Lower Insulin Levels Research Articles

Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection.

An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin-a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes.

Lower insulin level is associated with sarcopenia in community-dwelling frail and non-frail older adults.

Sarcopenia is common among older individuals with and without type 2 diabetes mellitus (T2DM). There are conflicting evidence in support of the role of insulin in the development of age-related and T2DM-related sarcopenia. We investigated the relationships between the levels of fasting insulin and other blood biomarkers related to insulin or lipid metabolism with the presence of sarcopenia in two independent studies. In 246 pre-frail frail older individuals with (n = 41) and without T2DM (n = 205) in the Singapore Frailty Interventional Trial, sarcopenia was defined by low appendicular lean mass (ALM) relative to total body mass (skeletal muscle index, SMI = ALM/height2) and low lower limb strength or gait speed according to the Asian Working Group for Sarcopenia (AWGS) criteria released in 2019, and related to levels of fasting insulin and glucose, C-peptide, IGF-1, leptin, and active ghrelin. This investigation was validated in another independent study sample of 189 robust and pre-frail frail elderly in the Singapore Longitudinal Aging Study Wave 2 (SLAS-2). Compared to non-sarcopenic individuals, those with sarcopenia and possible sarcopenia showed significantly lower fasting insulin (p < 0.05) in pre-frail/frail and non-frail older individuals. Consistent trends of relationships were observed for serum levels of C-peptide, IGF-1, leptin, and active ghrelin. In multivariable logistic regression models, sarcopenia was independently associated with low insulin (p < 0.05). Levels of fasting insulin, C-peptide, and leptin were also significantly associated with BMI, SMI, knee extension strength, gait speed, and physical activity score. Dysregulated insulin secretion in diabetic and non-diabetic older individuals may play an important role in age-related and diabetes-related sarcopenia.

Insulin Secretion and β-Cell Function Are Preserved in Patients with Treated Hematological Malignancies

INTRODUCTION Cancer survivors are at elevated risk for developing type 2 diabetes mellitus, which decreases quality of life and increases mortality during cancer survivorship. Type 2 diabetes results from a combination of insulin resistance and decreased insulin secretion. Assessing pancreatic β-cell function by measuring insulin secretion dynamics in response to hyperglycemia can provide insight into the pathogenesis of type 2 diabetes. We investigated insulin secretion in patients with treated hematological malignancies and compared them to non-diabetic controls without cancer. We hypothesized that patients with hematological malignancies will have decreased insulin secretion compared to controls without cancer due to β-cell toxicity from previous treatment and chemotherapy. METHODS We evaluated insulin secretion in 16 non-diabetic adult patients with treated hematological malignancies using a hyperglycemic clamp, which assesses pancreatic β-cell function by measuring insulin secretion in response to hyperglycemia (200 mg/dL) maintained by a dextrose infusion. Clamp outcomes included first phase (T0-10 minutes), second phase (T90-120 minutes), and maximal (L-arginine stimulated) insulin response. The insulin sensitivity index (ISI) and disposition index (DI, a measure of the β-cell function to compensate for insulin resistance) were calculated. Controls (n=32) matched for age, sex, race, and body mass index (BMI) were selected 2:1 from a database of 154 hyperglycemic clamps in participants without diabetes or cancer. Demographic characteristics and clamp outcomes were compared using χ2, Wilcoxon rank-sum test, or linear regression. RESULTS Hyperglycemic clamps were performed in 48 individuals without diabetes (16 patients with treated hematological malignancies and 32 matched controls without cancer). Cancer survivors and controls without malignancy were well-matched for age, sex, race (Table 1). Myeloid malignancies were the most common diagnosis (n=11; 69%) with a median time from diagnosis to metabolic testing of 6 months. Treatment included cytotoxic chemotherapy (n=15; 94%), glucocorticoids (n=7; 44%), and radiation (n=1; 6%) with 7 (44%) patients achieving a remission prior to testing. Compared to controls, patients with malignancy had lower fasting glucose levels (93.0 mg/dL [IQR 86.3-96.6] vs 101.5 [IQR 94.9-107.6], p<0.001) and lower fasting insulin levels (11.5 uU/mL [IQR 9.3-15.0] vs 16.3 [IQR 12.3-21.5], p=0.023), suggesting greater insulin sensitivity within the cancer cohort. In univariable analysis, there were no significant differences between first and second phase insulin response between patients with or without treated hematological malignancies (Table 1). Cancer survivors had a higher maximal (L-arginine stimulated) insulin secretion (3606 uU/mL [IQR 3255-4594] vs 2278 [IQR 1900-3555], p=0.026) and a higher disposition index (2521 mg/kg/min [IQR 1986-3360] vs 1300 [IQR 939-1923], p=0.01) than in controls. Cancer survivors demonstrated a trend toward greater insulin sensitivity compared to controls (6.82 mg/kg/min per uU/mL [IQR 5.53-10.83] vs 4.98 [IQR 3.65-7.28], p=0.092). After adjustment for BMI and fasting glucose in linear regression models, both second phase (β=242.5, p=0.005) and maximal insulin secretion (β=1225.6, p=0.019) were greater in cancer survivors then in controls without cancer (Table 2). CONCLUSION Cancer survivors had higher maximal phase insulin secretion and disposition index (a measure of β-cell function adjusted for insulin resistance) compared to non-diabetic controls without cancer. Our data suggests that cancer survivors have preserved β-cell function following treatment of their hematological malignancies, contrary to our hypothesis. Longitudinal follow-up is needed to determine factors that promote diabetes susceptibility in cancer survivors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Relationship between Serum Adipokines, miR-222-3p, miR-103a-3p and Glucose Regulation in Pregnancy and Two to Three Years Post-Delivery in Women with Gestational Diabetes Mellitus Adhering to Mediterranean Diet Recommendations.

