Glucose Infusion Research Articles

High-protein vegan and omnivorous diets improve peripheral insulin sensitivity to a similar extent in people with type 2 diabetes.

High-protein diets have been recognized as a potential strategy in the nutritional management of type 2 diabetes (T2D). Mycoprotein is a high-fibre, high-protein food ingredient previously shown to improve acute glycaemic control. We determined whether incorporating mycoprotein into a high-protein vegan diet would improve glycaemic control to a greater extent than an isonitrogenous omnivorous diet in people with T2D. Seventeen adults (f = 5, age = 58.3 ± 8.3 years, BMI = 32.9 ± 4.7 kg∙m-2, HbA1c = 60 ± 15 mmol∙mol-1) with T2D were randomly allocated to a 5-week eucaloric high-protein (30% energy from protein) diet, either an omnivorous diet (OMNI; 70% protein from omnivorous sources) or an isonitrogenous, mycoprotein-rich, vegan diet (VEG; 50% protein from mycoprotein). Glycaemic control was assessed using a two-step hyperinsulinaemic-euglycaemic clamp (HEC) with D-[6,6-2H2] glucose infusion, a mixed-meal tolerance test (MMTT) and continuous glucose monitoring. The rate of glucose disappearance (RdT), glucose disposal rate and endogenous glucose production, as well as postprandial time-course of blood glucose, serum insulin and C-peptide were assessed during the HEC and MMTT, respectively. Both groups had improved peripheral insulin sensitivity (intervention effect, p = 0.006; increased RdT/Insulin of 1.0 ± 0.6 and 1.0 ± 0.3 mg kg-1 min-1 in OMNI and VEG, respectively), HbA1c (intervention; p = 0.001) and glycaemic variability (intervention; p = 0.040; increased time in-range of 11.8 ± 9.3% and 23.3 ± 12.9% in OMNI and VEG). There were no improvements in hepatic insulin sensitivity or in postprandial blood glucose and serum C-peptide (p > 0.05) during the MMTT. High-protein diets, whether predicated on vegan or omnivorous proteins, can improve glycaemic control by increasing peripheral insulin sensitivity in people with T2D.

Dasiglucagon in Children with Congenital Hyperinsulinism up to 1 Year of Age: Results from a Randomized Clinical Trial.

Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia in childhood with considerable risk of lifelong neurological sequelae. Available pharmacological therapies are limited. Dasiglucagon is a glucagon analog for the treatment of hypoglycemia. To assess efficacy and safety of dasiglucagon in children with CHI up to 1 year of age. This study included a randomized, crossover, double-blind, placebo-controlled Part 1, and an open-label, single-arm Part 2 at four centers in Germany, UK, and USA. Participants comprised children with CHI aged 7 days to 12 months who were dependent on IV glucose. In Part 1, participants were randomized to dasiglucagon or placebo for 48 hours, then crossed over to the other treatment for 48 hours. In Part 2, all participants received dasiglucagon for 21 days. The primary outcome was mean IV glucose infusion rate (GIR) in the last 12 hours of Part 1. Between 6/19/2020 and 2/9/2022, 12 eligible participants were randomized to dasiglucagon-placebo (n = 7) or placebo-dasiglucagon (n = 5). The IV GIR was significantly reduced with dasiglucagon compared with placebo (least-squares mean 4.3 mg/kg/min [95% confidence interval [CI], 1.04 to 7.60 mg/kg/min] and 9.5 mg/kg/min [95% CI, 6.24 to 12.81 mg/kg/min], respectively; P = .004). The most frequent adverse events in both treatment groups were gastrointestinal, dermatological, and metabolism and nutritional disorders. In infants with CHI, dasiglucagon significantly reduced the amount of IV glucose needed to maintain euglycemia compared with placebo. Dasiglucagon represents a promising treatment for the management of CHI.

Late-gestation maternal undernutrition induces circulatory redistribution while preserving uteroplacental function independent of fetal glycaemic state.

