Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Congenital Hyperinsulinemia of Infancy: Role of Molecular Testing in Management and Genetic Counseling.

Congenital hyperinsulinemia (CHI) is a genetically and clinically heterogenous disorder. In addition to the standard care of management of the proband, genetic counseling regarding the risk of recurrence in the future siblings is an important part in the management of the disorder. The counseling needs identification of accurate etiology and is challenging due to the complexity of the molecular mechanisms of CHI. This case highlights the importance of molecular testing which not only helped in planning the management of the proband with CHI but also helped in providing genetic counseling for which the family had consulted the medical genetics department.

Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management.

Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.

Hyperinsulinemia Induced Altered Insulin Signaling Pathway in Muscle of High Fat- and Carbohydrate-Fed Rats: Effect of Exercise.

Insulin resistance is a state of impaired responsiveness to insulin action. This condition not only results in deficient glucose uptake but increases the risk for cardiovascular diseases (CVD), stroke, and obesity. The present work investigates the molecular mechanisms of high carbohydrate and fat diet in inducing prediabetic hyperinsulinemia and effect of exercise on InsR signaling events, muscular AChE, and lactate dehydrogenase activity. Adult male Wistar rats were divided into the control (C) diet group, high-carbohydrate diet (HCD) group, high-fat diet (HFD) group, and HCD and HFD groups with exercise (HCD Ex and HFD Ex, respectively). Acetyl choline esterase activity, lactate dehydrogenase activity, total lactate levels, IRS1 phosphorylations, and Glut4 expression patterns were studied in the muscle tissue among these groups. High carbohydrate and fat feeding led to hyperinsulinemic status with reduced acetylcholine esterase (AChE) activity and impaired phosphorylation of IRS1 along with increased lactate concentrations in the muscle. Exercise significantly upregulated phosphoinositide 3 kinase (PI3K) docking site phosphorylation and downregulated the negative IRS1 phosphorylations thereby increasing the glucose transporter (GLUT) expressions and reducing the lactate accumulation. Also, the levels of second messengers like IP3 and cAMP were increased with exercise. Increased second messenger levels induce calcium release thereby activating the downstream pathway promoting the translocation of GLUT4 to the plasma membrane. Our results showed that the metabolic and signaling pathway dysregulations seen during diet-induced hyperinsulinemia, a metabolic condition seen during the early stages in the development of prediabetes, were improved with vigorous physical exercise. Thus, exercise can be considered as an excellent management approach over drug therapy for diabetes and its complications.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.

Multidisciplinary approach in medicine: successful pregnancy in a patient with hyperinsulinism/hyperammonaemia (HI/HA) syndrome.

This case illustrates the importance of multidisciplinary counselling and management of pregnancies in women with complex medical conditions, especially concerning women with cognitive impairment. We present a woman with hyperinsulinism/hyperammonaemia (HI/HA) syndrome. This syndrome is characterised by recurrent episodes of hypoglycaemia and elevated ammonia levels, which are potentially harmful to both the patient and a developing fetus. We describe a successful multidisciplinary approach during the pregnancy of a mentally challenged patient with HI/HA syndrome. This case illustrates the importance of personalised counselling during the preconception period and emphasises to include all disciplines involved in the medical and daily care of such a patient. In our case, the extensive multidisciplinary care during the preconception period, pregnancy, delivery and postpartum period resulted in a good maternal and neonatal outcome.

Unveiling the presence of epigenetic mark by Lactobacillus supplementation in high-fat diet-induced metabolic disorder in Sprague-Dawley rats.

Gut dysbiosis, particularly bacteria from Firmicutes and Bacteroidetes phyla, plays a fundamental role in the progression of metabolic disorders. Probiotics have shown to restore the gut microbiota composition in metabolic disorders with subsequent beneficial effects. Recent studies have reported that several species of Lactobacillus as probiotic supplementation improve insulin sensitivity and glucose metabolism. Nonetheless, whether Lactobacillus could influence the epigenetic modifications that underlie insulin-resistant conditions is still unexplored. Therefore, the current study examined the therapeutic effects and underlying epigenetic mechanisms of three different species of Lactobacillus in the high-fat diet (HFD)-induced insulin-resistant rats. Three different species of Lactobacillus; Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus rhamnosus were individually supplemented orally (109 CFU/mL) to insulin-resistant SD rats for 12 weeks. Lactobacillus supplementation led to a significant reduction in the hyperglycemia, hyperinsulinemia, and hyperlipidemia associated with HFD-induced insulin resistance. Histopathological examination also indicated the protective effects of Lactobacillus supplementation against the hepatic and intestinal damage caused by the high-fat diet. Lactobacillus supplementation also down-regulated the expression of FOXO1, a major transcription factor of insulin signaling. In addition, at the epigenetic level, Lactobacillus supplementation predominantly prevented methylation and demethylation of H3K79me2 and H3K27me3, respectively. Chromatin Immunoprecipitation (ChIP) coupled with quantitative PCR (ChIP-qPCR) assay revealed the presence of cross-talk between these two histone modifications at the promoter region of FOXO1. Taken together, this is the first report to observe that the effects of Lactobacillus supplementation involve alteration in FOXO1 expression via cross-talking between H3K79me2 and H3K27me3 histone modifications.

