Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Mary B. Abraham ◽  
Vinutha B. Shetty ◽  
Glynis Price ◽  
Nicholas Smith ◽  
Martin de Bock ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Total Pancreatectomy ◽  
Efficacy And Safety ◽  
Neonatal Hypoglycaemia ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Common Cause

AbstractHyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous

scholarly journals Efficacy and safety of switching to pasireotide in acromegaly patients controlled with pegvisomant and somatostatin analogues: PAPE extension study

2018 ◽  
Vol 179 (5) ◽  
pp. 269-277 ◽  
Author(s):  
Ammar Muhammad ◽  
Eva C Coopmans ◽  
Patric J D Delhanty ◽  
Alof H G Dallenga ◽  
Iain K Haitsma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Somatostatin Analogues ◽  
Tolerance Test ◽  
Extension Study ◽  
Oral Glucose ◽  
Efficacy And Safety ◽  
Igf I ◽  
Core Study ◽  
Long Acting

ObjectiveTo assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.DesignThe PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.MethodsFifty-nine out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤1.2× the upper limit of normal (ULN)) at 48 weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).ResultsAt the end of the study, median IGF-I was 0.98× ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and nine patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = −0.37,P < 0.005).ConclusionsPAS-LAR normalizes IGF-I levels in most acromegaly patients, with a 50% pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.

scholarly journals Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy

2020 ◽  
Vol 2020 ◽  
Author(s):  
Jennifer R Snaith ◽  
Duncan McLeod ◽  
Arthur Richardson ◽  
David Chipps
Keyword(s):  
Endocrine Cell ◽  
De Novo ◽  
Total Pancreatectomy ◽  
Pancreatic Head ◽  
Management Approach ◽  
List Type ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Cell Clusters ◽  
Men 1 ◽  
The Ideal

Summary Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure. Learning points: Insulinomas are usually benign and managed surgically. Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare. Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis. Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones. The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.

Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Omer Babiker ◽  
Sarah E. Flanagan ◽  
Sian Ellard ◽  
Hesham Al Girim ◽  
Khalid Hussain ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Saudi Family ◽  
Key Genes

AbstractHyperinsulinaemic hypoglycaemia (HH) is caused by mutations in the key genes involved in regulation of insulin secretion from the pancreatic β-cells and mutations in

scholarly journals Increased plasma β-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia

2013 ◽  
Vol 169 (1) ◽  
pp. 91-97 ◽  
Author(s):  
Alexandre Buffet ◽  
Delphine Vezzosi ◽  
Jean Christophe Maiza ◽  
Solange Grunenwald ◽  
Antoine Bennet ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Plasma Glucose ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Partial Pancreatectomy ◽  
C Peptide ◽  
Fasting Test ◽  
Group 2 ◽  
Design And Methods ◽  
Rule Out ◽  
Group 1

ObjectiveThe objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).Research design and methodsWe retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-h fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels >2700 μmol/l (group 1), EHH patients with BOHB levels <2700 μmol/l (group 2) and 59 controls (median glycaemia: 3.2 mmol/l and median BOHB: 6095 μmol/l).ResultsDuring a 72-h fasting test, nine patients (group 1) had BOHB levels >2700 μmol/l (median 6140 and range 2957–7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0–2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.ConclusionDuring a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

scholarly journals Refinement of the critical genomic region for hypoglycaemia in the Chromosome 9p deletion syndrome

2019 ◽  
Vol 4 ◽  
pp. 149
Author(s):  
Indraneel Banerjee ◽  
Senthil Senniappan ◽  
Thomas W. Laver ◽  
Richard Caswell ◽  
Martin Zenker ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Chromosome 9 ◽  
Genetic Mechanism ◽  
Targeted Sequencing ◽  
Deletion Syndrome ◽  
Recessive Mutation ◽  
Potential Candidate ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Genetic Characteristics ◽  
Chromosome 9P