The San Carlos Gestational Diabetes Mellitus (GDM) prevention study, a nutritional intervention RCT based on a Mediterranean Diet (MedDiet), has been shown to reduce the incidence of GDM. The objective of this study is to investigate the relationship of leptin, adiponectin, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), insulin and HOMA-IRand circulating miRNAs (miR-29a-3p, miR-103a-3p, miR-132-3p, miR-222-3p) with the appearance of GDM and with MedDiet-based nutritional intervention, at 24-28 gestational weeks (GW), and in glucose regulation 2-3 years post-delivery (PD). A total of 313 pregnant women, 77 with GDM vs. 236 with normal glucose tolerance (NGT), 141 from the control group (CG, MedDiet restricting the consumption of dietary fat including EVOO and nuts during pregnancy) vs. 172 from the intervention group (IG, MedDiet supplemented with extra virgin olive oil (EVOO) and pistachios during pregnancy) were compared at Visit 1 (8-12 GW), Visit 2 (24-28 GW) and Visit 3 (2-3 years PD). Expression of miRNAs was determined by the Exiqon miRCURY LNA RT-PCR system. Leptin, adiponectin, IL-6 and TNF-α, were measured by Milliplex® immunoassays on Luminex 200 and insulin by RIA. Women with GDM vs. NTG had significantly higher leptin median (Q1-Q3) levels (14.6 (9.2-19.4) vs. 9.6 (6.0-15.1) ng/mL; p &lt; 0.05) and insulin levels (11.4 (8.6-16.5) vs. 9.4 (7.0-12.8) µUI/mL; p &lt; 0.001) and lower adiponectin (12.9 (9.8-17.2) vs. 17.0 (13.3-22.4) µg/mL; p &lt; 0.001) at Visit 2. These findings persisted in Visit 3, with overexpression of miR-222-3p (1.45 (0.76-2.21) vs. 0.99 (0.21-1.70); p &lt; 0.05)) and higher levels of Il-6 and TNF-α. When the IG is compared with the CG lower levels of insulin, HOMA-IR-IR, IL-6 levels at Visit 2 and 3 and leptin levels only at Visit 2 were observed. An overexpression of miR-222-3p and miR-103a-3p were also observed in IG at Visit 2 and 3. The miR-222-3p and miR103a-3p expression correlated with insulin levels, HOMA-IR, IL-6 and TNF-α at Visit 2 (all p &lt; 0.05). These data support the association of leptin, adiponectin and insulin/HOMA-IR with GDM, as well as the association of insulin/HOMA-IR and IL-6 and miR-222-3p and miR-103a-3p expression with a MedDiet-based nutritional intervention.

PSUN278 Factitious hypoglycemia, diagnostic delay due to insulin assay failure to detect insulin analogues.

Abstract Factitious hypoglycemia may be difficult to diagnose clinically. Hypoglycemia due to insulin self-administration is established by the presence of a low c-peptide and elevated plasma insulin levels. Commercial insulin assays often fail to detect insulin analogs and can create confusion among providers investigating causes of hypoglycemia. A 20 year old female with no significant past medical history presented to an Emergency Room (ER) with hypoglycemia. She was treated with a single dose of octreotide 150 mcg, dexamethasone 10 mg PO and started on a D10W drip at 100ml/hr prior to transfer. Laboratory studies on transfer reported plasma glucose 52ng/dL (RR: 70-100), low C-peptide 0.02 (RR: 0.78-5.19), low insulin level &amp;lt;0.087 uIU/mL, normal IGF-I level 122 ng/mL (RR: 85-370). Normal IGF-II level 401 ng/mL (RR: 333-967), and low Pro-insulin level 1.8 pmol/L (RR: 3.6-22 pmol/L). Sulfonylurea Screen was negative. The patient and her mother both denied exogenous insulin use. The patient and her mother both work in healthcare. The patient's boyfriend has type 1 diabetes mellitus and the patient stated she keeps insulin in her purse for him. The patient was admitted for a 72 hour fast and remained normoglycemic. An aliquot of the admission ER insulin blood sample was sent to second laboratory utilizing an assay able to detect analog insulins. The patient's sample previously reporting an undetectable insulin level (&amp;lt;0.087 uIU/mL) now reported an insulin level 8 uIU/mL. Factitious hypoglycemia is a challenging clinical diagnosis. The term factitious implies an attempt to deceive and creates mistrust between the physician and patient. However, hypoglycemia may be the result of medication errors or administered by a second party with the intent to harm. Analog insulins (glargine, aspart, lispro, glulisine, etc) are genetically modified insulins developed to mimic the physiologic pattern of pancreatic beta cell insulin secretion. The amino acid modifications in analog insulins result in structural variations which alters the ability of highly specific commercial automated immunoassays to accurately quantitate these analog insulins. The variation in lab assay detection may cause confusion when interpreting the results. The DiaSorin Liaison XL platform in our hospital utilizes a chemiluminescence immunoassay which does not detect insulin analogs, but detects regular and NPH insulin as they are structurally identical to endogenous human insulin. The second laboratory uses the Siemens Advia Centaur platform, an immunoassay which reacts with insulin analogs "on a nearly equimolar basis with the analogs insulin aspart, insulin glargine, and insulin lispro. Insulin detemir exhibits approximately 50 percent cross-reactivity. Test reactivity with insulin glulisine is negligible (&amp;lt; 3 percent)". Many commercial insulin assays do not detect analog insulins and none qualitatively distinguish between different insulins. Failure to recognize this detection flaw may result in misdiagnosis, patient safety issues and costly unneeded additional studies Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBODP032 Case Report Of A 13 Years Old Female With A Novel Pathogenic Variant In The Hnf1b Gene

