Comparative Study of the Impact of Metformin Versus Insulin on Adverse Pregnancy Outcomes in Women Diagnosed with Gestational Diabetes Mellitus: A Meta-Analysis.

Objective: This systematic comparative analysis aimed to assess the efficacy of metformin (MET) versus insulin (INS) in the treatment of gestational diabetes mellitus (GDM), providing valuable insights for future GDM management strategies. Methods: We conducted a comprehensive search of clinical studies related to MET and INS interventions in GDM through online literature databases, applying predefined inclusion and exclusion criteria. The quality of the included studies was rigorously evaluated. Data on fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), pregnancy weight gain (PWG), premature delivery rate (PDR), and neonatal outcomes among GDM patients were extracted and analyzed using Review Manager 5.3 software. Results: We identified eleven high-quality studies comprising 8679 participants following careful screening and assessment. Our meta-analysis revealed a significant reduction in the incidence of excessive PWG and neonatal hypoglycemia in the MET treatment group (research group) compared to the INS treatment group (control group) (P < .05). Conclusions: Our findings support the effectiveness and safety of MET in achieving optimal blood glucose control in GDM. These results suggest the potential for broader clinical adoption of MET in GDM management.

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia.

AIMS/HYPOTHESIS: Repeated exposures to insulin-induced hypoglycaemia in people with diabetes progressively impairs the counterregulatory response (CRR) that restores normoglycaemia. This defect is characterised by reduced secretion of glucagon and other counterregulatory hormones. Evidence indicates that glucose-responsive neurons located in the hypothalamus orchestrate the CRR. Here, we aimed to identify the changes in hypothalamic gene and protein expression that underlie impaired CRR in a mouse model of defective CRR. METHODS: High-fat-diet fed and low-dose streptozocin-treated C57BL/6N mice were exposed to one (acute hypoglycaemia [AH]) or multiple (recurrent hypoglycaemia [RH]) insulin-induced hypoglycaemic episodes and plasma glucagon levels were measured. Single-nuclei RNA-seq (snRNA-seq) data were obtained from the hypothalamus and cortex of mice exposed to AH and RH. Proteomic data were obtained from hypothalamic synaptosomal fractions. RESULTS: The final insulin injection resulted in similar plasma glucose levels in the RH group and AH groups, but glucagon secretion was significantly lower in the RH group (AH: 94.5±9.2 ng/l [n=33]; RH: 59.0±4.8 ng/l [n=37]; p<0.001). Analysis of snRNA-seq data revealed similar proportions of hypothalamic cell subpopulations in the AH- and RH-exposed mice. Changes in transcriptional profiles were found in all cell types analysed. In neurons from RH-exposed mice, we observed a significant decrease in expression of Avp, Pmch and Pcsk1n, and the most overexpressed gene was Kcnq1ot1, as compared with AH-exposed mice. Gene ontology analysis of differentially expressed genes (DEGs) indicated a coordinated decrease in many oxidative phosphorylation genes and reduced expression of vacuolar H+- and Na+/K+-ATPases; these observations were in large part confirmed in the proteomic analysis of synaptosomal fractions. Compared with AH-exposed mice, oligodendrocytes from RH-exposed mice had major changes in gene expression that suggested reduced myelin formation. In astrocytes from RH-exposed mice, DEGs indicated reduced capacity for neurotransmitters scavenging in tripartite synapses as compared with astrocytes from AH-exposed mice. In addition, in neurons and astrocytes, multiple changes in gene expression suggested increased amyloid beta (Aß) production and stability. The snRNA-seq analysis of the cortex showed that the adaptation to RH involved different biological processes from those seen in the hypothalamus. CONCLUSIONS/INTERPRETATION: The present study provides a model of defective counterregulation in a mouse model of type 2 diabetes. It shows that repeated hypoglycaemic episodes induce multiple defects affecting all hypothalamic cell types and their interactions, indicative of impaired neuronal network signalling and dysegulated hypoglycaemia sensing, and displaying features of neurodegenerative diseases. It also shows that repeated hypoglycaemia leads to specific molecular adaptation in the hypothalamus when compared with the cortex. DATA AVAILABILITY: The transcriptomic dataset is available via the GEO ( http://www.ncbi.nlm.nih.gov/geo/ ), using the accession no. GSE226277. The proteomic dataset is available via the ProteomeXchange data repository ( http://www.proteomexchange.org ), using the accession no. PXD040183.

