Oversecretion Of Insulin Research Articles

IAPP - oligomerisation levels in plasma of people with type 2 diabetes

Islet amyloid polypeptide (IAPP) is co-secreted with insulin from pancreatic ß-cells. Its oligomerisation is regarded as disease driving force in type 2 diabetes (T2D) pathology. Up to now, IAPP oligomers have been detected in affected tissues. IAPP oligomer concentrations in blood have not been analysed so far. Using the IAPP single-oligomer-sensitive and monomer-insensitive surface-based fluorescence intensity distribution analysis (sFIDA) technology, levels of IAPP oligomers in blood plasma from healthy controls and people with T2D in different disease stages where determined. Subsequently, the level of IAPP oligomerisation was introduced as the ratio between the IAPP oligomers determined with sFIDA and the total IAPP concentration determined with ELISA. Highest oligomerisation levels were detected in plasma of people with T2D without late complication and without insulin therapy. Their levels stand out significantly from the control group. Healthy controls presented with the lowest oligomerisation levels in plasma. In people with T2D without complications, IAPP oligomerisation levels correlated with disease duration. The results clearly demonstrate that IAPP oligomerisation in insulin-naïve patients correlates with duration of T2D. Although a correlation per se does not identify, which is cause and what is consequence, this result supports the hypothesis that IAPP aggregation is the driving factor of T2D development and progression. The alternative and conventional hypothesis explains development of T2D with increasing insulin resistance causing exhaustion of pancreatic ß-cells due to over-secretion of insulin, and thus IAPP, too, resulting in subsequent IAPP aggregation and fibril deposition in the pancreas. Further experiments and comparative analyses with primary tissues are warranted.

Using low-dose octreotide with diazoxide-resistant congenital hyperinsulinism resulting from compound heterozygous mutations in the ABCC8 gene.

Congenital hyperinsulinism (CHI) is an over-secretion of insulin by pancreatic ß-cells, causing hypoglycemia which can inhibit brain development in infants. CHI is primarily associated with mutations in the ABCC8 or KCNJ11 genes, which encode the SUR1 and KIR 6.2 subunits of the ATP-sensitive potassium (KATP) channel. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a full term, female, Korean infant who developed early onset hypoglycemia but was not subject to either genetic or metabolic workup. This infant was later admitted to the ER because of a hypoglycemic seizure, but her metabolic work up revealed that both her fasting insulin and C-peptide levels were within the normal range. Despite this glucagon stimulation produced positive results and the genetic workup revealed c.[298G>T(;)4252C>T] mutations in the ABCC8 gene. This indicated diazoxide treatment, but following an unsuccessful course of treatment we switched to octreotide which helped stabilize her glucose. Over 5 years of follow-up, the patient treated with a low dose of octreotide has had no hypoglycemic event, and her growth and psychomotor development remained within normal ranges. However, she is severely obese (BMI over 97 %) despite using octreotide. Thus, we report a mild case of CHI with octreotide treatment, wherein the patient has normal insulin and C-peptide levels and normal development, but is severe obese.

Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.

Tigecycline-induced sustained severe hypoglycemia: a case report

BackgroundTigecycline, the first glycylcycline-class drug, is a broad-spectrum antibiotic with activity against multi-drug resistant (MDR) organisms. We describe a case of sustained and severe hypoglycemia in a patient treated with tigecycline for pneumonia due to MDR Klebsiella pneumoniae.Case presentationA 74-year-old man was admitted for treatment of pneumonia. At admission he had prediabetes. In the hospital he developed renal failure. On day 3, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was cefoperazone and sulbactam (1 g every 12 h). Continuous Renal Replacement Therapy was started on that day. Test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure. Plasmapheresis, and high-dose methylprednisolone treatment were started on day 6, and there was obvious improvement in the patient’s condition. The steroid regimen was gradually tapered to oral prednisone (35 mg every day) on day 19. Afterwards, the patient’s pneumonia worsened. Sputum culture showed Klebsiella pneumoniae sensitive to only tigecycline. Tigecycline treatment (100 mg every 12 h) was administered on day 20. Hypoglycemia started about 37 h after the first dose of tigecycline. Infusion of 50% glucose through the femoral vein was required for over 20 h to maintain normal blood glucose concentrations. Tigecycline was stopped, but the hypoglycemia resolved only after a further 34 h. The insulin and C-peptide levels were found to be markedly elevated during the hypoglycemia. The Naranjo scale score of 7 indicated that the likelihood of tigecycline causing severe hypoglycemia was “probable.”ConclusionThis is the first report of sustained severe hypoglycemia due to tigecycline. Oversecretion of insulin appears to have been the cause of the hypoglycemia in our patient. The mechanism needs to be investigated.

