Insulin Exposure Research Articles

231-OR: Phase I Study Investigating the PD, PK, and Safety of AT247 in Comparison with Novorapid and Fiasp

Background: AT247, an ultra-rapid acting formulation of insulin aspart designed for faster absorption following s.c. injection, will lead to better postprandial glycaemic control and is key to the development of closed-loop pump systems. Method: Plasma glucose and serum insulin concentrations were measured in 19 adult male participants with T1DM following a single s.c. dose (0.3 U/Kg) of insulin in a randomised, double-blind, cross over euglycaemic clamp study. Results: Data presented as median; range. AT247 had a faster onset of glucose lowering effect than NovoRapid® and Fiasp® (onset of action: 17; 12-30 vs. 37; 20-88 vs. 23;16-50 mins). The early glucose lowering effect was greater for AT247 than NovoRapid® and Fiasp® (AUCGIR 0-60min: 212; 63-465 vs. 49; 0-303 vs. 91; 11-300 mg/kg; GIR=glucose infusion rate) (Fig 1A). Similarly, greater initial insulin exposure was seen for AT247 compared to NovoRapid® and Fiasp® (AUC Insulin 0-60min: 111; 48-205 vs. 41; 12-147 vs. 66; 25-188 mU*h/L). In addition, offset of exposure occurred earlier for AT247 than NovoRapid® and Fiasp® (time to late 50% Cmax Insulin: 173; 89-414 vs. 212; 106-389 vs. 221;106-441 mins). (Fig 1B). Comparisons are statistically significant with p<0.05. No safety signals were detected for AT247. Conclusion: AT247 has a superior (left-shifted) time-action and time-concentration profile as compared to both NovoRapid® and Fiasp®. Disclosure T.R. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K. T. Augustin: None. C. Magnes: None. D.J. Gerring: None. J. Jezek: None. S.J. Howell: None. L. Zakrzewski: None. F.J. Lawrence: None. E. Svehlikova: None.

105-LB: Evening Oral Insulin (ORMD-0801) Glycemic Effects in Uncontrolled T2DM Patients

ORMD-0801 is a novel oral human insulin formulated to increase hepatic insulin exposure, and subsequently reduce hepatic glucose production and improve glycemic control, with minimal hypoglycemia risk. In a recently completed randomized, placebo-controlled, multicenter, phase 2b, 12-week study, 354 subjects with T2DM uncontrolled by multiple oral antidiabetic drugs and with HbA1c levels ≥7.5%, received placebo or 8 mg, 16 mg or 32 mg ORMD-0801 capsules up to three times daily. Masked continuous glucose monitoring was performed during a 14-day run-in period and over the last 14 days of treatment. HbA1c levels improved from baseline for most active treatment regimens, with largest improvements recorded in the 8 mg once daily (QD) and twice daily (BID) cohorts. Glucose AUC improved from baseline following 8 mg or 32 mg QD and all tested BID treatments and was most pronounced in patients receiving 8 mg QD at bedtime. Hypoglycemia event rates were low and similar to the placebo arm. Body weight remained stable in all treatment arms and frequency of drug-related adverse events was similar across cohorts. In summary, ORMD-0801 elicited clinically significant HbA1c reductions in poorly controlled T2DM patients on standard therapies and with mean HbA1c levels >8%, without increasing hypoglycemia rate or weight. The 8 mg QD regimen appears most effective, warranting further studies to confirm the efficacy of this once daily evening dose. Disclosure R. Eldor: Advisory Panel; Self; Oramed. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; Oramed. G. Fleming: Consultant; Self; ADOCIA, Biocon, Caladrius Biosciences, Inc., Dance Biopharm Holdings, Inc., Diasome Pharmaceuticals, Inc., Intarcia Therapeutics, MannKind Corporation, NuSirt Biopharma, Inc., Oramed Pharmaceuticals, Sanofi, Tolerion, Inc. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi.

