Low-dose Insulin Research Articles

Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance.

Glucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We had previously shown that prolonged exposure of insulin-responsive cells to insulin in the absence of high levels of glucose led to insulin resistance. In the present study, we show that the underlying cause for the impaired insulin signalling is the defective PI3K/AKT pathway. The observed insulin resistance is likely due to epigenetic alterations, as it can be maintained for several generations even when insulin is not provided, and epigenetic modifiers can reverse it. We also show that liver cell line (BRL-3A) developed impaired insulin signalling upon prolonged exposure to insulin in the absence of high levels of glucose. Transcriptomic analysis of the insulin-sensitive and resistance cells uncover altered signalling networks involved in chromatin remodelling, Rho GTPases, and ubiquitination. Furthermore, trimethylation of histone H3 at lysine 4 (H3K4me3) is increased in insulin-resistant cells. We extended these studies to mice, and show that mice injected with low doses of insulin when fasting develop insulin resistance with impaired glucose tolerance and increased HOMA-IR index. Altogether, these findings suggest that dysregulated synthesis of insulin in the absence of glucose stimulus could lead to epigenetic alterations that may ultimately result in insulin resistance.

"TRATAMENTO DA CETOACIDOSE DIABÉTICA NA UNIDADE DE TERAPIA INTENSIVA"

Introduction: Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes caused by a lack of insulin, leading to hyperglycemia and acidosis. Factors such as infections and poor insulin administration can trigger it, and its urgent treatment in the ICU involves fluid replacement, intravenous insulin, and control of complications. Methodology: This article is a literature review on the treatment of diabetic ketoacidosis in the ICU, based on studies from the last 10 years available in English and Portuguese in the PubMed, SciELO, and BVS databases. Complete and free articles were included, excluding those that did not directly address the topic. Results and Discussion: The treatment of diabetic ketoacidosis (DKA) in the ICU follows protocols to quickly correct metabolic and hemodynamic alterations. Initial replacement of isotonic fluids treats severe dehydration and improves tissue perfusion. Low-dose intravenous insulin corrects ketosis and hyperglycemia, but should be adjusted accordingly, with potassium levels also need to be monitored and replaced. Continuous monitoring of blood glucose and electrolytes is crucial to avoid complications such as cerebral edema. Identifying and treating the underlying cause of DKA, such as infections, is essential to prevent recurrences. Conclusion: The treatment of diabetic ketoacidosis in the ICU is mainly based on rapid fluid replacement, controlled insulin administration, and continuous monitoring. Potassium management and identification of the cause are essential to prevent recurrences and improve prognosis, with the ICU being the ideal setting for intensive care and reducing mortality.

Effects of Sargassum Glaucescens Algae on Blood Glucose Level in Diabetic Rats With a High-Fat Diet and Streptozotocin

Background: Diabetes medications can have dramatic effects on controlling the disease and achieving the therapeutic goals of people with diabetes, but most of them have side effects. Given the role of brown algae in maintaining blood glucose levels, their investigation can provide valuable information for the control and treatment of type 2 diabetes (T2D). Accordingly, this study investigated the effect of Sargassum glaucescens on blood glucose levels in diabetic rats. Materials and Methods: Forty-six randomly selected rats were assigned to five groups. The control group was fed the normal diet, and diabetic rats were induced by streptozotocin (STZ) and a high-fat diet (HFD). The other groups included the diabetes+low dose insulin group, diabetes+high dose insulin, and diabetic rats that received Sargassum Glaucescens 20% alga powder added to fatty food. Weekly blood glucose, hemoglobin A1c (HbA1c), the amount of drinking water, food consumed, urine volume, glucose tolerance test (GTT), and insulin tolerance test (ITT) underwent measurement. Results: The mean of ITT in the diabetic group was significantly higher than in the control group (P=0.001), which indicates insulin resistance in these groups. The lowest blood glucose concentration was in the high-dose insulin group; weekly blood glucose, GTT, ITT, and HbA1c in the alga group did not change compared to diabetes. However, some indicators, such as HbA1c, were better in the group receiving algae than in the low-dose insulin group. The weight of the group receiving algae increased until the third week, but it decreased after that, and at the end of the study, it was lower in this group than in the control group (P<0.001). Conclusion: The study findings revealed that Sargassum Glaucescens algae had no significant effect on serum glucose, GTT, ITT, or HbA1c in the studied rats.

Simultaneous Pancreas and Kidney Transplantation from Donors after Circulatory Death in Switzerland.

