Excessive Insulin Secretion Research Articles

Clinical characteristics and treatment outcomes of patients with insulinoma-a single center's experience of 76 cases over a 10-year period.

Insulinoma is a rare pancreatic neuroendocrine neoplasm caused by pancreatic beta cell tumor or beta cell proliferation resulting in excessive insulin secretion. Due to its rarity, surgical analysis and summary studies on patients with insulinoma are few and the sample size is limited. In this study, we retrospective the cumulative experiences including demographics, clinical characteristics, detailed surgical reports and postoperative outcome of 76 patients diagnosed with insulinoma from 2010 to 2020at the First Affiliated Hospital of Xi'an Jiaotong University. Our cohort consisted of 48 females and 28 males with an average diagnosis age of 52 years. Loss of consciousness (68 %), sweating (59 %), vertigo (56 %) are three most shown symptoms. The average time from symptom onset to diagnosis of insulinoma was 33.4 month. When CT combined with MRI was used, the diagnostic rate was as high as 96.87%. Of the 76 patients, 48.68% of preoperative tumors were in the head/neck, and the remaining 51.32% were in the body/tail. Most of the patients received surgery for enucleation (65.79%). The duration of surgery was 216±105min. The incidence of postoperative pancreatic fistula was 53.95%. Postoperative pancreatic hemorrhage occurred in 6 patients (7.89%), all of whom were pancreatic head/neck surgery patients. The incidence of pancreatic fistula, bleeding and major complications after the operation of pancreatic head/neck insulinoma was higher than that of pancreatic body/tail insulinoma. CT combined with MRI can localize insulinoma in most patients. As a parenchyma-sparing pancreatectomy, enucleation is the procedure of choice if possible. The incidence of postoperative hemorrhage should be more vigilant after the surgery of pancreatic head/neck insulinoma. The intraoperative suture of high-risk vessels prone to bleeding should be performed if necessary.

Diet-enhanced LRG1 expression promotes insulin hypersecretion and ER stress in pancreatic beta cells.

Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells. Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects of LRG1 on insulin secretion and intracellular Ca2+ release. Antibodies targeting various LRG1 epitopes were used to neutralise LRG1 stimulation in MIN6 cells, and their effectiveness was tested in vivo to assess their ability to prevent LRG1-induced hyperinsulinaemia. We observed a significant positive association between human serum LRG1 levels and both age and BMI, with elevated levels observed in individuals with vs without type 2 diabetes. In mice fed a high-fat diet, LRG1 upregulation in serum was associated with hyperinsulinaemia. Lrg1 knockout protected mice from diet-induced islet hyperplasia and the loss of beta cell mass. Furthermore, neutralising LRG1 activity prevented the onset of diet-induced hyperinsulinaemia and preserved glucose tolerance. Mechanistically, LRG1 induces inositol triphosphate (IP3) production and intracellular Ca2+ release from the endoplasmic reticulum (ER) in a phospholipase C (PLC)-dependent manner, leading to excessive insulin secretion and ER stress in MIN6 beta cells. In summary, this study identifies LRG1 as a significant contributor to hyperinsulinaemia and beta cell dysfunction. Targeting LRG1 activity emerges as a promising therapeutic approach for addressing diet-induced beta cell dysfunction and managing type 2 diabetes.

Clinical and Genetic Characteristics of Congenital Hyperinsulinism in Norway: A Nationwide Cohort Study.

Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past 2 decades. The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients' phenotype (n = 75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (n = 23). Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (n= 40), and 5 novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, 8 probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in 1 proband each, the latter being noncoding. Neurologic sequelae were reported in 53% of the CHI probands. Of nonsurgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births. Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease onset than genetically unsolved patients.

Multiomics Analyses With Stool-Type Stratification in Patient Cohorts and Blautia Identification as a Potential Bacterial Modulator in Type 2 Diabetes Mellitus.