1004-P: Oral Insulin (ORMD-0801) Effects on Glucose Parameters in Uncontrolled T2DM on OADs

ORMD-0801 is a novel oral human insulin formulation which can potentially improve acceptance and adherence, as well as glycemic control by increasing hepatic insulin exposure, without increasing hypoglycemia risk. This randomized, placebo-controlled, multi-center, phase 2b 12-week study, in 273 T2DM subjects, on metformin ±1-2 oral antidiabetic drugs (OADs), including sulfonylurea, compared placebo vs. 32 mg ORMD-0801 capsules administered once daily (QD) at bedtime, or two (BID) or three (TID) times daily at bedtime, and 30-40 min before breakfast/lunch. Blinded continuous glucose monitoring (CGM) was performed during a two-week run-in period and over the last two weeks of treatment. HbA1c levels improved from baseline for all active treatment regimens (Table). Glucose AUC improved from baseline following QD and BID treatment. Hypoglycemia rates were low and relatively similar to the placebo arm, and body weight was unchanged in all treatment arms. Frequency of drug-related adverse events was similar across treatment groups. In conclusion, ORMD-0801 elicited clinically significant HbA1c reductions among T2DM patients inadequately controlled on standard therapies, without increasing hypoglycemia rates, or inducing severe or serious adverse effects or significant weight gain. Disclosure R. Eldor: Advisory Panel; Self; Oramed. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; Oramed. G. Fleming: Consultant; Self; ADOCIA, Biocon, Caladrius Biosciences, Inc., Dance Biopharm Holdings, Inc., Diasome Pharmaceuticals, Inc., Intarcia Therapeutics, MannKind Corporation, NuSirt Biopharma, Inc., Oramed Pharmaceuticals, Sanofi, Tolerion, Inc. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi.

3-Iodothyronamine Affects Thermogenic Substrates' Mobilization in Brown Adipocytes.

We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance.

MYL1501D Insulin Glargine: A Review in Diabetes Mellitus.

Subcutaneous MYL1501D insulin glargine 100 U/mL (hereafter referred to as MYL1501D insulin glargine) [Semglee®] is a long-acting human insulin analogue approved as a biosimilar of insulin glargine 100 U/mL (hereafter referred to as reference insulin glargine 100 U/mL) [Lantus®] in various countries, including those of the EU for the treatment of diabetes mellitus in patients aged ≥ 2 years, as well as Japan for diabetes where insulin therapy is indicated. MYL1501D insulin glargine has similar physicochemical characteristics and biological properties to those of EU- and US-sourced reference insulin glargine 100 U/mL, with the bioequivalence of pharmacodynamic and pharmacokinetic parameters between these agents shown in adults with type 1 diabetes. Once-daily MYL1501D insulin glargine demonstrated noninferior glycaemic efficacy to that of once-daily reference insulin glargine 100 U/mL in adults with type 1 or 2 diabetes, with its glycated haemoglobin-lowering benefits maintained over the longer-term (52 weeks) and unaffected by previous insulin exposure. Switching between MYL1501D insulin glargine and reference insulin glargine 100 U/mL did not appear to impact glycaemic efficacy in adults with type 1 diabetes. MYL1501D insulin glargine was well tolerated, demonstrating a safety and immunogenicity profile similar to that of reference insulin glargine 100 U/mL in patients with type 1 and 2 diabetes, and in those with type 1 diabetes switching between the two agents. As expected, hypoglycaemia was the most frequently reported treatment-emergent adverse event. Thus, MYL1501D insulin glargine provides an effective biosimilar alternative for patients requiring insulin glargine therapy.

Characterizing the Effects of Diabetes and Obesity on Insulin and Leptin Levels amongst Pregnant Women.

