Insulin Treatment Research Articles

Post-COVID syndrome and type 2 diabetes mellitus in Kazakhstan: clinical manifestations and vaccine efficacy

Purpose: In this article, we report the results of a survey investigating post–coronavirus disease 2019 (COVID-19) syndrome in patients with type 2 diabetes mellitus and the impacts of vaccination on long-term manifestations. From February 2022 to April 2023, a survey of patients with type 2 diabetes and people without diabetes who were treated for a coronavirus infection was conducted in Kazakhstan.Methods: Participants were invited via social media to voluntarily participate in this study. A total of 417 surveys were included in this study, comprising 212 patients with type 2 diabetes and 205 without diabetes. We compared persistent complaints after recovery in patients with and without diabetes mellitus (DM), as well as vaccination status.Results: The results of this study on self-reported symptoms of prolonged COVID show that more than half of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Kazakhstan have at least one persistent symptom after recovery. Based on the list of prolonged COVID-19 symptoms reported by patients with type 2 DM (T2DM), exertional dyspnoea, fatigue, respiratory discomfort, headaches, and sleep disturbances are among the most common ongoing conditions, and in many cases last more than 3 months after COVID-19.Conclusion: Patients with T2DM experience more severe and prolonged symptoms than those without diabetes. Additionally, vaccination lowers COVID-19 hospitalization risk and decreases the need for adjusting hypoglycemic therapy, such as insulin treatment, after recovering from SARS-CoV-2 infection.

Gestational diabetes and pregnancy outcome in Kurdish, Somali and general population in Finland

Abstract Gestational diabetes (GDM) increases the risk of type II diabetes and cardiovascular morbidity later in life but GDM incidence in women from different cultural backgrounds varies. This study aims to examine treatment of GDM and pregnancy outcomes in Somali, Kurdish and general population women. Patient data of 312 Kurdish, 254 Somali and 508 general population women was collected from Turku University Hospital records from 2008 to 2019. The general population was selected by randomization with matching year, BMI, age, and parity. Singleton deliveries after 34th gestational week with no prior diabetes mellitus were included. Descriptive and comparison analyses (SPSS, version 29.0) were used to identify associations between ethnic background and pregnancy outcomes in women with GDM. The incidence of GDM was 22 % (CI 95 % 17-27) in Somali, 36 % (CI 95 % 31-42) in Kurdish, and 16 % (CI 95 % 13-19) in the general population women. Kurdish women had medication for GDM more often (43 % CI 95 % 34-53) than the Somali (22 % CI 95 % 11-33) and general population women (18 % CI 95 % 9-26). Metformin was more commonly used among Kurdish (30 % CI 95 % 22-39) compared to the general population (12 % CI 95 % 4-18) and Somali women (13 % CI 95 % 4-22). There was no difference in insulin or combined metformin and insulin treatment between the groups. In GDM group, vaginal deliveries were more common in general population (89 % CI % 81-95) than in Somali women (67 % CI % 64-81). Induction of labour (indication GDM or other) and instrumental vaginal delivery rates were similar between the groups. Newborns of all Somali women had a lower weight (SD -0.3 CI 95 % -0.7 - -0.2) compared to the general population (SD 0 CI 95 % -0.1 - 0.3). The prevalence of GDM was increased and dietary treatment decreased in Kurdish women compared to the general population in Finland. In the future, the treatment of GDM should be adjusted to better optimize the care for different cultural background women. Key messages • Kurdish women have increased incidence of GDM and less dietary treatment compared to the general population with similar risk factors. The pregnancy outcomes remain good in all groups. • With Somali women, the birth weight of the child is lower despite GDM status. This might direct clinicians to underestimate the effect of GDM when considering individual treatment.

Insulin Stabilization Designs for Enhanced Therapeutic Efficacy and Accessibility.