Background: Simultaneous pancreas and kidney transplantation (SPK) remains the only curative treatment for type I diabetics with end-stage kidney disease. SPK using donors after circulatory death (DCD) is one important measure to expand the organ pool for pancreas transplantation (PT). After initial doubts due to higher complications, DCD SPK is now considered safe and equivalent to donation after brain death in terms of survival and graft function. Materials and Methods: We assessed pancreas and kidney graft function, as well as complications of the first three patients who underwent a DCD SPK in Switzerland. Two transplantations were after rapid procurement, one following normothermic regional perfusion (NRP). Results: Intra- and postoperative courses were uneventful and without major complications in all patients. In the two SPK after rapid procurement, pancreas graft function was excellent, with 100% insulin-free survival, and hemoglobin A1C dropped from 7.9 and 7.5 before SPK and to 5.1 and 4.3 after three years, respectively. Kidney graft function was excellent in the first year, followed by a gradual decline due to recurrent infections. The patient, after NRP SPK, experienced short-term delayed pancreatic graft function requiring low-dose insulin treatment for 5 days post-transplant, most likely due to increased peripheral insulin resistance in obesity. During follow-up, there was persistent euglycemia and excellent kidney function. Conclusions: We report on the first series of DCD SPK ever performed in Switzerland. Results were promising, with low complication rates and sustained graft survival. With almost half of all donors in Switzerland currently being DCD, we see great potential for the expansion of DCD PT.

Analysis of factors affecting the accuracy of low-dose insulin dosage using syringes and vials: a cross-sectional study in a Japanese regional hospital.

The online version contains supplementary material available at 10.1007/s13340-024-00726-5.

Implementation of perioperative blood glucose monitoring and insulin infusion protocol can decrease postoperative infection rate in diabetic patients undergoing elective craniotomy: An observational study

BackgroundSevere perioperative hyperglycemia (SH) is a proven risk factor for postoperative complications after craniotomy. To reduce this risk, it has been proposed to implement the standardized clinical protocol for scheduled perioperative blood glucose concentration (BGC) monitoring. This would be followed by intravenous (IV) insulin infusion to keep BGC below 180 mg/dl in the perioperative period. The aim of this prospective observational study was to assess the impact of this type of protocol on the postoperative infection rate in patients undergoing elective craniotomy. MethodsA total of 42 patients were prospectively enrolled in the study. Protocol included scheduled BGC monitoring in the perioperative period and rapid-acting insulin IV infusion when intraoperative SH was detected. The diagnosis of infection (wound, pulmonary, blood stream, urinary tract infection or central nervous system infection) was established according to CDC criteria within the first postoperative week. A previously enrolled group of patients with sporadic BGC monitoring and subcutaneous insulin injections for SH management was used as a control group. ResultsAn infectious complication (i.e., pneumonia) was diagnosed only in one patient (2 %) in the prospective group. In comparison with the control group, a decrease in the risk of postoperative infection was statistically significant with OR = 0.08 [0.009 – 0.72] (p = 0.02). Implementation of the perioperative BGC monitoring and the correction protocol prevented both severe hyperglycemia and hypoglycemia with BGC < 70 mg/dl. ConclusionScheduled BGC monitoring and the use of low-dose insulin infusion protocol can decrease the postoperative infection rate in patients undergoing elective craniotomy. Future studies are needed to prove the causality of the implementation of such a protocol with an improved outcome.

Smart Algorithms for Efficient Insulin Therapy Initiation in Individuals With Type 2 Diabetes: An in Silico Study.

Insulin-naive subjects with type 2 diabetes (T2D) start basal insulin titration from a low initial insulin dose (IID), which is adjusted weekly or twice per week based on fasting plasma glucose (FPG) measurement as recommended by the American Diabetes Association (ADA). The procedure to reach the optimal insulin dose (OID) is time-consuming, especially in subjects with high insulin needs (HIN). The aim of this study is to provide a fast and effective, but still safe, insulin titration algorithm in insulin-naive T2D subjects with HIN. To do that, we in silico cloned 300 subjects, matching a real population of insulin-naive T2D and used a logistic regression model to classify them as subjects with HIN or subjects with low insulin needs (LIN). Then, we applied to the subjects with HIN both a more aggressive insulin dose initiation (SMART-IID) and two newly developed titration algorithms (continuous glucose monitoring [CGM]-BASED and SMART-CGM-BASED) in which CGM was used to guide the decision-making process. The new titration algorithm applied to HIN-classified individuals guaranteed a faster reaching of OID, with significant improvements in time in range (TIR) and reduction in time above range (TAR) in the first months of the trial, without any clinically significant increase in the risk of hypoglycemia. Smart basal insulin titration algorithms enable insulin-naive T2D individuals to achieve OID and improve their glycemic control faster than standard guidelines, without jeopardizing patient safety.