Abstract Background MODY5 results from mutations in the gene encoding hepatocyte nuclear factor 1 homeobox B (HNF1B), a transcription factor critical in development of the pancreas, liver, intestines, and the urogenital tract (1). We report the case of a pediatric patient with a novel frameshift variant (p. Phe309SerfsTer18) in the HNF1B gene accounting for the co-occurrence of diabetes mellitus and structural renal abnormalities. Clinical case: A 13-years-old female with chronic kidney disease stage 3 (eGFR = 48 ml/min/1.73m2) secondary to congenital dysplastic-appearing left kidney and surgical removal of a cystic dysplastic right kidney was referred to our diabetes clinic for hyperglycemia. She reported long-standing polyuria and polydipsia previously attributed to her kidney disease. She required laparoscopic right nephrectomy at age 5 years due to increasing cyst size. Her left kidney also has small renal parenchymal cysts which have been monitored over time. There is no known family history of kidney disease, and grandparents have a history of diabetes. Laboratory investigation revealed a random blood glucose of 478 mg/dL and a hemoglobin A1c of 12.2%. She was not in diabetic ketoacidosis. She had a detectable insulin level of 5.1 mcIU/mL and C-peptide was 3.4 ng/mL. She was initially presumed to have Type 1 diabetes based on a relatively low insulin level and started on basal-bolus insulin (up to 0.59 units/kg of weight/day). Glycosylated hemoglobin was 8.7% one month after diagnosis. Glutamic acid decarboxylase, zinc transporter, islet cell, and insulin autoantibodies were not detected, however, and she was then suspected to have either Type 2 diabetes or MODY. Approximately one year later, she was taken off insulin due to hypoglycemia and managed only with metformin 500 mg twice daily. Next-generation sequencing revealed a de novo pathogenic variant in HNF1B causing a frameshift deletion (p. Phe309SerfsTer18). Genetic testing of parents was negative. Once her diagnosis of MODY5 was made, she was started on glipizide 2.5 mg once daily which has been titrated up to a dose of 5 mg with some success. However, she has since been re-started on insulin (up to 0.2 units/kg/day) due to hyperglycemia keeping in line with the MODY5 phenotype likely causing destruction of beta cells over time (1). Conclusion We report a case of MODY5 with a novel frameshift mutation (p. Phe309SerfsTer18) in the HNF1B gene. This case highlights the importance of screening for HNF-1B mutations in those patients with structural renal abnormalities and hyperglycemia, as diagnosis can guide management decisions and provide prognostic information. Reference Bellanné-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7): 510-517. doi: 10.7326/0003-4819-140-7-200404060-0000 Presentation: No date and time listed

ODP195 EUGLYCEMIC DIABETIC KETOACIDOSIS AFTER BARIATRIC SURGERY IN ASSOCIATION WITH USE OF SGLT2I.

