Hyperinsulinemic Hypoglycemia Research Articles

Advances of glucagon-like peptide-1 receptor imaging for localization of insulinoma

<p indent=0mm>The diagnosis and surgical treatment of insulinoma is dependent on accurate localization with imaging modalities. Glucagon-like peptide-1 (GLP-1) receptor imaging that targets pancreatic β cells, was recently established for localization of insulinoma in patients with hyperinsulinemic hypoglycemia. It has proven to be a sensitive and specific method for preoperative localization of insulinoma. This review introduces the development, clinical research, and perspective of GLP-1 receptor imaging mainly in insulinoma.

Sirolimus in infants with congenital hyperinsulinism (CHI) - a single-centre experience.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in neonates and infants. Medical treatment includes the use of high concentrations of glucose and combinations of diazoxide, octreotide and glucagon. We report our experience of using sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in the treatment of CHI in seven newborns who are poorly responding to standard medical therapy. Majority (87%) of infants achieved euglycaemia using a combination of oral feeding and the addition of sirolimus to standard medical treatment. One infant who failed to achieve euglycaemia even after surgery managed successfully with sirolimus. Diagnosis was confirmed by genetics evaluation; in three infants, novel mutations were detected. Outcome and long-term follow-up of all cases are described.Conclusion: Sirolimus can be considered in treatment of CHI refractory to standard medical treatment or in cases unresponsive to surgical treatment. What is Known: • Congenital hyperinsulinism (CHI) or persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) associated with mutations such as the ABBC8 or KCNJ gene known to cause hypoglycaemia refractory to standard medical treatment such as diazoxide and octreotide and may need subtotal pancreatectomy (STP). • Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, was recently reported to be useful for refractory CHI cases with variable efficacy. What is New: • Our case series describes efficacy and safety of sirolimus in seven genetically proven refractory CHI cases with mainly neonatal presentation. All patients' follow-ups are described. • Out of seven infants, six infants responded well to sirolimus, and among these one infant who failed to respond to surgery (STP) also successfully managed with sirolimus. • It highlights the right patient selection and right dose to successfully manage these cases without much adverse effects.

Hypoglycemia due to insulin autoimmune syndrome (Hirata’s disease): a rare cause of hypoglycaemia

Although the most common cause of recurrent hypoglycaemia is diabetes mellitus as patient is on antidiabetic medications which can be prevented by modification of antidiabetic doses, nutrition therapy and lifestyle modifications. Some endogenous hyperinsulinemic conditions like insulinoma, functional beta cell disorders and insulin autoimmune syndromes, hormonal deficiencies can cause serious and sometimes life threatening hypoglycaemia. So further laboratory evaluation like plasma/serum glucose levels, c-peptide levels, insulin levels, insulin antibodies and imaging studies are needed to evaluate unexplained hypoglycaemia. Here we report a case of insulin autoimmune syndrome in a 67 year old Indian male who had presented to us with multiple episodes of spontaneous hypoglycaemia. On further workup, the patient was found to have endogenous hyperinsulinemic hypoglycemia. As the patient’s abdominal imaging revealed no apparent cause of EHH, on further evaluation he came positive for insulin antibodies. Patient was diagnosed as IAS and he was given frequent small meals and complex carbohydrate diet and he had improved symptomatically. The incidence of IAS is most common in Japan and very few cases have been reported from India, so it should be kept in differential diagnosis of recurrent hypoglycaemia.

50 Years Ago in TheJournalofPediatrics: Advances in the Understanding of Congenital Hyperinsulinemic Hypoglycemia

50 Years Ago in TheJournalofPediatrics: Advances in the Understanding of Congenital Hyperinsulinemic Hypoglycemia

18F-6-Fluoro-l-Dopa PET/CT Imaging of Congenital Hyperinsulinism.

Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. 18F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of 18F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.