Programming effects of maternal undernutrition on fetal metabolic and cardiovascular systems are well elucidated, yet a detailed characterization of maternal haemodynamics is not available. This study used comprehensive cardiovascular magnetic resonance (CMR) imaging to quantify maternal haemodynamics after 29days (111-140 days) of late-gestation undernutrition (LGUN) in pregnant sheep. Control ewes received 100% of metabolizable energy requirements (MERs, n=15), whereas LGUN ewes were globally nutrient restricted to 50% MER (n=18), with a subset of fetuses undergoing continuous glucose infusion (LGUN+G, n=6/18). Ewes underwent CMR (138-140 days' gestation), and placental tissue was collected the next day. Ewes in both LGUN groups had reduced body weight and mean blood glucose concentration across gestation. Ventricular dimensions were lower in both LGUN groups. Uterine artery blood flow (QUtA) was elevated in the LGUN group compared with controls, whereas peripheral blood flow was reduced and further diminished in LGUN+G. Maternal weight change correlated with all haemodynamic parameters across all groups. Uteroplacental oxygen and glucose delivery were increased in LGUN compared to control ewes, whereas uteroplacental oxygen consumption was preserved. LGUN did not impact placental or fetal weight, and markers of brain-sparing physiology were absent. Placental expression of insulin-like growth factors (IGF-1 and IGF-2) and their receptors, glucose, fatty acid (FA) or amino acid transporters and markers of angiogenesis was not impacted. FA transporter expression was positively correlated with QUtA, and FA binding protein correlated negatively with maternal weight change. Maternal cardiovascular adaptations in response to LGUN manifest as preservation of placental growth and function, thereby preserving fetal growth. KEY POINTS: Maternal undernutrition during pregnancy alters fetal metabolic and cardiovascular physiology, but little is known about alterations in maternal haemodynamics. Late-gestation undernutrition (LGUN) and LGUN+G redirected maternal blood flow from the periphery to the uteroplacental unit, concomitantly increasing the delivery of glucose and oxygen to the uteroplacental unit. Substrate transporter expression and uteroplacental oxygen consumption were preserved in LGUN and LGUN+G, suggesting prioritization of the placenta. This study is the first to report detailed maternal haemodynamics in the setting of maternal undernutrition, where placental growth and function were maintained, ultimately preserving fetal oxygen metabolism and growth.

Acute hyperglycemia exacerbates neuroinflammation and cognitive impairment in sepsis-associated encephalopathy by mediating the ChREBP/HIF-1α pathway

ObjectivesDelirium is a prominent symptom of sepsis-associated encephalopathy (SAE) and is highly prevalent in septic patients hospitalized in the intensive care unit, being closely connected with raised mortality rates. Acute hyperglycemia (AH) has been recognized as a separate risk factor for delirium and a worse prognosis in critically sick patients. Nevertheless, the exact contribution of AH to the advancement of SAE is still unknown.MethodsThis research retrospectively evaluated the connection between blood glucose levels (BGLs) and the incidence of delirium and death rates in septic patients in the ICU of a tertiary comprehensive hospital. In addition, a septic rat model was induced through cecal ligation and puncture (CLP), after which continuous glucose infusion was promptly initiated via a central venous catheter post-surgery to evaluate the potential implications of AH on SAE. Next, septic rats were assigned to four groups based on target BGLs: high glucose group (HG, ≥ 300 mg/dL), moderate glucose group (MG, 200–300 mg/dL), normal glucose group (NG, < 200 mg/dL), and a high glucose insulin-treated group (HI, 200–300 mg/dL) receiving recombinant human insulin treatment (0.1 IU/kg/min). The sham group (SG) received an equivalent volume of saline infusion and denoted the NG group. The effects of AH on neuroinflammation and cognitive function in septic rats were evaluated using behavioral tests, histopathological examination, TUNEL staining, ELISA, and Western blot. The effects of glucose levels on microglial activation and glucose metabolism following lipopolysaccharide (LPS, 1 μg/mL) exposure were assessed using CCK8 assay, qRT-PCR, Western blot, and ELISA.ResultsOur findings revealed that AH during sepsis was a separate risk factor for delirium and assisted in predicting delirium occurrence. AH raised the levels of systemic and central inflammatory cytokines in septic rats, promoting neuronal apoptosis, blood–brain barrier disruption, and cognitive impairment. In addition, both in vivo and in vitro, an elevated glucose challenge increased the ChREBP, HIF-1α, glycolytic enzymes, and inflammatory cytokines expressions in microglia after exposure to CLP or LPS.ConclusionsThese results collectively suggest that hyperglycemia can exacerbate neuroinflammation and delirium by enhancing microglial glycolysis under septic conditions, potentially mediated by upregulation of the ChREBP/HIF-1α signaling pathway.Graphical abstract

TMET-19. REWIRING OF CORTICAL GLUCOSE METABOLISM FUELS HUMAN BRAIN CANCER GROWTH

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. In particular, we find that cortical tissue produces its own glucose-derived serine, whereas gliomas predominantly consume serine from the environment. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Combining dietary serine restriction with chemoradiation reduces brain tumor growth in mice, suggesting that such a dietary intervention could improve outcomes for patients with high grade glioma.