Abstract Introduction The risk of euglycemic DKA (EuDKA) is well-known with use of SGLT2i. We present two cases where EuDKA occurred despite discontinuing SGLT2i one week prior to bariatric surgery. Case 1 A 43 year old male with type II diabetes mellitus and obesity class III presented with nausea and vomiting two weeks following gastric sleeve surgery. Preoperatively, the patient was taking glargine, lispro, empagliflozin and metformin. Empagliflozin was discontinued seven days before surgery. After surgery, patient was discharged on empagliflozin only. Labs showed blood glucose 266 mg/dl, anion gap (AG) 32 mmol/L, HCO3 11 mmol/L and betahydroxybutyrate &amp;gt; 6 mmol/L. He was admitted to the ICU and managed according to the guidelines for DKA. On discharge, his empagliflozin was discontinued. Case 2 31 year old female with type II diabetes, obesity class III developed nausea and vomiting a day after Roux-en-Y gastric bypass surgery. Preoperatively patient was taking glargine, metformin, dulaglutide and empagliflozin. Patient discontinued empagliflozin seven days before surgery. Labs showed glucose 232 mg/dl, AG 23 mmol/L, HCO3 6 mmol/L and betahydroxybutyrate 6.96 mmol/L. She was admitted to the ICU and managed according to the guidelines for DKA. Empagliflozin was discontinued on discharge. Discussion In case 1, EuDKA occurred two weeks postoperatively. In case 2, EuDKA occurred one day postoperatively. In both cases the SGLT2i was discontinued seven days before the surgery. The use of SGLT2i is a cause of EuDKA. The pathophysiology of EuDKA is not clear but thought to be related to a relative carbohydrate deficit, increased glucosuria and low insulin levels. Additionally, SGLT2i may directly stimulate glucagon release leading to increased lipolysis. There have been number of case reports suggestive of EuDKA after gastric bypass surgery in association with use of SGLT2i. Bariatric surgery causes changes in incretin pathways which in turn changes insulin: glucagon ratio and responses to blood glucose in immediate post-operative period. Additionally, preoperatively these patients are on water or ketogenic diet causing ketogenic state. However, in our cases the SGLT2i were discontinued seven days before surgery. It is not known if the use of SGLT2i therapy in the preoperative period might pose an increased risk of EuDKA due to changes in incretin based pathways associated with weight loss surgery and SGLT2i. Conclusion It is important to recognize that use of SGLT2i in setting of bariatric surgery perioperatively increases the risk of EuDKA. Our cases suggest two things. One it may be necessary to discontinue SGLT2i more than seven days before bariatric surgery and second initiating SGLT2i for patients with history of bariatric surgery should be considered an additional risk factor for EuDKA due to permanent changes in incretin based pathways and other mechanisms. Presentation: No date and time listed

RF36 | PSUN93 A Role for Somatostatin in Regulating Weight Regain after Bariatric Surgery in Mice

Abstract Somatostatin is an inhibitory neuropeptide expressed in several neural and endocrine systems. For example, Somatostatin represses the secretion of growth hormone from the pituitary gland, and the secretion of gastrointestinal and pancreatic hormones. It is therefore surprising that Somatostatin knockout (sst-ko) mice have a very mild metabolic phenotype under normal conditions. Here, we studied the role of Somatostatin in weight gain and weight loss using sst-ko mice. We found that sst-ko mice gained weight, lost weight, and regained weight at an equal rate to heterozygous siblings following dietary interventions. However, overweight sst-ko mice did not regain weight after sleeve gastrectomy bariatric surgery compared to heterozygous siblings that underwent the same surgery. This phenotype persisted for three months after surgery, whilst a high-fat high-sucrose diet was provided. Mechanistically, the surgery led to hypersecretion of glucagon-like peptide 1 (Glp1), which was not observed in sham-operated sst-ko mice. Moreover, Glp1 hypersecretion was greater than that of heterozygotes sleeve gastrectomy operated mice. Sleeve gastrectomy sst-ko mice displayed lower levels of fasting insulin, and very rapid response to glucose loading. In conclusion, a metabolic and endocrine phenotype of sst-ko mice was exposed following bariatric surgery. These mice remained lean and increased Glp1 secretion, suggesting that somatostatin has an important role in regulating gastrointestinal hormone secretion, especially following bariatric surgery. Further study is required to determine whether pharmacological inhibition of somatostatin signaling can enhance the outcomes of bariatric surgery in mice and in patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.

PSUN286 A Rare Case of Non-Islet Cell Tumor Hypoglycemia in Young Female With Metastatic Neuroendocrine Tumor

Abstract Background Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a benign or cancerous tumor that over-secretes various hormones that lead to hypoglycemia. Multiple etiologies were described in literature, the most common of them is abnormal secretion of insulin-like growth factor-2 (IGF-2) known as Doege-Potter syndrome (first described in 1929). Other etiologies include oversecretion of proinsulin, IGF-1, and somatostatin. Estimated incidence of NICTH is one per one million person-years. Tumors of mesenchymal origin are most often described in association with NICTH. Laboratory diagnosis of fasting hypoglycemia associated with serum insulin levels below 3 μU/ml confirm the diagnosis of NICTH. In the case of Doege-Potter syndrome, lab findings show low levels of insulin, c-peptide, IGF-1 and a high IGF-2: IGF-1 ratio, which indicate non-insulin-mediated hypoglycemia due to IGF-2 oversecretion. Neuroendocrine tumors presented with NICTH are rare and only described in several case reports. Clinical Case We report a case of a 34 year old female with metastatic neuroendocrine high grade tumor (WHO grade 3, non small cell, diagnosed 3 years prior to presentation) with metastasis to the bone (status post debulking and radiation) and brain (status post radiation therapy). Patient was admitted due to left ankle cellulitis. Endocrinology was consulted due to incidental finding of hypoglycemia serum glucose of 44 mg/dL. Repeat serum levels showed c-peptide 1 ng/dL (normal 1.1 - 4.4) and glucose of 54 mg/dL. She denied a history of diabetes mellitus, alcohol intake, insulin or sulfonylurea use. She had normal renal and liver function. Continuous infusion of D10 started and after 24 hours the patient's hypoglycemia improved. However, hypoglycemia recurred every morning. Following morning hypoglycemia repeat serum labs showed insulin 1.3 (Normal 2.6-24.9), c-peptide 0.9 ng/dL, and serum glucose of 114 mg/dL confirming that her hypoglycemia was not insulin induced. She was not on any medications known to cause hypoglycemia. CT abdomen without contrast showed left upper quadrant heterogeneous hypoattenuating mass with calcifications, measuring approximately 8.5 cm×10.1 cm×2.6 cm. Conclusion This is a case of a patient with a high grade non small cell metastatic neuroendocrine tumor who presented with NICTH. This is the first case of a neuroendocrine tumor with non-small cell pathology causing NICTH that has been described to-date. Based on the patient's clinical presentation and available laboratory findings with recurrent fasting hypoglycemia, low insulin and c-peptide levels we confirmed diagnosis of NICTH. This patient`s hypoglycemia was most likely induced by IGF-2 overexpression (Doege-Potter syndrome) which is the most common cause of NICTH. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP187 Doedge-Potter syndrome and papillary thyroid carcinoma: An unusual association

