are associated with decreased renal clearance of insulin and increased prevalence of hypoglycemic episodes. Measurement of glucose/C peptide ratios may be useful to guide dosing in those patients who receive powerful insulin secretogogues as glomerular function decreases with age and disease. METHODS: In order to determine the relationship between glucose, C-peptide and renal function, we reviewed the records of patients with type 2 diabetes followed in our kidney hypertension clinic who met the following criteria: age 35-90 years, requirement of medications to control glycemia, at least 4 simultaneous measurements of C peptide, HbA1c, creatinine and blood glucose. RESULTS: 87 patients (67 males, 20 females), ages 67.1 ±â€¯10.6 years, BMI 32.5 ±â€¯5.2, A1c 8.2 ±â€¯1.2%, eGFR 73 ±â€¯27.2 ml/min, had glucose/C-peptide ratios 60.7 ±â€¯46.4. 59% of the total group were taking insulin secretogogues. Patients were divided into groups based upon mean eGFR and use or absence of insulin secretogogues. Glucose C-peptide ratios were lowest in the quartile of patients with the lowest eGFR (<50 ml/min). CONCLUSION: Diminished renal function and advanced age are associated with the lowest glucose/C-peptide ratios, independent of achieved glycemic control. With similar use of secretogogues, glucose/C-peptide ratio were lower when eGFR was ≤49 ml/min compared to >50-80 ml/min. Use of secretogogues was associated with decreased glucose/C-peptide levels. In patients with reduced renal function (eGFR < 50 ml/min), use of insulin secretogogues may be associated with lower glucose/C-peptide ratios associated with higher risks for hypoglycemic reactions.

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. METHODS: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. RESULTS: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 µg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 µg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). CONCLUSIONS: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.

Mechanisms of weight loss and improved metabolism following bariatric surgery.

Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole-body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients.

Medical nutrition therapy for post-bariatric hypoglycemia: practical insights.

Hypoglycemia is increasingly recognized as a complication of bariatric surgery. Although medications are often required, medical nutrition therapy remains the key cornerstone for successful prevention of hypoglycemia in patients with post-bariatric hypoglycemia (PBH). We provide suggested approaches to the dietary management of PBH, incorporating data from both the medical literature and extensive clinical experience in an academic referral center for PBH. The overall goal of medical nutrition therapy for PBH is to reduce postprandial surges in glucose, which often trigger surges in insulin secretion and promote subsequent hypoglycemia. Thus, strategies focus on controlled portions of low glycemic index carbohydrates, avoidance of rapidly-absorbed carbohydrates, adjustment of timing of meals and snacks, and attention to personal and cultural barriers to implementation.

Insulinoma After Bariatric Surgery: Diagnostic Dilemma and Therapeutic Approaches.

Hypoglycemia is increasingly recognized as a complication of bariatric surgery. Typically, hypoglycemia does not appear immediately postoperatively, but rather more than 1 year later, and usually occurs 1-3 h after meals. While rare, insulinoma has been reported after bariatric surgery. Clinical factors which should raise suspicion for insulinoma and the need for comprehensive clinical and biochemical evaluation include hypoglycemia occurring in the fasting state, predating bariatric surgery, and/or worsening immediately postoperatively, and lack of response to conservative therapy. Localization and successful resection of insulinoma can be achieved using novel endoscopic ultrasound and surgical approaches. In summary, hypoglycemia presenting shortly after gastric bypass or with a dominant fasting pattern should be fully evaluated to exclude insulinoma. Additionally, evaluation prior to gastric bypass should include screening for history of hypoglycemia symptoms.

Improvement in inpatient glycemic care: pathways to quality.

The management of inpatient hyperglycemia is a focus of quality improvement projects across many hospital systems while remaining a point of controversy among clinicians. The association of inpatient hyperglycemia with suboptimal hospital outcomes is accepted by clinical care teams; however, the clear benefits of targeting hyperglycemia as a mechanism to improve hospital outcomes remain contentious. Glycemic management is also frequently confused with efforts aimed at intensive glucose control, further adding to the confusion. Nonetheless, several regulatory agencies assign quality rankings based on attaining specified glycemic targets for selected groups of patients (Surgical Care Improvement Project (SCIP) measures). The current paper reviews the data supporting the benefits associated with inpatient glycemic control projects, the components of a successful glycemic control intervention, and utilization of the electronic medical record in implementing an inpatient glycemic control project.

