Chronic Hypoglycemia Research Articles

6981 Atypical hypoglycemia in a teenage boy with prediabetes

Abstract Disclosure: N. Shahid: None. C. salgado: None. N. Gurtunca: None. Background: Hypoglycemia in teenagers is seen less commonly than in younger children. Overweight children with prediabetes presenting with hypoglycemia symptoms are often considered to have reactive post-prandial hypoglycemia due to the degree of hyperinsulinemia with insulin resistance seen in these children. We present a 13-year-old boy with prediabetes, who presented with episodes of altered mental status and was found to have hypoglycemia due to a solitary insulin secreting tumor. Case presentation: A 13-yr old boy with pre-diabetes presented to the ER with altered consciousness and non-ketotic, non-acidotic hypoglycemia [25 mg/dl] & trace ketonuria in the setting of Influenza A infection. Weight and BMI above the 99th%ile and acanthosis nigricans in the skin creases. No access to oral hypoglycemic agents. Urine toxicology was negative. EEG was normal. Euglycemia and level of consciousness restored after IV dextrose & this was considered a possible hypoglycemic seizure episode secondary to poor oral intake. 4 months later he had another episode of altered mental status, jittery movements and was found to be hypoglycemic [41 mg/dl]. He was admitted for further workup of recurrent hypoglycemia. Adrenal insufficiency was ruled out and a diagnostic fast was started. After 15 hours, he developed non-ketotic hypoglycemia [<50 mg/dl]. Critical sample [Table 1] and Glucagon challenge [Table 2] at the termination of the fast confirmed hyperinsulinemic hypoglycemia. Given the unusual age and presentation, an MRI abdomen was done which showed a 1.6 cm lesion in the pancreatic body [Fig 1]. Dotatate whole body PET scan confirmed the insulinoma with no evidence of nodal or distant metastasis [Fig 2]. He underwent surgical enucleation of the insulinoma. Intraoperative secretin showed no evidence of pancreatic duct dilatation or leakage. Hereditary endocrine tumor panel including multiple endocrine neoplasia [MEN] gene analysis was negative. The postoperative course was complicated by a persistent pancreatic leak and pancreatitis eventually requiring an ERCP and stent placement 2 months post operatively. Conclusion: Insulinomas are very rare neuroendocrine tumors in pediatric population, with a prevalence of one in 250,000 and median age at presentation of 45-50 years. About 90% insulinomas are benign and less than 10% are associated with MEN-1 syndrome. Chronic hypoglycemia irrespective of the underlying insulin resistance of prediabetes can be seen with insulinoma and can cause hypoglycemia unawareness as seen in our patient. This has also been reported in literature to be misdiagnosed as refractory epilepsy or psychiatric disorders. Hypoglycemic symptoms at any age should be promptly worked up. Ruling out associated neuroendocrine hereditary tumor syndromes is crucial and prognosis of benign solitary insulinomas after surgical removal is mostly favorable. Presentation: 6/3/2024

Transglutaminase 2 in diabetes mellitus: Unraveling its multifaceted role and therapeutic implications for vascular complications.

Diabetes, a severe metabolic disease characterized by chronic hypoglycemia, poses debilitating and life-threatening risks of microvascular and macrovascular complications, including blindness, kidney failure, heart attacks, and limb amputation. Addressing these complications is paramount, urging the development of interventions targeting diabetes-associated vascular dysfunctions. To effectively combat diabetes, a comprehensive understanding of the pathological mechanisms underlying complications and identification of precise therapeutic targets are imperative. Transglutaminase 2 (TGase2) is a multifunctional enzyme implicated in the pathogenesis of diverse diseases such as neurodegenerative disorders, fibrosis, and inflammatory conditions. TGase2 has recently emerged as a key player in both the pathogenesis and therapeutic intervention of diabetic complications. This review highlights TGase2 as a therapeutic target for diabetic complications and explores TGase2 inhibition as a promising therapeutic approach in their treatment.