Abstract Hypoglycemia can occur in non-diabetic individuals. Doege-Potter is a rare paraneoplastic syndrome presented as a hypoinsulinemic hypoglycemia caused by ectopic secretion of insulin-like growth factor-2 (IGF-2) from a solitary fibrous tumor. There is recent evidence of the involvement of the IGF system in different malignancies as papillary thyroid carcinoma, being exceptional. A 69-year-old female was brought to Emergency after a routine analysis uncovered severe hypoglycemia. She mentioned a history of morning sickness, dizziness, and confusion for the last week that reverted after breakfast, and dry cough for three months. She had a 25-pack-year history of smoking, no history of alcohol use, no other antecedent of interest, no history ofdiabetes mellitus or weight loss surgery, nor chronic treatments. Physical examinations revealed diminished breath sounds in the left middle lung. A thorax radiography showed a submassive left pleural effusion and toracocentesis revealed a hemorrhagic exudate. Laboratory data showed normal GH, and cortisol levels. Despite marked hypoglycemia, insulin level was 0.4 μIU/mL (2,6-24,9), C-peptide 0.11ng/ml (1,1-4,4) and hydroxy butyrate &amp;lt;0.1 mg/dl. The serum IGF-2 level was 428μg/dL (350-1000), and the IGF-1 level was 55.4 μg/L(161-384). Anti-insulin antibodies and sulfonylureas concentration were negative. CT showed a solid mass concerning parietal pleura with areas of necrosis and calcifications, measuring 14.6×15.4×20cm. Low blood glucose with suppressed insulin, C-peptide and IGF-1 levels, elevated IGF-2/IGF-1 ratio (7,7, normal&amp;lt;3) and CT findings suggested the possibility of non-islet cell tumor hypoglycemia (NICTH). Corticoid treatment was initiated to manage the hypoglycemia. Biopsy of the mass showed a malignant solitary fibrous tumor, positive for CD34 and BCL2. After surgery, glucose and IGF-2 levels returned to normal, the patient didn't experience further episodes of hypoglycemia, and corticoid treatment was gradually suspended. A FDG-PET scan, part of extension study, found a PET-positive thyroid nodule. A thyroid ultrasound confirmed a solid, taller than wide thyroid nodule, measuring 6.7×6.4×9,5mm and fine-needle aspiration biopsy was suggestive of papillary thyroid carcinoma. Hemithyroidectomy was performed. The patient is with no evidence of disease. Doege-Potter syndrome is a rare cause of hypoglycemia, resulting from a tumor producing elevated levels of IGF-2. Diagnosis is suggested by low insulin, C-peptide and IGF-1 levels, normal or elevated IGF-2, and elevated IGF2/IGF1 ratio. High levels of ''big-IGF-2'' are associated with high risk papillary thyroid carcinoma, suggesting the relation between the IGF-system and tumor growth, nevertheless there are few cases reported describing this association. Surgical resection of the tumor is the treatment of choice. Presentation: No date and time listed

PSUN329 Non-islet Cell Tumor Hypoglycemia Secondary to Advanced Hepatocellular Carcinoma in a 29-Year-Old Male

Abstract Summary: Non-islet cell tumor hypoglycemia (NICTH) is a rare, but serious complication that can be seen in most all tumors. It is typically mediated by high levels of an incompletely processed form of insulin-growth factor 2 ("big IGF-2") that is produced by the tumor. We describe a case of a 29-year-old male with history of chronic hepatitis B and advanced stage hepatocellular carcinoma (HCC) who had failed prior chemotherapies. The patient was admitted to the hospital for a liver biopsy, following which he developed severe hypoglycemia, refractory to high dose, continuous dextrose infusion. Evaluation was remarkable for low levels of insulin, proinsulin, C-peptide, and IGF-1, normal cortisol, and an IGF-2: IGF-1 ratio of 8, suggestive of NICTH due to IGF-2, although the patient's hypoglycemia may additionally have been due to worsening, and strikingly extensive tumor invasion of the liver. This patient was unfortunately not considered a surgical candidate; hypoglycemia was ultimately controlled with initiation of high dose corticosteroids and total parenteral nutrition with high amounts of dextrose. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP267 Doege-Potter Syndrome in a Patient With Mediastinal Solitary Fibrous Tumor