Hyperinsulinism-Causing Mutations Cause Multiple Molecular Defects in SUR1 NBD1.

The sulfonylurea receptor 1 (SUR1) protein forms the regulatory subunit in ATP sensitive K+ (KATP) channels in the pancreas. SUR proteins are members of the ATP binding cassette (ABC) superfamily of proteins. Binding and hydrolysis of MgATP at the SUR nucleotide binding domains (NBDs) lead to channel opening. Pancreatic KATP channels play an important role in insulin secretion. SUR1 mutations that result in increased levels of channel opening ultimately inhibit insulin secretion and lead to neonatal diabetes. In contrast, SUR1 mutations that disrupt trafficking and/or decrease gating of KATP channels cause congenital hyperinsulinism, where oversecretion of insulin occurs even in the presence of low glucose levels. Here, we present data on the effects of specific congenital hyperinsulinism-causing mutations (G716V, R842G, and K890T) located in different regions of the first nucleotide binding domain (NBD1). Nuclear magnetic resonance (NMR) and fluorescence data indicate that the K890T mutation affects residues throughout NBD1, including residues that bind MgATP, NBD2, and coupling helices. The mutations also decrease the MgATP binding affinity of NBD1. Size exclusion and NMR data indicate that the G716V and R842G mutations cause aggregation of NBD1 in vitro, possibly because of destabilization of the domain. These data describe structural characterization of SUR1 NBD1 and shed light on the underlying molecular basis of mutations that cause congenital hyperinsulinism.

Cross sectional and nuclear medicine imaging of pancreatic insulinomas.

Insulinomas are rare neuroendocrine tumors which occur predominantly in the pancreas. Although majority of the insulinomas are benign, over-secretion of insulin by the tumor leads to debilitating hypoglycemic symptoms. The diagnosis is based on clinical and biochemical findings. After the diagnosis is made, the principal challenge lies in locating the tumor because most tumors are solitary and small in size. Locating the tumor is of paramount importance as complete surgical excision is the only curative treatment, and incomplete resection leads to persistence of symptoms. Different preoperative and intraoperative imaging techniques have been used with varying success rates for the insulinoma imaging. Besides localizing the tumor, imaging also helps to guide biopsy, detect metastatic lesions, and perform image-guided therapeutic procedures. This review will discuss the role of different Cross sectional and nuclear medicine imaging modalities in insulinomas.

THE CHANGE OF BLOOD INSULIN LEVEL IN PATIENTS WITH BRAIN GLIOBLASTOMA DURING ADJUVANT RADIATION THERAPY

Цель – проанализировать уровень гиперсекреции инсулина у пациентов с глиобластомой головного мозга, которые во время проведения адъювантной лучевой терапии получали дексаметазон в суточной дозе 4 или 8 мМатериал и методы. В исследование включен 81 пациент с глиобластомой головного мозга. В течение 6–7-недельного курса адъювантной лучевой терапии 66 пациентам, которым ранее не применяли дексаметазон (1-я группа), внутримышечно вводили дексаметазон в суточной дозе 4 м Во 2-ю группу вошли 15 пациентов, получавших дексаметазон в суточной дозе 8 мг внутримышечно в течение 6–7 недель до начала адъювантной лучевой терапии. Во время адъювантной лучевой терапии у этих пациентов суточная доза дексаметазона была снижена до 4 м За 1 день до начала и на следующий день после окончания адъювантной лучевой терапии у всех пациентов исследовали уровень С-пептида, инсулина, кортизола.Результаты. У пациентов 1-й группы после6–7-недельного курса введения дексаметазона в суточной дозе 4 мг на фоне адъювантной лучевой терапии отмечено статистически значимое повышение уровня инсулина (с 64,2 ± 40,9 до 105,2 ± 124,9 пмоль/л, р < 0,05) и C-пептида (с 2,3 ± 1,0 до 3,2 ± 1,3 нг/мл, р < 0,05) в крови (при этом показатели остались в пределах референтных значений), а также статистически значимое уменьшение уровня кортизола крови ниже референтных значений (с 513,1 ± 163,6 до 82,7 ± 114,7 нмоль/л, р < 0,001). Увеличение суточной дозы дексаметазона на 4 мг (с 4 до 8 мг) не привело к достоверному повышению уровня инсулина и С-пептида в крови, однако у пациентов 2-й группы уровень C-пептида крови превышал верхнюю границу референтных значений (3,8 ± 1,2 нг/мл). В целом во 2-й группе через 6–7 недель после уменьшения суточной дозы дексаметазона с 8 до 4 мг показатели инсулина и С-пептида в крови не изменились, а уровень кортизола крови продолжил снижение по сравнению с исходным значением (до 33,7 ± 13,4 нмоль/л, р < 0,05). Заключение. Применение дексаметазона в суточной дозе 4–8 мг у пациентов с глиобластомой головного мозга во время проведения им адъювантной лучевой терапии привело к гиперсекреции инсулина поджелудочной железой, что, скорее всего, является следствием возникновения инсулинорезистентности.