Effect of preinitiated glucose-insulin-potassium strategy for patients with undergoing planned percutaneous coronary intervention: a systematic review and meta-analysis.

OBJECTIVES: Whether the glucose-insulin-potassium (GIK) should be used as an adjuvant therapy for ischaemic myocardial disease remains controversial nowadays reperfusion era. This meta-analysis aimed to assess the effects of preinitiated GIK for patients undergoing planned percutaneous coronary intervention (PCI). DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Web of science, MEDLINE, Embase, Cochrane Library and ClinicalTrials.gov were searched through 27 November 2022. ELIGIBILITY CRITERIA: Only randomised controlled trials involving participants preinitiated with GIK or placebo before planned PCI were included. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers used standardised methods to search, screen and code included trials. Risk of bias was assessed with the Cochrane tool. Pooled analysis was conducted using random or effects models according to the heterogeneity. Subgroup analyses were carried out for dosage of GIK and if with ongoing myocardial ischaemia. RESULTS: 13 randomised controlled trials (RCTs) including 3754 participants were evaluated. We found patients preconditioned with GIK before PCI showed a significant increase in Thrombolysis in Myocardial Infarction 3 flow events after angioplasty (OR 1.59, 95% CI 1.03 to 2.46, p=0.04), also revealed improved in-hospital left ventricular ejection fraction (weighed mean difference, WMD 1.62, 95% CI 0.21 to 3.03, p=0.02) and myocardial salvage index (WMD 0.09, 95% CI 0.01 to 0.16, p=0.03). Nevertheless, no benefit was observed in all-cause mortality neither on 30-day (OR 0.81, 95% CI 0.59 to 1.11, p=0.18) nor 6 months (OR 1.02, 95% CI 0.42 to 2.46, p=0.97). Furthermore, GIK intervention was associated with higher occurrences of complications such as phlebitis (OR 10.13, 95% CI 1.74 to 59.00, p=0.01) and hypoglycaemia (OR 10.43, 95% CI 1.32 to 82.29, p=0.03), but not hyperkalaemia (OR 9.36, 95% CI 0.50 to 175.27, p=0.13), liquid overload (OR 1.02, 95% CI 0.25 to 4.13, p=0.98) or in-hospital heart failure (OR 0.42, 95% CI 0.06 to 2.96, p=0.39). CONCLUSIONS: Our study shows preconditioning GIK exhibits myocardial reperfusion and cardiac function benefits for patients planning to receive PCI intervention, while also some complications such as phlebitis and hypoglycaemia accompany. PROSPERO REGISTRATION NUMBER: CRD42022326334.

Insulin concentrations following termination of high-dose insulin euglycemic therapy.

INTRODUCTION: High-dose insulin therapy is used in patients with calcium channel blocker and beta-adrenergic antagonist overdoses. The pharmacokinetics of insulin are scantly reported following high-dose insulin therapy. We present two cases of persistently elevated insulin concentrations following high-dose insulin therapy. CASE REPORTS: A 50-year-old woman and a 45-year-old man experienced hypotension after overdosing on amlodipine and atenolol. They were treated with high-dose insulin therapy for 54 hours at 2 units/kilogram/hour and 48 hours at 10 units/kilogram/hour, respectively. Following termination, serum insulin elimination was studied. Insulin concentrations remained greater than 1,000 µU/mL (fasting reference 2.6-24.9 µU/mL) for longer than 4 hours (case 1) and 11 hours (case 2) and greater than 300 µU/mL for longer than 8 hours and 21 hours, respectively. Insulin concentrations decreased with apparent first-order elimination half-lives of 13.0 hours and 6.0 hours. DISCUSSION: Following high-dose insulin therapy, insulin concentrations remained elevated for longer than expected based on normal pharmacokinetics in therapeutic dosing. Three previous cases reported insulin half-lives of between 2.2 hours and 18.7 hours. The current cases add to the existing data that insulin has a variable but prolonged half-life following high-dose insulin therapy. CONCLUSIONS: These findings suggest that patients are at prolonged risk of hypoglycemia following cessation of high-dose insulin infusions.

Glucagon prescribing and prevention of hospitalization for hypoglycemia in a large health system.

