Fasting Hypoglycemia Research Articles

Evaluating the Clinical Effectiveness and Safety of Semaglutide in Individuals with Uncontrolled Type2 Diabetes. Real-World Evidence from Saudi Arabia: The Observational, Multicenter, 15-Month EVOLUTION Study.

This study aimed to assess the safety and effectiveness of semaglutide, administered either by weekly subcutaneous (SC) injection or orally, in real-life practice in Saudi Arabia in individuals with type2 diabetes mellitus (T2DM). A retrospective chart review study was conducted at 18 Saudi Arabia centers. An accredited centralized institutional review board approved the study. Medical records were included for individuals of any age ≥ 18years with uncontrolled T2DM. The primary outcome measure was the laboratory glycated hemoglobin (HbA1c) level.Secondary measures included fasting blood glucose (FBG), weight, and hypoglycemia. All variables were checked after 6 and 12months of semaglutide initiation. The analysis of this study included 1223 patients with uncontrolled T2DM (HbA1c > 7%). The mean (SD) baseline HbA1c was 10.02% (1.17). HbA1c was reduced by an average of 3.02% (0.84) and 3.17% (0.84) at 6 and 12months, respectively. Results of a repeated measure analysis of variance (ANOVA) indicated significant differences in HbA1c (pvalue < 0.001). HbA1c levels at 6 and 12months were significantly lower, 7.00% (0.70) and 6.85% (0.69), than at baseline, 10.02% (1.17). About 193 patients (56.4%) of the 295 patients having HbA1c < 9% achieved HbA1c of 5.7% or less. The frequency of hypoglycemia events was 4.60 (1.10) in the 3months before semaglutide was initiated. The frequency of hypoglycemia events in the last 3months was 2.30 (0.80) events and 0.80 (0.50) events at 6-month and 12-month follow-up visits, respectively. The percent reduction in body mass index (BMI) was an average of 13.07% (1.53) and 19.89% (4.07) at 6 and 12months, respectively. Lipid profile and blood pressure were improved at 6 and 12months. Semaglutide, administered either by SC injection or orally, provided substantial glycemic and weight-loss benefits in adults with T2DM.

Investigation and Causes of Spontaneous (Non-Diabetic) Hypoglycaemia in Adults: Pitfalls to Avoid.

Although adult spontaneous (non-diabetic) hypoglycaemia is rare, its recognition is important for the preventative or curative treatment of the underlying cause. Establishing Whipple's triad-low blood glucose, neuroglycopaenia and resolution of neuroglycopaenia on increasing blood glucose levels to normal or above-is essential to verify hypoglycaemia. Awareness that hypoglycaemia may occur in severely ill patients is important for its prevention. Further investigation in such cases is unnecessary unless another cause of hypoglycaemia is suspected. Patients are often asymptomatic and normoglycaemic at review. Their history of medication, self-medication, access to hypoglycaemic drugs, alcohol use and comorbidity may provide aetiological clues. The investigation involves obtaining blood samples during symptoms for laboratory glucose measurement or provoking fasting or postprandial hypoglycaemia as directed by symptoms. If confirmed, insulin, c-peptide, proinsulin and beta-hydroxybutyrate are analysed in hypoglycaemic samples. These will classify hypoglycaemia due to non-ketotic hyperinsulinaemia, non-ketotic hypoinsulinaemia and ketotic hypoinsulinaemia, and direct investigations to identify the underlying cause. There are, however, many pitfalls that may mislabel healthy individuals as "hypoglycaemic" or misdiagnose treatable or preventable causes of spontaneous hypoglycaemia. Clinical acumen and appropriate investigations will mostly identify hypoglycaemia and its cause.