High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism.

Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. We studied the distribution of genetic causes of CHI in a Czech population. Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.

Inwardly rectifying Kir2.1 currents in human β-cells control electrical activity: Characterisation and mathematical modelling

Pancreatic β-cells fire action potentials as do cardiac cells and neurons, and electrical activity plays a central role in glucose-stimulated insulin secretion, which is disturbed in diabetes. The inwardly rectifying Kir2.1 potassium channels (KCNJ2 gene) control cardiac electrical activity by stabilising the interspike interval. Loss-of-function abnormalities in cardiac Kir2.1 currents can lead to the long QT syndrome and alterations of cardiac excitability, and patients with some forms of long QT syndrome suffer from over-secretion of insulin, hyperinsulinemia and symptomatic hypoglycemia. The KCNJ2 gene is also expressed in human pancreatic islets, and we show that functional Kir2.1 currents are present in human β-cells. We characterised the human Kir2.1 β-cell current, and included it in a recent mathematical model of electrical activity in human β-cells. Based on our simulations we propose that Kir2.1 currents control the interspike interval, and predict that blocking Kir2.1 channels increases the action potential frequency, which should augment the rate of insulin secretion. Vice versa, the model suggests that hyperactive Kir2.1 channels may lead to reduced insulin secretion. Our findings provide a putative link between increased insulin secretion and the long QT syndrome, and give novel insight into normal and disturbed β-cell function.

A novel mechanism regulating insulin secretion involving Herpud1 in mice

Type 2 diabetes results from beta cell dysfunction after prolonged physiological stress, which causes oversecretion of insulin. We recently found that insulin hypersecretion is mediated by at least two genes. Among mouse models of type 2 diabetes, the DBA/2 mouse strain is more susceptible to diabetes than is the C57BL/6J (B6J) strain. One distinctive feature of the DBA/2 mouse is that it hypersecretes insulin, independent of changes in insulin sensitivity; we identified Nnt as a gene responsible for this trait. To identify the other gene(s) affecting insulin hypersecretion, we tested a panel of recombinant inbred BXD strains, which have different combinations of B6 and DBA/2 alleles. We found that 25% of the BXD strains hypersecreted insulin in response to glucose. Microarray profiling of islets from high- and low-secretor strains showed that at least four genes were differentially expressed. One gene was consistently underexpressed in islets from both DBA/2 and the high-secretor BXD strains. This gene (Herpud1 or Herp) encodes the 54kDa endoplasmic reticulum stress-inducible protein (HERP) that resides in the integral endoplasmic reticulum membrane. To test directly whether Herpud1 can interact with Nnt, Herpud1 was either knocked down or overexpressed in MIN6 cells. These results showed that when Herpud1 was suppressed, Nnt expression was reduced, while overexpression of Herpud1 led to increased Nnt expression. Furthermore, Herpud1 suppression resulted in significantly decreased glucose-stimulated insulin secretion in the DBA/2 islets but not B6J islets. We conclude that Herpud1 regulates insulin secretion via control of Nnt expression.

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G(i) and/or two G(o) proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G(i/o) proteins involved has been elucidated. Here we show that one of the two splice variants of G(o), G(o2), is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G(o2)α, but not those lacking α subunits of either G(o1) or any G(i) proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G(o2) protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism

BackgroundCongenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1...

Insulinoma: pathophysiology, localization and management.

Insulinoma is a rare neuroendocrine tumor that causes oversecretion of insulin and, as a result, patients present with symptoms of hypoglycemia. Fortunately, insulinomas are usually benign and solitary, and surgical cure rates are highly favorable. Most of these tumors occur sporadically, but they can also be associated with multiple endocrine neoplasia type-1 syndrome. The diagnosis is confirmed by a supervised fast, and early detection is important. Several preoperative and intraoperative techniques with various success rates have been employed in order to localize the lesion. When technically feasible, tumor enucleation is the procedure of choice; however, a more formal resection may be necessary for certain tumors. In the age of laparoscopy, the role of laparoscopic surgery in the management of insulinomas is continuing to attract attention. This review will discuss the historical background, pathogenesis, diagnosis, localization and management of insulinomas.