The effect of small increases in blood glucose on insulin secretion and endogenous glucose production in humans.

Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon. Glucose kinetics, hormones and metabolites were measured during a 1 mg/kg/min glucose infusion (90 min) which rapidly increased glucose by ∼0.3 mmol/L in control participants. Insulin concentrations and secretion quickly increased by ∼20%, resulting in a ∼40% suppression of EGP, while glucose disposal remained unchanged. Free fatty acids (FFA) and glucagon were gradually suppressed to ∼30% below baseline at 60 min. When repeated under constant basal insulin concentrations in participants with T1D, glucose infusion caused only partial and transient EGP suppression, hence glucose increased in a near-linear manner, reaching levels ∼2 mmol/L above baseline at 90 min. FFAs and glucagon remained unchanged, while glucose disposal modestly increased. This demonstrates that small glycemic increments exert subtle stimulatory effects on insulin secretion that have potent metabolic actions on the liver and adipose tissue. It is conceivable that subtle increases in glucose could potentially serve as a signal for β-cell adaptation.

Duration of morning hyperinsulinemia determines hepatic glucose uptake and glycogen storage later in the day.

The second-meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 h of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, the same total amount of insulin was administered either over 2 h in the first (Ins2h-A) or second (Ins2h-B) half of the morning or over the entire 4 h (Ins4h) of the morning. In the 4-h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared with the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.NEW & NOTEWORTHY Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

Host or the Hosted? Effects of Non-Nutritive Sweeteners on Intestinal and Microbial Mechanisms of Glycemic Control.

Background/Objective: High habitual consumption of non-nutritive sweeteners (NNS) is linked to increased incident type 2 diabetes, with emerging clinical evidence that effects on gut microbiota may, in part, drive this risk. However, the precise contribution of the effects of NNS on gut microbiota to host glycemic responses remains unclear. Methods: Ten-week-old male C57BL/6 mice (N = 10 per group) were randomized to drinking water with or without combined NNS (sucralose 1.5 mg/mL plus acesulfame-K 2.5 mg/mL) and with or without antibiotics to deplete gut microbiota (ABX, 1 mg/mL ampicillin and neomycin) over two weeks. Oral glucose tolerance tests (OGTT, 2 g/kg) were conducted on days -1 and 12. On day 14, mice underwent a jejunal infusion of glucose (300 mg) with 3-O-methyl glucose (30 mg, 3-OMG, a marker of glucose absorption) in 1.5 mL for 30 min, followed by blood collection and bioassays. Data were analyzed using ANOVA with NNS and ABX as factors. Results: Jejunal glucose absorption was augmented in NNS+ mice relative to NNS- (31%; 3-OMG T30; p ≤ 0.05) independent of ABX. ABX attenuated OGTT responses independent of NNS supplementation (-35%; incremental AUC, p ≤ 0.001). NNS+ ABX+ mice had augmented GLP-1 responses to intrajejunal glucose relative to other groups (69-108%, p < 0.05). Conclusions: These findings demonstrate that sub-acute NNS supplementation augments glucose absorption independent of gut microbiota in mice but does not disrupt glycemic responses. Antibiotic depletion of gut microbiota markedly increased glucose tolerance in mice, which may involve the actions of GLP-1.

Low availability of haematin (hemin) in Pakistan.