Abstract N on-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndromethat presents mostly with hypoinsulinemic hypoglycemia and is associated with benign and malignant neoplasms other than insulinoma. Doege-Potter Syndrome (DPS) is characterized when NICTH is secondary to a solitary fibrous tumor (SFT). The following is a case of DPS in which the patient presented with refractory hypoglycemia. An 81-year-old Caucasian male presented to emergency department with a 10-day history of worseningneuroglycopenic symptoms in fasting state. He experienced worsening night sweats, unsteadiness while walking, dizziness, and irritation, which resolved after breakfast each morning. Five years prior to this admission, he was diagnosed with a malignant mediastinal SFT (atypical spindle cell neoplasm). He was treated with radiation followed by mass resection (9.5×6.5×7.9 cm). Despite treatment with 3 lines of therapy of phase 1 clinical trial, his disease continued to progress with a right paraspinal mass and bilateral lung metastases being subsequently found. In ED, his initial blood glucose was 53 mg/dL. Despite receiving IV dextrose pushes and a continual dextrose infusion, he continued to be hypoglycemic. Upon admission, blood work revealed blood glucose of 41 mg/dL, low insulin level of 0.4 uIU/mL (2.6-24.9 uIU/mL) and low C-peptide level of 0.9 ng/mL (1.1-4.4ng/mL). Proinsulin (4.4pmol/L), Cortisol (17.2mcg/dL) and A1c (5.2%) were all within normal limits. Serum and urine ketones as well as a blood sulfonylurea panel were negative. He was started on hydrocortisone 50 mg 8 hourly for insulin-independent hypoglycemia. His IGF1 level was 46 ng/mL (55-166ng/mL), and IGF2 level was 564 ng/mL (333-967ng/mL) with a high IGF2: IGF1 ratio of 12. He was discharged home with same hydrocortisone regimen. On follow-up, hydrocortisone dose was reduced to 30-30-20 mg. He passed away 4 months later after being hospitalized for hypoxic respiratory failure secondary to a pleural effusion. Interestingly, he was maintained on the same regimen of hydrocortisone up until his death and did not have recurrence of severe hypoglycemic episodes. The main mechanism of NICTH is tumoral overexpression of the IGF2 gene and aberrant post-translational processing, resulting in partially processed high-molecular-weight IGF2 (big-IGF2). Big- IGF2 has a lower affinity for IGF-binding proteins, which favors its own availability to IGF1 and insulin related receptors resulting in profound hypoglycemia and occasionally acromegaloid features. Diagnosis of NICTH is typically made byan IGF2: IGF1 ratio of greater than 10 (normal 3: 1)due to unavailability of commercial assays for big-IGF2. Radical tumor resection is the definitive treatment of NICTH. In unresectable neoplasms, tumor debulking, or medical therapies such as glucocorticoids, recombinant GH, and glucagon are used to alleviate hypoglycemic symptoms. Exploring more about effectiveness of chemotherapy regimens in controlling NICTH will be helpful in inoperable tumors. Presentation: No date and time listed

Models predict change in plasma triglyceride concentrations and long-chain n-3 polyunsaturated fatty acid proportions in healthy participants after fish oil intervention.

Substantial response heterogeneity is commonly seen in dietary intervention trials. In larger datasets, this variability can be exploited to identify predictors, for example genetic and/or phenotypic baseline characteristics, associated with response in an outcome of interest. Using data from a placebo-controlled crossover study (the FINGEN study), supplementing with two doses of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), the primary goal of this analysis was to develop models to predict change in concentrations of plasma triglycerides (TG), and in the plasma phosphatidylcholine (PC) LC n-3 PUFAs eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), after fish oil (FO) supplementation. A secondary goal was to establish if clustering of data prior to FO supplementation would lead to identification of groups of participants who responded differentially. To generate models for the outcomes of interest, variable selection methods (forward and backward stepwise selection, LASSO and the Boruta algorithm) were applied to identify suitable predictors. The final model was chosen based on the lowest validation set root mean squared error (RMSE) after applying each method across multiple imputed datasets. Unsupervised clustering of data prior to FO supplementation was implemented using k-medoids and hierarchical clustering, with cluster membership compared with changes in plasma TG and plasma PC EPA + DHA. Models for predicting response showed a greater TG-lowering after 1.8 g/day EPA + DHA with lower pre-intervention levels of plasma insulin, LDL cholesterol, C20:3n-6 and saturated fat consumption, but higher pre-intervention levels of plasma TG, and serum IL-10 and VCAM-1. Models also showed greater increases in plasma PC EPA + DHA with age and female sex. There were no statistically significant differences in PC EPA + DHA and TG responses between baseline clusters. Our models established new predictors of response in TG (plasma insulin, LDL cholesterol, C20:3n-6, saturated fat consumption, TG, IL-10 and VCAM-1) and in PC EPA + DHA (age and sex) upon intervention with fish oil. We demonstrate how application of statistical methods can provide new insights for precision nutrition, by predicting participants who are most likely to respond beneficially to nutritional interventions.

Obesity and Metabolic Traits after High-Fat Diet in Iberian Pigs with Low Birth Weight of Placental Origin.