Glycogen storage disease type Ib: modern understanding of the pathogenesis of neutropenia and prospects for its treatment with empagliflozin

Glycogen storage disease type Ib (GSD Ib) — is a disease from the group of hereditary metabolic diseases caused by insufficiency of the glucose-6-phosphate transporter (G6PT, SLC37A4), which leads to a violation of both glycogenolysis and gluconeogenesis and, as a consequence, to excessive accumulation of glycogen and fat in the liver, kidneys and intestinal mucosa. The main clinical manifestations and laboratory data include growth retardation, hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Complications of this disease are hepatocellular adenoma with a possible risk of malignancy, nephropathy and osteoporosis. A specific sign of GSD Ib is neutropenia with impaired neutrophil function, which creates prerequisites for recurrent infections and the development of inflammatory bowel disease. Until the present, enzyme replacement therapy of GSD Ib has not been developed, therefore, the main methods of treatment are a specialized diet with the addition of raw corn starch (for relief of hypoglycemia) and the use of granulocyte colony stimulating factor (for relief of neutropenia). However, the recent establishment of the role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction in GSD Ib has led to a reprofiling of indications for the use of empagliflozin, a type 2 renal sodium—glucose cotransporter inhibitor (SGLT2). In the modern literature, it is reported about a minor, but very successful experience of its use in patients with GSD Ib (outside the framework of official indications for use) and a beneficial effect on neutrophil dysfunction and its clinical consequences. Oddly enough, this hypoglycemic drug improved not only metabolic, but also glycemic control in patients with GSD Ib, despite the fact that the pathology is based on chronic hypoglycemia. More and more evidence points to the role of empagliflozin in the regulation of cellular homeostasis (for example, fatty acid metabolism, glucose, cholesterol, apoptosis and cell proliferation, in particular in the liver) by influencing the activity of sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK) and signal molecules such as -serine/threonine protein kinase (Akt) and a mechanical target of rapamycin (mTOR), which leads to an improvement in the structure and function of mitochondria, stimulation of autophagy, reducing oxidative stress and suppressing inflammation. Modulation of these pathways shifts oxidative metabolism from carbohydrates to lipids and leads to a key decrease in insulin levels, resistance to it, glucose and lipotoxicity. This review presents current data on the pathogenesis of neutropenia and the possibility of using empagliflozin for its relief in patients with GSD Ib.

SAT149 In Vitro Characterization Of A Novel Long-acting Glucagon Analog (HM15136) And Its Potential Effect In Animal Models Of Chronic Hypoglycemic Diseases

Abstract Disclosure: J. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. Y. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. B. Ye: Employee; Self; Hanmi Pharm. Co., Ltd. W. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. J. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: Employee; Self; Hanmi Pharm. Co., Ltd. D. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. Glucagon plays an essential role in glucose homeostasis, and has been used to treat acute hypoglycemia in diabetic patients. However, due to poor solubility and stability at physiological pH as well as short duration of action, its utility was hampered when managing chronic hypoglycemic diseases. One such example is congenital hyperinsulinism (CHI). CHI is a rare genetic disorder characterized by unregulated insulin secretion which leads to severe hypoglycemia especially during fasting condition. Another example is post-bariatric hypoglycemia (PBH) which can also lead to postprandial neuroglycopenia. Despite this life-threatening condition, no drugs are approved for CHI and/or PBH, and available glucagon therapies are very inefficient and inconvenient due to abovementioned limitations. Thus, to provide more optimal therapy for these chronic hypoglycemic diseases, a novel long-acting glucagon analog (HM15136) was developed. Here, we evaluated HM15136’s 1) solubility and stability at physiologic pH, 2) in vitro properties, and 3) potential therapeutic effect in animal models of CHI or PBH. First, we demonstrated improved solubility of HM15136 (≥150 vs. 0.03 mg/mL) at pH 7.0 and stability at day 20, compared to those of native glucagon. Next, in vitro cAMP assay was performed in CHO cells expressing human glucagon receptor (hGCGR), and HM15136 selectively activated hGCGR as a full agonist (EC50 = 0.024 vs. 0.003 nM; relative activity = ca.12.7%). In line with this, HM15136 promoted glycogenolysis and gluconeogenesis in rat primary hepatocytes in a dose dependent manner (relative potency = ca.20%), confirming glucose producing nature of HM15136. To investigate in vivo therapeutic effect on CHI and PBH, chronic hypoglycemia rats induced by SC infusion of insulin (CHI rats) and postprandial hypoglycemia rats induced by vertical sleeve gastrectomy (VSG rats) were established, respectively. Notably, HM15136 treatment significantly restored FBG by 37.3 ∼ 69.7% (p<0.05 ∼ 0.001) in CHI rats. Consistently, HM15136 treatment significantly prevented a massive BG reduction during MMTT in VSG rats (ΔBG between 0 and 45 min = +21 vs. -30 mg/dL, p<0.001). Furthermore, weekly dosing potential and BG elevation effect of HM15136 were also demonstrated in healthy human subjects (1). Based on these results, HM15136 could be a potential therapeutic option for chronic hypoglycemic diseases including CHI and PBH. Phase 2 clinical study in CHI subjects is on-going to assess the clinical relevance of these findings. Reference: (1) Diabetes Obes Metab. 2022 Mar; 23(3):411-20 Presentation: Saturday, June 17, 2023