AIMS: To examine glucagon prescribing trends among patients at high risk of severe hypoglycemia and assess if a glucagon prescription is associated with lower rates of severe hypoglycemia requiring hospital care. METHODS: Retrospective analysis of electronic health records from a large integrated healthcare system between May 2019 and August 2021. We included adults (≥18 years) with type 1 diabetes or with type 2 diabetes treated with short-acting insulin and/or recent history of hypoglycemia-related emergency department visit or hospitalization. We calculated rates of glucagon prescribing overall and by patient characteristics. We then matched 1:1 those who were and were not prescribed glucagon and assessed subsequent hypoglycemia-related hospitalization. RESULTS: Of 9,200 high risk adults, 2063 (22.4%) were prescribed glucagon. Among patients more likely to be prescribed glucagon were those younger, female, White, living in urban areas, with prior severe hypoglycemia, and with a recent endocrinology specialist visit. In the matched cohort (N = 1707 per arm), 62 prescribed glucagon and 33 not prescribed glucagon were hospitalized for hypoglycemia (adjusted incidence rate ratio 1.71, 95% CI 1.10-2.66; P = 0.018). CONCLUSION: Glucagon prescribing was infrequent with significant racial and rural disparities. Patients with glucagon prescriptions did not have lower rates of hospitalization for hypoglycemia.

The Effect of Tang Forte (Royal Jelly) Capsule on Hypoglycemia and Clinical Course in COVID-19 Patients Under Corticosteroid Therapy.

Corticosteroids improve the complications of Covid-19 but may cause some side effects such as hyperglycemia. Royal jelly is one of the bee products that exert anti-inflammatory, insulin-like, and hypoglycemic activities. The present study was conducted to investigate the effect of royal jelly capsules on blood sugar and the clinical course of Covid-19 in the patients receiving corticosteroid therapy. In this clinical trial, 72 Covid-19 patients with positive reverse transcription polymerase chain reaction (RT-PCR) test and pulmonary involvement hospitalized in Shahrekord Hajar Hospital were enrolled and randomized into two groups: treatment (receiving corticosteroids and Royal Jelly 1000 mg capsules daily for 7 days) and placebo (given corticosteroids and placebo). Laboratory tests, blood sugar, and clinical courses were determined and compared. Data was analyzed using SPSS version 16. On day 7 after the onset of the intervention, the dosage and frequency of insulin, FBS level, and required corticosteroid showed a decrease in both groups but the inter-group difference was not significant (P > .05). As well, the Spo2 level indicated a non-significant increase and hospital stay length indicated a non-significant decrease in the intervention group (P > .05). Among the symptoms, only headache, cough, and dyspnea indicated an improvement in the intervention group (P < .05). Overall, the results indicated the short-term consumption of royal jelly could not significantly improve blood sugar and the clinical course of Covid-19; however, it could significantly improve headache, cough, and dyspnea in the patients.

In vitro and in vivo hypoglycemia effect of oxyberberine, a novel HO-1 agonist: A renewed evidence linking HO-1 to diabetes mellitus.

BACKGROUND: Oxyberberine (OBB), an important in vivo metabolite of berberine, exerts superior hypoglycemia effect. However, the underlying mechanism remains obscure. Heme oxygenase-1 (HO-1) holds a crucial status in the pathogenesis of diabetes. Previous research has indicated that OBB can specifically bind to hemoglobin and significantly up-regulated the HO-1 expression in diabetic rat. Based on cellular protection features of HO-1, this work aimed to probe the anti-diabetic effect of OBB and the association with the potential induction of HO-1 expression. METHODS: A type 2 diabetic mellitus rat model was established. Glucolipid metabolism and insulin sensitivity were analyzed. Immunohistochemistry, Western blotting and in silico simulations were also performed. RESULTS: Administration of OBB or HO-1 inducer hemin significantly reduced fasting blood glucose level, blood fat, and inflammatory cytokine levels, while increased antioxidant capacity of pancreas. Meanwhile, OBB treatment remarkably stimulated liver glycogenesis and inhibited gluconeogenesis. Besides, OBB improved the glucose utilizing of muscle. Noteworthily, OBB inhibited the islet cell apoptosis and improved pancreatic function. In addition, OBB effectively improved the consumption of glucose in insulin-resistant HepG2 cells. Moreover, OBB also reduced oxidative stress, promoted glucose-elicited insulin secretion and enhanced expression of ß-cell function proteins in INS-1 cells. Nevertheless, these effects were significantly reversed by treatment with Zincprotoporphrin (ZnPP). Additionally, in silico simulations indicated that OBB exhibited superior affinity with HO-1. CONCLUSION: OBB effectively ameliorated hyperglycemia, dyslipidemia, and insulin resistance, improved oral glucose tolerance, and maintained glucose metabolism homeostasis, at least in part, by promoting HO-1-mediated activation of phosphoinositide 3-kinase / protein kinase B (PI3K/Akt) and AMP-activated protein kinase (AMPK) pathways. These data eloquently suggest that OBB, as a novel HO-1 agonist, has good potential to be a promising candidate drug for the management of diabetes, and support a therapeutic role of HO-1 induction in diabetes that potentially paves the way to translational research.