Sustained insulin treatment restoring metabolic status, body weight, and cognition in an anorexia nervosa-like animal model in mice

IntroductionAnorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. MethodsAN-like model was established through dietary restriction (DR). On days 1–25, mice were on DR, and on days 26–31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. ResultsThe delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. ConclusionThe PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."

Low dose insulin infusion versus the standard dose in children with diabetic ketoacidosis: a meta-analysis.

Aim: This systematic review aims to consolidate findings from current clinical trials that compare the effectiveness of insulin infusion at 0.05IU/kg/h versus 0.1IU/kg/h in managing pediatric diabetic ketoacidosis. Methods: We searched several databases, including PubMed, Embase, Scopus, Cochrane Central and Web of Science. Our primary outcomes were time to reach blood glucose ≤250mg/dl and time to resolution of acidosis. Secondary outcomes included rate of blood glucose decrease per hour, incidence of hypoglycemia, hypokalemia, treatment failure, and cerebral edema. Results & conclusion: The present study establishes that a low insulin dose exhibits comparable efficacy to the standard dosage for managing pediatric patients suffering from diabetic ketoacidosis, with a lower incidence of complications.

Exploring Multiple Endocrinological Issues and Dysautonomia in a Rare Case: Hypoparathyroidism in MIRAGE Syndrome.

MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.

Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine

ObjectiveThis study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance.MethodsThis was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120–180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality.ResultsThe 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052–0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20–3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 19.7 h, SD ± 12.6 h X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 29.3 h, SD ± 19.6 h, Z-value − 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 29 h, SD ± 12.7 h, X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 55.1 h, SD ± 44.5 h, Z-value: − 1.92, p-value 0.05).ConclusionAdministration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

Performance of Tandem Control IQ During Outdoor Physical Activity in Children and Adolescents with Type 1 Diabetes.

Background: Few data are available in children with type 1 diabetes using automated insulin delivery systems during physical activity (PA). We evaluated the time in range (TIR) during 2-h of outdoor PA in children using t:slim X2 with Control-IQ® technology. Materials and Methods: Caucasian children and adolescents, aged 9-18 years using t:slim X2 with Control-IQ technology were recruited during a local sporting event. Participants were divided into two groups: Group A practiced endurance activities for 60 min (1000-meter run, a jump circuit) and then power activities for 60 min (80-meter run, long jump); Group B practiced power activities for 60 min and then followed by endurance activities for 60 min. Ninety minutes before the PA, participants had lunch and self-administered a low-dose insulin, reduced by 50% compared to their regularly calculated meal dose per pump calculator. DexcomG6® data were downloaded. Results: Twenty-six children were recruited, 2 refused PA. Participants were divided as follows: 13 in Group A (7 males, median age 14.6 years) and 11 in Group B (8 males, median age 13.5 year). The mean glucose level when PA started was similar between groups (P = 0.06). Subjects in Group B showed a higher TIR than those in Group A ([50.4%, 95% confidence interval, CI: 33.8-75] vs. 39.6% [95% CI: 26.9-58.3], respectively [P = 0.39]). A significantly better TIR in Group B (53.8%, 95% CI: 30.2-96.1) compared to Group A (17.4%, 95% CI: 7.3-41.7, P = 0.02) was recorded during the first session. During the second session, TIR increased in both groups. There were no episodes of serious or severe hypoglycemia. Conclusions: No serious or severe hypoglycemic episodes were recorded during PA performed 90 min after lunch. Future studies using t:slim X2 with Control-IQ technology are necessary.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

OR12-04 LEAP2 Deletion Does Not Counteract The Effects Of Ghrelin Deletion During Insulin-Induced-Hypoglycemia