Simultaneous SGLT2 inhibition and caloric restriction improves insulin resistance and kidney function in OLETF rats

SGLT2 inhibitors (SGLT2i) are emerging as a novel therapy for type 2 diabetes due to their effective hypoglycemic and potential cardio- and nephroprotective effects, while caloric restriction (CR) is a common behavioral modification to improve adiposity and insulin resistance. Therefore, both interventions simultaneously may potentially further improve metabolic syndrome by enhancing carbohydrate metabolism. To test this hypothesis, cohorts of 10-week old, male Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were treated with SGLT2i (10 mg luseoglifozin/kg/day x 4 wks) (OLETF only) and/or 30% CR (2 wks at 12 weeks of age). CR maintained body mass in both strains while SGLT2i alone did not have any effect on body mass. Simultaneous treatments decreased SBP in OLETF vs SGLT2i alone, decreased insulin resistance index (IRI), and increased creatinine clearance vs OLETF ad lib. Conversely, CR decreased albuminuria independent of SGLT2i. In conclusion, SGLT2i treatment by itself did not elicit significant improvements in insulin resistance, kidney function or blood pressure. However, when combined with CR, these changes where more profound than with CR alone without inducing chronic hypoglycemia.

Bitter brain: Hypoglycemia and the pathology of neurodegeneration and dementia.

Glucose poses the predominant energy source of the brain and its continuous uptake is vital for optimal brain function. Neurons metabolize glucose to generate adenosine triphosphate via glycolysis and the tricarboxylic acid cycle, whereas astrocytes utilize glucose both as an energy source and to generate glutamine - a neurotransmitter precursor- for neurons [Brekke et al., 2015]. Here, we prospectively examine the relationship between chronic hypoglycemia and the associated links between neurodegeneration and dementia. It is proposed that severe episodes or chronic hypoglycemia will induce an increased risk of dementia. A complex and specific literature search was conducted across various scientific, international databases for English, peer-reviewed articles and reviews published in the last two decades using the following terms: diabetes, insulin, glucose metabolism, hypoglycemia, and Alzheimer's disease (AD). Case reports were excluded. The main objectives were predominantly focused on animal- or human-based studies. When blood glucose levels are <55 mg/dL, neurons in the cerebral cortex and hippocampus experience synaptic dysfunction, with neurons in the basal ganglia and thalamus affected in parallel [Mergenthaler et al., 2014]. Evidence shows that chronic hypoglycemia leads to severe neuronal death as well as a significant decline in cognitive performance, spatial learning and memory [Bree et al., 2009; Page et., 2009; Suh et al., 2007]. Hypoglycemia induces oxidative injury in hippocampal dendrites, resulting in impaired synaptic plasticity, reduced MAP2 intensity and thickness in the stratum radiatum of the hippocampal CA1 region and microgliosis in the hippocampus and cerebral cortex [Won, et al., 2012]. A population-based cross-sectional study showed chronic hypoglycemia to have a 2-fold increased risk for developing dementia with poor late-life cognition, independent of premorbid cognition[Yaffe et al., 2013]. Recent evidence indicates that chronic hypoglycemia poses a risk factor for dementia, accelerating the progression of tau hyperphosphorylation, Aβ aggregation, cognitive dysfunction and AD. Understanding the pathologic mechanisms of hypoglycemia and monitoring the plasma glucose levels may be key factors in the prevention of AD and dementia.

A rare entity of malignant insulinoma diagnosed after 30 years of clinical manifestation of hypoglycemia: A case report and literature review

Malignant insulinomas, a rare life threatening pathology, exists in literature as an entity that constitutes 10% of all insulinomas and often present as multi-centric macro nodules with multiple lymph nodes or liver metastases before diagnosis. We report a rather rare case of a 68 year old male with a 30 years history of uninvestigated severe hypoglycemic attacks that improved on glucose intake. Blood tests showed a decreased value of glycemia (45 mg/dL) associated with increased insulin level (54 μU/ml) and an increased glycemia/ insulinemia ratio of 0.83 supporting the diagnosis of insulinoma. Abdominal CT showed a 4 cm mass localized in the head of the pancreas with atrophic body and tail, no signs of distant metastatic disease. A concomitant diagnosis of primary hyperparathyroidism raised, based on elevation of calcium associated and high level of PTH. The coexistence of the two endocrinopathies suggested the presence of type 1 multiple endocrine neoplasia (MEN I). Based on the workup suggesting a benign insulinoma with no signs of metastatic disease, co-existing with debilitating symptoms of hypoglycemia, pancreatectomy with lymph node dissection was performed. Histo-pathological examination returned surprisingly positive for malignant neuro-endocrine tumor with positive lymph nodes. In that domain, we summarized the literature discussion of neuroendocrine tumors, elaborating on malignant insulinoma diagnosis and management. Furthermore, what our article is trying to lay upon existing literature is a case of a long standing existent MEN 1 malignant insulinoma manifesting as a remarkably slow progressive disease of 30 years’ timeline versus a less likely chance of a transformation from benign insulinoma to malignant Keywords: neuroendocrine neoplasm; pancreatectomy; MENI; malignant insulinoma; chronic hypoglycemia.