Evaluation of high-dose insulin/euglycemia therapy for suspected ß-blocker or calcium channel blocker overdose following guideline implementation.

PURPOSE: High-dose insulin/euglycemia (HDIE) is targeted therapy for ß-blocker and calcium channel blocker overdose. A guideline using concentrated insulin infusions (20 units/mL), aggressive monitoring, and supportive recommendations was implemented. We sought to evaluate safety before and after HDIE guideline implementation and describe the patient population, insulin doses, supplemental dextrose, vasopressor use, hospital and intensive care unit (ICU) lengths of stay, and mortality. METHODS: Retrospective review was performed of patients receiving HDIE before and after guideline implementation at an academic medical center and community hospital from March 2011 through December 2019. Information on patient and overdose demographics, ingestion data, vital signs, interventions, adverse events, and disposition was collected. Data are presented descriptively with comparisons using Mann-Whitney U analysis and Fisher's exact tests. RESULTS: During the study period, 27 patients were treated with HDIE, 10 before guideline implementation (37%; mean [SD] initial insulin dose, 0.49 [0.35] units/kg/h; mean [SD] maximum insulin dose, 2.25 [3.29] units/kg/h; median [interquartile range] duration, 10 [5.5-18.75] hours) and 17 after guideline implementation (63%; mean [SD] initial insulin dose, 1.01 [0.34] units/kg/h; mean [SD] maximum insulin dose, 2.99 [5.05] unit/kg/h; median [interquartile range] duration, 16 [11.5-37] hours). Hypoglycemia, hypokalemia, and volume overload occurred in 80% vs 29% (P = 0.018), 40% vs 53% (P = 0.69), and 50% vs 65% (P = 0.69) of patients in the preguideline vs postguideline group, respectively. Most patients received an initial insulin bolus (85%; mean [SD], 70.3 [21.8] units, 0.9 [0.26] units/kg) and vasopressor infusion (85%). More postguideline patients received a dextrose infusion with a concentration of 20% or higher (93% vs 50%, P = 0.015). There were no differences in cardiac arrest, in-hospital mortality, or hospital or ICU length of stay between the groups. CONCLUSION: Hypoglycemia was reduced using an HDIE guideline and concentrated insulin.

Hypoglycemia Due to Acquired Carnitine Deficiency in a Pediatric Patient Receiving Chemotherapy.

We describe a 21-month-old male with relapsed clear cell sarcoma of the kidney receiving enteral nutrition who experienced recurrent, ketotic hypoglycemia. During relapse therapy, he had recurrent hypoglycemia episodes, in the setting of hematochezia and diarrhea. Evaluation revealed low carnitine levels. He received supplementation with oral levocarnitine throughout the remainder of treatment, resulting in normalization of serum carnitine levels and no further hypoglycemia. We believe adverse effects of the chemotherapy on his single kidney and gastrointestinal insult resulted in hypoglycemia and carnitine deficiency. Our case highlights that carnitine deficiency should be considered when acute onset hypoglycemia without obvious cause occurs.

The Impact of Hypoglycemia and EPA and DHA Supplementation on Brain-Derived Neurotrophic Factor Level in Pregnant Women with Type 1 Diabetes: A Prospective Cohort Study.