SAT158 Hypoglycemia After Bariatric Surgery Caused By Insulinoma

Abstract Disclosure: A. Yaseen: None. H. Lam: None. Introduction: Post bariatric surgery hypoglycemia occurs at least 6 to 12 months after bariatric surgery, presents as postprandial neuroglycopenia with documented blood glucose &amp;lt;54 mg/dl occurring 1 to 3 hours after meals, resolving with carbohydrate intake, and normal fasting glucose. Fasting hypoglycemia or hypoglycemia &amp;gt; 4 hours after caloric intake is not typical of post-bariatric hypoglycemia and should raise concern for other etiologies, specifically insulinoma. Clinical Case: A 62 year old female who had Roux-en-Y gastric bypass (RYGB) surgery 18 years ago presented with confusion and a blood glucose level of 35 mg/dl.She had been having episodic hypoglycemia fasting and nonfasting for 4 years prior to presentation. Initial workup revealed serum insulin 10 uIU/ml, C-peptide 2.3 ng/ml, and serum glucose of 19 mg/dl. A dextrose 20% in water intravenous infusion was started in addition to octreotide injections, acarbose, and diazoxide. Prednisone was added later and acarbose discontinued. Magnetic resonance imaging of the abdomen and magnetic resonance cholangiopancreatography showed a 1.8 x 1.3 cm enhancing lesion within the pancreatic tail. Selective arteriography and intra-arterial calcium stimulation with hepatic venous sampling revealed significant elevation of insulin after calcium gluconate injection into the accessory pancreatic tail artery arising from the superior mesenteric artery which supplies the hypervascular pancreatic tail mass. Patient had an exploratory laparotomy and splenic preserving distal pancreatectomy. Surgical pathology revealed a 2.1 cm grade 1, well-differentiated neuroendocrine tumor that was limited to the pancreas. Hypoglycemia resolved after surgery and she was discharged on glargine insulin and metformin. 1 month after surgery, C-peptide was 0.3 ng/ml, serum glucose was 101 mg/dl and HbA1c was 6.5%. Discussion and Conclusion: The incidence of hypoglycemia after RYGB is uncertain but has been reported to be 0.1 to 0.4% of cases. Only 9 cases of insulinoma in patients with a history of gastric surgery have been reported, 7 of 9 (78%) being female with an average age of 56 years old. Symptoms included fasting and postprandial hypoglycemia occurring 6 months to 20 years after bariatric surgery. CT, MRI, and endoscopic ultrasound have been found to have excellent sensitivity for preoperative localization of insulinoma. Selective arteriography and intra-arterial calcium stimulation with hepatic venous sampling is recommended when non-invasive imaging modalities fail to localize the tumor. Surgical resection remains the mainstay for cure. Dietary modification and pharmacological therapy with diazoxide or somatostatin analogues are used in poor surgical candidates. Insulinoma after RYGB is rare, but needs to be considered in patients with hypoglycemia occurring in the fasting state, as this is atypical for post-bariatric hypoglycemia Presentation: Saturday, June 17, 2023

SAT171 An Unusual Presentation Of Insulinoma With Postprandial Hypoglycemia

Abstract Disclosure: J.G. Melendez-Rivera: None. F.H. Morgan: None. A. Aneja: None. Background: Insulinomas are rare neuroendocrine tumors of the pancreas with an incidence of four cases per million individuals per year. The most common presentation of insulinoma is fasting hypoglycemia with associated neuroglycopenic symptoms. Postprandial hypoglycemia has been previously reported, usually in combination with fasting hypoglycemia. Exclusive postprandial hypoglycemia is estimated to occur in 6% of insulinomas. Clinical Case: A 61-year-old woman presented with episodes of postprandial blurry vision, diaphoresis, nausea, and dizziness occurring for the last 18 months that have become more frequent. The patient reported blood glucose measurements in the 35 - 40 mg/dL range at the time of symptoms. Fasting blood glucose levels remained consistently in the 70 - 90 mg/dL range. These symptoms were originally sporadic but progressively became more common to the point that they were occurring daily after meals, and she gained 20 pounds due to increased food intake. BMI was 36.28. Her physical exam was unremarkable. Fasting labs revealed a glucose of 82mg/dl and C-peptide of 2.8ng/ml with normal cortisol. After a short trial of a reactive hypoglycemia diet, the patient had no improvement in symptoms, and was admitted for a 72-hour fast. She developed hypoglycemia with a glucose of 42mg/dl within four hours of starting her inpatient fast. At the time of hypoglycemia, insulin and C-peptide were inappropriately normal (insulin 15.9 mIU/mL and C-peptide 2.57 ng/mL) with an elevated proinsulin (42.3 pmol/L). An MRI abdomen with and without IV contrast showed a 16 mm hypervascular mass in the head of the pancreas. She subsequently underwent endoscopic ultrasonography with fine needle aspiration showing findings consistent with a well-differentiated pancreatic neuroendocrine tumor. Ga-68 DOTATATE PET CT revealed increased DOTATATE avidity in the pancreatic head mass compatible with neuroendocrine tumor but no evidence of metastatic disease. She underwent surgical resection of the tumor with resolution of symptoms. Conclusion: The absence of fasting hypoglycemia does not rule out pancreatic neuroendocrine tumors. While rare, exclusive postprandial hypoglycemia can be seen in these types of tumors, especially proinsulin-secreting tumors. This case illustrates the importance of considering insulinoma during the evaluation of postprandial hypoglycemia in the absence of fasting hypoglycemia and persistent hypoglycemia despite dietary modifications. Presentation: Saturday, June 17, 2023

FRI359 Postprandial Hypoglycemia With Elevated Pro-insulin As A Rare Presentation Of Insulinoma