Tides of change: improving glucometrics in a large multihospital health care system.

BACKGROUND: This study explores the relationship between education for inpatient diabetes providers and the utilization of insulin order sets, inpatient glucometrics, and length of stay in a large health care system. METHODS: The study included patients with and without the diagnosis of diabetes. An education campaign included provider-directed diabetes education administered via online learning modules and in-person presentations by trained individuals. Relationships among provider-attended diabetes education, order set usage, and inpatient glucometrics (hypo- and hyperglycemia) were analyzed, as well as length of stay. RESULTS: Insulin use knowledge scores for all providers averaged 52%, and improved significantly to 93% (P < .001) by the end of the education intervention period. Likewise utilization of electronic basal-bolus order sets increased from a baseline of 20% for patients receiving insulin to 86% within 6 weeks (P < .01) of introduction of order sets. During the study, the incidence of hypoglycemia and hyperglycemia declined from 1.47% to 1.27% and from 23.21% to 17.80%, respectively. However, these improvements were not sustained beyond the completion of the education campaign. CONCLUSIONS: Education of diabetes health care providers was provided in a large, multihospital system through the use of online learning modules. Adoption of standardized insulin order sets was associated with an improvement in glucometrics. This educational and quality initiative resulted in overall improvements in insulin knowledge, adherence to recommended order sets, inpatient glucometrics, and patient length of stay. These improvements were not sustained, reinforcing the need for repeated educational interventions for those involved in providing inpatient diabetes care.

Pheochromocytoma presenting as acute decompensated heart failure reversed with medical therapy.

A 26-year-old woman presented to hospital with acute chest pain, hypertension, tachycardia and an elevated serum creatinine. She developed respiratory distress requiring endotracheal intubation and mechanical ventilation. She progressed to multiorgan failure due to decompensated congestive heart failure. Echocardiography demonstrated global hypokinesis and an ejection fraction of <10%. Her cardiac function improved with fluid resuscitation and ß blockade, and she was eventually discharged home. She was readmitted a few days later with pancreatitis after presenting with nausea, abdominal pain and hypertension. During hospitalisation she had paroxysms of headache, nausea and diaphoresis associated with hypertension and tachycardia. A CT scan of her abdomen revealed an adrenal mass and serum metanephrine studies confirmed the diagnosis of pheochromocytoma. After fluid resuscitation and sympathetic blockade her ejection fraction improved to 55%. The patient underwent an uneventful adrenalectomy and made a complete recovery.

High levels of thyrotropin-releasing hormone receptors activate programmed cell death in human pancreatic precursors.

OBJECTIVES: Thyrotropin-releasing hormone (TRH) is expressed in rodent and human adult pancreata and in mouse pancreas during embryonic development. However, expression of TRH receptors (TRHRs) in the pancreas is controversial. We sought to provide evidence that the TRH/TRHR system might play a role in fetal development. METHODS: We used quantitative reverse transcription-polymerase chain reaction to measure TRH and TRHR messenger RNA (mRNA). To study the effects of TRHR expression in a pancreatic progenitor population, we expressed TRHRs in human islet-derived precursor cells (hIPCs) by infection with adenoviral vector AdCMVmTRHR. Thyrotropin-releasing hormone receptor signaling was measured as inositol phosphate production and intracellular calcium transients. Thyrotropin-releasing hormone receptor expression was measured by [H]methyl-TRH binding. Apoptosis was monitored by release of cytochrome c from mitochondria. RESULTS: We show that TRH mRNA is expressed in human fetal and adult pancreata, and that TRHR mRNA is expressed in fetal human pancreas but not in adult human pancreas. Thyrotropin-releasing hormone receptors expressed in hIPCs were shown to signal normally. Most importantly, TRH treatment for several days stimulated apoptosis in hIPCs expressing approximately 400,000 TRHRs per cell. CONCLUSIONS: These findings suggest a possible role for TRH/TRHR signaling in pancreatic precursors to promote programmed cell death, a normal constituent of morphogenesis during embryonic development in humans.