Update of mutations in the genes encoding the pancreatic beta-cell KATPchannel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism

The beta-cell ATP-sensitive potassium (K(ATP)) channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis it is therefore not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1 (SUR1). It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinism of infancy, while activating mutations in KCNJ11 and ABCC8 have recently been described that result in the opposite phenotype of diabetes. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment on diagnosing patients with mutations in these genes.

Congenital hyperinsulinism – a review of the disorder and a discussion of the anesthesia management

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. In most affected infants, CHI is caused by a specific genetic defect that results in the altered expression of pancreatic beta cells causing unregulated oversecretion of insulin. Infants with CHI may have either focal or diffuse abnormalities of the pancreatic beta-cells. Both forms of CHI manifest as hypoglycemia, usually in the early newborn period. Focal disease can be treated effectively with surgical resection of the affected area, resulting in a total cure or rendering the patient amenable to medical management. Most children with diffuse disease are unresponsive to medical therapy, and require near-total pancreatectomy. At The Children's Hospital of Philadelphia, we have developed a multidisciplinary program for diagnosis and treatment of CHI. Anesthesiologists have played an integral role in the perioperative care of these infants, which includes diagnostic procedures, partial or near-total pancreatectomy, and postoperative pain management. In this review, we describe the clinical features, diagnostic methods and anesthetic concerns in children with CHI.

Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism

Neonatal hyperinsulinism is the most important cause of hypoglycemia in infancy (1,2). The inappropriate oversecretion of insulin is responsible for profound hypoglycemia, requiring aggressive treatment to prevent brain damage (1–3). Neonatal hyperinsulinism is often resistant to medical therapy (1–4), and pancreatectomy is required for many sufferers (1,5–6). The histopathological lesions associated with neonatal hyperinsulinism may be described as diffuse or focal (7–8). Focal adenomatous islet cell hyperplasia is sporadic and has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of the sulfonylurea receptor 1 ABCC8 gene (9,10) or the inward-rectifying potassium channel Kir6.2 (KCNJ11) (10) in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells (9–11). Diffuse hyperinsulinism may be familial and arises from the autosomal recessive inheritance of mutations in both ABCC8 (12) and KCNJ11 (13–14) genes. The therapeutic outcome for the patients is heavily dependent on distinguishing between the two histopathological lesions. Diffuse hyperinsulinisms, which are unresponsive to medical treatment, require extensive pancreatectomy, with a high risk of diabetes (5,15–16). Conversely, focal hyperinsulinism can be cured by limited pancreatectomy (6,17). Genetic counseling is dramatically different, as focal hyperinsulinism is considered a sporadic molecular event with a very low recurrence risk (10,18), while diffuse …

Mutations in the genes encoding the pancreatic beta-cell KATPchannel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism

The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1. It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinemia (HI) of infancy; however, heterozygous activating mutations in KCNJ11 that result in the opposite phenotype of diabetes have recently been described. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment when patients are diagnosed with mutations in these genes.

