Effect Of Insulin Research Articles

Modern views on pathogenesis of cognitive impairment in patients with type 2 diabetes mellitus

Currently, the features of the pathogenesis of cognitive impairment in patients with diabetes mellitus are being actively studied. The study of the mutual influence of these pathologies is of particular relevant not only in connection with a decrease in cognitive functions in patients with diabetes mellitus, but also due to the fact that the management of diabetes mellitus requires a thorough approach to the implementation of doctor’s recommendations and self-control on the part of the patient himself. The degree of cognitive impairment has a direct impact on patient compliance and, consequently, on the management and control of the disease. A comprehensive strategy is necessary for the prevention and progression of cognitive impairments in patients with diabetes mellitus. This strategy should include minimizing modifiable risk factors, controlling comorbidities, maintaining a healthy lifestyle, following a diet, engaging in regular physical activity, and medication therapy. Also, one of the key aspects is the control of blood glucose levels. Regular monitoring and maintaining a stable level of sugar can significantly reduce the risk of developing cognitive impairments in diabetic patients. This review also analyzes the effects of oral hypoglycemic drugs, incretin-based therapy and insulin on the risk of developing cognitive impairments. This review examines important aspects of the role of pathogenetic links and clinical manifestations of type 2 diabetes mellitus in the development of cognitive impairment and the possibility of influencing their development and rate of progression. Understanding these relationships will help develop effective strategies for the prevention and treatment of cognitive impairments in patients with diabetes mellitus.

Comparison of clinical characteristics, microvascular complications and inflammatory markers in type 2 diabetic patients under insulin versus metformin treatment: A cross-sectional study at Karbala Diabetic Center, Iraq.

Type 2 diabetes mellitus (T2DM) is a major global health issue associated with chronic inflammation, which contributes to both disease progression and its complications, including cardiovascular and microvascular disorders. Key inflammatory markers such as tumor necrosis factor-alpha, interleukin-6 (IL-6), E-selectin, and P-selectin are elevated in T2DM patients and are implicated in the development of these complications. Understanding how treatments such as insulin and metformin affect these markers is crucial for improving therapeutic strategies in T2DM. This study investigated the effects of insulin and metformin on these inflammatory markers in T2DM patients. This was a cross-sectional study involving patients with diabetes on insulin (group A), metformin only (group B), and healthy controls (group C). Participants were enrolled from the Diabetic Center in Karbala, Iraq and underwent clinical assessments including ophthalmologic examinations. Fasting blood glucose, HbA1c and lipids levels were assessed. The levels of inflammatory markers (IL-6 and TNF-α), and adhesion molecules (sE-selectin and sP-selectin) were measured using Enzyme-Linked Immunosorbent Assay (ELISA). The study included 522 patients with diabetes: 356 receiving insulin (group A), 70 receiving metformin (group B) and 96 healthy controls (group C). T2DM patients treated with insulin exhibited significantly more microvascular complications than those treated with metformin. Higher rates of retinopathy (64.3% vs 11.4%) and neuropathy (69.9% vs 11.4%) were observed in the insulin group, whereas the incidence of nephropathy did not differ significantly (14.6% vs 11.4%). Inflammatory markers were lower in the insulin group: TNF-α levels were 3-fold lower and IL-6 levels were 8-fold lower. Conversely, sE-selectin levels were 1.5-fold higher in the insulin group, and sP-selectin levels were 1.4-fold higher in the metformin group. This study highlights distinct differences in inflammatory markers and systemic complications between T2DM patients treated with insulin and those treated with metformin alone. Further research is needed to explore the mechanisms underlying these observations and optimize treatment strategies for T2DM patients.

Molecular Insights and Pharmacotherapy of Diabetic Neuropathy

Background: Diabetes mellitus is a chronic disorder of energy metabolism caused by lack or decrease in the effectiveness of insulin, and is characterised by an abnormally elevated blood glucose concentrations and the development of macrovascular, microvascular and/or neuropathic complications. Diabetic neuropathy (DN) is one of the most debilitating outcomes of diabetes mellitus, and may cause pain, decreased mobility as well as amputation. Diabetes can damage the peripheral nervous system (PNS), through the induction of de-myelination in neurones, precipitated by chronic hyperglycaemia-induced oxidative stress, and causing a condition that involves the upper and lower limbs. Objective: The study discussed the risk factors for insulin resistance and pre-diabetes, type II diabetes mellitus and vascular complications, cellular and molecular basis of DN, physiopathological mechanisms, and the pharmacological treatment of DN. Method: The study examined journal articles and standard textbooks, as it relates to diabetes mellitus and its complications. Search for articles on DN was carried out in the literature. These were identified and reviewed for selection using chemical abstracts service, pubmed, google scholar, crossreference, web of science, pubmed central free article, and scopus. The key words used for search were: diabetic neuropathy; diabetic peripheral neuropathy; peripheral neuropathy; microvascular complications of diabetes mellitus; and neuromuscular complications of diabetes mellitus. Result & Discussion: Two hundred and fifty (250) articles and other works were identified, while ninety-seven (97) articles and non-journal materials were extracted and reviewed, taking into account the criteria for selection. Studies done in the last 4.5 decades were included, while works written on other languages, outside English were excluded. Findings indicate that DN is a complex disorder that affects the peripheral and/or cranial nerves, which is caused by unattended or poorly attended, long-term increase in blood glucose concentrations. It relatively manifests early, affecting a significant proportion of the micro-blood vessels in the middle-aged and elderly diabetic patients. DN causes numbness, loss of sensation, and sometimes pain in the feet, legs, arms or hands. Hyperglycaemia causes the activation and inhibition of several molecular pathways that are crucial for homeostasis in neuronal and neuroglial cells. Conclusion: DN is the commonest complication of diabetes mellitus. It has no known definitive therapy. Treatment is essentially symptomatic with huge economic and psychological burden, hence the rationale for a cost effective and targeted therapies. Achieving euglycaemia using anti-diabetic regimens (i.e., insulin and oral hypoglycaemic agents), foot care, changes in feeding habits and lifestyle modification are critical to holistically address the problem.