Hyperinsulinemic Hypoglycemia in Neonates Due to Perinatal Stress: A Case Series

Hyperinsulinemic Hypoglycemia in Neonates Due to Perinatal Stress: A Case Series

Autoimmune hypoglycaemia: a narrative review from the laboratory perspective

: Whilst hypoglycaemia is common, autoimmune causes are relatively rare. Autoimmune causes of hypoglycaemia includes both insulin autoimmune syndrome (IAS), and type B insulin resistance syndrome (TBIR). IAS typically presents with post-prandial hypoglycaemia in adulthood and is characterised by inappropriately high plasma insulin, proinsulin and C-peptide concentrations during hypoglycaemia, with C-peptide:insulin molar ratios of <1, high insulin autoantibody titres and the presence of macroinsulin. TBIR typically presents with hyperglycaemia due to insulin resistance as a result of insulin receptor antibodies. TBIR may, however, also present with endogenous hyperinsulinaemic hypoglycaemia or hyperglycaemia-hypoglycaemia depending on the activating or inhibiting action of the insulin receptor antibodies. Very rarely, autoimmune hypoglycaemia may be due to insulin antibodies raised to therapeutic insulin or insulin-binding paraproteins with purported mechanisms similar to IAS in producing hypoglycaemia. This review summarises the pathophysiology and laboratory features of IAS and TBIR, and highlights the importance of considering these diagnoses in patients with hypoglycaemia associated with non-suppressed insulin levels, to prevent unnecessary pancreatic surgery.

Diagnostic Evaluation of Hypoglycemia Due To an Insulinoma in a Deployed Infantryman: Significance of Neuroglycopenia and the Role of the Military Health System.

Insulinoma, the prototype of endogenous hyperinsulinemic hypoglycemia, is a very rare condition, with an incidence of four cases per million person-years. Its rate of occurrence in the U.S. military population is unknown. Two cases of insulinomas involving active duty service members have been published. However, there has been no reported case of an insulinoma in a deployed service member. We report the case of a 21-year-old infantryman with clinical hypoglycemia of insidious onset, manifesting with overt neuroglycopenic symptoms during his deployment as a combatant soldier, and the ultimate diagnosis of an insulinoma as the underlying cause. The series of multiple clinical evaluations and the unique circumstances leading to the formal evaluation of the patient's hypoglycemia and treatment are chronicled. The significance of neuroglycopenia and the diagnostic approach to any suspected case of hypoglycemia, the potential challenges and opportunities, and educational aspects of evaluation and management of the insulinoma are elaborated. The potential role of the Military Health System in facilitating the detection and treatment of this rare condition in the service member is discussed as well.

A novel approach to a rare case of non-islet cell hypoglycaemia.

SummaryInsulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab.Learning pointsInsulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded.Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia.Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS).Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

Investigating difficult to detect pancreatic lesions: Characterization of benign pancreatic islet cell tumors using multiparametric pancreatic 3-T MRI.

IntroductionPancreatic islet-cell tumors (PICT) often present with atypical signal-characteristics and are often missed on preoperative imaging. The aim of this study is to provide a multiparametric PICT characterization and investigate factors impeding PICT detection.Material and methodsThis is a detailed MRI analysis of a prospective, monocenter study, including 49 consecutive patients (37 female, 12 male; median age 50) with symptoms due to endogenous hyperinsulinemic hypoglycemia (EHH) and mostly negative prior-imaging. All patients received a 3-T MRI and a 68Ga-DOTA-exendin-4-PET/CT. Pooled accuracy, sensitivity, specificity and inter-reader agreement were calculated. Reference-standard was histopathology and 68Ga-DOTA-Exendin-4-PET/CT in one patient who refused surgery. For PICT analyses, 34 patients with 49 PICTs (48 histologically proven; one 68Ga-DOTA-exendin-4-PET/CT positive) were assessed. Dynamic contrast-enhanced (DCE) Magnetic Resonance Images (MRI) with Golden-Angle-Radial-Sparse-Parallel (GRASP) reconstruction, enabling imaging at high spatial and temporal resolution, was used to assess enhancement-patterns of PICTs. Tumor-to-background (T2B) ratio for each sequence and the employed quantitative threshold for conspicuity of PICTs were analyzed in regard to prediction of true-positive PICTs.ResultsEvaluation of 49 patients revealed a pooled lesion-based accuracy, sensitivity and specificity of 70.3%, 72.9% and 62.5%, respectively. Mean PICT size was 12.9±5.3mm for detected, 9.0±2.9mm for undetected PICTs (p-value 0.0112). In-phase T1w detected the most PICT (67.3%). Depending on the sequence, PICTs were isointense and poorly visible in 29–68%. Only 2/41(4.9%) PICTs showed typical signal-characteristics across T1w, T2w, DWI and ceT1w combined. 66.6% of PICTs enhanced simultaneously to the parenchyma, 17.8% early and 15.6% late. Predictor screening analysis showed number of sequences detecting a PICT, lesion size and in-phase T1w T2B ratio had the highest contribution for detecting a true-positive PICT.ConclusionThe majority of PICTs enhance simultaneously to surrounding parenchyma, present with atypical signal-characteristics and thus are poorly visible. In non-enhancing PICTs, radiologists should search for small lesions most likely conspicuous on unenhanced T1w or DWI.