Exploring the Roots of Diabetes: Bisphenol A May Promote Insulin Resistance

Vol. 114, No. 1 EnvironewsOpen AccessExploring the Roots of Diabetes: Bisphenol A May Promote Insulin Resistance Cynthia Washam Cynthia Washam Search for more papers by this author Published:1 January 2006https://doi.org/10.1289/ehp.114-a48bCited by:2AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Poor diet and lack of exercise are known contributors to the epidemic of type 2 diabetes spreading around the world. Now researchers have implicated another possible culprit in the rise of the disease [EHP 114:106–112]. A team of Spanish and Mexican researchers reports discovering that the endocrine-disrupting chemical bisphenol A (BPA) causes insulin resistance in mice similar to that seen just before the onset of type 2 diabetes.Type 2 diabetes occurs when insulin receptors throughout the body fail; this is known as insulin resistance. Complications of diabetes include heart disease, kidney failure, blindness, and nerve damage. The World Health Organization estimates that at least 154 million people around the world have type 2 diabetes, and predicts that number will more than double within 25 years.Endocrine disruptors mimic the natural sex hormone 17β-estradiol (E2), which is involved in the development of sexual traits. Scientists have known for years that BPA and other endocrine disruptors can diminish sperm production, accelerate the onset of puberty, and damage sexual organs. But they had not studied a link between the chemicals and glucose metabolism, even though increases in E2 are known to cause insulin resistance.The researchers chose to study BPA because its use is so widespread. Since the 1950s, it has been used in plastics for water bottles and jugs, baby bottles, toys, and the linings of food and beverage cans. People ingest BPA that leaches from containers into foods and drinks. Studies in the United States showed that BPA appeared in the blood and urine of 95% of people tested.The researchers tested BPA’s effect on glucose regulation by measuring glucose and insulin levels in adult male mice treated with BPA injections, then comparing them with levels in mice treated with E2 and a control group treated with corn oil. BPA caused oversecretion of insulin in mice at a dose of 10 micrograms per kilogram body weight per day (μg/kg/day) via a rapid mechanism, taking only 15 to 30 minutes. Treatment over a course of four days with 100 μg/kg/day induced the insulin resistance that precedes type 2 diabetes. E2 had the same effects at the same doses. Glucose metabolism remained stable in the control rats.These results are novel because the mechanism reported is the lesser known of the two major pathways used by estrogens and other steroids. It involves signaling rapidly initiated from the plasma membrane rather than the nuclear transcription pathway depicted in most textbooks.The BPA dose high enough to cause insulin resistance in mice was in the same range as the 50 μg/kg/day reference dose established by the U.S. Environmental Protection Agency, which is based on a lowest-observed-adverse-effect level of 50 milligrams per kilogram per day. The researchers see the newly discovered link between BPA and insulin resistance as one more reason the agency should at least consider lowering the lowest-observed-adverse-effect level. They further suspect that because other endocrine disruptors mimic E2, they too may hinder glucose metabolism.FiguresReferencesRelatedDetailsCited by Scognamiglio V, Pezzotti I, Pezzotti G, Cano J, Manfredonia I, Buonasera K, Arduini F, Moscone D, Palleschi G and Giardi M (2012) Towards an integrated biosensor array for simultaneous and rapid multi-analysis of endocrine disrupting chemicals, Analytica Chimica Acta, 10.1016/j.aca.2012.09.010, 751, (161-170), Online publication date: 1-Nov-2012. YANG M, PARK M and LEE H (2006) Endocrine Disrupting Chemicals: Human Exposure and Health Risks, Journal of Environmental Science and Health, Part C, 10.1080/10590500600936474, 24:2, (183-224), Online publication date: 1-Dec-2006. Vol. 114, No. 1 January 2006Metrics About Article Metrics Publication History Originally published1 January 2006Published in print1 January 2006 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

The Relationship between BMI, Plasma Leptin, Insulin and Proinsulin Before and After Laparoscopic Adjustable Gastric Banding

Morbid obesity is associated with over-secretion of leptin and insulin, and predisposes to development of carbohydrate intolerance. In the current study, we explored the impact of BMI after laparoscopic adjustable gastric banding (LAGB) on leptin, insulin and proinsulin levels. 23 obese patients (8 males, 15 females) were included in the study. Their mean age was 36+/-6 yrs (range 21-56 yrs). Blood samples were collected for measurement of plasma leptin, insulin and proinsulin before and 6 and 14 months after LAGB. Mean BMI before surgery was 46.04 +/- 4.44 kg/m2, with significant and equal reduction of 18% in each of the follow-up periods, with total BMI reduction of 33% (P <.0001). The levels of circulating leptin, insulin and proinsulin before intervention were 119.3 +/- 53.1 ng/ml, 159 +/- 13 pmol/l, and 36.36 +/- 23.06 pmol/l respectively. Despite an equal BMI reduction in the 2 follow-up periods, the most significant decrease in hormone levels was observed in the immediate postoperative period (54, 53, and 45%, respectively), when compared to the second follow-up period (15, 30, 10%, respectively). The highest total decline in hormone level of 70% was obtained with insulin, compared to 52% in leptin, and 50% in proinsulin. Despite the significant decrease in proinsulin and insulin levels, their ratio increased from 0.22, to 0.28 and 0.36 after LAGB. Unlike insulin and proinsulin, leptin levels strongly and persistently correlated with BMI during the study. Following LAGB, weight loss was associated with decreased levels of circulating leptin, insulin and proinsulin, most prominent in the first follow-up period. Unlike insulin and proinsulin, leptin showed the most significant and persistent correlation with BMI, suggesting that morbid obesity acts through different feedback hormonal mechanisms which are probably not regulated only by absolute weight loss. Longer follow-up and larger numbers of patients are needed to clarify long-term hormonal profile, as well as the beneficial lasting effects of such interventions.

L'hyperinsulinisme congénital du nouveau-né et du nourrisson

Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K + ATP). The 2 subunits of the K + ATP channel are encoded by either the sulfonylurea receptor gene ( SUR1 or ABCC8) or the inward-rectifying potassium channel gene ( KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [ 18F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.