ConspectusInsulin has remained indispensable in the treatment of diabetes since it was first discovered in 1921. Unlike small molecular drugs, insulin and other protein drugs are prone to degradation when exposed to elevated temperatures, mechanical agitation during transportation, and prolonged storage periods. Therefore, strict cold-chain management is crucial for the insulin supply, requiring significant resources, which can limit the access to insulin, particularly in low-income areas. Moreover, although insulin formulations have advanced tremendously in the last century, insulin treatment still imposes a challenging regimen and provides suboptimal outcomes for the majority of patients. There is an increasing focus on pursuing improved pharmacology, specifically on safer, more user-friendly insulin therapies that minimize the self-management burden. These challenges underscore the need for developing novel insulin formulations with improved stability that are compatible with advanced insulin therapy.Insulin stabilization can be achieved through either chemical modification of insulin or formulation component design. Inspired by insulin-like peptides from invertebrates, we have developed novel stable insulin analogs based on a fundamental understanding of the insulin receptor engagement for insulin bioactivity. We created a novel four-disulfide insulin analog with high aggregation stability and potency by introducing a fourth disulfide bond between a C-terminal extended insulin A-chain and residues near the C-terminus of the B-chain. In an effort to stabilize insulin in its monomeric state to develop ultrafast-acting insulin with rapid absorption upon injection, we have developed a series of structurally miniaturized yet fully active insulin analogs that do not form dimers due to the lack of the canonical B-chain C-terminal octapeptide. Additionally, our study provided strategies for expanding the scope of cucurbit[7]uril (CB[7])-assisted insulin stabilization by engineering safe and biodegradable CB[7]-zwitterionic polypeptide excipients. We also explored insulin N-terminal substitution methods to achieve pH-dependent insulin stabilization without prolonging the duration of action.This Account describes our exploration of engineering stable insulin analogs and formulation design strategies for stabilizing insulin in aqueous solutions. Beyond conventional stabilization strategies for insulin injections, the unmet challenges and recent innovations in insulin stabilization are discussed, addressing the growing demand for alternative, less invasive routes of insulin administration. Additionally, we aim to provide a thorough overview of insulin stabilization from the perspective of commercially available insulin drugs and common pharmaceutical engineering practices in the industry. We also highlight unresolved insulin stabilization challenges and ongoing research strategies. We anticipate that further emphasis on collective efforts of protein engineering, pharmaceutical formulation design, and drug delivery will inform the development of stable and advanced insulin therapy.

Diabetes mellitus and adverse clinical events in patients with atrial fibrillation: implications of insulin treatment: a report from the GLORIA-AF Registry Phase III

Abstract Background Atrial Fibrillation (AF) and diabetes mellitus (DM) are both associated with adverse clinical events, but the associations has not been fully elucidated, especially in relation to insulin use. Purpose To analyze the associations between DM and the risk of clinical adverse events in patients with AF, and second, explore the impact of insulin treatment in these patients. Methods We studied patients with AF from the prospective Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry with 3-years follow-up. Clinical events included all-cause death, major bleeding, myocardial infarction (MI), stroke, thromboembolism (TE), and major adverse cardiovascular events (MACE). MACE was defined as a composite of stroke, MI and major bleeding. Kaplan-Meier curves were used to estimate the cumulative incidence of clinical events. Multivariable cox regression models with subgroups were used to estimate the association between DM and the risk of mortality and clinical events. Results A total of 15,861 AF patients were included (mean age 70.00 ± 10,21 years old; 55% male, 20% Asia), of which 3,666 had DM (mean age 70.04 ± 9.54 years old; 59% male, 21% Asia). Kaplan-Meier curves showed that AF patients with DM had higher cumulative hazard of all outcomes, including all-cause death (OR: 1.56, 95%CI: 1.38-1.77), CVD (OR: 1.72, 95%CI: 1.44-2.06), major bleeding (OR: 1.4, 95%CI: 1.17-1.67), stroke (OR: 1.29, 95%CI: 1.04-1.61), TE (OR: 1.26, 95%CI:1.02-1.56), MI (OR: 1.88, 95%CI: 1.48-2.39) and MACE (OR: 1.61, 95%CI: 1.41-1.84). After adjustment by prior disease and drugs, the outcomes of stroke (OR: 1.19, 95%CI: 0.95-1.49) and TE (OR: 1.22, 95%CI: 0.98-1.52) showed not significant. Subgroup analysis found that increased risks of stroke were found in female (OR: 1.43, 95%CI: 1.03-1.98, Pinteraction = 0.062) and non-Asian patients (OR: 1.39, 95%CI: 1.06-1.82, Pinteraction = 0.175) with DM. For all cause death, subgroup results were similar with overall patients. In addition, insulin use increased the risk of all cause death (OR: 1.82, 95%CI: 1.45-2.29), CVD (OR: 1.70, 95%CI: 1.22-2.37), major bleeding (OR: 1.54, 95%CI: 1.08-2.18), MI (OR: 1.72, 95%CI: 1.12-2.64), MACE (OR: 1.65, 95%CI: 1.28-2.11) in patients with AF and DM. Multivariable model showed similar result. Conclusions DM was independently associated with higher risk of all-cause death, CVD, MI, major bleeding, and MACE in patients with AF. Insulin use was associated with higher risk of all-cause death, CVD, MI, major bleeding, and MACE in patients with AF and DM.Figure 1Figure 2

Twelve-months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with type 1 diabetes mellitus