BACKGROUND: In addition to its neuroprotective effect, Brain-derived neurotrophic factor (BDNF) also plays a role in glucose and lipid metabolism. This study aims: a) to find changes in the BDNF concentration during pregnancy in type 1 diabetes. b) to prove the effect of DHA and EPA supplementation on changes in BDNF concentrations c) to investigate the impact of hypoglycemia on BDNF concentration. SUBJECTS AND METHODS: The data from this study were from the PRE-HYPO cohort study. Twenty-one of them were on a standard diabetic diet enriched with EPA and DHA (EPA 120 mg/day and DHA 616 mg/day; Exposed group), and nineteen pregnant diabetic women were on the standard diabetic diet without EPA and DHA supplementation (Non-exposed group). In the first trimester of pregnancy, fifteen pregnant women developed hypoglycemia episodes (≤3.9 mmol/L; HYPO+ group), and twenty-five pregnant women did not have hypoglycemia episodes (HYPO- group). RESULTS: BDNF concentration significantly decreased during pregnancy from the first to the third trimester, in Non-exposed from 25.1 (22.0-30.2) to 22.1 (16.3-28.2), P<0.05, in the Exposed group from 22.1 (19.8-25.9) to 18.1 (14.8-18.9), P<0.01. Pregnant patients with hypoglycemia episodes (HYPO+ subgroup) had significantly higher BDNF in the third trimester of pregnancy [22.5 (20.6-28.4)] when compared with patients who did not develop hypoglycemia [16.3 (14.3-18.8), P<0.001]. In the third trimester of pregnancy, BDNF and n-6 PUFAs were associated with hypoglycemia (OR 1.818 95 % CI 1.079-3.003, P=0.025; OR 1.103 95 % CI 1.001-1.217, P=0.048). Total F.A.s were inversely associated with hypoglycemia (OR 0.969 95% CI 0.939-0.998, P=0.048). CONCLUSION: Pregnant women with hypoglycemia (HYPO+ group) had higher concentrations of BDNF in the first and third trimesters of pregnancy compared to those without hypoglycemia. An increase in body weight during pregnancy leads to a decrease in BDNF concentration.

Predictive Low-Glucose Suspend Necessitates Less Carbohydrate Supplementation to Rescue Hypoglycemia: Need to Revisit Current Hypoglycemia Treatment Guidelines.

Current guidelines recommend 15-20 g of carbohydrate (CHO) for treatment of mild to moderate hypoglycemia. However, these guidelines do not account for reduced insulin during suspensions with predictive low-glucose suspend (PLGS). We assessed insulin suspensions, hypoglycemic events, and CHO treatment during a 20-h inpatient evaluation of an investigational system with a PLGS feature, including an overnight basal up-titration period to activate the PLGS. Among 10 adults with type 1 diabetes, there were 59 suspensions; 7 suspensions were associated with rescue CHO and 5 with hypoglycemia. Rescue treatment consisted of median 9 g CHO (range: 5-16 g), with no events requiring repeat CHO. No rescue CHO were given during or after insulin suspension for the overnight basal up-titration. To minimize rebound hyperglycemia and needless calorie intake from hypoglycemia overtreatment, updated guidance for PLGS systems should reflect possible need to reduce CHO amounts for hypoglycemia rescue associated with an insulin suspension. The clinical trial was registered with ClinicalTrials.gov (NCT03890003).

Glycerol Potentiates the Effects of Glucose in Promoting Glucose Recovery During Hypoglycemia: From Basic to Clinical Investigations and Their Therapeutic Application.

We compared the effect of oral glucose versus oral glucose combined with glycerol (glucose + glycerol) in promoting glucose recovery during hypoglycemia. These studies were carried out in two series of experiments. In the first series of experiments, 16 overnight fasted rats received an intraperitoneal injection of lispro insulin (1 IU/kg), and 25 min later, they received oral water (control), glucose (0.25 g/kg), glycerol (2.5 g/kg), or glucose (0.25 g/kg) + glycerol (2.5 g/kg). In the second series of experiments on 164 eligible type 1 diabetic (T1D) patients, 30 individuals with a history of hypoglycemia were recruited. Five volunteers did not meet the inclusion criteria and two subjects were excluded after starting the clinical investigation; 23 patients concluded the study. All patients with symptoms of hypoglycemia ingested oral glucose (15 g) or glucose (15 g) + glycerol (9.45 g). To treat hypoglycemia in T1D patients, preparations containing glucose alone or glucose + glycerol were used alternately (2 weeks/2 weeks) in a double-blind crossover scheme. Throughout the clinical research (4 weeks), glucose concentrations were assessed with a continuous glucose monitoring device and the results after the use of glucose alone or glucose + glycerol preparations were compared. Oral glucose combined with glycerol was more effective in promoting glucose recovery in comparison with glucose alone, not only in rats but also in T1D patients. Taken together, our experimental and clinical investigations reported the best performance of oral administration of glucose + glycerol in comparison with isolated glucose.