Инсулинома: подходы к диагностике и тактика лечения

Обзор литературы посвящен распространенной функционирующей нейроэндокринной опухоли β-клеток островков Лангерганса поджелудочной железы, которая характеризуется неконтролируемой продукцией инсулина. Патофизиологические основы клинических проявлений опухолей из β-клеток островков Лангерганса обусловлены гормональной активностью этих новообразований. При отсутствии подчинения физиологическим механизмам, регулирующим гомеостаз уровня глюкозы, β-клеточные аденомы приводят к развитию состояния хронической гипогликемии. В связи с тем, что симптоматология инсулиномы возникает вследствие гиперинсулинемии и гипогликемии, выраженность клинических проявлений заболевания в каждом отдельном случае свидетельствует об индивидуальной чувствительности больного к инсулину и недостатку сахара крови. Подавляющее большинство инсулинопродуцирующих опухолей поджелудочной железы имеет размер, не превышающий 0,5–2 см в диаметре, что создает трудности их обнаружения во время операции. Так, у 20 % больных при первой, а иногда и при второй и третьей операциях не удается выявить опухоль. Злокачественные инсулиномы встречаются в 10–15 % случаев, причем треть из них метастазируют. Единственным радикальным методом лечения инсулиномы остается оперативное вмешательство. Консервативные методы лечения применяются только у неоперабельных больных, а также как средства, временно устраняющие гипогликемию, и используются для подготовки больного к оперативному лечению. Подчеркивается, что для успешного лечения больных с эндогенным гиперинсулинизмом необходим комплексный командный подход, включающий применение современных методов визуализации и использование высокотехнологичных способов лечения.

A descriptive study to assess the awareness on management of hypoglycaemia among diabetic clients in PSG hospitals

Diabetes Mellitus (DM) is a foremost health problem in the globe. Diabetes mellitus describes a metabolic disorder of manifold etiologies characterized by chronic hypoglycemia with disturbances of carbohydrate, fat and protein metabolism. Creating alertness on signs and symptoms among diabetic clients may lessen the complications. The objectives were to assess the knowledge of diabetic clients regarding management of hypoglycemia and to find the association between the knowledge of diabetic clients on management of hypoglycemia and their selected demographic variable. The descriptive survey design was adopted by selecting 60 samples using purposive sampling technique. Out of sixty samples, 32(53.4%) were male and 28(46.6%) of the samples were female. Most of the samples 23 (38.33%) belongs to age group between 31-40 years. More than half of the samples, 40(66.66%) were using hypoglycemic agents. 33(55%) were taking medication once a day. 18 ((30%) samples were having the history of hypoglycemic symptoms. whereas, 7(11.66%) of them were not confident about the hypoglycemic symptoms. Only 24(40%) of them were conscious about the selfmanagement of hypoglycemia. The study highlights that the diabetes mellitus clients 13(21.6%) were having adequate knowledge, 39(65%) were having moderately adequate knowledge and 8(13.3%) had inadequate knowledge on management of hypoglycemia. The study concluded that it helped to identify the knowledge regarding hypoglycemia on diabetes mellitus patients and created awareness on hypoglycemic conditions using information booklet will enhance the patients to reduce the complications.