Abstract Background Individuals diagnosed with type 1 diabetes mellitus (T1DM) exhibit indications of vascular and endothelial dysfunction earlier in comparison to healthy individuals. Evidence shows that SGLT-2 inhibitors (SGLT-2i) have a beneficial impact on cardiovascular health in individuals with type 2 diabetes mellitus (T2DM). We investigated the effects of dapagliflozin on endothelial and cardiovascular function in patients with T1DM. Methods We recruited in total 40 patients with T1DM and pour glycemic control who were treated with insulin and received dapagliflozin (n=20) or intensification of insulin treatment (n=20) (control group). We measured at baseline and at twelve months post-treatment the: a) Carotid-femoral pulse wave velocity (PWV-Complior; ALAM Medical) b) Central systolic blood pressure (cSBP) c) Perfused boundary region (PBR) of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness) and d) Left ventricular global longitudinal strain (GLS) using speckle-tracking echocardiography. Results At baseline, patients among the two groups had similar age, sex, HbA1c and markers of endothelial and cardiovascular function (p>0.05). After 12 months of treatment, patients who received dapagliflozin displayed an improvement in PBR5–25 (−16%, p<0.05), in PWV (−9.3%, p<0.05), in cSBP (−6%, p<0.05) and in GLS (+4%, P<0.05) compared to baseline. However, no statistically significant changes in PBR5–25, in PWV, in cSBP and in GLS were observed after intensification of insulin treatment (PBR5–25: +0.4%, PWV: -1%, cSBP: −2%, GLS: −1% at 4 months, P>0.05), despite a similar HbA1c reduction (Table 1). Changes of PBR after one year treatment with dapagliflozin correlated with a concomitant reduction of PWV and cSBP (P<0.05). Conclusions Twelve months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with T1DM, independently of glycemic control.

Tests employed in the psychometric validation of the Insulin Treatment Appraisal Scale (ITAS) in T2DM patients; a systematic review of the literature

BackgroundPsychological Insulin Resistance (PIR) and negative perceptions regarding insulin treatment are noteworthy challenges in T2DM management, which hinder the timely initiation of insulin treatment. To get past these obstacles a reliable tool is required to evaluate patients’ perspectives on insulin administration. Our study aims to conduct a comprehensive systematic review to evaluate the validity and reliability of different validation tests used in the psychometric validation of the ITAS in T2DM patients.MethodsA literature search was carried out, using PubMed, Google Scholar, EMBASE, Cochrane Library and Science Direct. Only those studies assessing content validity, construct validity, concurrent validity, discriminant validity, internal consistency reliability (Cronbach’ α), and items-total correlation were retrieved.ResultsA total of 14 studies illustrated the validity and reliability of ITAS in T2DM patients. Content validity results of S-CVI was 0.97, and I-CVI was 0.8–1.00. Construct validity with factor loading was greater than the threshold value of 0.3. The concurrent validity of ITAS vs. PAID, WHO-5, and SPI was 0.35 (P < 0.05), −0.14 (P < 0.05), and 0.80 (P < 0.001) respectively. The mean difference between insulin and non-insulin group was significant (P < 0.001) showing reliable discriminant validity. Reported results of Cronbach’s α for the main scale (0.79–0.89), subscale-1 (0.72–0.9), and subscale-2 (0.61–0.89) showed “good to excellent” internal consistency reliability of ITAS. Item-total correlation results for the main scale, subscale-1, and subscale-2 were (0.40–0.82), (0.31–0.74) and (0.34–0.58) respectively. Test-retest reliability of ITAS was 0.571–0.87.ConclusionsStudy findings confirm the robustness of various validation tests utilized in the psychometric validation of ITAS in T2DM patients. ITAS is a well-validated and reliable tool for determining the perspectives, PIR, and changes in patients’ perception over time and it can be used to overcome hurdles in the timely initiation of insulin treatment in T2DM patients.

Prolonged treatment of compactin, atorvastatin, lovastatin or simvastatin decreased glucose consumption and expressions of proteins for glucose metabolism and insulin signaling in L6 skeletal muscle cells

Statins inhibit mevalonate synthesis and successfully lower plasma cholesterol levels and decrease the risk of cardiovascular diseases in humans, but also lead to myalgia in some patients. We hypothesize that statins may modulate glucose metabolism and insulin signaling in the skeletal muscle cells during and after differentiation, and in turn lead to side effects. Here, differentiating and differentiated L6 muscle cells were treated with 1 μM of different class of statins (compactin, pravastatin, atorvastatin, lovastatin and simvastatin) with or without insulin or mevalonate for extended periods of time. The glucose consumption and expression levels of proteins for glucose metabolism and insulin receptor (IR)/Akt signaling were determined. The prolonged statin treatments (except pravastatin) decreased glucose consumption in L6 skeletal muscle cells. In differentiating L6 cells, compactin, lovastatin or simvastatin decreased the expression levels of proteins involved in glucose metabolism and insulin signaling, including glucose transporter 4 (GLUT4), pyruvate dehydrogenase (PDH), glycogen synthase (GS), glycogen synthase kinase 3β (GSK3β) and insulin receptor β subunit (IRβ). In differentiated L6 cells, long-term treatment of compactin or simvastatin also decreased levels of proteins in glucose metabolism and IR/Akt signaling, including GLUT4, GSK3β, IRβ and PI3K p110α. Insulin treatment restored statin-mediated impairments in L6 cells. The insulin-mediated phosphorylation of Akt Ser473 was attenuated in differentiating and differentiated L6 cells in the presence of atorvastatin (differentiated only), compactin, lovastatin or simvastatin. In addition, mevalonate supplementation reversed the statin-mediated impairments in differentiated and differentiating L6 cells. Statin affected glucose usage and insulin signaling by inhibiting mevalonate synthesis in L6 cells. Our results provides a possible mechanism of adverse effects of statins in skeletal muscle and calls for cautious use of the medication in patients with impaired insulin sensitivity and glucose metabolism.