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on carotid intima-media thickness

Abstract Background/Introduction Type 2 diabetes mellitus (T2DM) is an additional factor for exacerbation of atherosclerosis increasing the risk for ischemic attacks such as coronary artery disease and ischemic stroke. Evaluation of carotid artery atherosclerosis through ultrasound techniques is a useful tool for risk stratification in type 2 diabetic patients. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on carotid intima-media thickness (cIMT) of T2DM patients. Methods A total of 320 T2DM patients were randomized to receive insulin (n = 80), liraglutide (n = 80), empagliflozin (n = 80) or their combination (GLP-1RA+SGLT-2i) (n = 80) as add-on to metformin. At baseline, at 6 and at 12 months of treatment, we measured the maximal thickness of six major points including right and left common carotid, carotid bifurcation and internal carotids. Finally, we calculated the average cIMT of all six segments (three on each side) to get mean cIMT. Results Compared to baseline, all patients had significantly reduced cIMT at 6 and at 12 months of treatment (p < 0.001; Table). A significant interaction of follow-up time with the type of treatment was observed regarding cIMT levels (F = 7.203, p for interaction < 0.001) in a model including age, sex, smoking, baseline body mass index, glucose levels, glycosylated hemoglobin, levels of blood lipids and their changes at 6 and 12 months of treatment as covariates. At 6 months, patients who were treated with GLP-1RA, SGLT-2i and those under the combination GLP-1RA+SGLT-2i showed a greater reduction of cIMT (-2.5%, -2.4% and -5.8%) compared to insulin (-0.8%; p = 0.008, p = 0.022, and p < 0.001, respectively). Moreover, at 12 months patients under GLP-1RA, SGLT-2i and their combination achieved remarkable reduction of cIMT (-7.4%, -4.9% and -10%) than those under insulin (-1.7%, p < 0.001 for all comparisons). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cIMT in T2DM. The combined treatment was superior and additive to each regimen separately.Table

Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on mitochondrial-derived peptide-c (MOTS-c), N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods A total of 160 T2DM patients were randomized to insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40) or their combination (GLP-1RA+SGLT-2i) (n = 40) as add-on to metformin. We measured at baseline, at 4 and at 12 months of treatment: a) plasma levels of MOTS-c, NT-proBNP and GDF-15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle-tracking imaging. Results Twelve months after treatment, treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP-1RA had a neutral effect on this biomarker (p > 0.05; Table). GLP-1RA, SGLT-2i and their combination showed a greater reduction of NT-proBNP (-43.1% vs. -54.2% vs. -56.9% vs. -14.7%; Figure) and GDF-15 (-14.8% vs. -15.2% vs. -16.1% vs. -0.9%) than insulin (p < 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP-1RA or GLP-1RA+SGLT-2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT-2i (p < 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT-proBNP was associated with the improvement of TBARS, GLS and GWI (p < 0.05). The percentage reduction of GDF-15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p < 0.05). In SGLT-2i group, the percentage increase of MOTS-c was related with the percentage reduction of GDF-15 (r = 0.81, p = 0.005) at 12 months. Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT-2i appears more effective in the improvement of MOTS-c and markers of neurohumoral activation.TableFigure

Proposed mechanisms of action participating in the hypoglycemic effect of the traditionally used Croton guatemalensis Lotsy and junceic acid, its main compound.

Croton guatemalensis Lotsy (Euphorbiaceae) is an important traditional medicine that is used by the Cakchiquels of Guatemala to control hyperglycemia in patients with type 2 diabetes. Previous studies have shown that administration of this plant induces an acute hypoglycemic effect during fasting and that the main compound is junceic acid, a diterpenoid with a clerodane skeleton; however, junceic acid has not been reported to have hypoglycemic activity in the literature. As the mechanisms involved in the hypoglycemic effect of C. guatemalensis remain unknown, the objective of the present investigation was to elucidate the hypoglycemic mechanisms of this species, as well as its major compound, junceic acid. The results indicated that, similar to complete extract, junceic acid exhibited a hypoglycemic effect in hyperglycemic rats. Both C. guatemalensis extract and junceic acid inhibited the activity of two rate-limiting enzymes involved in hepatic glucose production; however, compared with chlorogenic acid, junceic acid had a more potent effect on glucose-6-phosphatase levels than chlorogenic acid, which was used as a positive control. Furthermore, both fasting and postprandial insulin levels decreased in healthy and hyperglycemic rats despite reduced blood glucose levels in both metabolic states, suggesting a potential insulin-sensitizing effect. However, neither of these compounds potentiated the effect of insulin in insulin tolerance tests nor inhibited the enzyme activity of protein tyrosine phosphatase 1B, a negative regulator of the insulin pathway. Therefore, the insulin-sensitizing effect is thought to be independent of insulin and mediated by potential activation of the AMP-activated protein kinase pathway. The specific activation of this master regulator in β-cells results in the inhibition of insulin secretion in a healthy state and the restoration of the insulin response under conditions of glucotoxicity; these effects were observed after the administration of the extract and junceic acid in healthy and hyperglycemic rats. Overall, the main findings of this study establish a basis of the mechanisms of action of C. guatemalensis and its main compound, junceic acid, in terms of their hypoglycemic effect.