CRISPR/Cas9 ADCY7 Knockout Stimulates the Insulin Secretion Pathway Leading to Excessive Insulin Secretion.

AimDespite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI.PatientA 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative.MethodsA trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR.ResultsHyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/- Adcy7 ) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway.ConclusionThis study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.

Carcinoid Syndrome and Hyperinsulinemic Hypoglycemia Associated with Neuroendocrine Neoplasms: A Critical Review on Clinical and Pharmacological Management.

The carcinoid syndrome (CS) and hyperinsulinemic hypoglycemia (HH) represent two of the most common clinical syndromes associated with neuroendocrine neoplasms (NENs). The former is mainly related to the serotonin secretion by a small bowel NEN, whereas the latter depends on an insulin hypersecretion by a pancreatic insulinoma. Both syndromes/conditions can affect prognosis and quality of life of patients with NENs. They are often diagnosed late when patients become strongly symptomatic. Therefore, their early detection and management are a critical step in the clinical management of NEN patients. A dedicated and experienced multidisciplinary team with appropriate therapeutic strategies is needed and should be encouraged to optimize clinical outcomes. This review aims to critically analyze clinical features, evidence and treatment options of CS and HH and therefore to improve their management.

Clopidogrel induced autoimmune hypoglycemia

We report insulin autoimmune syndrome in a diet-controlled type 2 diabetes mellitus patient. She developed recurrent attacks of severe hypoglycemia 1 week after the initiation of clopidogrel. The evaluation revealed high insulin and C-peptide levels consistent with hyperinsulinemic hypoglycemia. The insulin-to-C-peptide ratio was reversed and &gt;50. Anti-insulin antibody titers were highly positive.

193-LB: A Puzzling Case of Hypoglycemia in a Patient with Type 1 Diabetes Mellitus and Cushing Syndrome

Introduction: Exogenous insulin antibodies are common in patients with type 1 diabetes mellitus (T1DM) on insulin. However, they are clinically irrelevant as a cause of hypoglycemia. We report a unique case of exogenous insulin antibody-mediated severe hypoglycemia in a patient with T1DM and Cushing syndrome. Case Report: A 55-year-old woman with T1DM on insulin pump presented with proximal muscle weakness and myalgia. She was diagnosed with Cushing syndrome due to an adrenal adenoma. Despite high serum cortisol, she had severe symptomatic episodic hypoglycemia with glucose levels &amp;lt;10 mg/dL requiring intermittent prolonged suspension of insulin pump. Surprisingly, she did not develop hyperglycemia or ketosis when off the insulin pump. During a witnessed hypoglycemic episode, serum insulin was 20.8 uIU/mL (NRR &amp;lt;19.7 uIU/mL), C-peptide &amp;lt;0.10 ng/mL (NRR 0.80-2.85 ng/mL), glucagon 11 pg/nl (NRR 8-57 pg/nl), and insulin antibody 4.1 U/mL (NRR &amp;lt;0.4/U/mL). She eventually underwent right adrenalectomy and was started on prednisone post-operatively resulting in a marked decrease in frequency of hypoglycemia. She was discharged on prednisone with plan for outpatient taper. Discussion: Our case highlights the complex nature of glycemic dysregulation in insulin antibody-mediated hypoglycemia. Literature review suggests that binding capacity and affinity to insulin, rather than the quantity of insulin antibodies, determines the severity of hypoglycemia. We hypothesize that high binding capacities in our patient resulted in rapid sequestration of exogenous insulin through formation of immunoglobulin-insulin complexes. The low affinity allowed for subsequent rapid release of insulin in a physiologically dyssynchronous manner resulting in hyperinsulinemic hypoglycemia. A distinctive aspect of our patient is the presence of severe hypoglycemia despite endogenous hypercortisolism, although she responded to prednisone. This finding may have implications for future research. Disclosure M. Amini: None. A. H. Khine: None. S. S. Lamba: None. S. Mishra: None. S. Naing: None. V. Babu: None.