Madam, Acute Intermittent Porphyria (AIP) is an autosomal dominant disorder that results from a defect in the enzyme named porphobilinogen deaminase.1 It is symptomatic porphyria, involving the accumulation of porphyrins and porphyrin precursors due to impaired conversion in haeme synthesis. Acute Intermittent Porphyria is clinically characterized by acute episodes of multiple gastrointestinal and neurologic symptoms; during which the patient remains healthy between episodes.2 Acute Intermittent Porphyria episodes are commonly observed in post pubertal females. The most common symptoms include periodic abdominal pain, vomiting and hypertension followed by neurologic damage that leads to peripheral and autonomic neuropathies (mostly motor) and psychiatric manifestations.2 Hormonal cycle regulation may worsen porphyria, since its symptoms coincide with the menstrual cycle. Although positive response has been noted in hormonal suppression by gonadotropin releasing hormone agonists.3 Currently, the most widely used treatment is hemin, a form of haeme that can be given intravenously. Its administration reduces the haeme deficit, hence limits the production of porphyrins precursors by the body. Availability of hemin in Pakistan is not promising while alternatives such as intravenous infusion of glucose, and pain relievers like Nalbuphine, a man-made opioid analgesic, and Morphine are short-term treatments. Haeme Arginate (HA), a compound of haeme and arginine, is equivalent to hematin in the treatment of AIP. Long-term weekly intravenous infusions of prophylactic HA prevent severity and frequency of porphyric attacks in patients with AIP.4 While haeme therapy is recommended if a patient exhibits neurological impairment, liver transplant appears to be the last resort in patients with recurrent clinical manifestations. To effectively mediate the growing need of Hemin in Pakistan, a systematic plan with effective and immediate steps must be introduced. The regulatory authorities must expedite the approval and licensing process of appropriate medication that would meet the growing need of the country, while not compromising on its quality. The possibility of local production should be explored, while strengthening international ties aimed at importing affordable medication. The government should focus on initiating partnerships with international organizations, non-governmental organizations (NGOs) and global health initiatives. Nationwide workshops and informative campaigns towards healthcare work should be a priority, to raise awareness of the situation and the proper steps that should be taken to minimize its adverse effects. Empowering patient advocacy groups would be beneficial in recognizing any shortcomings of the plan and to divert resources accordingly.

8255 Munchausen Syndrome After Partial Pancreatectomy for Insulinoma: A Case Report

Abstract Disclosure: C.R. de Macedo: None. T.D. Bertolacini da Silva: None. I.P. de Magalhães: None. M.A. Pereira: None. I.C. Marques: None. J.L. Pinheiro Filho: None. G.F. Darce: None. D.M. Lourenço Junior: None. Background: Insulinoma is a rare, insulin-secreting pancreatic neuroendocrine tumor, most commonly benign, solitary, sporadic, well differentiated and with a slight female predominance. The investigation of hypoglycemia requires a fasting test to exclude, among other causes, factitious hypoglycemia. Clinical Case: A 27-year-old woman was admitted to the emergency room after seizure by hypoglycemic crisis (capillary blood glucose &amp;lt; 55 mg/dL). She had recurrent episodes of adrenergic/neuroglycopenic symptoms since the age of 14, occurring during fasting, mainly in the morning, with improvement after eating. After confirming Whipple's triad, a fasting test showed hyperinsulinemic hypoglycemia (glycemia 53 mg/dL, normal value &amp;gt;55 mg/dL; insulin 11.5 mcU/mL, nv &amp;lt;3mcU/mL) and increased C-peptide (3.83 ng/mL, nv &amp;lt;0,6 ng/mL). Abdominal magnetic resonance showed a 1.4 cm nodule in the pancreas tail. During hospitalization, she experienced Raynaud's phenomenon, leading to the diagnosis of Raynaud's disease (RD). Distal pancreatectomy was performed, confirming the diagnosis of insulinoma by immunohistochemistry. There was brief remission of the hypoglycemic episodes once they recurred two weeks later. As imaging tests did not show new pancreatic lesions, somatostatin analogue was begun, resulting in improvement for a few more weeks. Due to recurrent hypoglycemia and new seizures, she required continuous intravenous infusion of glucose during hospitalization. A new fasting test revealed hyperinsulinemic hypoglycemia (glycemia 42 mg/dL, insulin 43.3 mcU/mL), low C-peptide (0.5 ng/mL) and normal proinsulin (2.39 pmol/L, nv &amp;lt;5 pmol/L) values. Due RD, auto-immune hypoglycemia was excluded by negative anti-insulin antibodies. Insulinomatosis was also considered, as potential etiology, but review of surgical specimen excluded this hypothesis. After 4 months of hospitalization, due suspicious behavior, a review of her personal belongings revealed insulin vials and needles for injection. The patient confessed to applying insulin to simulate the symptoms, also revealing a history of childhood trauma and previous suicide attempts. After psychiatric evaluation, borderline personality disorder was identified, and Munchausen syndrome was considered. Since then, the patient did not require intravenous glucose with no recurrence of hypoglycemia. Conclusion: The investigation of hypoglycemia can be challenging, requiring appropriate diagnostic protocols. Even in patients who appear to have a well-defined diagnosis, as in our case with anatomopathological confirmation of insulinoma, it is always important to rule out factitious hypoglycemia. The incorrect diagnosis can lead to inappropriate invasive and surgical procedures with definitive consequences, such as exogenous pancreatic insufficiency and insulin-dependent diabetes mellitus. Presentation: 6/1/2024