Diabetic patients' knowledge and related factors towards insulin therapy: A systematic review

This systematic review aimed to evaluate the knowledge of diabetic patients and related factors regarding insulin therapy. A comprehensive search was systematically conducted across several international electronic databases, including Scopus, PubMed, and Web of Science. The search employed Medical Subject Headings (MeSH) keywords including "knowledge", "insulin", and "diabetes", covering records up to May 1, 2024. The quality of the included studies was assessed using the appraisal tool for cross-sectional studies (AXIS tool). A thorough analysis of fourteen cross-sectional studies involving 2,471 diabetic patients revealed an average knowledge level of 56.51 out of 100 regarding insulin therapy. The study identified several significant factors influencing this knowledge level: age, education level, duration of insulin treatment, practical experience, marital status (specifically being single), participation in training courses, urban residence, and male gender. These findings underscore the crucial role of health policymakers and managers in improving diabetic patients’ knowledge of insulin therapy. By targeting interventions toward these specific factors, they can make a significant difference in the lives of diabetic patients.

Prevalence of Diabetic Retinopathy Among Diabetic Patients from Northeastern Bulgaria.

Diabetic retinopathy (DR) is a leading cause of visual impairment globally among working-aged individuals. This study aims to update data on DR prevalence in Bulgaria. The present cross-sectional study was conducted between 1 January 2022 and 1 January 2023, using a local diabetes registry from the city of Varna as a sampling framework. In total, 587 diabetic patients underwent DR examination. Data included demographics, diabetes type/duration, treatment, and ophthalmic history. DR status was assessed using indirect slit-lamp biomicroscopy or digital fundus photography, graded by the International Clinical Diabetic Retinopathy Scale. Of 587 participants, 13 were excluded due to cataract-related ungradable images. The median age was 65 years (IQR 56-73), with a slight female predominance (54%). The overall prevalence of any DR was 39.9% (95% CI 35.9-44.0), with non-proliferative DR (NPDR) at 27.5%, proliferative DR (PDR) at 7.3%, and macular edema (DME) at 5%. Type 1 diabetes patients had significantly higher DR prevalence (68.8%) than type 2 (34.1%, p < 0.001). Men exhibited higher DR prevalence. Age and diabetes duration correlated positively with DR prevalence. Insulin treatment was associated with higher DR prevalence (55.6%) than oral antidiabetic treatment (22.5%, p < 0.001) for type 2 diabetes patients. Among those diagnosed with DR, 70.9% received treatment, mainly laser therapy. These findings provide epidemiological insights for future research and emphasize the need for a comprehensive national DR screening program in Bulgaria. Technological advancements enable proactive measures to mitigate DR-related visual impairment and blindness, including widespread screening, even in rural areas.

Intestinal Region-Dependent Impact of NFκB-Nrf Crosstalk in Myenteric Neurons and Adjacent Muscle Cells in Type 1 Diabetic Rats.

Type 1 diabetes affects cytokines as potential inducers of NFκB signalling involved in inflammation and neuronal survival. Our goal was to assess the expression of NFκB p65 and its negative regulator, Nrf2, in myenteric neurons and adjacent smooth muscle of different gut segments after chronic hyperglycaemia and immediate insulin treatment. After ten weeks of hyperglycaemia, intestinal samples of control, streptozotocin-induced diabetic and insulin-treated diabetic rats were prepared for fluorescent immunohistochemistry, immunogold electron microscopy, ELISA and qPCR. In the diabetic rats, the proportion of NFκB p65-immunoreactive myenteric neurons decreased significantly in the duodenum and increased in the ileum. The density of NFκB p65-labelling gold particles increased in the ileal but remained unchanged in the duodenal ganglia. Meanwhile, both total and nuclear Nrf2 density increased in the myenteric neurons of the diabetic duodenum. In smooth muscle, NFκB p65 and Nrf2 density increased in the small intestine of diabetic rats. While on the mRNA level, NFκB p65 and Nrf2 were induced, on the protein level, NFκB p65 increased and Nrf2 decreased in muscle/myenteric plexus homogenates. Insulin treatment had protective effects. Our findings reveal a segment-specific NFκB and Nrf expression in myenteric neurons and ganglionic muscular environments, which may contribute to regional neuronal survival and motility disturbances in diabetes.