12548 Mammary De Novo Lipogenesis During A Hyperinsulinemic-euglycemic Clamp

Abstract Disclosure: T.M. Fordham: None. M. Ramos-Roman: None. E.J. Parks: Consulting Fee; Self; Simply Good Foods. Stock Owner; Self; Sagimet Biosciences. Other; Self; Past President of The Obesity Society. Introduction: The mammary produces large amounts of medium-chain saturated fatty acids. Long-chain saturated fatty acids found in human milk primarily derive from the maternal diet or from the mobilization of stored triglycerides. Previous studies have established the importance of insulin in stimulating mammary differentiation, milk synthesis, and lipogenesis. However, no studies have assessed how changes in insulin concentrations alter human mammary de novo lipogenesis (DNL) nor what effect gestational diabetes may have on insulin’s relationship to lipogenesis during lactation. Through the utilization of stable isotopes and the hyperinsulinemic-euglycemic clamp technique, we tested the differing concentrations of insulin to stimulate mammary DNL. Methods: Eight women (32±4 yrs) with (GDM, n=4) or without (NGT, n=4) recent gestational diabetes and overweight or obesity (28.2±2.9 kg/m2) were recruited to participate in this study at 6 weeks postpartum. The night before the study, participants orally consumed 3 doses of 70% deuterated water to label newly made fatty acids. Participants arrived in the morning for IV placement and immediately pumped milk contralaterally for 20 minutes. Milk was pumped two hours later, again at the end of step 1 of the clamp (10 mU/m2/min) and once more after step 2 (either 20 or 40 mU/m2/min). Milk triglycerides were extracted and prepared for analysis by gas chromatography-mass spectrometry. The incorporation of deuterium into milk triglyceride-fatty acids was the primary outcome. Results: Fasting insulin concentrations were significantly associated with newly-made 16:0 in milk triglycerides (r=0.85, P=0.01). Of all measured triglyceride 16:0, 1.6±1.0% were made de novo. This percentage increased 1.5-fold by the end of step 2 of the clamp (P=0.06). Fasting milk DNL 14:0 was 12.3±4.8% which was significantly greater than DNL 16:0 (P<0.01). DNL 14:0 increased 1.7-fold during step 2 (P=0.04). For both milk triglyceride 12:0 and 14:0 derived from DNL, a significant effect across clamp-stage was observed (P<0.001 for both), but not an effect of group (P=0.12, P=0.11, respectively). Bonferroni posthoc analyses revealed that the insulin effect was significant for both groups for 12:0 (GDM, P=0.02; NGT, P <0.01) and 14:0 (GDM, P<0.01; NGT, P=0.01). Interpretation: The present study is the first to assess the acute effect of a hyperinsulinemic-euglycemic clamp on the synthesis of newly-made triglyceride fatty acids in human milk. These results suggest that the increases in mammary DNL may be fatty acid specific, favoring that of lauric and myristic acids, but not longer chain fatty acids like palmitate. Mammary lipogenesis was stimulated by insulin in all subjects regardless of recent gestational diabetes diagnosis. The role mammary DNL plays in overall milk fat content deserves further investigation. Presentation: 6/3/2024

12548 Mammary De Novo Lipogenesis During A Hyperinsulinemic-euglycemic Clamp

Abstract Disclosure: T.M. Fordham: None. M. Ramos-Roman: None. E.J. Parks: Consulting Fee; Self; Simply Good Foods. Stock Owner; Self; Sagimet Biosciences. Other; Self; Past President of The Obesity Society. Introduction: The mammary produces large amounts of medium-chain saturated fatty acids. Long-chain saturated fatty acids found in human milk primarily derive from the maternal diet or from the mobilization of stored triglycerides. Previous studies have established the importance of insulin in stimulating mammary differentiation, milk synthesis, and lipogenesis. However, no studies have assessed how changes in insulin concentrations alter human mammary de novo lipogenesis (DNL) nor what effect gestational diabetes may have on insulin’s relationship to lipogenesis during lactation. Through the utilization of stable isotopes and the hyperinsulinemic-euglycemic clamp technique, we tested the differing concentrations of insulin to stimulate mammary DNL. Methods: Eight women (32±4 yrs) with (GDM, n=4) or without (NGT, n=4) recent gestational diabetes and overweight or obesity (28.2±2.9 kg/m2) were recruited to participate in this study at 6 weeks postpartum. The night before the study, participants orally consumed 3 doses of 70% deuterated water to label newly made fatty acids. Participants arrived in the morning for IV placement and immediately pumped milk contralaterally for 20 minutes. Milk was pumped two hours later, again at the end of step 1 of the clamp (10 mU/m2/min) and once more after step 2 (either 20 or 40 mU/m2/min). Milk triglycerides were extracted and prepared for analysis by gas chromatography-mass spectrometry. The incorporation of deuterium into milk triglyceride-fatty acids was the primary outcome. Results: Fasting insulin concentrations were significantly associated with newly-made 16:0 in milk triglycerides (r=0.85, P=0.01). Of all measured triglyceride 16:0, 1.6±1.0% were made de novo. This percentage increased 1.5-fold by the end of step 2 of the clamp (P=0.06). Fasting milk DNL 14:0 was 12.3±4.8% which was significantly greater than DNL 16:0 (P<0.01). DNL 14:0 increased 1.7-fold during step 2 (P=0.04). For both milk triglyceride 12:0 and 14:0 derived from DNL, a significant effect across clamp-stage was observed (P<0.001 for both), but not an effect of group (P=0.12, P=0.11, respectively). Bonferroni posthoc analyses revealed that the insulin effect was significant for both groups for 12:0 (GDM, P=0.02; NGT, P <0.01) and 14:0 (GDM, P<0.01; NGT, P=0.01). Interpretation: The present study is the first to assess the acute effect of a hyperinsulinemic-euglycemic clamp on the synthesis of newly-made triglyceride fatty acids in human milk. These results suggest that the increases in mammary DNL may be fatty acid specific, favoring that of lauric and myristic acids, but not longer chain fatty acids like palmitate. Mammary lipogenesis was stimulated by insulin in all subjects regardless of recent gestational diabetes diagnosis. The role mammary DNL plays in overall milk fat content deserves further investigation. Presentation: 6/3/2024