A Case Involving Massive Insulin Overdose: Direct and Indirect Conditions Requiring Extended Management of Serum Potassium.

BACKGROUND Insulin lowers not only blood glucose levels but also serum potassium levels by driving potassium into the cells. Hypokalemia can occur during aggressive treatment of hypoglycemia in patients with insulin overdose and is a well-documented clinical phenomenon; however, there are no studies describing delayed hyperkalemia occurring after initial treatment in patients with insulin overdose. CASE REPORT A 23-year-old male with a history of type 2 diabetes mellitus and self-medicating with insulin, attempted suicide by subcutaneously injecting 2100 units of insulin. He was admitted to our emergency department due to recurrent hypoglycemia. Continuous administration of 50% glucose and potassium via a central venous catheter was performed to maintain his glucose levels above 80 mg/dL and serum potassium level between 3.5 and 4.0 mEq/L. Because his serum potassium level exceeded 4.5 mEq/L at day 3 after admission, the dosage was adjusted accordingly. After his serum potassium level declined to 3.0 mEq/L, his potassium level abruptly increased to 6.0 mEq/L at day 5 after admission. The patient was placed on a potassium-restricted diet and administered furosemide. Potassium infusion was also discontinued. After serum potassium levels returned to the normal range without interventional therapies, the patient was discharged to home on day 14. CONCLUSIONS In cases of high-dose insulin overdose, management of hyperkalemia following recovery from hypoglycemia is a critical aspect of patient management. Conservative administration of potassium to correct initial hypokalemia may be considered in patients with high-dose insulin overdose.

Medicinal effects of Peruvian maca (Lepidium meyenii): a review.

Peruvian maca (Lepidium meyenii) is a root native to the Andean region, cultivated for at least 2000 years. Maca is rich in fiber, a large number of essential amino acids, fatty acids, and other nutrients, including vitamin C, copper, iron, and calcium. Besides these essential nutrients, this root contains bioactive compounds responsible for benefits to the human body, which has caused a considerable increase in its consumption in the last 20 years worldwide. This review documents the Peruvian maca composition and the recent findings regarding the medicinal effects of this root in sexual dysfunction regulation, neuroprotective effects, action in memory enhancement, antidepressant, antioxidant, anti-cancer, and anti-inflammatory activities, and skin protection.

Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons.

Growth hormone (GH) is secreted during hypoglycemia, and GH-responsive neurons are found in brain areas containing glucose-sensing neurons that regulate the counter-regulatory response (CRR). However, whether GH modulates the CRR to hypoglycemia via specific neuronal populations is currently unknown. Mice carrying ablation of GH receptor (GHR) either in leptin receptor (LepR)- or steroidogenic factor-1 (SF1)-expressing cells were studied. We also investigated the importance of signal transducer and activator of transcription 5 (STAT5) signaling in SF1 cells for the CRR. GHR ablation in LepR cells led to impaired capacity to recover from insulin-induced hypoglycemia and to a blunted CRR caused by 2-deoxy-d-glucose (2DG) administration. GHR inactivation in SF1 cells, which include ventromedial hypothalamic neurons, also attenuated the CRR. The reduced CRR was prevented by parasympathetic blockers. Additionally, infusion of 2DG produced an abnormal hyperactivity of parasympathetic preganglionic neurons, whereas the 2DG-induced activation of anterior bed nucleus of the stria terminalis neurons was reduced in mice without GHR in SF1 cells. Mice carrying ablation of Stat5a/b genes in SF1 cells showed no defects in the CRR. In summary, GHR expression in SF1 cells is required for a normal CRR, and these effects are largely independent of STAT5 pathway.-Furigo, I. C., de Souza, G. O., Teixeira, P. D. S., Guadagnini, D., Frazão, R., List, E. O., Kopchick, J. J., Prada, P. O., Donato, J., Jr. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.

AIM: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 µg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

Insulin Autoimmune Syndrome Diagnosis and Therapy in a Single Chinese Center.