Validation of the JH-SEFAC Questionnaire on Knowledge on Insulin Management by Patients with Diabetes in Community Pharmacies

To review and validate a questionnaire on knowledge of injectable insulin management (JH-SEFAC) by patients with diabetes for use in community pharmacies. Study design: cross-sectional observational in Spanish community pharmacies during the first half of 2023. Inclusion criteria: patients with diabetes, of legal age, on insulin treatment. Questionnaire design: a nominal group of community pharmacists reviewed and piloted the initial questionnaire to determine its feasibility. It was approved by the CEIC of Aragón (PI22/375). Content validation: by a multidisciplinary group of experts in diabetes, using an ad hoc evaluation questionnaire of 10 questions (Likert scale of 1-5). Reliability: by means of the internal consistency index (Cronbach's alpha) and the intraclass correlation coefficient (ICC). Reproducibility (test/retest): the results of the questionnaire administered twice 2-3 weeks apart to the group of patients were compared. Pharmacists members of the SEFAC Diabetes Working Group collaborated. Sample: calculated in 127 subjects (95% CI and precision of 10%). 20 community pharmacies from 13 autonomous communities included 131 patients. The expert assessment was 4.52 out of 5 (90.4%). The Keiser-Meyer-Olkin test was 0.626 and Bartlett's test was significant (p<0.001). The Cronbach's alpha of the global questionnaire was 0.804 and the ICC was 0.902. The mean score of the questionnaire was 15.98 out of 31 points. The JH-SEFAC questionnaire was validated to evaluate the management of insulin injectables, providing community pharmacists with a valuable tool for therapeutic education.

Identification and Characterization of a Novel Insulin-like Receptor (LvRTK2) Involved in Regulating Growth and Glucose Metabolism of the Pacific White Shrimp Litopenaeus vannamei.

The insulin receptor (IR) plays a crucial role in the growth and metabolism of animals. However, there are still many questions regarding the IR in crustaceans, particularly their role in shrimp growth and glucose metabolism. In this study, we identified a novel insulin-like receptor gene in Litopenaeus vannamei and cloned its full length of 6439 bp. This gene exhibited a highly conserved sequence and structural characteristics. Phylogenetic analysis confirmed it as an unreported RTK2-type IR, namely, LvRTK2. Expression pattern analysis showed that LvRTK2 is primarily expressed in female reproductive and digestive organs. Through a series of in vivo and in vitro experiments, including glucose treatment, exogenous insulin treatment, and starvation treatment, LvRTK2 was confirmed to be involved in the endogenous glucose metabolic pathway of shrimp under different glucose variations. Moreover, long-term and short-term interference experiments with LvRTK2 revealed that the interference significantly reduced the shrimp growth rate and serum glucose clearance rate. Further studies indicated that LvRTK2 may regulate shrimp growth by modulating the downstream PI3K/AKT signaling pathway and a series of glucose metabolism events, such as glycolysis, gluconeogenesis, glycogen synthesis, and glycogenolysis. This report on the characteristics and functions of LvRTK2 confirms the important role of RTK2-type IRs in regulating shrimp growth and glucose metabolism.

High-intensity exercise alongside insulin alleviates muscle atrophy in type 1 diabetes mellitus concomitant with modulation of mitophagy-related proteins in skeletal muscle

Background: Diabetes patients’ quality of life can be severely impacted by diabetic muscle atrophy.Aim: This study aimed to explore the impact of high-intensity exercise (HIE) alongside insulin treatment on muscle atrophy in a rat model of type 1 diabetes mellitus (T1DM).Methodology: Fifty rats were allocated into five groups; Group 1, control sedentary (CS), T1DM was elicited in the rest of the groups by giving them Streptozotocin (STZ) (60 mg/kg), where group 2 (DS) remained sedentary, while groups 3,4,5 were treated with insulin after induction of diabetes. Group 4 (DI+MIE) and 5 (DI+ HIE) underwent moderate and high-intensity exercise, respectively.Results: HIE for 14 days combined with insulin treatment significantly restored muscle strength and mass with a significant modification in the mitophagy-related proteins and fibroblast growth factor 21 (FGF 21) compared to other treated groups.Conclusion: This study concluded that there is a therapeutic role for HIE with insulin against T1DM-induced muscle atrophy.

8569 Defining Cell-Intrinsic Defects In Hepatic Insulin Resistance In Type 2 Diabetes Using A Human iPS Cell-Derived Disease-In-A-Dish Model