8207 Insights From a Case of Insulinoma and Possible Genetic Variants in a Young Woman With Recurrent Hypoglycemia

Abstract Disclosure: M.A. Brandao: None. A. Bharara: None. V.I. Moncada Castro: None. T.C. Tsai: None. Y. Wu: None. S. Marquez Flores: None. K. Divari: None. Introduction: Insulinomas are neuroendocrine neoplasms causing hyperinsulinemic hypoglycemia. They are rare, with a prevalence of 1-4 people per million of the general population. Key features are symptoms of hypoglycemia, low plasma glucose, and symptom relief by correcting hypoglycemia. Here, we report a patient with recurrent hypoglycemia who was found to have insulinoma. Several variants of uncertain significance (VUS) were detected in this patient. This gives us some insights into a broader perspective. Clinical case: A 28-year-old healthy female was found unresponsive by her partner. Blood glucose (BG) was 40 mg/dL when paramedics arrived. She received dextrose and rapidly recovered. She was briefly hospitalized and received glucose infusion with improvement. Subsequently, the patient developed episodes of blurry vision and weakness. She had been eating more frequently to prevent symptoms. Her weight was stable at 65.77 kg. She had not been on any medications. She continued to experience hypoglycemic episodes with BG dropping to 30 mg/dL, so she sought evaluation from an endocrinologist. Laboratory work-up showed Proinsulin of 530.6 pmol/L, C-peptide 5 ng/ml, TSH 1.01 mciu/ml, Beta-hydroxybutyrate (BHOB) 0.7 mg/dL, hemoglobin A1c 4.7%, calcium 8.9 mg/dL, albumin 4.1. Abdominal computed tomography (CT) scan showed an 11 mm nodule anterior to the pancreatic tail. No discrete calcification was noted. Magnetic resonance imaging (MRI) of the abdomen redemonstrated the 10 x 6mm, slightly exophytic lesion in the pancreatic tail. Therefore, she underwent laparoscopic enucleation with pathology showing a 1.7cm well-differentiated grade 2 neuroendocrine tumor, with positive margins. Given its indolent nature, further surgical resection was not recommended. Germline testing showed several VUS: the AXIN2 gene (c.1822C&amp;gt;G), GPC3 gene (c.565G&amp;gt;T), NF2 gene (c.296A&amp;gt;G), RECQL4 gene (c.2791C&amp;gt;G). However, no pathogenic variants were identified. Surveillance MRI of the abdomen six months after the surgery has shown no evidence of recurrent disease. The patient has remained euglycemic and symptoms have not recurred. Conclusion: Insulinomas are typically sporadic but may occur due to an activating T372R mutation in the Yin Yang. It may also occur in the setting of multiple endocrine neoplasia type 1 (MEN-1) syndrome caused by MEN1 gene mutations. Although no pathogenic variant mutations associated with insulinoma were found, several VUS that have not yet been described as related to insulinoma were detected in this patient. Routine genetic testing in newly diagnosed patients is not always recommended. Therefore, further efforts are required to understand genetic mutations and epigenetic modifiers associated with insulinoma. Validation of identified VUS and additional genetic testing in young patients with insulinoma are crucial. Presentation: 6/2/2024

8721 A Case of Congenital Hyperinsulinism Manifesting as Transient Hypoglycemia During Illness Due to Mosaic Variant of Unknown Significance in ABCC8