Abstract Disclosure: K. Shankar: None. S. Varshney: None. D. Gupta: None. O. Singh: None. S.B. Ogden: None. S. Osborne-Lawrence: None. N.P. Metzger: None. C.P. Richard: None. J.M. Zigman: Grant Recipient; Self; Novo Nordisk. Objective: The hormones ghrelin and LEAP2 both are endogenous ligands for the growth hormone secretagogue receptor (GHSR). Whereas ghrelin activates GHSR, LEAP2 blocks ghrelin from activating GHSR and also inhibits GHSR constitutive activity. It is via GHSR that the glucoregulatory actions of ghrelin and LEAP2 are mediated. These glucoregulatory actions are highlighted by the findings of severe hypoglycemia in ghrelin-KO mice and LEAP2-overexpressing mice when they are submitted to an acute-on-chronic caloric restriction protocol. Also, recently, our group showed that ghrelin-KO mice require a much higher glucose infusion rate (GIR) and exhibit markedly reduced elevation of counterregulatory hormones when submitted to a hyperinsulinemic-hypoglycemic clamp. In the current study, we investigated the potential of LEAP2 to protect against insulin-induced-hypoglycemia and counteract the effects of ghrelin deletion during the hypoglycemic clamp. Methods: Eight-ten week-old male wild-type (WT), Ghrelin-KO, LEAP2-KO, and LEAP2/Ghrelin-doubleKO (lacking both ghrelin and LEAP2 ) littermates were used for this study (n=7-10 per genotype). Mice were implanted with a right jugular vein catheter. Five days later, hyperinsulinemic-hypoglycemic clamps were performed in conscious, unrestrained mice. A low dose of insulin was infused at 4 mU/kg/min i.v. over 2 hr. A 20% glucose solution was simultaneously infused at a variable rate to achieve hypoglycemia (35–45 mg/dL) during the final 30 min. Blood glucose was measured via tail nicks every 5 min. Results: We were able to achieve the target hypoglycemic range in all four genotypes using this protocol. As compared to WT mice, Ghrelin-KO mice required markedly elevated (∼110% higher) GIRs (10±4 mg/kg/min in WT vs. 22±2 mg/kg/min in Ghrelin-KO mice; p=0.03) by the end of the 2-hr clamp. The GIRs required by LEAP2-KO mice were equivalent to those of WT mice (7±2 mg/kg/min in LEAP2-KO; p=n.s.). Furthermore, although during the first 60 min of the clamp, LEAP2/Ghrelin-doubleKO mice exhibited slightly lower blood glucose levels than the other genotypes and during the middle 60 min of the clamp, they required higher GIRs than the other genotypes, by the end of the 2-hr clamp, their GIRs were similar to Ghrelin-KO mice (25±3 mg/Kg/min in Ghrelin/LEAP2-doubleKO mice, p=n.s.). Conclusions: These data suggest a complex effect of LEAP2 on blood glucose. Alone, LEAP2 deletion does not impact insulin sensitivity. When coupled with ghrelin deletion, LEAP2 deletion lowers fasting blood glucose and causes greater insulin sensitivity early on during the hyperinsulinemic-hypoglycemic clamp. By the end of the clamp, this effect of LEAP2 deletion when coupled to ghrelin deletion is gone. Altogether, these results suggest that LEAP2 deletion does not counteract the effects of ghrelin deletion during insulin-induced hypoglycemia. Presentation: Friday, June 16, 2023

Effect of Immersion Treatment in Bovine Insulin on Growth, Nutrient Retention and Proteolytic Enzyme Activity in Chaivna Punctatus (BLOCH)

Effect of bovine insulin immersion on growth response in Channa punctatus fingerlings was studied. The fish were immersed in insulin at 10 or 50 14/100 distilled water for 15 minutes weekly for 11 weeks, with treatment without hormone as control. They were maintained under laboratory conditions (LD 12:12 at 25LC) for 80 days. Growth performance including nutrient retention were significantly (P &lt; 0.05) enhanced in fingerlings treated with the lower dose (10 j.tg) of insulin in comparison with control or fish treated with the higher dose (50 lig) of hormone. The percent gain in body weight was 100.9±0.46 at the lower dose of insulin treatment while at higher dose (70.70.22) and controls (60.70.038) the values remained low. Food conversion values and excretion of metabolites (N-NHe and o-PO4-) remained significantly low (P &lt; 0.05) and nutrient retention (PER, GPR and GER) high at the lower dose of insulin. The fingerlings treated with lower dose of insulin also showed significantly high (P &lt; 0.05) intestinal proteolytic enzyme activity, hepato-somatic index (HSI) and viscero-somatic index (VSI) while a reduction in hepatic glycogen levels was observed. Carcass composition determined at the end of treatment period indicated high accumulation of protein and fat in fish treated with the lower dose of hormone. These findings indicate that at the lower dose insulin acts as an anabolic hormone in C. punctatus.