Abstract Disclosure: A. Gattu: None. M. Tanzer: None. T. Yaron: None. L. Cantley: None. C.R. Kahn: None. Hepatic insulin resistance is central to type 2 diabetes (T2D). Understanding the cellular drivers underlying insulin resistance in the liver is challenging since, in vivo, this can be due to cell-intrinsic defects in insulin signaling, as well as the effects of multiple circulating factors that can modify insulin signaling. Here, we have utilized inducible pluripotent stem cells (iPS) from 8 control and 8 T2D patients differentiated in vitro into hepatocytes (iHeps) to dissect the cell-intrinsic defects in hepatic insulin resistance. We find that following stimulation with insulin, T2D iHeps displayed “pathway-selective insulin resistance,” in which insulin failed to suppress gene expression of critical gluconeogenic enzymes (PCK1, G6PC) but continued to stimulate expression of the lipogenic enzymes (FASN, ACACA). This was associated with a 1.5-fold higher level of insulin stimulation of C[1]4 acetate into lipids, i.e., de novo lipogenesis. Immunoblotting analysis showed T2D iHeps exhibited a 50% reduction in phosphorylation of the insulin receptor IRY[1][1]35 and ∼ 30% reductions in AKTT308, GSK3αS2[1]/GSK3βS9, and FOXO1T24/FOXO3aT32 in T2D following insulin stimulation for 10 minutes. To define the full spectrum of alterations in signaling in iHeps, we used unbiased LC-MS/MS-based phosphoproteomics. This revealed alterations in 987 insulin-regulated phosphosphorylations that had increased phosphorylation after insulin treatment and alterations in 723 sites for which insulin decreased phosphorylation (with a |fold-change| &amp;gt;1.5 and adj. p &amp;lt; 0.05). These alterations were of two types: 43% of the altered insulin-regulated phosphosites showed reduced or “impaired” insulin regulation, but 57% of the phosphosites displayed new or significantly increased insulin-regulated phosphorylations in T2D, i.e., “emergent” signaling. The impaired signaling in T2D included losses in the insulin receptor signaling cascade, Rho-GTPase pathway, Notch-HLH, and anti-viral mechanisms of IFN-stimulated genes. In contrast, emergent signaling included other components of the Rho-GTPase pathway, metabolism of RNA, membrane trafficking, and chromatin-modifying enzymes. Using an AI-based kinase-substrate association analysis, we found that the deficiencies in signaling represented reduced actions of kinases AKT2, AKT3, PKCθ, CHK2, PHKG2, and/or STK32C kinases, while the emergent changes represented increases in ROCK1, ROCK2, MST4 and/or BCKDK kinase activity. In summary, phosphoproteomic analyses of iHeps revealed a comprehensive insulin signaling network disrupted in insulin resistance in the liver in T2D, which underlies the etiology of insulin resistance. These alterations can be ascribed to changes in the activity of two classes of upstream kinases, representing potential new targets for treating T2D. Presentation: 6/1/2024

6674 Non-Progressive Diabetes Leading to Neurologic Diagnosis

Abstract Disclosure: F.L. Thelmo: None. M. Murugesh: None. B. Simon: None. Introduction: The autoantibody GAD (anti-glutamic acid decarboxylase) is highly associated with Type 1 diabetes (T1DM) and Latent Autoimmune Diabetes in Adulthood (LADA). If GAD is detected before the onset of overt diabetes, typically 80% of patients with abnormal glucose tolerance progress to insulin deficiency and the need for insulin treatment after 5 years.[1] Stiff Person Syndrome (SPS) is also associated with GAD antibodies, but in SPS, the GAD antibodies are believed to be different epitopes that target GABA production in neuromuscular pathways. We present a case of presumed LADA that did not progress for 30 years, with progressive neurologic symptoms leading to a diagnosis of SPS in later adulthood.Case: A 52-year-old female presented for evaluation of T1DM and worsening neuropathies. She had a long history of prediabetes, with mildly elevated glucose values noted on labs since her early twenties. There was no family history of T1DM or autoimmune conditions. Six years ago, she sought endocrine evaluation. HgbA1c values were 6.1 to 6.6%. Intermittent use of continuous glucose monitoring (CGM) revealed post-prandial hyperglycemia up to 180mg/dL, occasionally (but rarely) exceeding 200mg/dL. She recalls being told that she had positive antibodies (unclear which ones tested) and given a diagnosis of T1DM. She declined insulin and maintained glycemic control with carbohydrate restriction and exercise; there were no episodes of diabetic ketoacidosis. She then developed neurologic symptoms: fullness, tightness and bloating in the abdomen (diagnosed with gastroparesis on scanning) and after a COVID 19 booster in 2021, muscle spasms in the legs and back with worsening abdominal tightness. At the time of her current presentation, A1C was 6.4%, glycated albumin was 14.4% (prediabetes range 13.6 - 15.5%) and CGM time in range was 99%. A non-fasting C-peptide was 3.6 ng/mL (1.1- 4.4ng/mL) with glucose of 119 mg/dL. Repeat antibody testing revealed undetectable IA-2 and ZnT8 antibodies, but GAD was grossly elevated at 1,015.3 U/mL. Given the unusually high GAD titer, SPS was suspected, and this diagnosis was confirmed on referral to neurology. The patient was advised to liberalize diet and will be monitored with HgbA1c and serial C-peptide levels to assess progression in the future. Discussion: While high GAD antibody levels are associated with progression to insulin dependence in adults with LADA, in SPS the GAD titers tend to be even higher2. The presence of only one auto-antibody for T1DM (and not multiple), long-standing non-progressive hyperglycemia, and normal C-peptide pointed away from autoimmune diabetes being the etiology for mild glucose intolerance in this patient. If neurologic symptoms are present, high GAD should prompt the evaluation for other syndromes associated with GAD antibody epitopes such as SPS. Presentation: 6/2/2024