In this study, we assess the impact of obesity and diabetes on maternal brain and periphery, as well as fetal exposure to insulin and leptin, and two hormones that play an important role in regulating energy homeostasis. Fasting maternal plasma, fetal cord vein and artery plasma, and maternal cerebrospinal fluid (CSF) were collected in 37 women (12 lean, nondiabetic [prepregnancy body mass index (BMI): 22.9 ± 1.7 kg/m2]; 12 overweight/obese nondiabetic [BMI: 37.8 ± 7.3 kg/m2]; 13 gestational/type 2 diabetes mellitus [BMI: 29.8 ± 7.3 kg/m2]) with uncomplicated singleton pregnancies undergoing elective Cesarean delivery. HbA1C, insulin, glucose, and leptin levels were measured. Compared with lean mothers, mothers with obesity and diabetes mellitus (DM) had significantly lower CSF-to-plasma ratios of insulin. Moreover, mothers with obesity and DM had significantly lower cord arterial and cord venous to maternal plasma ratios of insulin, but not leptin, compared with lean mothers. There were no differences in CSF and cord blood insulin and leptin levels between obese and DM mothers. Compared with lean individuals, mothers with obesity and DM have relative deficiencies in insulin exposure. The patterns observed in mothers with obesity and diabetes were similar highlighting the importance of the maternal metabolic environment in obesity and suggesting obese patients warrant further clinical focus.

Increased placental mitochondrial fusion in gestational diabetes mellitus: an adaptive mechanism to optimize feto-placental metabolic homeostasis?

IntroductionGestational diabetes mellitus (GDM), a common pregnancy disorder, increases the risk of fetal overgrowth and later metabolic morbidity in the offspring. The placenta likely mediates these sequelae, but the exact...

Characterising hyperinsulinemia-induced insulin resistance in human skeletal muscle cells.

Hyperinsulinaemia potentially contributes to insulin resistance in metabolic tissues, such as skeletal muscle. The purpose of these experiments was to characterise glucose uptake, insulin signalling and relevant gene expression in primary human skeletal muscle-derived cells (HMDCs), in response to prolonged insulin exposure (PIE) as a model of hyperinsulinaemia-induced insulin resistance. Differentiated HMDCs from healthy human donors were cultured with or without insulin (100 nM) for 3 days followed by an acute insulin stimulation. HMDCs exposed to PIE were characterised by impaired insulin-stimulated glucose uptake, blunted IRS-1 phosphorylation (Tyr612) and Akt (Ser473) phosphorylation in response to an acute insulin stimulation. Glucose transporter 1 (GLUT1), but not GLUT4, mRNA and protein increased following PIE. The mRNA expression of metabolic (PDK4) and inflammatory markers (TNF-α) was reduced by PIE but did not change lipid (SREBP1 and CD36) or mitochondrial (UCP3) markers. These experiments provide further characterisation of the effects of PIE as a model of hyperinsulinaemia-induced insulin resistance in HMDCs.

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins

The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats.

Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance and a high risk of miscarriage during pregnancy. Similarly, in rats, maternal exposure to 5α-dihydrotestosterone (DHT) and insulin from gestational day 7.5 to 13.5 leads to hyperandrogenism and insulin resistance and subsequently increased fetal loss. A variety of hormonal and metabolic stimuli are able to trigger different types of regulated cell death under physiological and pathological conditions. These include ferroptosis, apoptosis and necroptosis. We hypothesized that, in rats, maternal hyperandrogenism and insulin-resistance-induced fetal loss is mediated, at least in part, by changes in the ferroptosis, apoptosis and necroptosis pathways in the gravid uterus and placenta. Compared with controls, we found that co-exposure to DHT and insulin led to decreased levels of glutathione peroxidase 4 (GPX4) and glutathione, increased glutathione + glutathione disulfide and malondialdehyde, aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition and activated ERK/p38/JNK phosphorylation in the gravid uterus. In addition, we observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction in the uteri of rats co-exposed to DHT and insulin. However, in the placenta, DHT and insulin exposure only partially altered the expression of ferroptosis-related markers (e.g. region-dependent GPX4, glutathione + glutathione disulfide, malondialdehyde, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). Moreover, we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA in placentas of rats co-exposed to DHT and insulin. Further, DHT + insulin-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal hyperandrogenism and insulin resistance causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Our data also suggest that apoptosis and necroptosis may play a role in coordinating or compensating for hyperandrogenism and insulin-resistance-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