Ultra-High-Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry for High-Neuroanatomical Resolution Quantification of Brain Estradiol Concentrations

Ventromedial hypothalamic nucleus (VMN) control of glucostasis is estradiol (E-2)-dependent. E-2 regulation of VMN reactivity to hypoglycemia may involve changes in signal volume due to altered aromatase expression. Here, high-resolution micropunch dissection tools for isolation of segmental VMN tissue were used with Design of Experiments-refined uHPLC-electrospray ionization-mass spectrometry (LC-ESI-MS) methodology to investigate the premise that effects of acute and/or recurring hypoglycemia on VMN E-2 content are sex-dimorphic. Relationships among multiple independent mass spectrometric operational variables were assessed by Central Composite Design (CCD) to amplify E-2 chromatogram area. Combinations of spectrometric temperature and gas pressure variable combinations were screened by Akaike Information Criterion correction modeling. A Fibonacci Sequence design using CCD minimum and maximal variable limits produced a small-run model that replicated maximal response from CCD. E-2 chromatographic response was further enhanced by optimization of solid phase extraction and instrument source and collision-induced dissociation voltages. In male rats, acute and chronic hypoglycemia respectively elevated or diminished E-2 concentrations relative to baseline in both rostral and caudal VMN. However, females exhibited regional variability in tissue E-2 profiles during acute (increased, rostral VMN; no change, caudal VMN) and recurring (no change, rostral VMN; increased, caudal VMN) hypoglycemia. Outcomes demonstrate requisite LC-ESI-MS sensitivity for E-2 quantification in small-volume brain tissue samples acquired with high-neuroanatomical specificity. Current methodology will facilitate efforts to investigate physiological consequences of VMN rostro-caudal segment-specific acclimation of E-2 profiles to recurring hypoglycemia, including effects on gluco-regulatory function, in each sex.

Incidence and Risk Factors Associated with Outpatient Hypoglycemia in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Nationwide Study

ABSTRACT Background Chronic kidney disease and hypoglycemia are common complications in individuals with diabetes. Currently, the association of renal function with hypoglycemic complications in type 2 diabetes mellitus (T2DM) is inconclusive. This study aims to assess the associations between estimated glomerular filtration rate (eGFR) and cumulative incidence of hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia among T2DM patients in Thailand using a nationwide patient sample. Methods We conducted a nationwide retrospective cohort study based on the DM/HT study of the Medical Research Network of the Consortium of Thai Medical Schools. This study assessed adult T2DM patients from 831 public hospitals in Thailand in the year 2012–2013. eGFR was categorized into ≥90, 60–89, 30–59, 15–29, and <15 mL/min/1.73 m2. The associations between eGFR and hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia were assessed using multivariate logistic regression and Poisson regression. Results A total of 25,056 T2DM patients with available eGFR were included in the analysis. The mean age was 60.9 ± 10.5 years. The cumulative incidence of hypoglycemia and hypoglycemia-related hospitalizations was 3.6% and 1.7%, respectively. Incidence of outpatient hypoglycemia, mild hypoglycemia, and severe hypoglycemia was 2.99 (2.59–3.43), 2.47 (2.11–2.88), and 0.52 (0.36–0.72) per 100 patient-years, respectively. Patients with eGFR of 30–59, 15–29, and <15 mL/min/1.73 m2 were significantly associated with an increased risk of hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia when compared to patients with eGFR of ≥90 mL/min/1.73 m2. Conclusion Reduced eGFR was independently associated with increased hypoglycemia, hypoglycemia-related hospitalizations, and risk of outpatient hypoglycemia. Increasing awareness of the heightened risk of hypoglycemia with declining renal function may prompt changes to diabetic management for at-risk individuals.

286-OR: Biomedical Predictors of Cognitive Decline in Older Participants with T1DM: Longitudinal Follow-Up of the DCCT/EDIC Cohort

DCCT/EDIC participants have been followed for an average of 32 years (N=1,054; mean age 60±7 years; duration T1DM 38±5 years). To evaluate cognitive function in T1DM, mental efficiency and memory were assessed five times during the study. Standardized z-scores were calculated relative to the DCCT baseline evaluation and averaged to obtain three summary domain scores (immediate recall, delayed recall, mental efficiency). Generalized linear mixed models were used. In 2018, mean HbA1c levels were 7.9±0.9% and 46% of participants had experienced ≥1 hypoglycemic coma/seizure. Adjusted for age, sex, and education, cognition declined over time (p&amp;lt;0.0001 each domain). In multivariable analysis, higher mean HbA1c (β±SE, -0.105±0.017 per 1%, p&amp;lt;0.0001), higher mean systolic blood pressure (-0.083±0.013 per 5 mmHg, p&amp;lt;0.0001), and history of coma/seizure (-0.175±0.041 ≥1 vs. none, p&amp;lt;0.0001) were independently associated with declining mental efficiency. Decreased mental efficiency was also associated with microalbuminuria (AER ≥30 mg/hr), lower levels of HDL cholesterol, and higher daily insulin dose (u/kg/day) (each p&amp;lt;0.0001). Biomedical predictors did not influence recall. These findings demonstrate the effects of increasing age, glycemic excursions (chronic hyperglycemia and clinically-significant hypoglycemia), and blood pressure on mental efficiency. Disclosure A.M. Jacobson: None. C.M. Ryan: None. B.H. Braffett: None. R. Gubitosi-Klug: None. G.M. Lorenzi: None. J.A. Luchsinger: Consultant; Self; vTv Therapeutics. V.R. Trapani: None. I. Bebu: None. N. Chaytor: Consultant; Self; Eli Lilly and Company. S.M. Hitt: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. J.M. Lachin: Board Member; Self; Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