Abstract Disclosure: S. Kalik: None. S. Dehghani: None. J. Zaidan: None. Background: Insulinoma, a neuroendocrine neoplasm, typically presents with fasting hypoglycemia with abnormally elevated insulin levels but can infrequently present with post-prandial hypoglycemia with elevated pro-insulin levels. Clinical Case: A 49-year-old non-diabetic male, presented with a 3-year history of episodes of blurry vision, sweating, and palpitations associated with low finger stick glucose (45-70mg/dL). Episodes primarily occurred 2-3 hours post-meals particularly after eating a high carbohydrate meal. Symptoms improved after taking glucose tabs consistent with Whipple’s triad. He denied fasting hypoglycemia symptoms. Patient had symptoms at the office 2 hours after eating breakfast and Lab work done at that time showed glucose &amp;lt;35 of mg/dL (70-99 mg/dL), inappropriately high-normal c-peptide level of 3.57 ng/mL (0.81-3.85 ng/mL), elevated pro-insulin level of 12.8 pmol/L (&amp;lt;8.0 pmol/L), and a high insulin level of 29.8 uIU/mL (3-25.0 uIU/mL). Insulin antibodies and Sulfonylurea screen were negative. Review of old imaging revealed unremarkable pancreas on Ct scan done three years ago and a month prior to presentation. Given persistent symptoms and lab results Patient underwent an endoscopic ultrasonography with advanced gastroenterology which showed a 14.2 x 11mm hypoechoic, well circumscribed, regularly shaped and homogenous mass at the pancreatic head that was sampled using fine needle biopsy. Pathology confirmed pancreatic neuroendocrine neoplasm, low grade, consistent with insulinoma. Patient went for MRI of abdomen and pelvis which confirmed a 1.4 x 1.2cm slightly T2 hyperintense, hyper-enhancing lesion in the uncinate process suspicious for islet cell tumor. In addition, a 0.6cm liver lesion was identified although not clearly characterized but small metastatic lesion could not be excluded. PET/CT scan did not reveal any metastatic lesions except the focal uptake at the pancreatic uncinate process. Patient was evaluated by surgery and underwent a successful Whipple procedure for resection of the insulinoma. Discussion: 20% of all insulinomas are misdiagnosed with a seizure disorder or psychiatric disorder before an insulinoma is recognized. This case highlights the fact that insulinoma can be present as post prandial hypoglycemia and the superior imaging modality of EUS and MRI for localizing and identifying smaller functional insulinomas. Conclusion: Insulinoma can present as postprandial hypoglycemia with elevated pro-insulin levels. If high clinical and biochemical suspicion for insulinoma, patient should be evaluated with EUS or MRI even in the setting of a negative CT due to higher diagnostic specificity for insulinoma. Presentation: Friday, June 16, 2023

THU276 The Use of Continuous Glucose Monitors for Management of Postbariatric Hypoglycemia

Abstract Disclosure: S. Jani: None. S. Bao: None. Postprandial hypoglycemia is a known complication of bariatric surgery. Mixed meal tolerance test performed in these patients often revealed hypoglycemia 1-3 hours after meals. Recent clinical studies using continuous glucose monitors (CGM) have shown the incidence of postbariatric hypoglycemia is much higher than previously identified. In addition to diet modification and medication treatment, CGM has become a more popular and useful tool in managing severe cases. We present a case of using CGM to manage postbariatric hypoglycemia. A 47 year old female with prior history of class 3 obesity treated with sleeve gastrectomy presented with hypoglycemia 2.5 years after her bariatric surgery. She complained of headache, anxiety, dizziness, and fatigue during a routine clinic visit, two hours after consuming a carbohydrate rich meal with simple sugars. Blood glucose was obtained and revealed severe hypoglycemia (glucose 38 mg/dL). This prompted an urgent referral to endocrinology. Review of glucose trends revealed multiple instances of postprandial hypoglycemia. Further labs suggested a low likelihood for insulinoma with no fasting hypoglycemia and HA1C normal at 5.3%. Postprandial hyperinsulinemic hypoglycemia was suspected clinically. Dietary modification with multiple small meals consisting of high protein, fiber and complex carbohydrates was recommended. Additionally, she was started on Libre 2 CGM for monitoring and prevention of severe hypoglycemia. Review of her CGM data during follow up visit demonstrated very low incidence of hypoglycemia and absence of severe hypoglycemia. Over time with continued use of her CGM and low incidence of hypoglycemia, she did not require medical therapy. Postprandial hypoglycemia after bariatric surgery can be severe and lead to disabling neuroglycopenic symptoms. With increased utilization of bariatric surgery, these postoperative complications will likely become more prevalent. In a Swedish nationwide study, the prevalence of postbariatric hypoglycemia was close to 0.2% in a cohort of 5040 patients. However, a more recent prospective study with a two-year observation of 333 patients after bariatric surgery using 2-hour glucose tolerance test revealed much higher prevalence of severe postprandial hypoglycemia (25.6%). Hypoglycemia was highest after gastric bypass surgery (32.6%), followed by sleeve gastrectomy (22.6%). Currently, there is no official guideline on utilization of CGM in management of hypoglycemia in nondiabetic patients. This case highlights the role of CGM in managing postbariatric hypoglycemia. CGM provides continuous glucose data, trends and alerts that can be a critical tool for patients to monitor, anticipate and prevent hypoglycemic events. Additionally, the real time data provided by CGM’s can help clinicians identify high risk patients who may benefit from the addition of medications to treat hypoglycemia. Presentation: Thursday, June 15, 2023

SAT155 Insulin Receptor Autoantibody Syndrome (Iras): A Rare Occurrence In Lymphoproliferative Disease