Insulin dysregulation in horses with induced obesity

ABSTRACT: Insulin deregulation (ID) is a central player in the pathophysiology of equine metabolic syndrome (EMS), which is associated with generalized and/or regional obesity. The objective of this experiment was to characterize the alterations in the hormonal profile in horses exposed to a hypercaloric diet. A total of nine Mangalarga Marchador adult horses with initial body condition score (BCS) of 2.9±1/9 (mean±SD) were submitted to a high calorie grain-rich diet for 5 months. The data was collected before the start of the experiment and every 15 days until the end of the experiment and glucose and insulin concentrations were measured in the plasma. Proxies G:I, RISQI, HOMA-IR and MIRG were calculated. The low-dose oral glucose tolerance test (OGTT) was performed and the total area under the glucose (GTA) and insulin (ITA) curves at three different timepoints (before inducing obesity, after 90 days and after 150 days) was used. Analysis of variance of the results was performed considering the time effects and the means were compared with repeated measures by the Tukey’s test (P≤0.05). The ID was observed during the first 90 days of the experiment and was characterized as a decompensated ID, showing an increase of basal glucose and insulin plasma levels, changes in all proxies and a significant increase in GTA (P<0.001) and ITA (P<0.05). However, a clear compensation of the ID was evident after 150 days of experiment, which was supported by data from the insulin secretory response of β cells of the pancreas that showed an increase in insulin plasma levels, after fasting or exposure to gastric glucose, with a concomitant decrease in fasting glucose and fructosamine levels, and a decrease of GTA and marked increase of ITA (P<0.0001) in the dynamic test. These findings confirm the occurrence of hyperinsulinemia associated with insulin deregulation in Mangalarga Marchador horses exposed to hypercaloric diets.

Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates

Diabetes mellitus is a delayed effect of radiation exposure in human and nonhuman primates. Diabetes mellitus is characterized by peripheral tissue insulin resistance, and as a result, irradiation exposure may cause important changes in insulin-sensitive tissues such as muscle and adipose. We prospectively investigated changes in response to irradiation (4 Gy whole body exposure) in 16 male rhesus macaques. We evaluated changes in body composition and glycemic control for 2 years. Insulin responsiveness, lipolysis, inflammation, and fibrosis were evaluated at study end. Irradiated animals accumulate less fat and significantly increased percent glycation of hemoglobin A1c over time, such that 40% of irradiated monkeys had values that define them as diabetic at 2 years. Subcutaneous (SQ) adipose tissue was insulin resistant, as evidenced by reduced phosphorylation of the insulin receptor substrate-1 in response to insulin challenge and had increased basal lipolysis despite comparable insulin exposures to control animals. Irradiated SQ adipose tissue had more macrophage infiltration and adipocytes were larger. The observed hypertrophy was associated with decreased glycemic control and macrophage infiltration correlated with decreased adiponectin, signifying that inflammation is associated with worsening health. No evidence of SQ adipose fibrosis was detected. Our study is the first to prospectively illustrate that sublethal irradiation exposures directly propagate metabolic disease in the absence of obesity in nonhuman primates and implicate SQ adipose dysfunction as a target tissue.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.

Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series

BackgroundInsulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS.Case presentationWe report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed.ConclusionHigh levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.

Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy.

Women with hyperinsulinism and insulin resistance have reduced fertility, but the underlying mechanism is still poorly understood. Aberrant endometrial decidualization in early pregnancy was linked to pregnancy complications. In this study, we aimed to test whether elevated insulin levels compromise decidualization in early-stage pregnancy. C57BL/6Jmice in high insulin-exposed group were given a subcutaneous injection of recombinant insulin at a concentration of 0.05IU daily. During decidualization in early pregnancy, serum levels of insulin, E2, P4, LH, FSH and blood glucose were significantly altered in mice treated with high insulin levels. The number of embryo implantation sites and endometrial decidual markers BMP2, ER, PR was significantly decreased by high insulin levels in vivo. Artificial decidual induction in primary mouse endometrial stromal cells and immortal human endometrial stromal cells line were all compromised after treated with 100nmol/L insulin levels. All these results on flow cytometry, transmission electron microscopy and western blotting of Bax, Bcl2, cleaved Caspase3, cleaved PARP proteins level showed that decidual cells apoptosis was significantly decreased. Mitochondrial transmembrane potential also significantly increased by the influence of high insulin levels. PI3K and p-Akt were much higher after insulin exposure and the compromised decidualization by high insulin treatment was rescued by PI3K/Akt inhibitor LY294002 both in vitro and in vivo. In conclusion, we demonstrated that elevated insulin levels could compromise mice decidualization in early-stage pregnancy and PI3K/p-Akt-regulated apoptosis was essential for this role. It provides a clue for future investigation on compromised reproduction in women with hyperinsulinemia.