INSULINOMA CAMOUFLAGED BY VAGUE NEUROGLYCOPENIC SYMPTOMS: A CASE REPORT

Pancreatic endocrine tumors are rare lesions, with a reported incidence of four cases per 1 million patients per year. Of them, insulinomas are the most common. These are usually benign, solitary, and small size (<2 cm in diameter). Most are sporadic; however, 10% are multiple and occur as part of multiple endocrine neoplasia syndrome type I. Chronic hypoglycemia due to an insulinoma often presents with neuroglycopenic symptoms that can easily be mistaken for neurological or psychiatric symptoms, especially in developing countries. This may result in delayed diagnosis with associated complications. We hereby present the case of a 45-year-old female from the rural background that initially sought treatment by a psychiatrist for her vague neurological symptoms and were later diagnosed to have insulinoma.

MON-620 Ademolus Hypoglycemic Index

This article proposes ADEMOLUS HYPOGLYCEMIC INDEX (AHI) which is a mathematical representation of hypoglycemic episode (HE) in a patient with recurrent hypoglycemia over a consecutive three months period. It also apply it to clinical practice using diabetic patients in order to demonstrate and emphasize its relevance in present day medical practice worldwide.This is a retrospective study of 65 HE occurring in 6 randomly selected diabetes mellitus patients from 86 case files studied who had attended the endocrinology unit. The data was analyzed by using Ademolus Classification of hypoglycemia (ACH) and the 2018 ADA/EASD Classification of hypoglycemia to define hypoglycemia. AHI was calculated from the HE using the proposed mathematical formula. SPSS version 23 was used for data analysis. All six patients had a series of hypoglycemic episodes occurring in three consecutive months. Patient 1 had an AHI of 0.53 using both ACH and 2018 ADA/EASD classification.By using the Pearson correlation statistics, AHI using ACH correlated well with AHI using 2018 ADA/EASD classification of hypoglycemia with a value of 0.993.Similarly the findings of AHI derived using ACH is significant with values derived using ADA/EASD 2018 classification of hypoglycemia with a p-value of 0.000 (correlation is significant at values of 0.01). One of the clinical implication of AHI is that the risk of developing reversible or irreversible neurological damage can be reduced clinically as patient with mild to moderate form of chronic hypoglycemia yet to develop irreversible neurological damage or neurological sequelae can be prevented early enough from progressing since a reduced AHI value out of a series will be a pointer towards progression to neurological damage if it has not occurred! In patient 1 her AHI was not in the severe range. In patient 3, in the last quarter of 2016, her AHI was 0.60, in the first quarter of 2017, her AHI was zero, then between June, July and August 2017 her AHI was 0.64. At this juncture in this patient management, it will be good to evaluate the etiological factors in this chronic kidney disease diabetic patient who once again has started having recurrent hypoglycemia as it was some 6 months earlier. Patient 6 had two consecutive reading of AHI for two consecutive quarters of a year.The result reveals that she is chronically deteriorating gradually and tending towards more severity in her development of HE as her AHI fell from 0.52 in the preceding quarter to 0.46., this connotes worsening chronic hypoglycemic state over time and a poorer prognosis. The lower the AHI, the poorer the prognosis.AHI is relevant for monitoring of chronic or long term recurrent HE in susceptible individuals whether diabetic or not.