Simple SummaryIntrauterine growth restriction is an increasingly concerning issue for human pregnancies because of its perinatal and longer-term consequences on offspring health. We have explored, in a swine model, differences in the adult phenotype of offspring with low birth weight induced by maternal malnutrition or placental insufficiency.Intrauterine growth restriction (IUGR) and later obesity and metabolic disorders have classically been associated with maternal malnutrition, but most cases of IUGR are related to placental insufficiency. The current study, using a swine model for IUGR and obesity, aimed to determine the interaction of birth weight (categorized as low birth weight [LBW] or normal birth-weight [NBW]) and postnatal diet (categorized as maintenance diet [MD] or fattening diet [FD]) on body weight, adiposity and metabolic traits. FD induced higher body weight and adiposity (both p < 0.0001), with higher fructosamine levels (p < 0.005) and a trend toward higher HOMA-β index (p = 0.05). NBW pigs remained heavier than LBW pigs during the early juvenile period (p < 0.005), but there were no differences at later stages. There were no differences in metabolic traits during juvenile development, but there were differences in adulthood, when LBW pigs showed higher glucose and lower insulin levels than NBW pigs (both p < 0.05). These results suggest that (a) FD allows LBW offspring to achieve similar obesity in adulthood as NBW offspring, and (b) glucose metabolism is more compromised in obese LBW than obese NBW pigs. The comparison of our data with previous studies highlights significant differences between offspring with LBW induced by maternal malnutrition or placental insufficiency, which should be considered when studying the condition.

The Effects of Hydroalcoholic Extract of Silk Cocoon on Hypothalamic-Pituitary -Gonadal Axis in Streptozotocin-Induced Diabetic Male Rats.

Background Diabetes mellitus impairs the reproductive system by damaging the glands and changing their function and hormone secretions. Given the previous studies on medical properties of silk cocoon, the aim of this study was to investigate the effect of the hydroalcoholic extract of silk cocoon on pituitary-gonadal axis hormones and the testis changes in diabetic male rats. Methods In this experimental study, 35 male rats were divided into 5 equal groups. Control (C), nontreated diabetic rats (DNT1), and experimental diabetic rats treated (DT1) with a silk cocoon extract at concentrations of 200, 400, and 800 mg/kg for 56 days. Diabetes was induced by an injection of streptozotocin. Blood sampling was performed by the tail and heart after fasting. Body weight, serum levels of glucose, prolactin, leptin, inhibin A, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH were measured along with the testis weight and diameter as the outcome of the study. Data were analyzed by SPSS version 20. Results Investigation of hormonal factors indicated that all diabetic groups had higher prolactin, inhibin A levels than those in C group and lower leptin, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH levels than controls. Silk cocoon treatment significantly decreased prolactin and inhibin in comparison of DNT1 group. While there was a significant increase in leptin, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH levels compared with DNT1 (P < 0.05). A significant decrease in both the testis weights and diameters was observed in diabetic male rats compared to controls (P < 0.05). While silk cocoon treatment improved gonadal weight, the diameter of tunica albuginea, and seminiferous tubules as long as increased in numbers of spermatocytes and Sertoli-Leydig cells. Spermatogonia, spermatocyte, spermatid, spermatozoid, Sertoli cells, and Leydig cell count were significantly lower in the DNT1 group in comparison with the control group, while all groups receiving the highest dose of SC800 mg/kg daily had a higher count of cells than the DNT1 group. Conclusion It seems that silk cocoon treatment decreases the effects of diabetes on hypothalamic-pituitary–gonadal axis.

Replenishment of vitamin A for 7 days partially restored hepatic gene expressions altered by its deficiency in rats.

We investigated the effects of vitamin A (VA) status on metabolism of Zucker rats with different genders and genotypes, and of short-term refeeding of a VA sufficient (VAS) diet on VA deficient (VAD) animals. First, male and female Zucker lean (ZL) and fatty (ZF) rats at weaning were fed a VAD or VAS diet for 8 weeks. Second, male VAD ZL rats were fed a VAS diet for 3 (VAD-VAS3d) or 7 (VAD-VAS7d) days. The body weight (BW), blood parameters, and hepatic expressions of genes for metabolism were determined. VA deficiency reduced BW gain in ZL and ZF rats of either gender. VAD ZL rats had lower plasma glucose, insulin, and leptin levels than VAS ZL rats. VAD-VAS3d and VAD-VAS7d rats had higher plasma glucose, insulin, and leptin levels than that in the VAD rats. The hepatic mRNA levels of Gck, Cyp26a1, Srebp-1c, Igf1, Rarb, Rxra, Rxrg, Pparg, and Ppard were lowered by VA deficiency. Refeeding of the VAS diet for 3 days restored the Gck and Cyp26a1 expressions, and for 7 days restored the Gck, Cyp26a1, Igf1, and Rxrb expressions significantly. The 7-day VA replenishment partially restored the hepatic gene expressions and metabolic changes in VAD ZL rats.

Comprehensive Review on Neuro-degenerative Type 3 DM.