7363 Comparing the Effectiveness of Various Insulin in Insulin Naive Type 2 Diabetes Mellitus Patients: A Study from Central India

Abstract Disclosure: K. Dash: None. S. Verma: None. U. Ayyagari: None. N. Kumari: None. A. Gwal: None. Introduction: Insulin is the cornerstone of treatment of type 2 diabetes mellitus (T2DM) and is the most efficacious treatment option. The evaluation of efficacy and safety of insulin therapy in real world setting is desirable as numerous options are currently available. This study aimed to compare the efficacy and safety of four different insulins in patients with T2DM. Methods: We conducted a retrospective observational study at our tertiary care hospital using medical records of patients with glycated hemoglobin (HbA1c) >8.5% who were not controlled on oral antidiabetic (OAD) medication and received add-on insulin treatment (Glargine U300, Lispro Biphasic 25/75, Glargine U100, IdegAsp). Glycemic control and incidence of hypoglycemia were analyzed from baseline to 6 months. Results: 101 patients were included. Mean age 56.4 years. 61.4% men. Mean duration of T2DM 13.3 years. 23 (22.8%), 27 (26.7%), 27 (26.7%), and 24 (23.8%) patients received Glargine U300, Lispro Biphasic 25/75, Glargine U-100, IdegAsp insulin respectively. At baseline, the mean (SD) HbA1c were 11.93% (1.85), 10.61% (1.55), 10.65% (1.59), and 10.58% (1.89) in patients receiving Glargine U300, Lispro Biphasic 25/75, Glargine U100, and IdegAsp, respectively. HbA1c, fasting plasma glucose (FPG) & post-prandial plasma glucose (PPG) improved significantly from baseline to 6 months across all four treatment groups (p<0.001). Glargine U300 showed a significantly greater mean reduction in HbA1c by 4.57% compared to Lispro Biphasic 25/75 (3.39%; p=0.032), Glargine U100 (2.88%; p=0.004), and IdegAsp (2.38%; p<0.001). The mean reduction in FPG, PPG, total cholesterol and triglycerides were comparable across all four treatment groups. The mean insulin doses (SD) were 15.48 (5.65) U, 23.83 (9.49) U, 20.44 (8.76) U, and 34.17 (14.57) U at baseline and 18.89 (5.39) U, 35.52 (10.37) U, 26.07 (8.92) U, and 43.58 (15.76) at 6 months, respectively. The doses of all insulins were titrated to fasting, post-meal, or pre-dinner SMBG readings as appropriate. There were no significant changes observed in the mean body weight and insulin dose in all four subgroups. The incidence of hypoglycemia (<70 mg/dL and <54 mg/dL) was numerically lower in Glargine U300 (3 and 1) group, than in Lispro Biphasic 25/75 (8 and 5), Glargine U100 (3 and 2), and IdegAsp (7 and 3) groups. As expected, biphasic insulin had a higher numerical incidence of hypoglycemia. Conclusion: All insulins demonstrated significant improvements in glycemic parameters over the study period. However, Glargine U300 demonstrated a significantly higher reduction in HbA1c with minimal hypoglycemia events compared to other insulins and can be considered in OAD uncontrolled patients. Our results should be interpreted with caution as the study was retrospective and had a small sample size. Presentation: 6/3/2024

7086 Disrupted Mitochondrial Function in Alström Syndrome- A Monogenic Model of Insulin Resistance and Obesity

Abstract Disclosure: S. Ali: None. S. Heising: None. V. Veeranna: None. A. Vincent: None. G.S. Xavier: None. T. Geberhiwot: None. Alström syndrome (ALMS) is a rare monogenic disease typified by severe insulin resistance (IR) and obesity. IR and obesity are cardinal features of metabolic syndrome. The metabolic effects of insulin at key target tissues leads to metabolic haemostasis by promoting glucose and lipid uptake and metabolism to generate energy in cells. Although insulin is a major regulator of fuel metabolism, its effects on mitochondrial ATP production in severe insulin resistance are unclear. RNASeq data from adipose tissue (AT) from patients with ALMS show downregulation of the expression of genes associated with mitochondrial respiratory chain function, pointing towards possible altered mitochondrial function in ALMS. We therefore undertook a detailed assessment of mitochondrial oxidative phosphorylation capacity (OXPHOS) in skeletal muscle (SM) in ALMS. We performed SM biopsy in 10 ALMS and 10 healthy control volunteers that were age, gender and Body Mass Index matched. The SM was subjected to high resolution respirometry, the gold standard method to quantify mitochondrial function ex vivo, using OROBOROS Oxygraph -2k (O2k) system. Overall OXPHOS was higher in control SM compared to ALMS, with maximal respiration of 62.96±19.2 and 44.24 ± 12.53 pmol/(s*mg), respectively (p<0.05).Reduced oxygen influx was observed in ALMS SM in comparison to controls for fatty acid ß oxidation (6.7±5.96 vs 7.87±2.7 pmol/(s*mg);p<0.05, at complex I (19.4 ± 8.98 vs 29.7 ±5.3 pmol/(s*mg);p<0.05, and at complex II (34.98 ±11.75 vs 53.52± 13.2 pmol/(s*mg) ;p<0.05. Mitochondrial membrane integrity was unaffected during these experiments. Therefore, our analysis unveils a consistent reduction in mitochondrial respiration across all the electron transport pathway. This noteworthy finding suggests impairment in respiratory function and the electron transport chain in mitochondria, a crucial aspect of cellular energy metabolism. Several studies have previously linked IR with mitochondrial dysfunction, where insulin-resistant rodents and humans have shown blunted mitochondrial response to ATP generation. Our results align with this body of evidence emphasizing the significance of investigating the underlying mechanism contributing to this phenomenon. These findings could pave the way to exploring potential mitochondrial-targeted therapies to restore mitochondrial function and therefore, improve insulin sensitivity to tackle IR in ALMS. Presentation: 6/2/2024