Heterogeneity in host and gut microbiota hampers microbial precision intervention of type 2 diabetes mellitus (T2DM). Here, we investigated novel features for patient stratification and bacterial modulators for intervention, using cross-sectional patient cohorts and animal experiments. We collected stool, blood, and urine samples from 103 patients with recent-onset T2DM and 25 healthy control subjects (HCs), performed gut microbial composition and metabolite profiling, and combined it with host transcriptome, metabolome, cytokine, and clinical data. Stool type (dry or loose stool), a feature of the stool microenvironment recently explored in microbiome studies, was used for stratification of patients with T2DM as it explained most of the variation in the multiomics data set among all clinical parameters in our covariate analysis. T2DM with dry stool (DM-DS) and loose stool (DM-LS) were clearly differentiated from HC and each other by LightGBM models, optimal among multiple machine learning models. Compared with DM-DS, DM-LS exhibited discordant gut microbial taxonomic and functional profiles, severe host metabolic disorder, and excessive insulin secretion. Further cross-measurement association analysis linked the differential microbial profiles, in particular Blautia abundances, to T2DM phenotypes in our stratified multiomics data set. Notably, oral supplementation of Blautia to T2DM mice induced inhibitory effects on lipid accumulation, weight gain, and blood glucose elevation with simultaneous modulation of gut bacterial composition, revealing the therapeutic potential of Blautia. Our study highlights the clinical implications of stool microenvironment stratification and Blautia supplementation in T2DM, offering promising prospects for microbial precision treatment of metabolic diseases. Article Highlights

Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity.

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

THU530 What Works For Ferret, Works For Man

Abstract Disclosure: P.J. Bhatt: None. S. Bendaram: None. V. Kantorovich: None. Insulinomas are rare pancreatic neuroendocrine tumors with an incidence of 4 cases per million per year and present with hypoglycemic symptoms due to uncontrolled and excessive insulin secretion by the tumor. Although most commonly benign and treated with surgery, 5-10% are malignant, inoperable and are managed medically with somatostatin analogs, chemotherapy, mTOR inhibitors and diazoxide. A 28 year old male with a history of metastatic insulinoma with progressive disease and refractory hypoglycemia presented with lethargy, diaphoresis, and blood glucose (BG) level of 32mg/dL [65-99]. He was previously admitted for severe hypoglycemia and was treated with FOLFOX, LUTATHERA, Octreotide, TPN, steroids and diazoxide suspension. Sugars were monitored via continuous glucose monitor (CGM) and insulin and C-peptide levels were closely monitored outpatient. Treatment was effective and medications were tapered off so that he no longer needed a CGM and was only on FOLFOX and octreotide prior to presentation. On admission, insulin level was 172 uIU/mL [<17], peaking at 312 uIU/mL and BG dropping to 22mg/dL. He was placed on a dextrose 10% infusion, TPN, diazoxide suspension, and CGM. This admission, however, his insulin levels were much higher requiring higher doses of diazoxide, but he was unable to tolerate the diazoxide solution due to extreme nausea and projectile vomiting, resigning him to a long-term stay in the ICU. Due to a lack of availability of other oral formulations in the US, compounding pharmacies were contacted and pharmaceutical grade diazoxide powder was compounded into 100mg capsules by an outside pharmacy. Dose was adjusted while monitoring BG and insulin levels. Prior to discharge, insulin level was 77.7 uIU/mL and BG levels had normalized. He was sent home on diazoxide 200mg twice a day, TPN, and CGM. FOLFOX was resumed. Outpatient follow up revealed euglycemia and suppressed insulin level of 12.3 uIU/mL [<17], allowing for further tapering of diazoxide dose and discontinuation of TPN. Diazoxide is known to be a safe and effective treatment for hypoglycemia in humans and ferrets alike. It inhibits insulin secretion in pancreatic B cells and increases hepatic glucose production. Side effects of nausea and vomiting can be a barrier to compliance, as seen in our patient. Currently, only oral solutions of diazoxide have been approved for human consumption whereas ferrets, commonly afflicted with insulinomas, are treated with oral pills. Changing the oral formulation to pill form allowed for better compliance, easy dose adjustments using insulin as a marker for response, and symptom resolution due to adequate suppression of insulin levels. Most importantly, it allowed for our patient to transfer out of the ICU and be discharged home with improved quality of life, a feat that was impossible without this change in formulation. Presentation: Thursday, June 15, 2023

Sosialisasi Tindakan Pencegahan Kondisi Kritis Dari Diabetes Mellitus Tipe II

Patients with impaired glucose tolerance due to excessive insulin secretion and glucose levels will be maintained at normal levels or slightly increased. However, the role of B cells if they are unable to keep up with the increased need for insulin, then glucose levels will increase and type II DM will occur. Despite the impaired insulin secretion that is characteristic of type II DM, there is still insulin in adequate amounts to prevent the breakdown of fat and the production of ketone bodies that accompany it, therefore diabetic ketoacidosis does not occur in type II DM, however, type II DM does. Uncontrolled will cause other acute problems such as non-ketotic hypoglycemic hyperglycemic syndrome (HHNK). The problems that arise here are Mrs. Y's partners/family do not know 1) the conditions that pose a risk of a critical condition in people with diabetes mellitus, her family/Mrs. Y do not know what can prevent DM people from being in a critical condition. 2) Mrs. Y stated that his blood sugar tends to rise because he is not disciplined in consuming and managing food intake. The results of the conversation between the Tuanku Tambusai Hero University service team and one of the residents of the Bangkinang Seberang Village, Muara Uwai Village, namely Mrs. Y, who also has diabetes mellitus from heredity and unhealthy eating habits, which results in an increase in blood sugar. Mrs. Y was diagnosed with DM in May 2022, when her blood sugar level was detected at 350 mg/dL. She was advised by her doctor to undergo insulin therapy for life. If you experience critical signs and symptoms of DM, immediately go to the health service so that you can get action quickly and precisely.