According to research, Alzheimer's disease (AD) is considered a metabolic illness caused by defective insulin signaling, insulin resistance, and low insulin levels in the brain. Type 3 diabetes has been postulated for AD because reduced insulin signaling has molecular and physiological consequences that are comparable to type I and type 2 diabetes mellitus, respectively. The similarities between type 2 diabetes and Alzheimer's disease suggest that these clinical trials might yield therapeutic benefits. However, it is important to note that lowering your risk of Alzheimer's dementia, whether you have diabetes or not, is still a multidimensional process involving factors like exercise, smoking, alcohol, food, and mental challenges. The current aim is to show that the relationship between T3D and AD is based on both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ, which are the results of impaired insulin signaling. The brain's metabolism, with its high lipid content and energy needs, places excess demands on mitochondria and appears more susceptible to oxidative damage than the rest of the body. Current data suggests that increased oxidative stress relates to amyloid-β (Aβ) pathology and the onset of AD.

The Association of Serum Calcium and Vitamin D with Insulin Resistance and Beta-Cell Dysfunction among People with Type 2 Diabetes.

Cross-sectional studies have linked vitamin D deficiency and alteration of calcium levels to an increased incidence of type 2 diabetes and insulin resistance. This study investigated a possible correlation between blood vitamin D and calcium levels with insulin resistance and beta-cell dysfunction in type 2 diabetes, pre-diabetes, and healthy individuals. This cross-sectional study involved 300 participants. Participants were divided into three groups (n=100), type 2diabetic, prediabetic, and healthy. In order to measure insulin resistance and β -cell function, the HOMA IR and HOMA B were assessed, respectively. Also, the other parameters such as serum 25(OH)D, blood insulin (FPI), glucose (FBS), HbA1c, and calcium were assessed in this study. In simple regression analysis, a high vitamin D level is linked to lower levels of FBS, HbA1c, Insulin, and HOMA IR, and higher levels of HOMA B. Calcium has a positive connection with FBS and HbA1c and a negative connection with insulin level and HOMAB. Hypovitaminosis D may substantially influence diabetes patients' glycemic dysregulation. "An increased incidence of type 2 diabetes has been related to a disruption in calcium homeostasis. All in all an increament in calcium levels may have a role in developing type 2 diabetes".

Early-onset Type 2 Diabetes Mellitus and Cardiometabolic Risk in India

Introduction: The Indian patient phenotype with early-onset type 2 diabetes mellitus (T2DM) merits a more holistic understanding of the cardiometabolic risk profile. As per the principles of precision medicine, such understanding can help appraise the clinical place of interventions like sodium-glucose cotransporter-2 inhibition (SGLT2-i), for this population. Methodology: This observational study represents cases with T2DM, aged ≤40 years, who were newly initiated on empagliflozin on top of standard therapy. Analysis was performed for demographics and clinical characteristics at baseline and 3 months following empagliflozin use. Parameters for analysis included clinical and laboratory indicators of glycemic control, adiposity, insulin sensitivity, inflammation, and derived indicators for cardiometabolic risk. Descriptive statistics have been used for the analysis. Further, subgroups by body mass index (BMI) status (&lt; or ≥25 kg/m2) have been compared for certain continuous variables, using an unpaired t-test. Results: The study included 70 patients, with a mean age of nearly 36 years. The mean BMI was 25.57 kg/m2; approximately 43% of patients had a BMI ≥25 kg/m2. The nonobese patients had a higher triglyceride-glucose index and lower fasting insulin levels, compared to obese patients. The risk of advanced nonalcoholic steatohepatitis was low in this population. The addition of empagliflozin to background therapy improved the HbA1c level by 1.21% with 44% goal-achievement and other metabolic parameters. Weight loss and anthropometric changes were modest. Empagliflozin use was associated with meaningful improvements in cardiometabolic parameters, including triglyceride-glucose index, atherogenic index of plasma, homeostatic model assessment for insulin resistance, quantitative insulin-sensitivity check index, visceral adiposity index, Fibrosis-4 index, and aspartate transaminase-to-platelet ratio index scores, in this population. Insulin resistance remained higher than normal in most patients, despite improvement with empagliflozin use over 3 months. Conclusion: The study findings for people with early-onset T2DM in India indicate: (1) the need for opportunistic screening for T2DM at an earlier age; (2) a high prevalence of insulin resistance regardless of obesity status; (3) meaningful improvements in overall cardiometabolic risk profile with SGLT2-i use; and (4) the importance of long-term optimization of diabetes care in this population.

A Rare Cause of Severe Hypoglycemia in Intracranial Hemangiopericytoma Associated With Non-Islet Cell Tumor Hypoglycemia

A 60-year-old man with a history of metastatic intracranial hemangiopericytoma and type 2 diabetes mellitus presented with acute episodes of confusion and dizziness. A magnetic resonance imaging scan of the brain showed progressing calvarial metastasis without intracranial abnormality. He was found to have severe persistent hypoglycemia. The initial hypoglycemia work-up revealed low serum insulin and C-peptide level and negative panel for oral hypoglycemic agents. Further laboratory testing revealed an elevated insulin-like growth factor II (IGF II):IGF-I ratio and low β-hydroxybutyrate, consistent with nonislet cell tumor hypoglycemia. The patient received prednisone and his hypoglycemia improved.