8537 Refractory Hypoglycemia Secondary To Metastatic Insulinoma Treated With Novel Insulin Receptor Antibody - A Case Report

Abstract Disclosure: J. Lloyd: None. S. Abu Omar: None. L. Lester: None. L. Wilson: None. Introduction: Insulinoma is the most common functional pancreatic neuroendocrine tumor, characterized by hypersecretion of insulin, causing hypoglycemia. Insulinomas are mostly benign, however malignant neoplasms account for 5-10 % of cases. Surgical resection is the preferred treatment for solitary tumor, however metastatic insulinoma requires a more aggressive approach with medications to prevent hypoglycemia, resection of primary tumor, resection of metastasis, and chemoembolization. We describe a case of metastatic insulinoma with refractory hypoglycemia despite treatment with multiple medications, surgical resection of tumor, embolization of liver metastasis and successfully treated with a novel monoclonal antibody that blocks insulin receptor. Clinical Case: 43-year-old female was initially diagnosed with metastatic insulinoma in 2021. The primary tumor was pancreatic with metastasis to the liver. She was treated with surgical resection of the primary tumor and three hepatic embolizations for liver metastasis. She required a progressive number of medications to treat frequent, debilitating hypoglycemia. These medications included diazoxide, verapamil, lanreotide then changed to pasireotide, everolimus, and dexamethasone. Despite these treatments, she experienced refractory hypoglycemia and was admitted to the hospital. She required continuous dextrose infusion up to 100ml/hr of D50. Due to the large volume of fluid from dextrose infusion and other medications, she developed severe edema and AKI and required aggressive diuretic regimens and briefly intermittent CRRT. As there were no additional medications to add and prospects for future liver embolization were limited, we requested use of RZ358 through the manufacturer’s Expanded Patient Access program. This medication is a monoclonal antibody that blocks the insulin receptor to counteract the effects of insulin and thereby reduce hypoglycemia. This mechanism of action is unique from medications used to manage insulinoma induced hypoglycemia. She received her first infusion of RZ358 which she tolerated well. She had baseline elevation of ALP due to liver metastasis with further rise after liver embolizations, most recently 4 weeks prior. There was a rise in ALP levels which stabilized after 3 days. She experienced no significant side effects. For the first time in two months, five days after her first infusion of RZ358, the dextrose infusion could be stopped. She received her second infusion of RZ358 one week after first infusion. She was discharged home in a stable condition shortly after the second infusion. Conclusion: The Insulin receptor blocking monoclonal antibody, RZ358, offers a promising approach to patients with metastatic insulinoma who have refractory hypoglycemia despite maximal medical and surgical therapy. Presentation: 6/1/2024

6692 Proarrhythmic Risk Of Hypoglycemia; A Case Of Insulin-Induced Hypoglycemia Provoking Torsade De Pointes-Cardiac Arrest

Abstract Disclosure: A.M. San Hernandez: None. A. Adelkhanova: None. H. Ashraf: None. J. Aguayo Herrera: None. M.F. Siddiqui: None. Introduction: Torsade de Pointes is a life-threatening polymorphic ventricular tachycardia which is associated with QTc prolongation caused by medications, metabolic and electrolyte abnormalities. Very few cases of hypoglycemia causing QTc prolongation and Torsades de Pointes have been reported in the literature. Although the mechanism is unclear, the effects of low blood glucose have been proposed to induce a sympathetic response, hypokalemia and calcium disturbances. We report a case of an insulin-induced hypoglycemia causing Torsades de Pointes cardiac arrest, highlighting the proarrhythmic risk of hypoglycemia. Case presentation: A 57-year-old female with a history of Insulin-dependent Type 2 Diabetes Mellitus (DM) was brought in by EMS due to severe symptomatic hypoglycemia (POC blood glucose of 30 mg/dL), requiring treatment with dextrose. Patient reported reduced oral intake due to vomiting for 1 week and continued insulin administration without self-monitoring of blood glucose. Laboratory work up on presentation revealed severe hypoglycemia VBG= 55 mg/dL and mild hypomagnesemia Mg=1.4mg/dL (Ref Range 1.7-2.2mg/dl) which was treated. There was no hypokalemia or hypocalcemia. ECG showed sinus rhythm with prolonged QTc interval of 573ms and non-specific ST changes.Few hours later, patient developed torsades de pointes, requiring ACLS resuscitation. ROSC was achieved after two rounds of CPR. Patient received dextrose infusion to maintain euglycemic state. She was not taking any QTc prolonging medication. There was no history of autoimmune disease. Except for hypoglycemia, no other metabolic abnormality could be identified. Cardiac and pulmonary etiologies of cardiac arrest were ruled out. Post-ROSC ECG showed sinus tachycardia with normalization of QTc to 454ms. Thus, Insulin-induced hypoglycemia was appointed as the main culprit for her cardiac arrest, in the setting of QTc prolongation. Patient received diabetes self-management and hypoglycemia education. Conclusion: Several studies support strong correlation between hypoglycemia and arrhythmic events during bedtime in people with diabetes “The dead in bed syndrome”. Hypoglycemia causes an acquired long QT syndrome independent of other risk factors such as cardiac autonomic neuropathy. Possible mechanisms include; sympathoadrenal activation, which regulates potassium, calcium and chloride channels or altered autonomic regulation caused by hypoglycemia itself regardless of the effect of insulin or hypokalemia. QT prolongation is a risk factor for sudden cardiac death by causing torsades de pointes ventricular tachycardia (VT).People with insulin dependent diabetes are at high risk of hypoglycemia and should be cautioned about the proarrhythmic risk of hypoglycemia. Education is crucial, and Continuous glucose monitor (CGM) is a valuable tool to be use in such a patient population. Presentation: 6/3/2024