Congenital hyperinsulinism in a Nigerian infant: A case report and review of literature

Congenital hyperinsulinism, a rare genetic disorder characterized by excess insulin secretion even during hypoglycemic episodes, has two histological subtypes; diffuse and focal. Genotypes denote which of the two subtypes presents, and this is the first case being reported in Nigeria. The aims of this study were to report the first case of genetically confirmed compound heterozygote inheritance for two non-sense mutations in the ABCC8 gene in a Nigerian child and her family. A full-term average weight (7.5 lb) female baby presented with severe hyperinsulinemic hypoglycemia [HH] after birth and failed medical treatment with dextrose infusion. She had several hypoglycemic seizure episodes and spastic diplegic cerebral palsy, despite frequent feeding. Following physiotherapy, her spasticity was regressing and she was also able to say polysyllabic words. Genetic testing done 2 years after birth showed that her father was heterozygous for the ABCC8 non-sense mutation, P.W143*, and her mother was heterozygous for the P.Q416* ABCC8 mutation. This report shows the need for quick and early genetic testing for rare disorders and the possibility of collaboration with more specialized genetic laboratories. When diagnosed, diffuse or focal diazoxide unresponsive hypoglycemia may be treated by partial or complete pancreatectomy with the potential complication of diabetes mellitus later in life.

CRISPR/Cas9 ADCY7 knockout stimulates the insulin secretion pathway leading to excessive insulin secretion

Brief Summary: This is a single case report describing a possible new candidate gene (ADCY7) for congenital hyperinsulinism. Mutations in the ADCY7 gene may be a new cause of congenital hyperinsulinism but more cases are needed and the molecular mechanisms studied in more detail.

Tratamiento del Insulinoma maligno con radionúclidos: nuevos horizontes

Malignant insulinoma is a rare neuroendocrine tumor, located exclusively in the pancreas, characterized by severe hypoglycemia secondary to excessive insulin secretion. Somatostatin analogs (SSA) and everolimus have been added to the classic treatment with diazoxide in the last years. Peptide receptor radionuclide therapy (PRRT) has also been recently tested in a few patients with insulinoma with apparently satisfactory results. We present a 49-year-old woman with a loss of consciousness in the context of severe hypoglycemia that was diagnosed of malignant insulinoma. She underwent tumor excision and a total pancreatectomy and after an extended hospital stay, she was discharged without hypoglycemia under treatment with ASS. After observing tumor progression, treatment with 4 cycles of PRRT was performed with symptomatic control, reduction of some of the metastatic lesions and stabilization of other lesions with excellent tolerance to treatment. PRRT is a possible alternative for the symptomatic and etiological treatment of malignant insulinoma.

Is the Size of Insulinoma Predictive for its Endocrine Behavior? An Endoscopic Ultrasound Study.

Insulinoma is a rare tumor of the pancreas that can lead to spontaneous hypoglycemia due to excessive insulin secretion. Seventy-two-hour fast is the gold standard for finding the correct diagnosis. Endoscopic ultrasound (EUS) is an established examination method to identify the suspicious lesion. Previous studies correlate the measured size of insulinoma and their endocrine behavior. This study was designed to find a relation between these variables. We took the data of patients who had a histologically confirmed insulinoma after receiving an endoscopic ultrasound in our department. Size and echogenicity were correlated with the endpoint of the 72-hour fast and hormone levels. A total of 45 patients were identified. Most insulinomas were small with a volume of<2 cm3 (median 1.15 cm3). There was no correlation between the duration of fasting, hormone levels, and the size of the insulinoma. In addition, in a subgroup analysis, no connection could be established between the size of the insulinoma and the amount of insulin released after oral glucose exposure. We found that homogeneous tumors were significantly smaller and had a lower Ki-67 index. Furthermore, there was a tendency towards a shorter duration for the 72-hour fast for the small tumors. This data suggests that the measured size of insulinoma by EUS is not related to the time until termination of the 72-hour fast and measured hormone levels. The echogenicity seems more important, showing that homogenous tumors are an indicator of a higher differentiation, which can result in a shorter duration of the fasting period. The differences in the secretion behavior of the insulinomas could complicate the correlation of size and the 72-hour fast period.

Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.

Muscle fiber composition is associated with peripheral insulin action. We investigated whether extreme differences in muscle fiber composition are associated with alterations in peripheral insulin action and secretion in young, healthy subjects who exhibit normal fasting glycemia and insulinemia. Relaxation time following a tetanic contraction was used to identify subjects with a high or low expression of type I muscle fibers: group 1 (n = 11), area occupied by type I muscle fibers = 61.0 ± 11.8%, and group 2 (n = 8), type I area = 36.0 ± 4.9% (P < 0.001). Biopsies were obtained from the vastus lateralis muscle and analyzed for mitochondrial respiration on permeabilized fibers, muscle fiber composition, and capillary density. An intravenous glucose tolerance test was performed and indices of glucose tolerance, insulin sensitivity, and secretion were determined. Glucose tolerance was similar between groups, whereas whole-body insulin sensitivity was decreased by ~50% in group 2 vs group 1 (P = 0.019). First-phase insulin release (area under the insulin curve during 10 minutes after glucose infusion) was increased by almost 4-fold in group 2 vs group 1 (P = 0.01). Whole-body insulin sensitivity was correlated with percentage area occupied by type I fibers (r = 0.54; P = 0.018) and capillary density in muscle (r = 0.61; P = 0.005) but not with mitochondrial respiration. Insulin release was strongly related to percentage area occupied by type II fibers (r = 0.93; P < 0.001). Assessment of muscle contractile function in young healthy subjects may prove useful in identifying individuals with insulin resistance and enhanced glucose-stimulated insulin secretion prior to onset of clinical manifestations.

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

ContextIn focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery.ObjectiveWe describe surgical and nonsurgical outcomes of focal CHI in a national cohort.MethodsPatients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018.ResultsOf 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose.ConclusionDespite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

Clustering of Hypoglycemia Events in Patients With Hyperinsulinism: Extension of the Digital Phenotype Through Retrospective Data Analysis.

BackgroundHyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal.ObjectiveThis study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events.MethodsPatients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L.ResultsA total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes.ConclusionsThis is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.

1246-P: Microcirculatory Circuit of Pancreatic Islets in Diabetic Fetopathy and Congenital Hyperinsulinism

The main cause of diabetes is the loss or dysfunction of beta cells that leads to insulin deficiency and hyperglycemia. However, there are some opposite pathologies, in which insulin secretion results in hypoglycemia. Data on the islets morphology in such diseases may be useful for understanding of the pathogenesis of diabetes. Diabetic fetopathy (DF) is a complication of gestational diabetes or preexisting maternal diabetes mellitus, which is characterized by the accelerated fetal growth and neonatal hypoglycemia. These complications mainly develop due to fetal hyperinsulinemia as a compensatory response to the increased delivery of the glucose to the fetus. Congenital hyperinsulinism (CHI) is a severe genetic disease, in which hypoglycemia is caused by excessive insulin secretion. There are two main CHI forms based on histology: diffuse and focal. Pancreatic samples of 4 newborns with DF from mothers with diabetes, 7 infants with diffuse CHI, and 7 infants with focal CHI were compared to 6 control infants without hypoglycemia. The diagnosis of CHI and histological form were established based on increased insulin level during hypoglycemia, presence of pathologic mutations in ABCC8/KCNJ11 genes, and immunohistochemistry results. All pancreatic samples were examined by immunohistochemistry with antibodies against insulin, glucagon, and vimentin. Histological changes such as nuclei enlargement in some beta-cells, islets hypertrophy, and prominent islets vascularization were observed in the endocrine pancreas of infants with DF as well as in patients with CHI. Swelling of the perivascular space was the distinguishing feature, which was revealed only in newborns with DF. In children with CHI, the abundant vascularization in large islets was not accompanied by swelling. We assume that a long-term increase of blood glucose in fetuses with DF leads to vasodilatation, which subsequently causes impaired endothelial permeability and swelling. Disclosure A. Proshchina: None. D. Gubaeva: None. Y. Krivova: None. D. Otlyga: None. M. Melikyan: None.