7481 Beyond the Operation Room: A Retrospective Study on Diabetes and Post-Operative Hyperglycemia Outcomes

Abstract Disclosure: P. Aron: None. T. Zaihra Rizvi: None. M. Hodge: None. J. Upadhyay: None. Introduction: Optimal, evidence based intraoperative and postoperative glycemic management may reduce poor surgical outcomes. Research design: This is a retrospective study from a single center to estimate quality gaps in perioperative glycemic management in patients with diabetes undergoing major surgery requiring general anesthesia between Oct 2022 and Dec 2022. Study Cohort: Patients &amp;gt; 18 years old, who underwent major surgery (&amp;gt;3 hrs) under general anesthesia, had diabetes mellitus based on Hba1c &amp;gt; 6.5% within last 1 year or as listed diagnosisThis is an ongoing study. We have currently looked at 79 patients of which 61 were in the hyperglycemic group (glucose &amp;gt; 180 mg/dL) and 18 in normoglycemic group (glucose &amp;lt; 180mg/dL) post-operatively. Methods: Baseline characteristics, perioperative outcomes, and operative details between the hyperglycemic and normoglycemic groups were compared using Kruskal-Wallis's rank sum test for continuous variables and χ2 or Fisher's exact tests using categorical variables. Results: Patients who were found to have hyperglycemia in the first 24 hours after surgery had a higher preop A1c of 7.4% vs 6.7% in the normoglycemia group (p-value = 0.047). They also had a higher BMI of 32 as compared to 30 respectively and a reduced GFR of 60 vs 73 in the normoglycemic group (P=0.069). 24 hours leading into surgery, the hyperglycemia group had a high average glucose of 196 mg/dL as compared to 135 mg/dL (p-value = 0.001). During the intraoperative period which lasted on average of 350 minutes (5.5 hours) there was an average glucose check of 3.2 times averaging 221 mg/dL for the hyperglycemia group compared to 2.2times averaging 174 mg/dL (P = 0.017). 62% of patients with intraoperative hyperglycemia DIDNOT receive IV insulin treatment in the hyperglycemic group. Steroid use was equal in both groups. 24 hours after surgery, patients in the hyperglycemia group had an average glucose reading of 252 mg/dL compared to 145 mg/dL in the normoglycemia group (P &amp;lt; 0.001).Endocrinology was not consulted in 87% of patients with hyperglycemia. Looking at our endpoints, readmission rate was 23% in the hyperglycemia group as opposed to 11% in normoglycemia. There were 4 patients who had a 90-day mortality from the hyperglycemia group compared to no patients in normoglycemia. 37% of patients had post-op complications in the hyperglycemia vs 22% in the euglycemia group (P 0.269). The hospital stay was the same for both groups averaging 8 days. Conclusions: Intraoperative hyperglycemia leads to poor outcomes. Formulating policy around insulin administration, frequency and monitoring of blood sugars during major surgeries and endocrine consultation in patients with Type 2 DM can achieve better glycemic management and postoperative outcomes. Presentation: 6/2/2024

7834 Case Series using intravenous insulin to treat Severe Hypertriglyceridemia

Abstract Disclosure: F. Khan: None. M. Eltayeb: None. J. Ryan: None. M. Murphy: None. Background: Very severe hypertriglyceridemia (&amp;gt;22.4 mmol/L) is associated with high risk of acute pancreatitis and atherosclerotic cardiac events. Conventional treatments tend not to yield immediate results. There is a lack of clinical guidelines for acute very severe HTG; and potential therapeutic options such as insulin, heparin, plasmapheresis, and octreotide have been tested and shown to be effective. We present a series of four cases where intravenous insulin was useful as an emergency treatment for severe HTG. Clinical Cases: Case 1: 48-year-old male was admitted with very severe hypertriglyceridemia with triglycerides levels of 45.3mmol/L (reference range: 0-1.7 mmol/L), new diagnosis Diabetes Mellitus with ketosis and was started on intravenous insulin. After three days of intravenous insulin, triglyceride levels reduced by 47.93%. Case 2: 28-year-old male, admitted with acute pancreatitis secondary to very severe hypertriglyceridemia (66.9mmol/L), a new diagnosis of Diabetes Mellitus with ketosis, was commenced on intravenous insulin. There was a reduction in triglycerides by 77.5% in 3 days and 96.6% in 9 days with intravenous insulin treatment. Case 3: 29-year-old female, admitted with new diagnosis Diabetes Mellitus with ketosis and very severe hypertriglyceridemia (50.67mmol/L) was treated with intravenous insulin. Total triglyceride reduction was 65.8% in 48 hours. Case 4: 27-year-old female, admitted Diabetic Ketoacidosis (DKA), new diagnosis Diabetes Mellitus, very severe hypertriglyceridemia (24.3mmol/L) was treated with intravenous insulin. 65.8% reduction in triglycerides was seen in after 72 hours. Conclusion: These cases show the efficacy of insulin infusion with encouraging results, especially when plasmapheresis is not readily available however larger studies including a randomized controlled trials is needed to confirm the efficacy and safety for the use of intravenous insulin to establish a universal and effective treatment for this severe life-threatening metabolic disorder. Reference: Simha V. Management of hypertriglyceridemia BMJ 2020; 371 :m3109 doi:10.1136/bmj.m3109 Presentation: 6/3/2024