Insulin enhances and metformin reduces risk of colorectal carcinoma in type-2 diabetes.

Identifying colorectal cancer associated risks is important for conducting a program for the survey and prevention of colorectal cancer. To investigate the association between use of insulin or metformin with colorectal cancer (CRC) in type 2 diabetes (T2DM). Population-based cohort study. Through analysis of National Health Insurance (NHI) database between 1998 and 2010 in Taiwan, we identified 66 324 T2DM patients aged ≥ 20 years and selected subjects without diabetes by 1: 1 randomly matching with the study cohort based on age, sex and index date. We followed up the participants until 31 December 2011 or when they withdrew from the NHI program. Compared with non-diabetic subjects, the T2DM patients exhibited an increased risk of CRC [adjusted HR (aHR) = 1.56, 95% confidence interval (CI) = 1.39-1.75], after adjustment for age, sex, urbanization level, comorbidities and examinations of colonoscopy, sigmoidoscopy, or stool occult blood test. Among the T2DM patients, insulin usage increased the risk of CRC (aHR = 1.86, 95% CI = 1.58-0-2.19) after adjustment for age, sex, urbanization level, comorbidities, metformin usage and examinations; nevertheless, metformin decreased the risk of CRC (aHR = 0.65, 95% CI = 0.54-0.77) after adjustment for age, sex, urbanization level, comorbidities, insulin usage and examinations. Compared with the non-insulin cohort, the risk of CRC tended to increase with the incremental dosage of insulin exposure. Our population-based cohort study demonstrated an association between T2DM and CRC. Among the T2DM patients, insulin use was associated with an increased risk of CRC and metformin use was associated with a decreased risk of CRC. Inability to obtain information on several potential confounding factors, such as lifestyle and dietary habits, is the major limitation of the study.

Effect of V-Go Versus Multiple Daily Injections on Glycemic Control, Insulin Use, and Diabetes Medication Costs Among Individuals with Type 2 Diabetes Mellitus.

Coping with discomfort and the uncertainties of daily adjustments are prominent challenges confronting individuals with type 2 diabetes mellitus (T2DM) who require multiple daily injections (MDI) of insulin. For this growing population, wearable, disposable devices capable of delivering consistent and sustained doses of basal-bolus therapy may help to alleviate concerns and improve outcomes. However, studies on the comparative effectiveness of new, innovative delivery systems versus MDI on insulin requirements, glycemic control, and health care costs are sparse. To examine glycemic control, insulin use, and diabetes medication costs for users of the V-Go Wearable Insulin Delivery device compared with MDI insulin therapy among individuals with T2DM in a commercially insured population in the United States. This retrospective cohort study queried administrative claims data from the HealthCore Integrated Research Database from July 1, 2011, through July 31, 2017. Cohorts included individuals with T2DM aged 21-80 years either newly initiating V-Go or using MDI for basal/bolus insulin. The date of earliest claim for V-Go prescription fill or for bolus insulin was defined as the index date, depending on the cohort. Previous insulin therapy was required in both cohorts. Baseline hemoglobin A1c (A1c) values were identified during the 6 months before and 15 days after the index date; results closest to 12 months after the index date were selected as follow-up. Insulin use and diabetes medication cost data were examined during the 6 months baseline and the second half of the 1-year follow-up. V-Go and MDI users were 1:1 matched on baseline insulin exposure, A1c level, and other characteristics of interest. Univariate and multivariate tests were used to compare follow-up outcomes. Matched cohorts included 118 well-balanced pairs (mean age: 56 years; mean baseline A1c: 9.2%). During follow-up, both cohorts experienced improvements in glycemic control relative to baseline (% with A1c ≤ 9%, baseline/follow-up: V-Go 49/69, P < 0.001; MDI 50/60, P = 0.046). With similar baseline insulin prescription fills and diabetes medication costs, V-Go users required fewer insulin prescription fills (mean change: -0.8 vs. +1.8 fills, P < 0.001; -17% vs. +38%); had a smaller increase in diabetes medication costs (mean change in 2016 USD: $341 vs. $1,628, P = 0.012; +10% vs. +47%); and a decrease in insulin total daily dose (mean change in insulin units per day: -29.2 vs. +5.8, P < 0.001; -21% vs. +4%), compared with MDI users, during the last 6 months of follow-up. This study was the first to evaluate clinical and economic outcomes associated with the use of V-Go for up to a 1-year follow-up period. Relative to MDI users, V-Go users had similar glycemic control but lower insulin use and lower diabetes medication costs during follow-up. V-Go therapy may provide an opportunity to improve quality measures more cost-effectively in people with T2DM who require basal-bolus therapy. This study was funded by Valeritas. Nguyen is an employee of Valeritas. Zhou, Grabner, Barron, and Quimbo are employees of HealthCore, which received funding for this study from Valeritas. Raval was an employee of HealthCore at the time the study was conducted. Partial findings from this study were presented at the International Society of Pharmacoeconomics and Outcomes Research 23rd Annual International Meeting; May 19-23, 2018; Baltimore, MD; and the 54th European Association for the Study of Diabetes Annual Meeting; October 1-5, 2018; Berlin, Germany.