Glycerol‐3‐phosphate phosphatase/ Pgp in Pancreatic ß‐cells Functions as a Glucose Excess Security Valve Preventing Oversecretion of Insulin Secretion and Glucotoxicity

Objective The recently identified enzyme in mammalian cells, glycerol-3-phosphate (Gro3P) phosphatase (G3PP), gene name Pgp, was proposed to regulate intermediary metabolism. G3PP was shown in in vitro studies to regulate metabolism and glucose stimulated insulin secretion (GSIS) in ß-cells. We now examined the in vivo role of G3PP in the control of insulin secretion and ß-cell glucotoxicity. Methods Glucose and insulin tolerance were studied in ß-cell specific G3PP-KO (BKO) mice. Body weight gain, fed glycemia and insulinemia were measured. Pancreatic islets were isolated for ex vivo GSIS and biochemical measurements. Results BKO mice show increased body weight gain, unaltered fed glycemia and insulinemia, and enhanced insulin secretion in response to glucose load in an intraperitoneal but not oral glucose tolerance test, reaching 21 and 14 mM glucose, respectively. Insulin sensitivity in vivo remains unchanged in the BKO mice. GSIS response ex vivo at 16 mM but not 8 mM glucose is higher in BKO mouse islets. BKO islets show reduced glucose-induced glycerol release and elevated O2 consumption and ATP production at high (16 mM) but not low (4 mM) glucose levels. Glucotoxicity at 30 mM glucose for 7 days led to increased apoptosis, reduced insulin content and expression of Pdx-1 and Ins-2 genes in BKO islets. Conclusion G3PP impacts insulin secretion in vivo and ex vivo only under conditions of high but not intermediate and low glucose levels. G3PP plays a role in preventing ß-cell glucotoxicity. These effect likely result from the capacity of G3PP to redirect the excess glucose carbons from intermediate metabolism to glycerol that exits ß-cells. We propose that G3PP acts as a glucose excess security valve to prevent excessive insulin secretion and ß-cell dysfunction when blood glucose reaches very high levels.

A case of reactive hypoglycemia caused by Kampo medicine

ABSTRACTCaseReactive hypoglycemia can occur due to postprandial insulin hypersecretion. However, no Kampo medicine is known to cause this effect. Herein, we describe a case of reactive hypoglycemia that occurred postprandially as an effect of Kampo medicine. A 42‐year‐old woman was admitted because of chest pain. We prescribed saikokaryukotsuboreito, following which the patient's symptoms improved. However, after 9 months, she experienced persistent fatigue after developing a cold. Therefore, we changed the prescription to hochuekkito and keishikaryukotsuboreito. Nevertheless, discomfort in the epigastric region and back pain developed within a few hours after administration of these medications.OutcomeResults of 75 g oral glucose tolerance test (OGTT) showed excessive insulin secretion, potentially as a result of changing Kampo administration. Therefore, the treatment was changed back to saikokaryukotsuboreito, which resolved the postprandial symptoms. Moreover, the insulin hypersecretion disappeared on subsequent 75 g OGTT.ConclusionThe promotion of gastric peristaltic function as an effect of Kampo may cause reactive hypoglycemia.

Congenital Hyperinsulinism

Background: Congenital hyperinsulinism (CHI) is a rare condition that usually presents in the newborn period. It is characterized by hypoketotic hypoglycemia due to excessive insulin secretion. We describe below a case of CHI due to a paternally inherited mutation of the ABCC8 gene and the challenges in its management. Clinical Description: A term female appropriate for gestational age baby with an uneventful antenatal period and delivery presented at 46 h of life with fever, decreased oral acceptance, lethargy, and hypoglycemic seizures. On examination, the baby was febrile but hemodynamically stable with no other clinical evidence of sepsis. Management: Child had recurrent episodes of hypoglycemia and required a glucose infusion rate of 12 mg/kg/min for maintaining euglycemia. The baby required diazoxide and octreotide for maintaining euglycemia. The hypoglycemia was nonketotic and associated with hyperinsulinism. 18-fluoro-dihydroxyphenylalanine positron emission tomography-computerized tomography scan showed diffuse uptake in the pancreas suggestive of diffuse hyperinsulinism. However, genetic testing showed heterozygous mutation for paternally transmitted pathogenic ABCC8 splicing variant. The child was stabilized and discharged on oral diazoxide and long-acting octreotide. Conclusion: CHI is an important cause of persistent hypoglycemia in neonates. Early diagnosis and management are important to prevent long-term sequalae. Establishing a correct molecular diagnosis is essential to decide about appropriate line of management (surgical/conservative) and provide genetic counseling to the family.

Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake.

The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m-2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal-1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal-1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d-1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d-1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .

Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1.

SummaryTyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.Learning pointsEvery child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia.If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected.Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects.The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.