An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin.

The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere® Insulin dose (22U or 20U). In the 30-120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin. Moreover, the supra-basal area-under-the-curve of endogenous insulin in the test with inhaled insulin was significantly lower than that in the test without (2.1 ± 1.7 × 104 pmol·min/L vs 4.2 ± 1.8 × 104 pmol·min/L, p < 0.01). The percentage of exogenous insulin reaching the plasma, relative to the inhaled dose, was 42 ± 21%. The proposed in-silico approach separates exogenous and endogenous insulin contributions to total plasma insulin, provides individual bioavailability estimates, and can be used to assess the effect of inhaled insulin on endogenous insulin secretion during a meal.

Effects of Consuming Beverages Sweetened with Fructose, Glucose, High-Fructose Corn Syrup, Sucrose, or Aspartame on OGTT-Derived Indices of Insulin Sensitivity in Young Adults.

(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.

The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice.

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.

Surgery for locally advanced gastric cancer in the era of neoadjuvant therapies: something new?

BACKGROUND: Locally advanced gastric cancer (LAGC) represents a therapeutic challenge, particularly as it often involves adjacent organs. The necessity of neoadjuvant treatments for LAGC patients is still controversial. The aim of this study was to analyze the factors affecting prognosis and survival in patients with LAGC with particular regard to the effect of neoadjuvant therapies. METHODS: Between January 2005 and December 2018, the medical records of 113 patients with LAGC who underwent curative resection were retrospectively reviewed. Patient characteristics, related complications, long-term survival, and prognostic factors were analyzed at uni- and multivariate analyses. RESULTS: Postoperative mortality and morbidity rates of patients undergoing neo-adjuvant therapies were 2.3% and 43.2%, respectively. Whereas in patients undergoing upfront surgery were 4.6% and 26.1%, respectively. R0 resection was achieved 79.5% and in 73.9% of patients undergoing neoadjuvant therapy and upfront surgery, respectively (P<0.001). Multivariate analysis revealed that neoadjuvant therapy, completeness of resection (R0), number of lymph nodes retrieved, N status and the adoption of hyperthermic intraperitoneal chemotherapy were independent prognostic factors associated with longer survival. Five-year overall survival for NAC group and upfront surgery group was 46% and 32%, respectively (P=0.04). Five-year disease-free survival for NAC group and upfront surgery group was 38% and 25%, respectively (P=0.02). CONCLUSIONS: Patients with LAGC undergoing surgery plus neoadjuvant therapy had a better OS and DFS with respect to patients treated with surgery alone.

Persistence of remission after lengthening of golimumab in inflammatory joint diseases.

OBJECTIVES: In refractory inflammatory joint diseases (IJDs) biological disease-modifying anti-rheumatic drugs (bDMARDs) may achieve remission. EULAR recommends bDMARD tapering when remission persists. However, guidelines on tapering modalities and criteria for patient selection are lacking. We aimed to evaluate remission persistency after lengthening the time between injections of golimumab in patients affected by IJD and to identify any patient or disease characteristics associated to flare after lengthening. METHODS: Patients affected by rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and juvenile idiopathic arthritis (JIA) treated with golimumab were enrolled in a retrospective observational study. Demographic data, ESR, cRP, DAS28/ BASDAI, were collected at baseline and during the follow-up (T1- defined as a medical check-up after 1 year of treatment or, for patients with longerg exposure, the first medical check-up in 2016, when at our unit we began to experience drug tapering- and T2- 12 months after the lengthening was started). In 22/80 patients in remission at T1, injection time was lengthened. RESULTS: Eighty patients were enrolled, 34 AS, 33 PsA, 9RA and 4 JIA. At baseline, all had an active disease. At T1, 60/80 patients reached remission and 22/60 patients started tapering. At T2, 20/22 pts (91%) were in remission. At T1 BASDAI was higher (2.2, SD 0.28 vs. 0.58, SD 0.47; p<0.001) in patients who lost remission at T2.Patients who flared recovered remission once taken back to a 28-day interval. 4/38 patients maintained at the standard dose flared up and switched/swapped bDMARD. The difference in retention rate toward patients on reduced dose was not significant. CONCLUSIONS: Results show that golimumab lengthening is safe and successfully maintains remission. In patients who experienced a flare after lengthening, the standard regimen promptly restored remission.

Phase 2 trial with imeglimin in patients with Type 2 diabetes indicates effects on insulin secretion and sensitivity.

INTRODUCTION: The aim of the present study was to evaluate the effect of 18-week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients. METHODS: The study was an 18-week, double-blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h-glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity. RESULTS: A total of 59 subjects were randomized, 30 receiving imeglimin and 29 receiving placebo. The study met its primary endpoint. Least squares (LS) mean difference between treatment groups (imeglimin - placebo) for AUC glucose from baseline to week 18 was -429.6 mmol/L·min (p = .001). Two-hour post-dose fasting plasma glucose was significantly decreased with LS mean differences of -1.22 mmol/L (p = .022) and HbA1c was improved with LS mean differences of -0.62% (p = .013). The AUC0-180min ratio C-peptide/glucose [LS mean differences of 0.041 nmol/mmol (p < .001)] and insulinogenic index were significantly increased by imeglimin treatment. The increase in insulin secretion was associated with an increase in beta-cell glucose sensitivity. Additionally, the insulin sensitivity indices derived from the OGTT Stumvoll (p = .001) and Matsuda (not significant) were improved in the imeglimin group vs placebo. Imeglimin was well tolerated with 26.7% of subjects presenting at least one treatment-emergent adverse event versus 58.6% of subjects in the placebo group. CONCLUSIONS: Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients.

Mathematical model of insulin kinetics accounting for the amino acids effect during a mixed meal tolerance test.