Insulin Protects Cortical Neurons Against Glutamate Excitotoxicity.

Glutamate excitotoxicity is implicated in the pathogenesis of numerous diseases, such as stroke, traumatic brain injury, and Alzheimer’s disease, for which insulin resistance is a concomitant condition, and intranasal insulin treatment is believed to be a promising therapy. Excitotoxicity is initiated primarily by the sustained stimulation of ionotropic glutamate receptors and leads to a rise in intracellular Ca2+ ([Ca2+]i), followed by a cascade of intracellular events, such as delayed calcium deregulation (DCD), mitochondrial depolarization, adenosine triphosphate (ATP) depletion that collectively end in cell death. Therefore, cross-talk between insulin and glutamate signaling in excitotoxicity is of particular interest for research. In the present study, we investigated the effects of short-term insulin exposure on the dynamics of [Ca2+]i and mitochondrial potential in cultured rat cortical neurons during glutamate excitotoxicity. We found that insulin ameliorated the glutamate-evoked rise of [Ca2+]i and prevented the onset of DCD, the postulated point-of-no-return in excitotoxicity. Additionally, insulin significantly improved the glutamate-induced drop in mitochondrial potential, ATP depletion, and depletion of brain-derived neurotrophic factor (BDNF), which is a critical neuroprotector in excitotoxicity. Also, insulin improved oxygen consumption rates, maximal respiration, and spare respiratory capacity in neurons exposed to glutamate, as well as the viability of cells in the MTT assay. In conclusion, the short-term insulin exposure in our experiments was evidently a protective treatment against excitotoxicity, in a sharp contrast to chronic insulin exposure causal to neuronal insulin resistance, the adverse factor in excitotoxicity.

Descriptive Analysis of Long- and Intermediate-Acting Insulin and Key Safety Outcomes in Adults with Type 2 Diabetes Mellitus.