Abstract Disclosure: E.E. Bell-Sambataro: None. L. Mamilly: None. Background: Congenital hyperinsulinism (CHI) is characterized by inappropriate secretion of insulin during periods of low blood glucose. CHI can lead to significant complications such as seizures, developmental delays and neurologic damage. CHI can be caused by multiple genetic variants. The most common genetic etiologies are loss of function mutations in the genes ABCC8 and KCNJ11 encoding the pancreatic Beta (β)-cell ATP-sensitive potassium channel causing over secretion of insulin from the β-cells. We report a challenging pediatric case with a clinical presentation of CHI in an infant with a de novo mosaic ABCC8 gene variant of unknown significance manifesting only during times of illness. Clinical Case: A male infant born at 36 weeks gestational age was transferred to a tertiary center NICU secondary to seizure activity and hypoglycemia after the 24 hours of life with glucose levels as low as 32 mg/dL. His birth weight was normal and there was not maternal history of diabetes mellitus. The hypoglycemia persisted throughout the first week of life and required a glucose infusion rate of 11 mg/kg/min, without success in obtaining a critical sample. He had multiple seizures and MRI brain showed signs of hypoglycemic encephalopathy. Subsequently, he was weaned off IV dextrose and completed a 6 hour safety fast prior to discharge. Rapid genome testing resulted in a de novo, mosaic variant of unknown significance in ABCC8 (C.3622G&amp;gt;A resulting in amino acid substitution p.Glu1208Lys). His family reported significant but transient hypoglycemia during times of illness. At the age of 11 months, he was hospitalized for significant hypoglycemia during an episode of acute gastroenteritis and was treated with dextrose-containing fluids for 36 hours. A subsequent diagnostic fasting study resulted in hypoglycemia within 5.5 hours with capillary glucose of 49 mg/dL. At the time of hypoglycemia, beta hydroxybutyrate was inappropriately low at 0.78 mm, insulin level was suppressed &amp;lt;2 mcIU/mL. Glucagon (30 mcg/Kg) was administered after the initial sample was drawn with a significant increase in glucose from 49 mg/dL to 103 mg/dL. Based on the positive glucagon response and low serum ketone, the clinical diagnosis of CHI was made and diazoxide was initiated while awaiting other results. After the second dose of diazoxide, all glucose levels remained above 80 mg/dL. He was sent home on a continuous glucose monitor and diazoxide. Conclusion: CHI can occur due to autosomal recessive or autosomal dominant ABCC8 loss-of-function mutations of which more than half are not responsive to diazoxide. In this case report, we describe the diagnosis of hyperinsulinemic hypoglycemia in an infant with an ABCC8 variant classified with unknown significance. We describe a good initial response to diazoxide in normalizing blood glucose levels in this infant. Presentation: 6/2/2024

6611 ACTH deficiency due to TBX19 mutation mimics complete adrenal insufficiency in a newborn

Abstract Disclosure: T. Reinehr: None. P.M. Holterhus: None. S.A. Wudy: None. A. Richter-Unruh: None. C. Spratte: None. C. Roll: None. Isolated ACTH deficiency (IAD) is a rare cause of adrenocortical insufficiency. T-box transcription factor 19 (TBX19) mutations are responsible for more than 60% of neonatal cases of IAD. To the best of our knowledge, we present for the first time a newborn with ACTH deficiency due to a TBX19 mutation with almost steroid-free plasma and urine: At day 2 of life, the female newborn (birth weight 3190g, length 52 cm, 40+1 gestational age) was transferred to our neonatal intensive care unit for severe hypoglycemia (12 mg/dl), which responded to intravenous glucose infusion. Surprisingly, the sodium serum concentrations decreased from 140 mmol/l at day 2 of life to 126 mmol/l at day 7 of life. There were no clinical signs of adrenal insufficiency such as vomiting or hypotonia. Treatment with oral sodium-chloride 5.85% was started. Endocrine diagnostic work-up performed at day 8 of life demonstrated normal values of fT4, HGH and IGFBP-3 ruling out pituitary involvement of these axes, while ACTH serum concentrations were markedly decreased (1.5 pg/ml). Liquid- chromatography-mass spectrometry (LC-MS/MS) revealed nearly absent glucocorticoids (17-hydroxyprogesterone &amp;lt;0.12 nmol/l, 11-deoxycortisol &amp;lt;0.08 nmol/l, cortisol &amp;lt;4.2 nmol/l, and cortisone 1.3 nmol/l (norm value [nv]: 17-138 nmol/l)). Androgens were undetectable (testosterone &amp;lt;0.02 nmol/l, androstenedione &amp;lt;0.08 nmol/l). Mineralocorticoids were severely reduced (11-desoxycorticosterone 0.1 nmol/l (nv: 0.2-1.0 nmol/l), corticosterone 0.6 nmol/l (nv: 1-24 nmol/l), aldosterone 0.1 nmol/l (nv: 0.8-2.3 nmol/l)). In urine spot, gas chromatography-mass spectrometry (GC-MS) demonstrated subnormal excretion of C19 and C21 steroids including fetal zone steroids. Serum and urine measurements were interpreted by the labs as a typical finding similar to StAR defect. The genetic analyses revealed a normal female karyotype (46,XX) and ruled out CYP11A1 and StAR, mutations but demonstrated a homozygous missense mutation in TBX19 (c.172A&amp;gt;G, p.(Thr58Ala)). After 3 months of life under treatment with hydrocortisone (10mg/m² divided in 3 doses) and fludrocortisone (0.05 mg divided in 2 doses), cortisol was normal (320 nmol/l) and DHEAS was undetectable (&amp;lt;3 nmol/l). While androgens were in normal range (testosterone 2.6 nmol/l, androstenedione 0.28 nmol/l), 11-deoxycorticosterone was normal (0.74 nmol/l), corticosterone was undetectable (&amp;lt;0.5 nmol/l) and aldosterone was decreased (0.12 nmol/l nv: 0.8-1.2 nmol/l). At this time point, ACTH was &amp;lt;4 pg/ml, renin 1.6 mIU/l, LH 0.7 mIU/l and FSH 24.5 mIU/ml. This case demonstrated that isolated ACTH deficiency should be considered as a potential differential diagnosis in complete adrenal steroid insufficiency in newborns. Our data suggest that ACTH is not only necessary for cortisol biosynthesis but also for sufficient mineralocorticoid and androgen production by the adrenals in neonates. Presentation: 6/3/2024