Abstract Disclosure: C. Villatoro Santos: None. E.A. Oral: None. Insulin receptor antibody syndrome (IRAS) may present as fasting hypoglycemia, high serum insulin, and serum autoantibodies to insulin receptor at low titers. We present a case of a patient with multiple myeloma (MM) who developed hypoglycemia suspected to be related to insulin receptor antibodies. The patient is a 60-year-old male with history of prediabetes, MM, anemia, and thrombocytopenia treated with carfilzomib, dexamethasone 20 mg weekly, and prior radiation to the right pelvis, who presented to the hospital for increased right hip pain and cough. Patient reported 4 days of markedly decreased appetite with poor intake. He noted increased chronic right hip and low back pain. On exam, he was cachectic, had hyperpigmentation under bilateral eyes, and muscle wasting. Hypoglycemia as low as 38 mg/dL (70-180 mg/dL) was noted. MM studies on hospital day 4 showed increased kappa-M protein and kappa-free light chains with worsening anemia and thrombocytopenia, concerning for progression of his disease. He later developed recurrent hypoglycemia; endocrinology was consulted on hospital day 6. He also had hyponatremia and borderline low blood pressure. Cortisol on hospital day 7 at 9:00 am was 15.4 μg/dL (5.3-22.5 μg/dL) in the setting of normoglycemia. On hospital day 9, hematology started dexamethasone 40 mg daily for 3 days for MM relapse, which resulted in marked improvement in his mental status, appetite, and resolution of hypoglycemia. On hospital day 11, he started weekly cyclophosphamide, bortezomib, plus dexamethasone for 3 weeks. Results for hypoglycemia workup returned on hospital day 12 from samples of Day 7: glucose 53 mg/dL (70-180 mg/dL), C-peptide 0.2 ng/mL (1-5.2 ng/mL), insulin 14.6 μU/mL (1-21 μU/mL), insulin antibodies undetectable, negative serum screen for oral hypoglycemic agents. His course was complicated by sepsis with gram-negative bacteremia treated with antibiotics and stress dose hydrocortisone. He was discharged to rehab on hospital day 34 on dexamethasone 4 mg daily. Glucose, c-peptide and insulin levels could be consistent with exogenous hyperinsulinemic hypoglycemia but may also represent delayed insulin clearance due to insulin receptor antibodies and autocrine suppression of pancreatic insulin production in a patient with no access to insulin. Therefore, the most likely diagnosis was IRAS. The insulin antibody radioactive essay was negative for native IgG and IgM antibodies; testing for insulin receptor antibodies is in progress as a clinical test is unavailable. Treatment is common with high doses of steroids. IRAs can be seen in patients with lymphoproliferative disorders and would respond to steroid treatment for hospital management. Definitive treatment should be tailored with oncology guidance. There is a need for an accessible clinical test for IRAS in the US. Presentation: Saturday, June 17, 2023

FRI663 A Rare Case Of Igf-2 Induced Hypoglycemia Associated With Metastatic Colon Cancer

Abstract Disclosure: A. Alshaakh Mohd Mari: None. A. Varshney: None. A. Sidhu: None. M. Matos: None. M. Kinaan: None. Introduction: The diagnosis of hypoglycemia in patients without diabetes is uncommon and nonislet cell tumor hypoglycemia (NICTH) represent a minority of these cases. The most common mechanism is related to IGF-2 production from tumor cells. Case description: A 66-year-old man with a history of stage IV colon cancer presented to the hospital due to breathlessness while receiving chemotherapy (Bevacizumab plus FOLFOX4). He had partial colectomy and chemotherapy 3 years earlier but was recently found to have metastatic disease to the liver. A CT abdomen during hospitalization showed a 15 cm hepatic mass occupying the entire right hepatic lobe. Endocrinology was consulted due to persistent postprandial and fasting hypoglycemia despite dextrose infusion. He had no history of diabetes and denied taking any diabetes medications. Plasma blood glucose (BG) was noted to be 74 mg/dl (74-106) while on dextrose. An 8AM cortisol was checked to exclude adrenal insufficiency and was 8.08 mcg/dL (4.30-22.40). A 72 hour fast was done but discontinued at 8 hours when plasma BG dropped to 48 and patient became symptomatic. At the time C-peptide and Insulin levels were low &amp;lt;0.05 ng/mL (0.48-5.05) and &amp;lt;1.0 mU/L (3.0-25) respectively, with normal Beta-hydroxybutyrate (BHB) 1.1 mg/dL (0.2-2.8). At the end of the fast 1 mg of glucagon was administered and his BG increased to 112 mg/dl in 2 hrs. IGF-1 levels were undetectable &amp;lt;15 ng/mL and IGF-2 levels were found to be 175 ng/mL. The IGF2:IG1 ratio was at 11 confirming IGF-2 mediated NICTH. Dexamethasone 10 mg daily was started, and BG were maintained &amp;gt; 70mg/dl without dextrose infusion. Discussion: In approximately 50% of NICTH, the tumor is identified prior to the onset of hypoglycemia, but up to 50% of these patients may be asymptomatic despite hypoglycemia. Our patient had a known hepatic lesion and was minimally symptomatic despite very low BG. The mechanism for NICTH can include insulin secretion from the tumor, replacement of hepatic tissue and increased glucose utilization by the tumor, or most commonly, IGF-2 secretion. In the case of IGF-2 mediated hypoglycemia insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are low. An elevated IGF-2:IGF-1 ratio (&amp;gt;10) confirms the diagnosis. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated. Presentation: Friday, June 16, 2023