7187 Non-islet Cell Tumor Hypoglycemia in a Patient With Metastatic Renal Cell Carcinoma

Abstract Disclosure: G.W. Bao: None. A.Y. Yin: None. We report a rare case of non-islet cell tumor hypoglycemia (NICTH) in a patient with metastatic renal cell carcinoma. NICTH is a paraneoplastic syndrome due to increased production of an incompletely processed form of insulin-like growth factor 2 (“big IGF-2”). It requires a high-level of suspicion for diagnosis and is challenging to manage. Our patient is a 69 year old gentleman with a history of deceased donor renal transplant in 1994 and 2008. He was diagnosed with renal cell carcinoma (RCC) metastatic to bone, lymph nodes, and lungs, which was initially treated with cabozantinib, later switched to lenvatinib and everolimus due to disease progression. On admission, he presented with anasarca and weakness. He had recurrent fasting hypoglycemia associated with confusion and lethargy. The lowest serum glucose was 28 mg/dL. He was also diagnosed with primary hypothyroidism (TSH 25.1 uIU/mL and free T4 0.31 ng/dL), suspected to be due to tyrosine kinase inhibitor therapy. Levothyroxine was initiated. Cosyntropin stimulation resulted in a post-stimulation cortisol of 7 ug/dL, although this was felt not to be reliably diagnostic of adrenal insufficiency in the setting of profound hypoalbuminemia. IGF-1 and IGF-2 were 16 ng/mL and 388 ng/mL, respectively; IGF-2: IGF-1 ratio was 24.3. He was treated with intravenous dextrose and prednisone 30mg daily with stabilization of glucoses for a few days. On hospital day 19, he acutely decompensated and passed away shortly after being transitioned to comfort-focused care. Non-diabetic hypoglycemia is relatively uncommon, and may be seen in patients with liver disease, sepsis, adrenal insufficiency, and malignancy. We report a case of NICTH in a patient with metastatic RCC, which is a particularly rare cause of hypoglycemia. NICTH is due to tumor production of “big IGF-2”, a precursor of IGF-2, which mimics the effects of insulin and causes fasting hypoglycemia. NICTH is more commonly associated with mesenchymal and epithelial tumors such as fibromas, fibrosarcomas, and hepatocellular carcinomas. NICTH due to RCC appears to be a much more rare entity, with as few as four cases reported in the literature. Laboratory findings of NICTH include low insulin, pro-insulin, C-peptide, and β-hydroxybutyrate during hypoglycemia. An IGF-2: IGF-1 ratio >10 is considered virtually diagnostic. Surgical excision is curative, although often delayed or not feasible, and patients frequently require intravenous dextrose. High-dose steroids (ie, prednisone 30-60mg daily) can be used, which promotes “big IGF-2” clearance. NICTH is likely under-recognized in patients with advanced malignancies. This diagnosis should be considered in those with refractory hypoglycemia, although management is challenging if tumor control cannot be achieved. Presentation: 6/1/2024

Chromium and Palmitic Acid Supplementation Modulate Adipose Tissue Insulin Sensitivity in Postpartum Dairy Cows

Periparturient dairy cows exhibit intense lipolysis driven by reduced dry matter intake, enhanced energy needs, and the loss of adipose tissue (AT) insulin sensitivity. Extended periods of low insulin sensitivity and negative energy balance induce lipolysis dysregulation, leading to increased disease susceptibility and poor lactation performance. Chromium (Cr) supplementation improves systemic insulin sensitivity, while palmitic acid (PA) increases energy availability for milk production. However, the effect of supplementing Cr and PA alone or in combination on insulin sensitivity in AT is unknown. Thirty-two multiparous cows were used in a randomized complete block design experiment and randomly assigned to one of 4 diets fed from 1 to 24 DIM. Diets included: control, no supplementation (CON, n = 8); Cr (Cr-propionate at 0.45 ppm Cr/kg DM, n = 8); PA (1.5% DM, n = 8); or Cr+PA (n = 8). Plasma samples were collected at -13 ± 5.1 d prepartum (PreP), and 14.4 ± 1.9d (PP1) and 21 ± 1.9d (PP2) after calving for albumin, BHB, BUN, calcium, cholesterol, glucose, nonesterified fatty acids (NEFA), total protein, iron, transferrin, triglycerides, and oxylipids quantification. Subcutaneous AT (SCAT) explants were collected at PreP, PP1 and PP2 and incubated in the presence of the lipolytic agent isoproterenol (ISO = 1 µM, BASAL = 0 µM) for 3 h. The antilipolytic effect of insulin (1µL/L) on SCAT explants was evaluated during ISO stimulation (IN+ISO). Lipolysis was quantified by glycerol release in the media (nmol glycerol/mg AT). Macrophage infiltration and adipocyte size were measured using hematoxylin and eosin-stained AT sections and immunohistochemistry. Cr tended to reduce postpartum NEFA concentrations when compared with CON, PA, and Cr+PA. Likewise, Cr increased the percentage of large adipocytes (>9000 µm2) postpartum compared with other diets. In line with higher lipid content, Cr-fed cows had higher ex-vivo BASAL lipolysis at PP2 when compared with PA and Cr+PA. ISO induced higher lipolysis at PP1 and PP2 but it was not affected by Cr and PA. IN+ISO reduced lipolysis by 29.91 ± 11% in Cr compared with ISO. In contrast, IN+ISO did not affect ISO lipolysis in CON, PA, and Cr+PA. Plasma transferrin was reduced by Cr. At PP2, PA cows had 3.3-fold higher macrophage infiltration in SCAT when compared with CON and Cr. Plasma 9-HODE and 9-oxoODE were increased by Cr+PA. PA increased plasma 13-oxoODE and Cr increased the ratio of 13-HODE:13-oxoODE. PA increased 5-iso Prostaglandin F2α-VI. Our results demonstrate that supplementing Cr during the immediate postpartum enhances SCAT insulin sensitivity and lipid accumulation. Further studies should determine the effects and mechanisms of action of Cr and PA on AT lipogenesis, adipogenesis, and their impact on lactation performance.