6680 GLP-1 Agonists in Type 1 Diabetes - Indications and Use

Abstract Disclosure: P. Panjawatanan: None. N. Radovanovic: None. R.J. Comi: None. Introduction: Insulin therapy is the mainstream treatment in patients with Type 1 diabetes. The use of insulin, though mimicking normal physiology, is associated with weight gain. Glucagon-like peptide 1 (GLP-1) agonists are a class of antidiabetic medication that lowers blood sugar levels and helps promote weight loss. We propose that GLP-1 agonists can reverse the trend of weight gain and help lower hemoglobin A1C (A1C) levels in patients with Type 1 diabetes who were gaining weight. Method: A retrospective chart review was performed at a single institution’s endocrine practice over five years. Patients with Type 1 diabetes with concomitant GLP-1 agonists used for at least one year were included. Observed outcomes were the change in A1C, weight, and basal insulin use compared at baseline, 6 months, and 12 months using mixed models repeated measures. The result was reported as estimated means (95%CI). Statistical significance was determined by a p-value less than 0.05. Results: There were 49 patients included in the study. The mean age was 44.7 years old. There were 32 females (65.3%) and 17 males (34.7%). The mean duration of diabetes was 24.6 years. Thirty-five patients (71.4%) used insulin pumps, and fourteen (28.6%) were on multiple daily injections. Overall, patients had been gaining an average of 2.0 kg per year. After the treatment with GLP-1 agonists, weight was significantly reduced at 12 months (90.0 kg (95%CI 84.9-95.1), p&amp;lt;0.001) compared to baseline (97.6 kg (95%CI 92.7-102.5)). The A1C was significantly improved at 12 months (7.6% (95%CI 7.2-7.9), p&amp;lt;0.001) compared to the baseline (8.2% (95%CI 7.9-8.6)). Total daily basal dose was significantly reduced at 12 months (35.8 units (95%CI 29.8-41.9), p&amp;lt;0.001) compared to the baseline (39.2 units (95%CI 33.3-45.1)). The improvement in the parameters was more pronounced at 6 months after treatment but persisted at 12 months. Conclusion: Weight gain is a consequence of insulin usage in both Type 1 and Type 2 diabetes, which considerably impacts treatment outcomes and the development of comorbidities. We conclude that GLP-1 agonists are helpful to reverse the trend of weight gain and help lower A1C levels in patients with Type 1 diabetes who require life-long insulin treatment. 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) &amp;gt;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) &amp; post-prandial plasma glucose (PPG) improved significantly from baseline to 6 months across all four treatment groups (p&amp;lt;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&amp;lt;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 (&amp;lt;70 mg/dL and &amp;lt;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

Improved treatment satisfaction with once-weekly insulin icodec compared with once-daily basal insulin in individuals with type 2 diabetes: An analysis of patient-reported outcomes and participant interviews from ONWARDS 2 and 5 and a physician survey from ONWARDS 1

AimsThe ONWARDS phase 3a clinical trials evaluated once-weekly insulin icodec (icodec) versus once-daily basal insulin in type 2 diabetes. This analysis investigated the treatment-related experiences of participants from ONWARDS 5 and 2, and physicians from ONWARDS 1. MethodsPatient-reported outcomes were only collected during ONWARDS 5 (icodec with a dosing guide app vs. once-daily basal analogues) and 2 (icodec vs. once-daily insulin degludec). ONWARDS 1 (icodec vs. once-daily insulin glargine U100) physicians’ treatment preferences and satisfaction were obtained via an online survey. ResultsIn ONWARDS 5 and 2, there was a statistically significantly greater increase in total treatment satisfaction from baseline to end of treatment for icodec/icodec with app versus once-daily comparators, mostly driven by participants’ willingness to continue and recommend treatment. In ONWARDS 2, 93.7 % of icodec users preferred once-weekly over once-daily basal insulin, mainly owing to less frequent injections and ease of use. ONWARDS 1 physicians reported greater satisfaction with once-weekly than with once-daily basal insulin and were more likely to recommend once-weekly injections. ConclusionsThese results demonstrate improved treatment satisfaction with, and strong preferences for, once-weekly versus once-daily basal insulin. Treatment convenience and willingness to continue and recommend once-weekly basal insulin treatment were highlighted.Clinical trial registrations: ONWARDS 1: NCT04460885; ONWARDS 2: NCT04770532; ONWARDS 5: NCT04760626