High performance liquid chromatography-electrospray ionization mass spectrometric (LC-ESI-MS) methodology for analysis of amino acid energy substrates in microwave-fixed microdissected brain tissue

Hypoglycemia deprives the brain of its primary energy source glucose. Reductions in whole-brain amino acid energy substrate levels suggest that these non-glucose fuels may be metabolized during glucose shortage. Recurring hypoglycemia can cause mal-adaptive impairment of glucose counter-regulation; yet, it is unclear if amplified reliance upon alternative metabolic substrates impedes detection of continuing neuro-glucopenia. This research aimed to develop high-sensitivity UHPLC-electrospray ionization mass spectrometric (LC-ESI-MS) methodology, for complementary use with high-neuroanatomical resolution microdissection tools, for measurement of glucogenic amino acid, e.g. glutamine (Gln), glutamate (Glu), and aspartate (Asp) content in the characterized glucose-sensing ventromedial hypothalamic nucleus (VMN) during acute versus chronic hypoglycemia. Results show that VMN tissue Gln, Glu, and Asp levels were significantly decreased during a single hypoglycemic episode, and that Gln and Asp measures were correspondingly normalized or further diminished during renewed hypoglycemia. Results provide proof-of-principle that LC-ESI-MS has requisite sensitivity for amino acid energy substrate quantification in distinctive brain gluco-regulatory structures under conditions of eu- versus hypoglycemia. This novel combinatory methodology will support ongoing efforts to determine how amino acid energy yield may impact VMN metabolic sensory function during persistent hypoglycemia.

Combinatory high-resolution microdissection/ultra performance liquid chromatographic–mass spectrometry approach for small tissue volume analysis of rat brain glycogen

Cyto-architectural diversity of brain structures emphasizes need for analytical tools for discriminative investigation of distinctive neural structures. Glycogen is the major energy reserve in the brain. There is speculation that brain utilization of this fuel source may affect detection of hypoglycemia. To evaluate sex-specific regulation of glycogen mass and mobilization in the glucose-sensory ventromedial hypothalamic nucleus (VMN), current research coupled UHPLC-electrospray ionization mass spectrometric (LC-ESI-MS) analysis capabilities with novel derivatization protocols for high-sensitivity measurement of glucose and glycogen in small-volume neural tissue samples. This work also sought to demonstrate utility of pairing this approach with optimized Western blot methods for measurement of glycogen metabolic enzyme protein expression. Here, high-resolution micropunch dissection tools for discriminative isolation of VMN tissue were used in conjunction with newly developed glycogen analytical methods and an experimental treatment paradigm for intra-cranial hindbrain-targeted administration of estrogen receptor-alpha (ERα) or -beta (ERβ) receptor antagonists to address the hypothesis that estradiol activates one or both hindbrain ER populations to exert sex-specific regulatory effects on VMN glycogen mass and hypoglycemia-associated mobilization. Outcomes validate a novel multi-analytical platform for investigation of in vivo sex-dimorphic regulation of glycogen metabolism in precisely-defined brain elements under conditions of energy balance versus imbalance. This combinatory approach will facilitate ongoing efforts to elucidate effects of acute versus chronic hypoglycemia on glycogen metabolism in characterized brain glucose-sensory loci and determine effects local glycogen mass and/or mobilization adaptions on sensory monitoring and signaling of recurring hypoglycemia in each sex.

Needle-free glucagon formulation aims to simplify emergency treatment of severe hypoglycemia

In July, FDA approved glucagon nasal powder (Baqsimi—Eli Lilly), the first glucagon therapy that can be administered without an injection for emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and older. The agent comes in a single-use dispenser containing one dose of glucagon 3 mg, which is administered into one nostril. Because inhalation is not required, the drug can be successfully administered by another person if the receiver is unconscious. “[U]ntil now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process,” noted Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research. “This new way to administer glucagon may simplify the process, which can be critical during an episode [of severe hypoglycemia], especially since the patient may have lost consciousness or may be having a seizure.” Injectable glucagon has been approved for use in the United States for several decades. Efficacy and safety of glucagon nasal powder to treat severe hypoglycemia was evaluated in two studies of 83 and 70 adults with diabetes. The studies compared a single 3-mg dose of glucagon nasal powder to a single 1-mg dose of I.M. glucagon injection in causing a blood glucose response to insulin-induced hypoglycemia. Glucagon nasal powder adequately increased blood glucose levels. Similar results were observed in a pediatric study of 48 patients with type 1 diabetes who were older than 4 years. In addition, a Phase I study determined that absorption of glucagon nasal powder was not impaired by nasal congestion resulting from the common cold with or without the use of decongestants. Counsel patients and their family members or caregivers on how to recognize the signs and symptoms of severe hypoglycemia and the risks of prolonged hypoglycemia. Tell them to administer a dose of glucagon nasal power by inserting the device tip into one nostril and pressing the plunger all the way in until the green line is no longer showing. Explain that the medication does not need to be inhaled and will work even if the receiver has a cold or is using cold medication. Family members or caregivers should call emergency assistance immediately after administering the dose. If there has been no response after 15 minutes, an additional 3-mg dose may be administered while waiting for emergency assistance. Be sure to explain that each device contains one dose of glucagon and cannot be reused, so they must use a new dispenser if an additional dose is required. When the receiver responds to treatment, the family member or caregiver should provide oral carbohydrates. Glucagon nasal powder (Baqsimi)Manufacturer: Eli LillyDrug class: AntihypoglycemicIndication: Emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and olderDosage: 3 mg administered as one actuation of the I.N. device into one nostrilOf note: The agent should not be taken by patients with pheochromocytoma (a rare tumor of adrenal gland tissue) or by patients who have insulinoma (a tumor of the pancreas). Manufacturer: Eli Lilly Drug class: Antihypoglycemic Indication: Emergency treatment of severe hypoglycemia in patients with diabetes ages 4 years and older Dosage: 3 mg administered as one actuation of the I.N. device into one nostril Of note: The agent should not be taken by patients with pheochromocytoma (a rare tumor of adrenal gland tissue) or by patients who have insulinoma (a tumor of the pancreas). Explain that the most common adverse reactions associated with glucagon nasal powder are nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. Adverse effects are similar to those of injectable glucagon, with the addition of nasal and eye-related symptoms (e.g., watery eyes and nasal congestion) because of the way the drug is administered. Inform patients and their family members or caregivers that allergic reactions can occur and to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions. The agent also carries a warning that it should be used with caution by those who have been fasting for long periods, have adrenal insufficiency, or have chronic hypoglycemia, because these conditions result in low levels of releasable glucose in the liver. Patients who are pregnant or plan to become pregnant or are breastfeeding or plan to breastfeed should discuss use with their doctor. Inform patients that it is not known if the agent passes into breast milk.