79-LB: Pharmacokinetics and Pharmacodynamics of Avexitide (Exendin 9-39) in Neonates and Infants with Congenital Hyperinsulinism

Congenital hyperinsulinism (HI) is an ultra-rare pediatric disease with high unmet medical need. Avexitide, a first-in-class GLP-1 receptor antagonist, has been shown to reduce hyperinsulinemic hypoglycemia in children and adolescents with HI. Among neonates, maintenance of euglycemia often depends on high glucose infusion rates (GIR) by central lines. Those whose GIR exceeds 10 mg/kg/min frequently require subtotal pancreatectomy, leading to prolonged hospitalization, life-threatening complications, and induction of insulin-dependent diabetes. In this Phase 2 trial, 13 neonates and infants ages 11 days to 5 months with diazoxide-unresponsive HI were randomized to single ascending doses of avexitide and placebo by continuous IV infusion for up to 12 hours on two days in crossover design. Plasma glucose was monitored with GIR adjusted to maintain euglycemia. The primary endpoint was GIR. Relationships between avexitide exposure and absolute difference in GIR during avexitide vs. placebo were evaluated. A pharmacokinetic (PK) simulation of avexitide following subcutaneous (SC) injection in neonates was performed based on a modified PopPK model previously established with inclusion of weight-based allometric scaling. Relative to placebo, avexitide significantly reduced GIR when evaluated across dose levels (p=0.0087) with dose-dependent improvements observed. On average, avexitide infused at 100, 200 and 1000 pmol/kg/min demonstrated 1.3 (15%), 2.9 (24%), and 4.3 (56%) mg/kg/min reductions in GIR relative to placebo and entirely abolished glucose requirements in 50% of patients at the top dose. PK/PD analysis demonstrated an exposure-response relationship best described by an Emax model. PK simulation indicated that avexitide dosed by SC injection may achieve adequate steady-state exposure to lower GIR requirements. Subcutaneous avexitide may represent a promising therapeutic approach for treatment of neonates and infants with HI. Disclosure C. Craig: Consultant; Self; Eiger BioPharmaceuticals. D. D. De leon: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Hanmi Pharmaceutical, Heptares Therapeutics, Poxel SA, Soleno Therapeutics, Inc., Employee; Spouse/Partner; Merck &amp; Co., Inc., Research Support; Self; Crinetics Pharmaceuticals, Tiburio, Zealand Pharma A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK083670); Clifford and Katherine Goldsmith Foundation; National Center for Research Resources (UL1RR024134); Eiger BioPharmaceuticals

Is Bariatric Surgery Brain Surgery?