Amino acids (AAs) are well known to be involved in the regulation of glucose metabolism and, in particular, of insulin secretion. However, the effects of different AAs on insulin release and kinetics have not been completely elucidated. The aim of this study was to propose a mathematical model that includes the effect of AAs on insulin kinetics during a mixed meal tolerance test. To this aim, five different models were proposed and compared. Validation was performed using average data, derived from the scientific literature, regarding subjects with normal glucose tolerance (CNT) and with type 2 diabetes (T2D). From the average data of the CNT and T2D people, data for two virtual populations (100 for each group) were generated for further model validation. Among the five proposed models, a simple model including one first-order differential equation showed the best results in terms of model performance (best compromise between model structure parsimony, estimated parameters plausibility, and data fit accuracy). With regard to the contribution of AAs to insulin appearance/disappearance (kAA model parameter), model analysis of the average data from the literature yielded 0.0247 (confidence interval, CI: 0.0168 - 0.0325) and -0.0048 (CI: -0.0281 - 0.0185) µU·ml-1/(µmol·l-1·min), for CNT and T2D, respectively. This suggests a positive effect of AAs on insulin secretion in CNT, and negligible effect in T2D. In conclusion, a simple model, including single first-order differential equation, may help to describe the possible AAs effects on insulin kinetics during a physiological metabolic test, and provide parameters that can be assessed in the single individuals.

Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis. Summary: We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10-84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression. Conclusions: Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.

The rs10830963 Polymorphism of the MTNR1B Gene: Association With Abnormal Glucose, Insulin and C-peptide Kinetics.

Background: The MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm. Results: 13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women. Conclusion: In a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function: Review on Mathematical Modelling Approaches.

Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.

The Dose-Response Effects of Consuming High Fructose Corn Syrup-Sweetened Beverages on Hepatic Lipid Content and Insulin Sensitivity in Young Adults.

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m2). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.

Ceftobiprole and daptomycin concentrations in valve tissue in a patient with mitralic native valve endocarditis.

Ceftobiprole (CFB), especially in combination, could be a promising alternative treatment for infective endocarditis. A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on CFB and Daptomycin (DPT) heart valve penetration are lacking.Here we report a clinical case of CFB and DPT treatment combination for endocarditis. Then, we measured CFB and DPT concentrations in a native infected valve to verify their pharmacokinetic penetration and relationship with pharmacodynamic microbiological markers.The isolated microorganism was a MRSA with CFB and DPT MIC < 2 mg/L and <1 mg/L, respectively. The CFB and DPT plasma concentrations were 36.2 and 14.1 mg/L, respectively and the extrapolated concentration, based on each half-life, at the operatory time were 16.4 and 19.1 mg/L for CFB and DPT, respectively; the corresponding median CFB and DPT valve concentrations were 2.26 (IQR 2.14-2.69) and 12.9 µg/g (IQR 5.69-20.9), respectively; the estimated tissue/plasma ratios for CFB and DTP were 0.14 and 0.67, respectively.The association of CFB and DPT showed a good efficacy in this single endocarditis clinical case, confirmed by plasma and tissue PK/PD data.This report shows the first data on CFB valve tissue penetration, and it needs to be confirmed in other patient valve tissues. Moreover, relative studies of correlation with clinical efficacy are needed.

Insulin clearance and incretin hormones following oral and "isoglycemic" intravenous glucose in type 2 diabetes patients under different antidiabetic treatments.

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

Rheumatology residency in a European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases centre: opportunities and challenges.

Rheumatology is a growing medical speciality with many attractive points to young doctors. Residency is a demanding period of a physician's life, and choosing the right hospital for one's residency may not be easy. We report on our personal experience as Rheumatology residents in European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN-ReCONNET) centres.

Model-Based Assessment of Hepatic and Extrahepatic Insulin Clearance from Short Insulin-Modified IVGTT in Women with a History of Gestational Diabetes.

Insulin clearance is an integral component of insulin metabolism. Yet, little is known about separate contribution of hepatic and extrahepatic insulin clearance in type 2 diabetes and in high-risk populations, such as women who experienced gestational diabetes mellitus (pGDM). A model-based method was recently proposed to assess both contributions from 3-hour insulin-modified intravenous glucose tolerance test (IM-IVGTT); the aim of this study was to assess the reliability of short (1 hour) IM-IVGTT in the application of such model-based method and to evaluate the role of the two contributions in determining insulin clearance in pGDM. A total of 115 pGDM women and 41 who remained healthy during pregnancy (CNT) were analyzed early postpartum and underwent a 3-hour IMIVGTT. Peripheral insulin clearance (CLP), hepatic fractional extraction (FEL) and extrahepatic distribution volume (VP) were estimated by performing a best-fit procedure on insulin IMIVGTT data considering firstly the overall 3-hour duration and then limiting data to 1 hour. Results showed no significant difference in parameter values between the 3-hour and the 1-hour IM-IVGTT. Comparison between pGDM and CNT (1-hour) showed no significant difference in CLp (0.23 [0.29] vs. 0.27 [0.43] L·min-1; p=0.64), FEL (50.2 [15.1] vs. 50.9 [11.7] %; p=0.63) and VP (2.01 [2.99] vs. 2.70 [4.00] L; p=0.92). In conclusion, short IM-IVGTT provides a reliable assessment of hepatic and extrahepatic insulin clearance through such model-based method. Its application to the study of pGDM women showed no alteration in hepatic and extrahepatic contributions with respect to women who had a healthy pregnancy.Clinical Relevance- This study proves the reliability of short (1 hour) IM-IVGTT to assess hepatic and extrahepatic insulin clearance in women who experienced gestational diabetes.