Insulin alleviates murine colitis through microbiome alterations and bile acid metabolism

BackgroundInsulin has been reported to exhibit anti-inflammatory activities in the context of bowel inflammation. However, the role of the interaction between insulin and the microbiota in gut health is unclear. Our goal was to investigate the mechanism of action of insulin in bowel inflammation and the relationship between insulin and the gut microbiota.MethodsWe used acute and chronic murine models of inflammatory bowel disease (IBD) to evaluate whether insulin influences the progression of colitis. Colonic tissues, the host metabolome and the gut microbiome were analyzed to investigate the relationship among insulin treatment, the microbiome, and disease. Experiments involving antibiotic (Abx) treatment and fecal microbiota transplantation (FMT) confirmed the association among the gut microbiota, insulin and IBD. In a series of experiments, we further defined the mechanisms underlying the anti-inflammatory effects of insulin.ResultsWe found that low-dose insulin treatment alleviated intestinal inflammation but did not cause death. These effects were dependent on the gut microbiota, as confirmed by experiments involving Abx treatment and FMT. Using untargeted metabolomic profiling and 16S rRNA sequencing, we discovered that the level of the secondary bile acid lithocholic acid (LCA) was notably increased and the LCA levels were significantly associated with the abundance of Blautia, Enterorhadus and Rumi-NK4A214_group. Furthermore, LCA exerted anti-inflammatory effects by activating a G-protein-coupled bile acid receptor (TGR5), which inhibited the polarization of classically activated (M1) macrophages.ConclusionTogether, these data suggest that insulin alters the gut microbiota and affects LCA production, ultimately delaying the progression of IBD.Graphical

Prolonged clinical remission of type 1 diabetes sustained by calcifediol and low-dose basal insulin: a case report.

Herein, we describe an unusually prolonged duration (31months) of the clinical remission phase in a 22-year-old Italian man with new-onset type 1 diabetes. Shortly after the disease diagnosis, the patient was treated with calcifediol (also known as 25-hydroxyvitamin D3 or calcidiol), coupled with low-dose basal insulin, to correct hypovitaminosis D and to exploit the anti-inflammatory and immunomodulatory properties of vitamin D. During the follow-up period, the patient retained a substantial residual β-cell function and remained within the clinical remission phase, as evidenced by an insulin dose-adjusted glycated hemoglobin value <9. At 24 months, we detected a peculiar immunoregulatory profile of peripheral blood cells, which may explain the prolonged duration of the clinical remission sustained by calcifediol as add-on treatment to insulin.

Efficacy of switching from basal-bolus insulin therapy to twice-daily insulin degludec/insulin aspart co-formulation plus insulin aspart in patients with poorly controlled type 2 diabetes.

The aim of this study was to evaluate the efficacy of twice-daily (BID) insulin degludec/insulin aspart (IDegAsp) co-formulation + once-daily (OD) bolus insulin aspart (IAsp) injection (IDegAsp BID-Plus) as simplified intensive insulin therapy in patients with poorly controlled type 2 diabetes mellitus (T2DM) with basal-bolus insulin therapy (BBIT). The retrospective study included 155 patients who switched from BBIT to IDegAsp BID-Plus. After the initiation of the treatment, 73 patients continued regular follow-up and insulin doses, number of injections, hemoglobin A1c (HbA1c) levels, and other parameters were recorded from their files at baseline, 24, and 52 weeks. The mean age of the study population was 54.3±10.2 years, the duration of T2DM was 9.7±5.7 years, fasting plasma glucose (FPG) was 252.7±66.7 mg/dl, and HbA1c levels were 10.5±1.5%. Among the included patients, 15 patients received five injections, 51 patients received four injections, and 7 patients received three injections per day. There was a significant decrease in HbA1c (respectively; 10.46±1.54%, 7.97±1.24%, 7.98±1.23%, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001), FPG (respectively; 251.6±66.5 mg/dl, 136.1±34.7 mg/dl, 125.4±67.0 mg/dl, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) and daily dose of insulin (respectively; 102.9±29.0 Unit, 73.2±18.2 U, 63.7±20.3 Unit, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) at the end of week 24 and 52. Based on real-world data, this study demonstrated that IDegAsp BID-Plus treatment provides rapid and sustainable blood glucose control with lower insulin doses and fewer injections than previous intensive insulin therapy.