Effect of exercise training on insulin sensitivity, hyperinsulinemia and ectopic fat in black South African women: a randomized controlled trial.

OBJECTIVE: We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. RESEARCH DESIGN AND METHODS: Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). RESULTS: Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. CONCLUSION: Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.

Bone Marrow-Derived Mesenchymal Stem Cells Restored High-Fat-Fed Induced Hyperinsulinemia in Rats at Early Stage of Type 2 Diabetes Mellitus.

Numerous studies have proposed the transplantation of mesenchymal stem cells (MSCs) in the treatment of typical type 2 diabetes mellitus (T2DM). We aimed to find a new strategy with MSC therapy at an early stage of T2DM to efficiently prevent the progressive deterioration of organic dysfunction. Using the high-fat-fed hyperinsulinemia rat model, we found that before the onset of typical T2DM, bone marrow-derived MSCs (BM-MSCs) significantly attenuated rising insulin with decline in glucose as well as restored lipometabolic disorder and liver dysfunction. BM-MSCs also favored the histological structure recovery and proliferative capacity of pancreatic islet cells. More importantly, BM-MSC administration successfully reversed the abnormal expression of insulin resistance-related proteins including GLUT4, phosphorylated insulin receptor substrate 1, and protein kinase Akt and proinflammatory cytokines IL-6 and TNFα in liver. These findings suggested that MSCs transplantation during hyperinsulinemia could prevent most potential risks of T2DM for patients.

Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine and Head and Neck Disease Site Working Group, Part 2 of 2: Perioperative Management and Outcomes of Pheochromocytoma and Paraganglioma.

This is the second part of a two-part review on pheochromocytoma and paragangliomas (PPGLs). In this part, perioperative management, including preoperative preparation, intraoperative, and postoperative interventions are reviewed. Current data on outcomes following resection are presented, including outcomes after cortical-sparing adrenalectomy for bilateral adrenal disease. In addition, pathological features of malignancy, surveillance considerations, and the management of advanced disease are also discussed.

The effects of curcumin supplementation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: The aim of the current study was to assess the effects of curcumin supplementation on glycemic status, lipid profile and high sensitivity C-reactive protein (hs-CRP) serum levels in women with polycystic ovary syndrome (PCOS). DESIGN: This randomized double-blind placebo-controlled clinical trial was conducted on 60 women who were randomly assigned to the intervention or control groups using block randomization. SETTING: Infertility referral center. INTERVENTIONS: Curcumin (500 mg/d) or placebo twice daily for 6 weeks. MAIN OUTCOME MEASURES: Serum evaluation of lipid profile (triglycerides (TG), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol concentrations, LDL/HDL-C and TG/HDL-C ratios), glycemic index (fasting blood sugar (FBS), insulin concentrations, homeostasis model of assessment insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)) and hs-CRP levels. RESULTS: Glycemic index, lipid profile and hs-CRP serum levels were measured at first and at the end of trial. Serum insulin (p = 0.020) and Quantitative Insulin Sensitivity Check Index (QUICKI) (p = 0.003) were improved significantly, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.067) improved marginally in curcumin treated group (within group analysis). CONCLUSIONS: Curcumin supplementation might be beneficial for improving serum insulin and QUICKI, however, future investigations are suggested in order to draw a firm link between curcumin and glycemia control.

Management of Ornithine Carbamoyltransferase Deficiency with Underlying Hyperammonia Hyperinsulinemia Syndrome.