FRI665 Hirata's Syndrome: Autoimmune Hypoglycemia Diagnostic Pathway, A Mexican Case Report

Abstract Disclosure: G. Gonzalez De La Cruz: None. D. Porras Farret: None. Introduction: Autoimmune hypoglycemia or Hirata syndrome is a very rare cause of hypoglycemia in western populations, as an example, in Mexico until 2015, there was only a single case reported with these characteristics. Diagnosis is based on episodes of spontaneous, fasting or postprandial hypoglycemia, with endogenous hyperinsulinism, without pancreatic lesions on imaging and positive tests. Objective: To describe the approach to a patient with hypoglycemia, specifically to those with characteristics of autoimmune hypoglycemia syndrome, as well as the general approach to hypoglycemia of endogenous origin and the differential approach in those with a history of type 2 diabetes or drug use with secondary effects. Case description: An 86-year-old woman with a history of high blood pressure, prediabetes, and osteoporosis, presented episodes of dizziness, palpitations, diaphoresis, and syncope, documenting plasma glucose of 40 mg/dl. She was attended by paramedics responding adequately to oral glucose. She was evaluated by Cardiology, Holter was performed with predominant sinus rhythm, frequent atrial extrasystoles (2%) and infrequent ventricular extrasystoles. Next, she was referred to Endocrinology for evaluation and treatment, she was taken empagliflozin as prediabetes medication, and it was suspender. Laboratory studies are requested to address hypoglycemia, with serum insulin levels greater than 600 mU/l, c-peptide 3.9 ng/ml, TSH 6.1, T4T 7.5, T3T 67.8, T4L 1.1, ALT 26 U/L, AST 18 U/L, DHL 247 U/L, GGT 26 U/L, Cortisol 13.8 mcg/dl. An MRI of the upper abdomen was performed where there is no evidence of pancreatic injury. A profile of serum hypoglycemic agents (sulfonylureas in blood) was requested, which were not detected. Subsequently, anti-insulin studies were requested, which were reported in amounts greater than 100 U/ml. The diagnosis of autoimmune hypoglycemia syndrome was made, starting management with prednisone 70 mg every 24 hours, in addition to dietary changes. Conclusion: The approach to hypoglycemia in patients without clear evidence of exogenous administration of hypoglycemic agents must be ordered, taking into account differential diagnoses such as autoimmune causes. In the case of autoimmune hypoglycemia, remission is expected at 6 months, with constant monitoring and adjustment of drugs for underlying pathologies. Presentation: Friday, June 16, 2023

THU392 Type B Insulin Resistance: A Rare Cause Of Hypoglycemia

Abstract Disclosure: S.Z. Bhat: None. A. Sidhaye: None. A.H. Hamrahian: None. Introduction: Non-diabetic hypoglycemia in patients with diabetes mellitus is rare. Type B insulin resistance syndrome (TBIRS), caused by insulin receptor antibodies, presents with severe insulin resistance, but can uncommonly result in a hypoglycemic picture. Clinical Case: A 59-year-old woman with a history of SLE, T2DM, and primary hyperparathyroidism was admitted for acute confusion and found to have a POC glucose of 30 mg/dl. Her symptoms improved after IV glucose administration. She was on a stable basal-bolus insulin regimen of 0.8 U/kg/day and had unintentional 100-pound weight loss over 1 year. Significant exam findings included BMI of 29 kg/m2, gingival hyperplasia, and acanthosis nigricans. Aside from insulin, she took no medications strongly associated with hypoglycemia. Labs including CBC, CMP, TFTs, and morning cortisol were normal. HbA1C and adiponectin levels were 7.7%, and 28 µg/ml (5-28), respectively. Given the suspicion of exogenous insulin-mediated hypoglycemia, only correctional insulin was used during hospitalization. She had a repeat hypoglycemic episode on the 2nd day with minimal insulin use. A 72-hour fasting test showed a whole blood glucose of 44 mg/dL with concurrent serum C-peptide of 1.72 ng/mL, serum insulin 55 mIU/L and pro-insulin 21.9 pmol/L 12 hours into fasting. MRCP showed an 11 mm cystic lesion in the pancreas and widespread lymphadenopathy. The CGM noted significant fasting and post-prandial hypoglycemia. Diagnosis of insulinoma was considered unlikely due to persistent post-prandial hyperglycemia. Oral hypoglycemic panel and insulin autoantibodies were negative. The patient’s history of SLE, high-normal adiponectin, history of hyperglycemia and the presence of acanthosis nigricans favored work-up for insulin resistance syndromes. Due to the non-availability of insulin receptor antibody testing in the US, blood work was sent to Dr. Lutz Schomburg’s lab at Institute for Experimental Endocrinology, Berlin, Germany. The patient’serum was positive for insulin receptor antibodies, tested via an immunoassay technique, with elevated binding index (BI) of 248, 251 and 247 on 3 different samples of the patient, and normal binding index in the control sample, leading to the diagnosis of type B insulin resistance syndrome (BI &amp;gt;3 is positive, &amp;gt;10 indicates high positivity). The patient was treated with diet modification and CGM use, with improvement in the frequency of hypoglycemic episodes. She declined immunomodulation therapy. Conclusion: Hypoglycemia is an uncommon presentation of TBIRS and should be considered in the differential of non-diabetic hypoglycemia, particularly in patients with a history of auto-immune disease. The mechanism for hypoglycemia is purported to be an insulin-mimetic effect of insulin receptor antibodies at low titers. Presentation: Thursday, June 15, 2023