OCTREOTIDE FOR TREATMENT RECURRENT HYPOGLYCEMIA INDUCED BY SULFONYLUREA: A CASE REPORT AND LITERATURE REVIEW

Overdose can cause hypoglycemia, which is unresponsive to dextrose treatment alone. Octreotide, though not universally used, is an antidote for sulfonylurea overdose. We present a case report of a 62-year-old male who mistakenly consumed six tablets of sulfonylurea (Glibenclamide®), thinking they were loperamide for diarrhea. He developed dizziness, diaphoresis, vomiting, and unconsciousness. Physical examination revealed a GCS of 225, blood pressure of 188/79 mmHg, heart rate of 85 bpm, respiratory rate of 24/min, and oxygen saturation of 99%. Blood results showed RBS at 13 mg/dl, normal CBC, unremarkable blood gas analysis, hypokalemia at 2.87 mmol/l, and normal RFT and LFT. The patient was treated with bolus Dextrose 40%, maintenance Dextrose 10%, and hydrocortisone 100 mg, but blood sugar remained refractory for 1 hour despite increasing glucose infusion. After 5 hours without satisfactory results, we administered the first dose of octreotide (50 IU IV), resulting in a hypoglycemic interval lasting 2.5 hours. After a second dose of 50 IU octreotide, hypoglycemia was resolved. The patient was moved to the general ward and survived. In this case, octreotide extended the interval of hypoglycemia and reduced the need for dextrose. Using octreotide for conditions other than sulfonylurea overdose is not recommended.

Amylase intrapancreatic infusion delays insulin release during an intravenous glucose tolerance test, proof of acini-islet-acinar interactions.

The possible existence of an acini-islet-acinar (AIA) reflex, involving mutual amylase and insulin interactions, was investigated in the current acute experiment on pigs. To confirm the existence of an AIA reflex and justify the placement of the exocrine and endocrine pancreatic components within the same organ. The study was performed on six pigs under general anesthesia. An intravenous glucose tolerance test was performed, with a bolus infusion of 50% glucose to the jugular vein, while amylase (5000 U/kg) or vehicle intrapancreatic infusions were administered via the pancreaticoduodenalis cranialis artery during 30 min with a 1 mL/min flow rate. The amylase infusion to pancreatic arterial circulation inhibited and delayed the insulin release peak which is usually associated with the highest value of blood glucose and is typically observed at 15 min after glucose infusion, for > 1 h. The intrapancreatic infusion of the vehicle (saline) did not have any effect on the time frame of insulin release. Infusion of 1% bovine serum albumin changed the insulin release curve dramatically and prolonged the high range of insulin secretion, far beyond the glucose peak. Intrapancreatic arterial infusion of amylase interrupted the integrated glucose-insulin interactions. This confirms an AIA reflex and justifies placement of the exocrine and endocrine pancreatic components within the same organ.

Prolonged hypoglycemia after the resection of pheochromocytoma in a hemodialysis patient.

Hypoglycemia occasionally develops after the resection of pheochromocytoma due to decreased catecholamine secretion. The unique glucose metabolism in dialysis patients may potentially affect postoperative hypoglycemia, although few reports have focused on this issue. A 47-year-old woman who had chronic renal failure under hemodialysis was diagnosed with right pheochromocytoma and underwent an adrenalectomy. Three hours after surgery, she experienced symptomatic hypoglycemia, which was repeated until postoperative day 3. Continuous glucose infusion was required until postoperative day 8 and asymptomatic hypoglycemia was repeated until postoperative day 11. In hemodialysis patients, more careful management of hypoglycemia may be required after the resection of pheochromocytoma compared with non-hemodialysis patients.