BACKGROUND The urea cycle converts amino acids to urea and is excreted by the kidneys. Ornithine carbamoyltransferase (OTC) deficiency is a rare X-linked urea cycle disorder which results in hyperammonemia. Diagnosis is made based on a clinical presentation of poor feeding, hypotonia, biochemical profile, and genetic testing. Another genetic cause for hyperammonemia is hyperammonia hyperinsulinemia (HAHI) syndrome. A mutation coding for glutamate dehydrogenase (GDH) results in increased alpha-keto glutarate and ATP, triggering the secretion of pancreatic insulin. However, unlike OTC deficiency, these patients are asymptomatic but do have symptoms of hypoglycemia. The purpose of this article is to present the case of a 66-year-old woman with an unusual late-onset of OTC deficiency compounded with an underlying HAHI syndrome with co-disease management. CASE REPORT A 66-year-old female with a history significant for transient ischemic attack (TIA) and urea cycle disorder was admitted for new adverse symptoms. Further evaluation revealed hyperammonemia and hypoglycemia. Despite standard previous treatment for her underlying urea cycle disorder, high ammonia levels and hypoglycemia persisted. The contradicting values with continued hypoglycemia regardless of dextrose treatment was suspicious for underlying HAHI. Further genetic testing during her admission revealed a deletion in GLUD-1 gene concurrent with diagnosis of HAHI. After co-diagnosis was established, effective management required medications for both disorders in concordance with dietary restriction. CONCLUSIONS This is an extremely rare case of OTC deficiency, with a vague presentation in an elderly female. Exploring compounding genetic disorders in the presence of one that is already established and early recognition are crucial for prompt diagnosis and management.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

BACKGROUND: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. METHODS: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. RESULTS: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). CONCLUSION: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention.

Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

Polycystic ovary syndrome (PCOS) and the accompanying disorders of glucose homeostasis among girls at the time of puberty.

Polycystic ovary syndrome (PCOS) usually arises during puberty and is marked by insulin resistance, hyperinsulinemia, and hyperandrogenism. The principle is that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. The diagnosis of PCOS in adolescents is particularly difficult due to developmental problems in this group. Many symptoms of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Adolescents with PCOS are at an increased risk of developing health problems later on in life, such as diabetes, cardiovascular disease, and infertility. One should reckon with the frequent occurrence of the PCOS in type 1 diabetes, when the ovaries and the adrenals are exposed to excessive insulin concentrations. Ovarian hyperandrogenism is common in adolescent girls with type 1 diabetes. Methods of treatment for an adolescent with PCOS include diet and exercise. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with anti-androgen medications.

Barriers and Facilitators of Intensivists' Adherence to Hyperinsulinemia-Euglycemia Therapy in the Treatment of Calcium Channel Blocker Poisoning.

INTRODUCTION: Adherence to poison center (PC) recommendations for the management of calcium channel blocker (CCB) poisoning is inconsistent. This study aimed to identify behaviors that determine adherence to hyperinsulinemia-euglycemia therapy (HIET) for CCB poisoning. METHODS: Semistructured interviews were conducted involving a convenience sample of 18 intensivists. Interview responses were analyzed using the theoretical domains framework (TDF) to identify relevant domains influencing physician adherence to HIET. Two independent reviewers performed qualitative content analysis of the interview transcripts to identify beliefs influencing decisions to initiate HIET. Initially, beliefs were classified and frequencies reported as being likely to facilitate, likely to decrease, or unlikely to affect adherence. Subsequently, beliefs were linked to a domain within the TDF. Based on the potential impact on physician behavior and frequency of reported behavior, we selected the most relevant domains likely to influence physician adherence to HIET for CCB poisoning. RESULTS: Positive beliefs were identified in the following domains: "behavioral regulation" (e.g., algorithm for adjustment of perfusions), "belief about capabilities" (e.g., confidence about being able to manage HIET), "belief about consequences" (e.g., fear of clinical deterioration), and "reinforcement" (e.g., clinical instability). Negative beliefs were identified in the following domains as "nature of behavior" (e.g., preference for vasopressors over HIET) and "environmental context and resources" (e.g., accessing dextrose 50% and increased nurse workload). CONCLUSION: This qualitative study identified potential behavioral targets for future implementation strategies to address to improve adherence to HIET.

Changes in lipid metabolism and capillary density of the skeletal muscle following low-intensity exercise training in a rat model of obesity with hyperinsulinemia.

Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long-Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight.

Hyperinsulinism in the Neonate.

Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Prompt recognition and treatment, independent of whether infants have transient or permanent HI, are essential to decrease risk of neurologic damage. The most common form of congenital HI is due to inactivating mutations of the ß-cell ATP-sensitive potassium (KATP) channel (KATP-HI) and is typically diazoxide unresponsive. KATP-HI occurs in diffuse and focal forms. Distinguishing between the 2 forms is crucial, because pancreatectomy is curative in the focal form but palliative in the diffuse form. The 18-fluoro-L-3,4-dihydroxyphenylalanine PET scan has revolutionized HI management by allowing accurate localization of focal lesions prior to surgery.