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown.  Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

scholarly journals Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial

2020 ◽  
Vol 15 (1) ◽  
pp. 35-48 ◽  
Author(s):  
Kamal Hamed ◽  
Marc Engelhardt ◽  
Mark E Jones ◽  
Mikael Saulay ◽  
Thomas L Holland ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Options ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Common Cause ◽  
Staphylococcus Aureus Bacteremia ◽  
Parallel Group ◽  
Advanced Generation

Although Staphylococcus aureus is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant S. aureus bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant S. aureus. This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficacy and safety of ceftobiprole compared with daptomycin in the treatment of SAB, including infective endocarditis. Anticipated enrollment is 390 hospitalized adult patients, aged ≥18 years, with confirmed or suspected complicated SAB. The primary end point is overall success rate. Target completion of the study is in the second half of 2021. Clinicaltrials.gov identifier: NCT03138733

Advances in Antidiabetic Drugs Targeting Insulin Secretion

2019 ◽  
Vol 24 (34) ◽  
pp. 3990-3997
Author(s):  
Yanting Ding ◽  
Yilian Li ◽  
Qin Chen ◽  
Bing Niu
Keyword(s):  
Insulin Secretion ◽  
Drug Targets ◽  
Metabolic Disorders ◽  
Clinical Stage ◽  
Current Medical Research ◽  
New Drugs ◽  
Efficacy And Safety ◽  
Related Drug ◽  
Multiple Signaling ◽  
Target Design

Background: Diabetes mellitus (DM) is a disease of systemic metabolic disorders caused by the decrease of secretion or sensitivity of insulin. In recent years, the study of insulin-related drug targets and the development of new drugs have become the popular topic of current medical research, and studies have shown that multiple signaling pathways are associated with diabetes treatment. At present, some new drugs based on the new target design have been listed on the market and have achieved good hypoglycemic effect. However, most of the drugs are still in the clinical or pre-clinical stage. The efficacy and safety of the drugs need further clinical validation. Objective: This article will introduce the advancements of targets and drugs to promote insulin secretion.

scholarly journals Somatostatin analogues for the treatment of hyperinsulinaemic hypoglycaemia

2020 ◽  
Vol 11 ◽  
pp. 204201882096506
Author(s):  
Basma Haris ◽  
Saras Saraswathi ◽  
Khalid Hussain
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Glucose Metabolism ◽  
Therapeutic Effect ◽  
Glucagon Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Glucose Levels ◽  
Blood Glucose Levels

Hyperinsulinaemic hypoglycaemia (HH) is a biochemical finding of low blood glucose levels due to the dysregulation of insulin secretion from pancreatic β-cells. Under normal physiological conditions, glucose metabolism is coupled to β-cell insulin secretion so that blood glucose levels are maintained within the physiological range of 3.5–5.5 mmol/L. However, in HH this coupling of glucose metabolism to insulin secretion is perturbed so that insulin secretion becomes unregulated. HH typically occurs in the neonatal, infancy and childhood periods and can be due to many different causes. Adults can also present with HH but the causes in adults tend to be different. Somatostatin (SST) is a peptide hormone that is released by the delta cells (δ-cells) in the pancreas. It binds to G protein-coupled SST receptors to regulate a variety of location-specific and selective functions such as hormone inhibition, neurotransmission and cell proliferation. SST plays a potent role in the regulation of both insulin and glucagon secretion in response to changes in glucose levels by negative feedback mechanism. The half-life of SST is only 1–3 min due to quick degradation by peptidases in plasma and tissues. Thus, a direct continuous intravenous or subcutaneous infusion is required to achieve the therapeutic effect. These limitations prompted the discovery of SST analogues such as octreotide and lanreotide, which have longer half-lives and therefore can be administered as injections. SST analogues are used to treat different forms of HH in children and adults and therapeutic effect is achieved by suppressing insulin secretion from pancreatic β-cells by complex mechanisms. These treatments are associated with several side effects, especially in the newborn period, with necrotizing enterocolitis being the most serious side effect and hence SS analogues should be used with extreme caution in this age group.

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