As new biosimilar and follow-on insulins enter the market, more data are needed on safety, effectiveness, and patterns of use for these products to inform prescriber and patient decision-making regarding treatment. Additionally, data are needed regarding real-world patterns of use to inform future studies comparing the safety and effectiveness of bio-similars to already approved agents for diabetes treatment. To analyze the medication use patterns, adverse events, and availability of glycated hemoglobin (A1c) values for adult patients with type 2 diabetes mellitus (T2DM) who use long-acting insulin (LAI) or neutral protamine Hagedorn (NPH), an intermediate-acting insulin. We used the Biologics and Biosimilars Collective Intelligence Consortium's (BBCIC) distributed research network (DRN) for this descriptive analysis. The analysis time frame was January 1, 2011, to September 30, 2015, and included patients continuously insured for at least 183 days before the first date of a filled prescription for LAI or NPH insulin alone or with rapid- or short-acting insulin or sulfonylureas, whether newly starting insulin or switching to a different product. Insulin exposure episodes were the unit of analysis, and patients were classified in cohorts according to treatment. We followed patients until end of health plan enrollment or the end of the study period. We used occurrence of a study outcome, switch to another medication regimen, discontinuation of the current medication, or study end date to mark the end of an insulin episode. We describe demographics and availability of A1c values for analysis. Study outcomes included severe hypoglycemic events and major adverse cardiac events (MACE). We identified 103,951 patients with T2DM from a database of 39.1 million patients with commercial or Medicare Advantage pharmacy and medical benefits, who contributed 279,533 unique insulin exposure episodes. Most episodes (89%) included patients using LAI, and 52% of patients contributed data to 2 or more exposure cohorts. Insulin episodes lasted an average of 3.5 months, and patients had an average follow-up of 8.6 months. The unadjusted rate of severe hypoglycemic events requiring medical attention was 96.9 per 10,000 patient-years at risk (10kPYR). The unadjusted incident MACE rate was 676.9 events per 10kPYR. 38,330 T2DM patients in the BBCIC DRN had a baseline A1c available, and of those, less than 50% had a follow-up A1c result. Among patients with T2DM, our observed insulin patterns of use and rates of severe hypoglycemic outcomes and MACE are consistent with other studies. We noted a paucity of A1c results available, which implies that additional data sources may be needed to augment the BBCIC DRN. This study was coordinated and funded by the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) and represents the independent findings of the BBCIC Insulins Principal Investigator and the BBCIC Insulins Research Team. Lockhart is employed by the BBCIC and the Academy of Managed Care Pharmacy (AMCP). Eichelberger was employed by the BBCIC and AMCP at the time of this study. McMahill-Walraven is employed by Aetna, a CVS Health business. Panozzo, Marshall, and Brown are employed by Harvard Pilgrim Healthcare Institute. Aetna was reimbursed for data and analytic support from Harvard Pilgrim Healthcare Institute and the Reagan Udall Foundation for the U.S. Food and Drug Administration. Aetna receives external funding through research grants and subcontracts with Harvard Pilgrim Healthcare Institute, which are funded by the FDA, NIH, PCORI, BBCIC, Pfizer, and GSK; the Reagan-Udall Foundation for IMEDS; and PCORI for the ADAPTABLE Study. This work was previously presented as a poster at AMCP Nexus 2018; October 22-25, 2018; in Orlando, FL.

Insulin attenuates apoptosis in neuronal cells by an integrin-linked kinase-dependent mechanism

Insulin promotes neuronal survival by activating a phosphatidylinositol 3-kinase (PI 3-kinase)/AKT-dependent signaling pathway and reducing caspase activation. We investigated a role for integrin-linked kinase (ILK) in insulin-mediated cell survival in cultured neurons and differentiated R28 cells. We used a serum and depolarization withdrawal model to induce apoptosis in cerebellar granule neurons and a serum withdrawal model to induce apoptosis in differentiated R28 cells. ILK knock-out decreased insulin-mediated protection as did the addition of pharmacological inhibitors of ILK, KP-392 or QLT-0267. Prosurvival effects of insulin were rescued by Boc-Asp (O-methyl)-CH2F (BAF), a pancaspase inhibitor, in the presence of KP-392. Insulin and IGF-1 decreased caspase-3 activation, an effect that was inhibited by KP-392 and QLT-0267. Western blot analysis indicates that insulin-induced stimulation of AKT Ser-473 phosphorylation was decreased after the ILK gene was conditionally knocked-out, following overexpression of AKT-DN or in the presence of QLT-0267. Insulin and IGF-1 stimulated ILK kinase activity in primary neurons and this was inhibited following ILK-DN overexpression. Western blot analysis indicates that insulin exposure upregulated the expression of the cellular inhibitor of apoptosis protein c-IAP2 in an extracellular matrix-dependent manner, an effect blocked by KP-392. These results indicate that ILK is an important effector in insulin-mediated neuroprotection.