SAT164 Hypoglycemia Risk And Glucose Parameters In Pregnant Women With Or Without Diabetes During Fasting Ramadan

Abstract Disclosure: R.M. Alamoudi: None. A. Theyab: None. T. Shams: None. H. Alhashemi: None. Background: Pregnancy increases the risk of fasting hypoglycemia and is considered an exemption for fasting during Ramadan. Glucose patterns and hypoglycemia risk in relation to fasting Ramadan in pregnant women are not well studied. Objectives: To compare the risk of hypoglycemia, glucose patterns, and tolerance of fasting in pregnant women with gestational diabetes (GDM) versus women without GDM during fasting Ramadan. Methods: A prospective observational study conducted in the Obstetrics/Endocrine clinics at King Abdulaziz Medical City, Jeddah, Saudi Arabia. Pregnant women without GDM, and with GDM managed by diet or metformin, who were planning on fasting Ramadan and were dedicated to applying a flash glucose monitoring (CGM) device for two weeks were recruited. Women with GDM received standard-of-care diabetes education regarding fasting during Ramadan. Participation was entirely voluntary. Results: 30 women with gestational age ≥ 24 weeks completed the study; 8 without GDM (Gp. 1), 16 with GDM on diet (Gp. 2), and 6 with GDM on metformin (Gp. 3). Mean demographics respectively: Age 30.13 ±4.9 vs. 33.56 ±6.4 vs. 34.50 ±5.8 (p=0.2), BMI 34.36 ±5.88 vs. 30.74 ±3.75 vs. 36.75 ±8.01 (p=0.4), Gravida 3 ±2.2 vs. 3.38 ± 2.48 vs. 4.33 ±2.88 (p=0.6). Breaking Ramadan fasting was reported in 13 (43%) of all participants; 3 (37.5%) vs. 6 (37.5%) vs. 4 (66.7%), respectively. The median (IQR) days fast broken were 2 vs 2 (4) vs 1 (11) days, p=0.2, with the reason being hypoglycemia in 1 vs 4 vs 2, and hyperglycemia in 0 vs 1 vs 2, the other reasons included fatigue and acute illness, p=0.3. The average hypoglycemia glucose reading in mg/dl (M± S.D) associated with breaking the fast was 56 ±4.8, p=0.54. The usual timing of hypoglycemia was late evening, while for hyperglycemia it was post-midnight meal followed by post-Suhoor (predawn meal). Ambulatory glucose profile (AGP) parameters per 450 patient days for the three groups respectively: Average glucose (mg/dl) (median - IQR) 89 (13) vs. 95 (24) vs. 103 (34), p=0.3, Time spent within range (BG 63-140 mg/dl) 87 (6)% vs. 81 (16)% vs. 80 (44) %, p=0.1, Glucose management indicator (M ±S.D) 5.4 ±0.2%, 5.6 ±0.4%, 5.5 ±0.3%, p=0.5, and Glucose variability 17.6 ±1.9%, 20.8 ±2.9%, 24.7 ±11.5%, p=0.07. Time spent above range (BG &amp;gt;140 mg/dl) 7 ±6% vs. 18 ±19% vs. 25 ±26%, p=0.2, Time spent below range (BG &amp;lt;63 mg/dl) 8 ±8% vs. 7 ±8% vs. 10 ±21%, p=0.8, and Duration spent in hypoglycemia (minutes) 90 ±117.4, 65.8 ±61.1, 70 ±108.03, p=0.8. CGM-detected hypoglycemic events (BG &amp;lt;63 mg/dl) were found in 20 (66.7%) of all participants, the average number of events (median-IQR) per group was: 4 (5) vs. 6 (8) vs. 1 (15), p=0.8. Conclusion: Pregnant women with non-insulin-treated GDM compared to those without GDM experienced similar difficulties in tolerating fasting during Ramadan and increased risk of hypoglycemia. The potential perinatal harm needs more research. ClinicalTrials.gov NCT04862390 Presentation: Saturday, June 17, 2023