BARRIERS TO INITIATE INSULIN THERAPY AND ITS ASSOCIATION WITH DURATION OF DIABETES MELITIS AND DEMOGRAPHIC FACTORS IN UNCONTROLLED TYPE 2 DIABETIC PATIENTS, A CROSS SECTIONAL STUDY

Objectives: To determine different barriers to initiate insulin therapy and association of duration of diabetes mellitus and demographic factors with barriers in initiation of insulin therapy in Uncontrolled type 2 diabetic patients.Materials and Methods: We conducted a cross sectional study conducted among patients with type 2 diabetic patients presenting to endocrinology outpatient clinics in two Tertiary care hospitals of Peshawar ie. Khyber Teaching hospital and hayatabad medical complex Peshawar. The duration of study was 03 months after approval of synopsis. The sample size was 257.The study population was selected by consecutive non probability sampling technique. The data was collected by pre designed questionnaire. All the included patients were interviewed on pre designed questionnaire. Data was processed in SPSS version 22.Results: In study we found that patients face different barriers to initiate insulin therapy. In our study, side effects of insulin was the barrier for 97(37.7%) of the patient, difficulty in carrying insulin was barrier for 128(49.8%) patients , dose adjustment of insulin was barrier for 90(35%) patients, fear if insulin needle was barrier for 89 (34.6%) patients, self administration of insulin was barrier for 98(38.1%) patients , affordability of insulin was barrier accounting for 114(44%) patients , frightened about insulin therapy by someone was barrier for116 (45.1%) patients. The association between economic status of patient and the barrier that they are frightened by someone was statistically significant. Chi-square test was also run between duration of diabetes with all barriers in which one association was found nearly signifi cant i.e. the association of duration of diabetes with difficulty in carrying insulin with the p value of 0.064.Conclusion: The most common barrier in insulin therapy initiation of patients in the study was difficulty in carrying insulin. We found that there is near to signifi cant association between duration of diabetes and difficulty in carrying insulin. There is significant association between economic status of patient and frightened by someone. The lower the economic status the more frightened about Insulin use.

Diminished expression of the ubiquitin-proteasome system in early treatment-naïve patients with rheumatoid arthritis and concomitant type 2 diabetes may be linked to IL-1 pathway hyper-activity; results from PEAC cohort

ObjectiveBased on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin–proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs).MethodsThe synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot.ResultsSynovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin–proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM).ConclusionsA different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin–proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.

Effect of Intranasal Insulin on Olfactory Recovery in Patients with Anosmia .

Olfactory dysfunction, defined as either a complete or partial impairment of smell, is a common condition that may substantially affect a person’s quality of life and is frequently difficult to treat. Physical activity, heredity, nutrition, smoking, head trauma, medical treatments, and virus exposure all influence one’s capacity to smell. Hyposmia or anosmia, or loss of smell, affects 3% to 20% of the population. Intranasal insulin can improve cognitive performance, reduce food intake, and boost olfactory thresholds in healthy individuals. As people age, they are more likely to experience olfactory dysfunction, which may be affected by a variety of reasons, such as acute and chronic sino-nasal illness, upper respiratory infections, toxic chemical exposure, and degenerative diseases. About ten percent of those over 65 develop olfactory impairment, which can range from mild loss to total anosmia. Insulin resistance in the central nervous system has been linked to conditions like type II diabetes, Alzheimer’s disease, obesity, and poor odor identification. Reduced odor perception may contribute to reduced olfactory function in anosmic patients.

The use of Oral Anti-Diabetic Medications in Diabetes Mellitus type 1: An Educational Article and Expert Opinion

Diabetes mellitus type 1 is lifelong condition resulting from failure of production of insulin because of the loss of pancreatic islet beta-cells because of autoimmune damage. Patients with this type of diabetes need lifelong treatment with insulin to remain alive. Poor diabetic control which predisposes to a variety of complications is not uncommon in patients treated with insulin alone. Therefore, the use of medications that can possibly enhance the therapeutic effect of insulin and reduce the risk of diabetic complications has been considered. Oral anti-diabetics including acarbose, an inhibitor of intestinal α-glucosidase, metformin, a biguanide, sulfonylureas including glipizide, and sitagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP-4) are primarily used for the treatment of non-insulin dependent diabetes (Type 2). The aim of this paper is to provide an overview of the use of oral anti-diabetics in the treatment of insulin dependent diabetes (Type 1). Expert opinion: The current evidence-based expert opinion recommends the judicious use of oral anti-diabetics especially acarbose and metformin in the treatment of unsatisfactorily controlled insulin dependent diabetes type 1. These medications can help in improving diabetic control through reducing glucose levels after meals, and can contribute to lowering the levels of glycosylated hemoglobin (HbA1c). The use of these oral anti-diabetics can also help in reducing insulin requirement.