Usefulness of hemoglobin A1c and glycated albumin measurements for insulinoma screening: an observational case-control study

BackgroundInsulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study.MethodsIn a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma.ResultsHbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399).ConclusionsIn the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.

Differential diagnosis of morphological forms of congenital hyperinsulinism using [18F]-DOPA PET/CT

Congenital hyperinsulinism (CHI) is caused by insulin hyperproduction by β-pancreatic cells. CHI is associated with high risk of complications of chronic hypoglycemia, and therefore timely diagnosis of the disease and immediate initiation of therapy is a top-priority task. The choice of treatment tactics largely depends on the morphological form of the disease. Morphological form cannot be established based on clinical and laboratory presentation of the disease, ultrasound, MRI, computed and positron emission tomography (PET) with [18F]-fluorodeoxyglucose. Calcium stimulation test and percutaneous transhepatic blood sampling from the portal vein were previously used for differential diagnosis, but the results provided by these invasive studies are imprecise. At present, preoperative differential diagnosis of diffuse and focal forms of CHI is based on the data of genetic testing and radionuclide diagnosis ([18F]-DOPA PET). The article presents the first results of the use of [18F]-DOPA PET in CHI patients in the Russian Federation. Radionuclide study was performed in 17 patients with pharmacoresistant CHI followed by comparative analysis of the results of 18F-FDG PET/CT and histological picture of intraoperative pancreatic tissue samples, which is known as the gold standard for the differential diagnosis of HI histological forms.

CLINICAL VALUE OF FRUCTOSAMINE MEASUREMENTS AND FRUCTOSAMINE-ALBUMIN RATIO IN HYPOGLYCEMIC FERRETS (MUSTELA PUTORIUS FURO)

The objective of this preliminary study was to establish a reference range for plasma fructosamine concentration and fructosamine-albumin ratio in healthy ferrets and to compare these reference intervals to values obtained from hypoglycemic ferrets. Fructosamine concentration has been shown to reflect blood glucose concentration over the previous 1 to 2 weeks in other animal species, and may be a useful indicator of chronic hypoglycemia in ferrets diagnosed with insulinoma. Plasma fructosamine was measured with an automated colorimetric assay using nitroblue tetrazolium. Thirty-two clinically healthy and 5 hypoglycemic ferrets were included in the study. The reference interval in healthy ferrets for fructosamine was 110 (98 to 123) – 203 (191 to 218) μmol/L, and the reference interval for plasma fructosamine-albumin ratio was 5.1 (4.6 to 5.6) – 8.6 (8.2 to 9.0) μmol/g. Results for hypoglycemic ferrets were within the ranges for both fructosamine and fructosamine-albumin ratio. As there were no significant differences between the healthy and hypoglycemic ferrets, this study suggests that fructosamine concentration and fructosamine-albumin ratio are not likely to be useful in determining insulinoma-associated chronic hypoglycemia in ferrets.