PURPOSE: Insulin autoimmune syndrome (IAS) is a relatively rare cause of hypoglycemia characterized by endogenous hyperinsulinism and autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. We present a series of IAS cases and describe the clinical characteristics of these cases. METHODS: The medical records of inpatients with the final diagnosis of IAS were collected from August 2007 to August 2017 in Peking Union Medical College Hospital. Clinical characteristics and laboratory test results were summarized. The results of serum glucose, insulin, true insulin, and C-peptide testing during 5-h oral glucose tolerance tests were also summarized. Circulating immune complexes were assessed qualitatively by precipitation with polyethylene glycol (PEG) in some patients. FINDINGS: Sixteen patients were included in this study. Insulin autoimmune antibody test results were found positive in 12 patients and weakly positive in 1 patient. Nine patients had an insulin to C-peptide molar ratio >1, whereas 6 patients had an insulin to C-peptide molar ratio <1. Circulating immune complexes were verified in all 4 patients who had been assessed with PEG. During 5-h oral glucose tolerance tests, the C-peptide level responded earlier to the glucose tolerance and had a shorter peak value period compared with insulin, although C-peptide's fluctuation still lagged behind the glucose fluctuation. Three patients presented with self-limited disease courses or limited disease course after discontinuing use of the sulfhydryl group drugs. Some patients' symptoms were relieved after small frequent meals, and some were relieved after taking acarbose. Only 3 patients took glucocorticoids as the anti-immune therapy. IMPLICATIONS: The insulin to C-peptide molar ratios were not consistently >1 in patients with confirmed diagnoses of IAS in our study, which suggested the low sensitivity of insulin to C-peptide molar ratio to detect IAS. The therapy in our study also revealed the self-limited disease course of IAS, and despite the effectiveness of anti-immunity therapy, convenient therapy, such as frequent small meals and adding acarbose, performed well in many patients.

Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4.

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

Oral dextrose gel to treat neonatal hypoglycaemia: Clinician survey.

AIMS: To determine the use of oral dextrose gel to treat neonatal hypoglycaemia in New Zealand (NZ), to identify barriers and enablers to the implementation of the guideline and to determine if there is variation in management between clinical disciplines caring for at-risk babies. METHODS: An online survey was distributed to clinicians (including doctors, midwives and nurses) caring for babies with neonatal hypoglycaemia via stakeholders and maternity hospitals. RESULTS: A total of 251 clinicians from all 20 District Health Boards (DHBs) completed the survey. Of the responding clinicians, 148 (59%) from 15 (75%) DHBs reported oral dextrose gel use in their hospital, and of these, 129 (87%) reported a local guideline. In 12 of 15 (80%) DHBs, oral dextrose gel could be prescribed by midwives. For a clinical scenario of a baby with neonatal hypoglycaemia, doctors were more likely to prescribe oral dextrose gel than midwives (odds ratio (95% confidence interval), 2.9 (2.2-3.8), P < 0.0001). Of 32 possible combinations of treatment options for this scenario, 31 were selected by one or more clinicians. A guideline was perceived to be the most useful enabler, and availability of oral dextrose gel was seen as the most important barrier. CONCLUSIONS: Oral dextrose gel is widely used to treat neonatal hypoglycaemia in NZ. Increasing availability of dextrose gel and the clinical practice guideline are likely to further increase the use of oral dextrose gel.

Severe Hypoglycemia Due to Cryptic Insulin Use in a Bodybuilder.

BACKGROUND: Bodybuilding is a demanding sport, which requires high-volume, high-resistance weight training and augmented nutritional intake, toward an increase of overall body muscle mass accompanied by an overall decrease of body fat percentage and mass. Among bodybuilders, the use of various legal and illegal supplements is common. These supplements may be naturally occurring or man-made. CASE REPORT: We discuss the case of a 30-year-old male bodybuilder presenting with coma due to severe hypoglycemia from unknown cause, necessitating iterative glucose infusions, which was subsequently found to be related to cryptic insulin injections. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In strength athletes, especially amateurs, the recourse to performance-enhancement drugs (e.g., insulin) is frequent. Beyond the specificity of care required for surreptitious insulin intoxication, emergency physicians should be alert to the possibility that exogenous insulin has been injected for use as an ergogenic aid by bodybuilders and others seeking to increase their body muscle mass when they encounter a patient with a decreased level of consciousness and treatment-refractory hypoglycemia. Moreover, in case of suspicion of such intoxication, the use of other illegal supplements should be screened, due to potentially associated risks of complication.