Abstract C043: Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism

Abstract Metabolic diseases, such as type 2 diabetes (T2D), insulin resistance, and obesity, often accompany pancreatic ductal adenocarcinoma (PDAC), and they are associated with reduced survival. Hyperinsulinemia is a common hallmark symptom shared by those disorders and is independently associated with reduced survival of PDAC patients. While it has been established that endogenous hyperinsulinemia accelerates PDAC initiation by promoting the formation of KRAS-driven pre-cancerous lesions, its role in the progression of established tumors remains poorly understood. This represents a major knowledge gap in our understanding of whether insulin needs to be monitored and controlled during PDAC treatment, as it is not typically considered in current treatment paradigms. We hypothesized that hyperinsulinemia promotes the progression of PDAC tumors. Using patient-derived PDAC organoids (PDOs) and a mouse model of metabolic disorders, we found that insulin may promote PDOs’ growth by reprogramming tumor metabolism. A High-fat diet (HFD) treatment that induces hyperinsulinemia, but not hyperglycemia in mice accelerated the growth of PDO-derived orthotopic xenografts. Importantly, the fasting insulin level showed a significant positive correlation with the endpoint tumor volume, suggesting that endogenous insulin may positively contribute to PDOs’ growth in vivo. To assess the direct effect of insulin on the growth and molecular profile of PDOs, we treated an early passage PDO line with different concentrations of insulin and glucose at physiologically relevant levels. We observed a ∼1.2-fold increase in cell number after 7 days of culture in high insulin (10 nM) conditions with high (15 mM) or physiological (6 mM) levels of glucose, relative to the low insulin control. Phosphoproteomic analysis demonstrated significantly greater PI3K/AKT/mTOR, but not RAF/MEK/ERK, activity under high insulin with high or physiological levels of glucose compared to the control, directing the investigation toward the metabolic effects of insulin. Consistently, unbiased proteomics profiling revealed that metabolic proteins were significantly enriched in both high insulin conditions, and interestingly insulin enriched different sets of proteins in various metabolic pathways depending on glucose levels. Together, our preliminary results suggest that hyperinsulinemia may enhance the growth and progression of PDAC by altering tumor metabolism to support cell growth. Further experiments are needed to functionally link the insulin-mediated metabolic changes with increased PDO growth, as well as testing the direct effect of endogenous insulin on PDAC cells in vivo. Citation Format: Jeffrey Lin, James D Johnson, David Schaeffer, Vincent Richard, Christoph Borchers, Janel L Kopp. Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C043.

POLYCYSTIC OVARY SYNDROME AND BONE TURNOVER IN POSTMENOPAUSAL WOMEN

Considering the metabolic and hormonal changes associated with polycystic ovary syndrome (PCOS), their potential affect bone health has been proposed. The aim of the current study was to evaluate the effect of several hormonal and metabolic alterations associated with polycystic ovary syndrome on bone in postmenopausal women. Materials and methods: The study included 56 patients with PCOS and 42 women without this disease aged 50–65 years. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) of the lumbar spine and femoral neck. Serum levels of amino-terminal propeptide of procollagen 1 (P1NP) and carboxy-terminal telopeptide of type I collagen (b-CTx), as well as levels of parathyroid hormone (PTH), vitamin D (25(OH)D3), anti-Mullerian hormone (AMH), insulin, testosterone (T), 17-hydroxyprogesterone (17-OHP), dehydroepiandrostenedione sulfate (DHEAS), follicle stimulating hormone, luteinizing hormone, and estradiol were determined. The HOMA-IR index and anthropometric indicators were calculated. Statistical data were analyzed by nonparametric testing using BioStat Pro 6.2.2.0 software (AnalystSoft Inc., Walnut, USA). Quantitative data are presented as median and quartiles 1 and 3 (Me [Q1; Q3]); The significance of intergroup differences was established using the Mann–Whitney U test (p&lt;0.05). To identify relationships between indicators, a univariate analysis was carried out with the calculation of the Spearman rank correlation coefficient (r). Results. Women with PCOS had late-onset menopause (p=0.007) and a higher body mass index (BMI, p=0.009) than the control group. Additionally, women with PCOS had higher levels of DHEAS, total T, and 17-OHP than controls. P1NP and b-CTx were significantly different from controls (p=0.028 and p=0.032, respectively). A direct relationship was found between BMI and the activity of the resorption marker b-CTx (r=0.342, p=0.002) and an inverse collinear relationship between AMH values with b-CTx (r=–0.507, p=0.001). BMD in PCOS was higher compared to controls. An inverse relationship exists between BMD of L1–L4 and b-CTx level (r=–0.387, p=0.026) and positive with insulin (r=0.267, p=0.042), AMH (r=0.561, p=0.031) and testosterone (r=0.458, p=0.039). Higher DHEAS levels were associated with higher femoral neck BMD (r=0.473, p=0.035). P1NP was negatively correlated with femoral neck BMD (r=-0.429, p=0.038). Conclusions. Bone mineral density in women with polycystic ovary syndrome declines more slowly with age compared to their peers, possibly due to the effects of excess androgens and insulin. In postmenopausal women with polycystic ovary syndrome, metabolic processes in bone tissue accelerate, while bone resorption exceeds bone formation. Thus, women affected by polycystic ovary syndrome may be considered at risk of developing osteopenic syndrome.