SAT134 CGM Use During Pregnancy Complicated By CF-Induced Diabetes

Abstract Disclosure: A.Y. Mazori: None. E.S. Markovic: None. C.J. Levy: Advisory Board Member; Self; Dexcom, Eli Lilly &amp; Company. Research Investigator; Self; Abbott Laboratories, Insulet Corporation, Tandem Diabetes Care, Dexcom. Introduction: Glycemic control remains challenging in pregnancies complicated by diabetes mellitus. Strict glycemic targets are required to optimize maternal and neonatal outcomes, but euglycemia is hindered by fluctuating insulin sensitivity and the need for frequent blood-glucose monitoring (BGM). Consensus guidelines recommend therapeutic continuous glucose monitoring (CGM) for pregnant and nonpregnant individuals with type 1 and type 2 diabetes, but current data support therapeutic CGM use in cystic fibrosis (CF)-related diabetes (CFRD) only outside of pregnancy. We report the case of a patient with CFRD who achieved recommended glycemic targets with a therapeutic CGM during a singleton pregnancy. Methods: A case report and literature review are presented. Results: A 32-year-old nulliparous woman with CF became pregnant via frozen-embryo transfer. Prior CF complications included CFRD, pancreatic insufficiency, and recurrent pancreatitis. A therapeutic Dexcom G6 CGM and intermittent BGM were used to monitor glycemic control before and during pregnancy; sensor use exceeded 96%. Pressure-induced sensor attenuations yielded sporadic hypoglycemic values discordant with simultaneous BGM. CGM analysis for the 90 days preceding conception revealed: time in range of 63-140 mg/dL (TIR) was 90.8%, time above range (TAR) 6.3%, and time below range (TBR) 2.9%. Throughout pregnancy, TIR was 92.9%, TAR 3.4%, and TBR 3.6%; no severe hypoglycemia occurred. Daytime (6AM to midnight) and nighttime hypoglycemia were 4.6% and 2.2%, respectively. In the first trimester, TIR was 90.8%, TAR 3.7%, and TBR 5.5%. During the second trimester, the patient achieved TIR 94.2%, TAR 2.6%, and TBR 3.2%. In the third trimester, TIR was 95.7%, TAR 0.9%, and TBR 3.4%. The pregestational CFRD regimen consisted of insulin glargine 12 units and lispro 3-8 units. The basal-insulin dose was 10 units at 13 weeks’ gestation, 9 units at 27 weeks’ gestation, and 8 units at 38 weeks’ gestation. The prandial-insulin doses varied between 1.5-5 units at 13 weeks’ gestation, 0-7 units at 27 weeks’ gestation, and 0-5 units at 38 weeks’ gestation. After an uncomplicated vaginal delivery at 38 weeks and six days’ gestation, maternal fasting hypoglycemia occurred after one dose of glargine 3 units. Euglycemia was obtained without basal, prandial, or correctional insulin. The neonate experienced mild hypoglycemia that resolved with oral glucose gel and feeding. The neonate was neither macrosomic nor large for gestational age (birth weight, 3.54 kg, 71st percentile) and did not require intensive-care unit management. Both the patient and neonate were discharged on postpartum day two. Conclusion: Therapeutic CGM use in a pregnancy complicated by CFRD was effective for maternal and neonatal outcomes. Further study is warranted to examine CGM use and efficacy in this population. Presentation: Saturday, June 17, 2023

A rare case of autoimmune dysglycemia syndrome associated with systemic lupus erythematosus and dermatomyositis

Autoimmune dysglycemia syndrome (ADS) is a rare condition that presents as episodes of hypoglycemia as well as hyperglycemia and is classified as insulin autoimmune syndrome (IAS) and type B insulin resistance (TBIR). Autoimmunity plays a key role in the pathogenesis of this disorder, as evidenced by the presence of autoantibodies against endogenous insulin or the insulin receptor, and by its association with rheumatologic disorders. Treatment usually includes glycemic control and immunomodulatory agents. We report a case of a 31-year-old woman who was admitted for severe hypoglycemia. Further workup revealed underlying systemic lupus erythematosus (SLE) with renal involvement. During hospitalization, she continued to experience episodes of fasting hypoglycemia, as well as episodes of postprandial hyperglycemia. Hypoglycemia associated with a high serum insulin concentration and positive anti-insulin antibodies were consistent with IAS. Likewise, hyperglycemia and hypoglycemia in association with weight loss, acanthosis nigricans, polycystic ovarian syndrome, and normotriglyceridemia strongly suggested TBIR, although testing for antibodies against the insulin receptor was not available in Peru. Immunosuppressive therapy and metformin were indicated, resulting in remission of SLE and ADS. Years later, the patient exhibited features of dermatomyositis, such as Raynaud’s phenomenon, muscular weakness, heliotrope exanthema, and elevated muscle enzymes. Once again, the patient received immunosuppressive therapy. ADS is an infrequent cause of hypoglycemia, and the coexistence of its two pathophysiological mechanisms in a patient with SLE and subsequent development of dermatomyositis is even more rare. Our case is the first one reported describing this association.

Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts.

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis.

Glycogen storage diseases: An update.

Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.

Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

1581-P: Systemic Alteration of Amino Acids Metabolism in Glutamate Dehydrogenase Gain-of-Function Mutation Knockin Mice

Patients with gain-of-function (GoF) mutations of glutamate dehydrogenase (GDH) have protein-sensitive hypoglycemia, hyperammonemia, epilepsy, and intellectual disability (HI/HA syndrome). Studies of mouse models with a beta-cell specific expression of H454Y hGDH suggest that the mechanisms of HI are caused by increased glutaminolysis induced by GDH GoF in islets. However, the mechanism of hyperammonemia is still unknown. In order to study the systemic effects of GDH GoF, H454Y GDH knockin mice (H454Y-GDH-KI) were created. Enzyme kinetic of GDH in the brain, kidney and liver confirmed that H454Y was successfully expressed with impaired GTP inhibition. H454Y-GDH-KI mice have a ~2.5-fold elevation of plasma ammonia and fasting hypoglycemia, similar to HI/HA patients. Tissues (brain, liver and kidney) and plasma amino acids profiles were determined by LC-MS. Compared to wildtype, the amino acids profile in the kidney was unaltered in KI mice. In contrast, KI liver had 60% lower glutamine, unchanged glutamate and aspartate, increased branch chain amino acids, etc. The glutamine of KI brain was 40% lower than the wildtype, glutamate and GABA was unchanged. Interestingly, plasma glutamine in KI mice was 30% higher compared to controls. A similar phenomenon has also been observed in HI/HA patients. We hypothesize that hyperammonemia is mainly caused by the increased glutaminolysis in KI liver. Higher plasma glutamine can be explained by the increased activity of tissue glutamine synthetase (GS). GS and glutamine serve as an ammonia sink, which is the main mechanism for the removal of increased ammonia in KI mice. We therefore applied the GS inhibitor, methionine sulfoximine (MSO) to KI mice. MSO significantly increased ammonia levels in KI mice after a single dose of injection. These studies in H454Y-GDH-KI mice suggest that GDH GoF in the liver is the main cause of hyperammonemia. GS plays an important role in ammonia removal. Disclosure C.Su: None. D.Han: Employee; Nanjing AscendRare Pharmaceutical Technology. S.Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. Q.Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. X.Zhou: Employee; Nanjing AscendRare Pharmaceutical Technology. H.Jiang: None. J.Li: None. C.Gong: None. C.Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology. Funding Beijing Natural Science Foundation (L212037)

A minimal mathematical model to study insulin synthesis and secretion process

Insulin, secreted from pancreatic β-cells, plays a vital role in maintaining glucose homeostasis in our body. In various pathophysiological conditions like diabetes, cancer, etc., this glucose-insulin relationship is altered. However, the underlying mechanisms behind the β-cell malfunctioning under these pathophysiological conditions remain a research topic. The current study aimed to explore the key factors responsible for impaired insulin secretion from β-cells. We studied insulin synthesis and secretion processes through a minimal mathematical model incorporating insulin mRNA, proinsulin pool, and insulin granules. Defects in the insulin granule trafficking and exocytosis processes hamper first- and second-phase insulin secretion and might be one of the main reasons for β-cell dysfunction in type 2 diabetes. The long-term effect of abnormal insulin synthesis could hamper insulin secretion and make the scenario more critical, causing complete insulin loss inside the β-cells. Besides, uncontrolled insulin synthesis could increase basal insulin secretion and drive toward fasting hypoglycemia. The present study also hypothesizes that regulation of insulin synthesis through targeting transcription and translation is a potential therapeutic strategy for controlling impaired insulin secretion.

Clinical and genetic spectrum of GSD type 6 in Korea

BackgroundGlycogen storage disease type VI (GSD VI) is a rare disease in which liver glycogen metabolism is impaired by mutations in the glycogen phosphorylase L (PYGL). This study aimed to examine the clinical features, genetic analyses, and long-term outcomes of patients with GSD VI in Korea.MethodsFrom January 2002 to November 2022, we retrospectively reviewed patients diagnosed with GSD VI using a gene panel at Seoul National University Hospital. We investigated the clinical profile, liver histology, molecular diagnosis, and long-term outcomes of patients with GSD VI.ResultsFive patients were included in the study. The age at onset was 18–30 months (median, 21 months), and current age was 3.7–17 years (median, 11 years). All patients showed hepatomegaly, elevated liver transaminase activity, and hypertriglyceridaemia. Hypercholesterolaemia and fasting hypoglycaemia occurred in 60% and 40% of patients, respectively. Ten variants of PYGL were identified, of which six were novel: five missense (p.[Gly607Val], p.[Leu445Pro], p.[Gly695Glu], p.[Val828Gly], p.[Tyr158His]), and one frameshift (p.[Arg67AlafsTer34]). All patients were treated with a high-protein diet, and four also received corn starch. All patients showed improved liver function tests, hypertriglyceridaemia, hepatomegaly, and height z score.ConclusionsThe GSD gene panel is a useful diagnostic tool for confirming the presence of GSD VI. Genetic heterogeneity was observed in all patients with GSD VI. Increased liver enzyme levels, hypertriglyceridaemia, and height z score in patients with GSD VI improved during long-term follow-up.

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model, but also in healthy human islets and islets from HI patients.