788-P: Predictors of Achieving Target HbA1c &amp;lt;7% in People with Type 2 Diabetes Advancing Treatment with iGlarLixi

This post-hoc, pooled analysis of 4 trials aimed to identify factors associated with achieving target HbA1c &amp;lt;7.0% in people with type 2 diabetes (T2D) treated with iGlarLixi. People with T2D advancing from oral (LixiLan-O), GLP-1 RA (LixiLan-G), or insulin (LixiLan-L; SoliMix) therapies were randomized to iGlarLixi vs active comparators for 26 or 30 weeks. HbA1c was assessed at baseline (BL) and end of treatment, and responses were classified by the achievement or non-achievement of target HbA1c &amp;lt;7.0% (&amp;lt;53 mmol/mol). Predictive factors for achieving target were analyzed by univariable and multivariable stepwise logistic regression. Pooled analyses (N=1455) showed mean [SD] HbA1c, T2D duration, and insulin total daily dose at BL were lower in those who achieved (8.0 [0.7]%, 10.7 [6.7] y, 0.23 [0.15] U/kg) vs those who did not achieve (8.4 [0.7]%, 12.1 [7.0] y, 0.29 [0.15] U/kg) target HbA1c, respectively. Predictors of achieving target glycemic response (p&amp;lt;0.05) included lower BL HbA1c, lower T2D duration, and lower insulin dose at BL, as well as weight change (decrease) from BL. Age, BMI, and fasting plasma glucose at BL had no predictive value (Table). In conclusion, HbA1c, T2D duration, and insulin dose at BL, in addition to weight change from BL, were predictors of achieving target HbA1c &amp;lt;7.0% in people with T2D treated with iGlarLixi. Disclosure A.Y.Cheng: Advisory Panel; Merck &amp; Co., Inc., Pfizer Inc., GlaxoSmithKline plc., Other Relationship; Diabetes Canada, Research Support; Applied Therapeutics Inc., Speaker's Bureau; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., HLS Therapeutics Inc., Medtronic, Novo Nordisk, Sanofi, Insulet Corporation, Dexcom, Inc., Bausch Health, Canada. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. F.Lauand: Employee; Sanofi. L.Melas-melt: None. A.Alvarez: Employee; Sanofi. E.Souhami: Employee; Sanofi, Stock/Shareholder; Sanofi. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. Funding Sanofi

1521-P: Healthy, Nonobese South Asian Men Have Both Greater Peripheral and Hepatic Insulin Resistance than Chinese Men

Introduction: South Asian individuals, despite a healthy weight, are at a greater risk of type 2 diabetes mellitus than Chinese individuals. This may be secondary to higher peripheral and/or hepatic insulin resistance (IR). Using the 2-stepped hyperinsulinemic-euglycemic clamp, we examined the differences in peripheral and hepatic insulin resistance between healthy and non-obese South Asian and Chinese men. Bioimpedance analysis was performed to assess body composition. Methods: A 2-stepped hyperinsulinemic-euglycemic clamp was performed together with a “pancreatic” clamp by infusing somatostatin. A low-dose insulin (10 mU/m2/min) was infused for 2 hours, followed by high-dose insulin infusion (40 mU/m2/min) for 2 hours. Intravenous 20% glucose was infused to maintain euglycemia (blood glucose = 95-100 mg/dl) for the clamp duration. A higher M value (mg glucose per kg bodyweight per minute) during low-dose insulin infusion reflects lower hepatic IR while a higher M value during high-dose insulin infusion reflects lower peripheral IR. Results: The 2 groups (26 South Asian and 26 Chinese men) had similar age (27.3 vs 26.2 years, p = 0.338), but the South Asian group had slightly higher BMI (24.6 vs 22.9 kg/m2, p = 0.027) and body fat % (23.9 vs. 20.6%, p &amp;lt; 0.05). During low-dose step, the M-value was lower among South Asians compared to Chinese (0.8 ± 0.58 vs. 1.1 ± 0.55 mg/kg/min, p = 0.027). During high-dose step, the M-value was also lower among South Asians compared to Chinese (3.2 ± 2.6 vs. 5.2 ± 3.3 mg/kg/min, p = 0.015). The differences in the M-values between South Asian and Chinese individuals remained significant after correcting for body weight and fat-free mass. Conclusion: Despite a healthy weight, young South Asians have both greater hepatic and peripheral muscle IR than Chinese. Disclosure A.Y.L.Lim: None. H.Tan: None. C.Khoo: None. Funding National Medical Research Council of Singapore (MOH-CNIG19NOV-0002)