A comparative evaluation of bioequivalence of Gan & Lee glargine U300 and Toujeo® in Chinese healthy male participants.

To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants. A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax). GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0-24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12-24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events. The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®. https://www.chinadrugtrials.org.cn/, identifier CTR20212419.

Pharmacokinetics and Alterations in Glucose and Insulin Levels After a Single Dose of Canagliflozin in Healthy Icelandic Horses.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor that has shown promising results as a drug for the treatment of insulin dysregulation in horses. Even though CFZ is used clinically, no pharmacokinetic data has previously been published. In this study, the pharmacokinetics of CFZ after administration of a single oral dose of 1.8 mg/kg in eight healthy Icelandic horses was examined. Additionally, the effect of treatment on glucose and insulin levels in response to a graded glucose infusion was investigated. Plasma samples for CFZ quantification were taken at 0, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 5, 6, 8, 12, 24, 32, and 48 h post administration. CFZ was quantified using UHPLC coupled to tandem quadrupole mass spectrometry (UHPLC-MS/MS). A non-compartmental analysis revealed key pharmacokinetic parameters, including a median Tmax of 7 h, a Cmax of 2350 ng/mL, and a t1/2Z of 28.5 h. CFZ treatment reduced glucose (AUCGLU, p = 0.001) and insulin (AUCINS, p = 0.04) response to a graded glucose infusion administered 5 h after treatment. This indicates a rapid onset of action following a single dose in healthy Icelandic horses. No obvious adverse effects related to the treatment were observed.

The incretin effect in type 2 diabetes in a Sub-Saharan African population

AimType 2 diabetes is increasing in Sub-Saharan Africa, but the pathophysiology in this population is poorly investigated. In Western populations, the incretin effect is reduced in type 2 diabetes, leading to lowered insulin secretion. The aim of this study was to investigate the incretin effect in a group of Sub-Saharan Africans with type 2 diabetes.MethodsTwenty adults diagnosed with type 2 diabetes, based on either an oral glucose tolerance test (n = 10) or on glycated hemoglobin A1c (n = 10), and 10 non-diabetic controls were included in an interventional study in Tanzania. We investigated the incretin effect as the difference between the plasma insulin area under the curve during an oral glucose tolerance test and that obtained during an intravenous glucose infusion. Differences between diabetes groups were analyzed by Kruskal–Wallis one-way analysis of variance.ResultsThe incretin effect did not differ between groups (p = 0.45), and there was no difference in plasma concentrations of the incretin hormones during the OGTT.ConclusionA reduced incretin effect appears not to contribute to hyperglycemia in type 2 diabetes in this Tanzanian population. More research is needed to explain the diabetes phenotype often seen in Sub-Saharan Africa.Trial registrationClinicaltrials.gov: NCT03106480, date of registration: 04/10/2017.

Intentional Insulin Overdose and Depression in Subjects with and Without Diabetes Mellitus: A Commentary.

Insulin is an essential medication for people with type 1 diabetes mellitus and for some people with type 2 diabetes. Interestingly, insulin abuse has been reported as a mode of suicide, not only among people with diabetes, but also among their relatives, and among medical and paramedical personnel who have access to insulin. The aim of the present commentary was to raise awareness of potential depression-related intentional insulin overdose and its complications, as well as of the diagnosis and treatment of this entity. Insulin overdose may lead to severe and prolonged hypoglycemia, hypoglycemic coma, and death. Moreover, hypokalemia, hypomagnesemia, hypophosphatemia, and elevated liver enzymes are common. Insulin overdose should be suspected among people with diabetes in case of unexplained prolonged hypoglycemia and among people without diabetes who exhibit hypoglycemia and may have access to diabetic medications. The ratio of insulin to C-peptide helps distinguish exogenous insulin administration from endogenous secretion. The cornerstone of therapy is prompt administration of concentrated glucose infusions for days with simultaneous oral intake, when possible, and intense glucose monitoring to prevent hypoglycemia. Moreover, monitoring of serum electrolyte levels is recommended. Finally, psychiatric evaluation aiming at early identification of depression and suicidality is of paramount importance.