Roux-en-Y gastric bypass (RYGB) reliably produces sustained weight losses, reduces circulating blood glucose, and lowers risk of type 2 diabetes (1). Accompanying these benefits, however, is symptomatic hypoglycemia, reported by up to one-third of post–bariatric surgery patients (2,3). In an estimated <1% of RYGB patients (4), postprandial hyperinsulinemic hypoglycemia causes severe symptoms including neuroglycopenia with significant morbidity. New mechanistic insights and treatment options for these patients are needed. Potential contributors include rapid glucose delivery into the bloodstream, improved β-cell function, and gut adaptations, but the role of the central nervous system (CNS) is an important and underdeveloped area of research (3). In their article in this issue of Diabetes , Almby et al. (5) investigate whether RYGB alters the brain response to hypoglycemia in humans—a topic with further relevance to the CNS contribution to RYGB’s modification of overall glucose homeostasis. Human neuroimaging studies document RYGB-induced changes in brain function and suggest reversibility of obesity-associated findings (6–8). Studies of cerebral metabolism measuring [18F]-fluorodeoxyglucose uptake by positron emission tomography (FDG-PET) show that brain glucose uptake is elevated in participants with obesity and partially reversed post-RYGB (6,7), but controlled studies of the cerebral metabolic response to insulin-induced hypoglycemia are lacking. Cerebral blood flow response to insulin-induced hypoglycemia assessed by arterial spin labeling (ASL) showed increased regional blood flow (vs. euglycemia) in the cortex, thalamus (9), and hypothalamus (10) in healthy adults. Almby et al. provide novel data on the effect of RYGB on brain response to hypoglycemia (5). Almby et al. included 11 participants that underwent, before and …

245-OR: Comprehensive Genome-Wide Association Study (GWAS) Meta-analysis Using TOPMed Imputation in Latinos Identifies Rare Variation Associated with Type 2 Diabetes (T2D)

The high prevalence of T2D among Latino individuals emphasizes the importance of studying both environmental and genetic factors that influence disease in this population. However, Latino is a recently admixed population with complex linkage disequilibrium patterns that impose methodological challenges, especially when using genotype imputation to test association with rare variation. The recent release of the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) reference panel, comprising more than 100,000 samples (~10% are Latinos), represents a unique opportunity to explore rare genetic variation in this population. We performed the largest T2D GWAS meta-analysis in the Latino population imputed to the TOPMed panel. Our analysis includes 18,294 individuals (7,556 cases and 10,738 controls) with genotyping array and whole-exome sequencing data. We were able to impute 38M high-quality variants (rsq&amp;gt;0.8) with TOPMed (5M with minor allele frequency [MAF] 0.001-0.0005) compared to 16M with 1000G Phase 3 panel (1.6M with [MAF] 0.001-0.0005). This allowed us to replicate previously reported T2D-associated common variants, and to identify a novel genome-wide significant variant (MAF=0.016, OR=2.06, P=1.7×10-9) near ORC5, a gene implicated in familial hyperinsulinemic hypoglycemia 2. Two additional suggestive novel signals merit further research: a variant in ROR2 (MAF=0.066, OR=1.3, P=8.8×10-8) and a Latino specific variant in HDAC2 only identified with the use of TOPMed (MAF=0.013, OR=1.82, P=3.2×10-7) and associated with insulin secretion in individuals without diabetes in this study. Our results demonstrate the utility of the TOPMed imputation for the identification of novel and population-specific rare variation associated with T2D in understudied populations, which could lead to the identification of novel therapeutic targets and the improvement of polygenic risk scores. Disclosure A. Huerta: None. Mgb biobank: n/a. J. B. Cole: None. P. Dornbos: None. D. A. Dicorpo: None. A. Leong: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. J. M. Mercader: None. Sigma t2d consortium: n/a. Mx biobank: n/a. Funding American Diabetes Association (1-19-ICTS-068 to J.M.M.)

Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan.

SummaryActivating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative.Learning pointsConsider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative.Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness.Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia.Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK.Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

Increased C-Peptide Immunoreactivity in Insulin Autoimmune Syndrome (Hirata Disease) Due to High Molecular Weight Proinsulin.

BackgroundDetermination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS.MethodsPrecipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC–MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC–MS/MS analysis. Gel filtration chromatography coupled to LC–MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay.ResultsPolyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC–MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC–MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes.ConclusionsAntibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results.

Familial Hyperinsulinism due to HNF4A Deficiency and Benign Premature Adrenarche: A Case Report

Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-HNF4A deficiency and benign premature adrenarche (BPA) is unknown.&#x0D; The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings of hyperandrogenism.&#x0D; Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine the association between HNF4A dysfunction and BPA.