Insulin Clearance in Obesity and Type 2 Diabetes

Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

Plasma Insulin/Erythrocytic Aldose Reductase Ratio as a Predictor for Hepatocellular Carcinoma Among Type II Diabetics and Hepatitis C Virus-Infected Patients

Purpose Hepatocellular carcinoma (HCC) is a possible oncogenic progression during persistent hepatitis C-infection +/- type II diabetes mellitus (DM). To investigate the plasma insulin, erythrocytic aldose reductase (AR) and sorbitol dehydrogenase (SDH) as possible predictive tools for HCC in hepatitis C-infected patients (HCV) +/- DM. Erythrocytes (RBCs) were adopted as a possible vehicle for pre-malignant variations being of short life span. Methods The study included 20 healthy control and 100 patients of 48–64 years old, divided into 5 equal groups as; type II DM, HCC, HCC with DM, DM- HCV infected and non-DM HCV infected. Plasma levels of AFP and insulin were measured. Results It showed an elevated AR, significant reduction of SDH in RBCs and plasma of DM patients. These values were greatly elevated among HCV, HCC, diabetic HCV, and diabetic HCC patients. All DM patients showed elevated insulin levels than normoglycemic controls. Conclusion The study substantiated the use of RBCs as a vehicle for early diagnostic markers better than plasma. We recommend the use of insulin/ erythrocytic AR ratio as a new laboratory marker for predicting HCC among type II diabetics or non-treated HCV-infected patients with control insulin/ erythrocytic AR ratio by each laboratory.

The Impact of Re-Mating Interval and Genotype on Physiological Response of Rabbits after First Kindling

This is an experiment aimed to study the effect of re-mating interval on rabbit does after first kindling on hormonal (insulin, leptin, and T3) and metabolites (triglycerides, urea, and glucose) levels. DNA damage in ovary cells of rabbit does during the 2nd parity was also studied. Two varieties were used: APRI (synthetic line) and Baladi Black (BB, Egyptian breed). A total number of 120 mature rabbit does (60 does for each breed) were 6 months of age and were used at the beginning of the breeding season. Does of each breed were divided into three equal groups according to reproductive rhythm. The 1st group was postpartum (PP). The 2nd group was 11 days after parturition (P11). The 3rd group was post-weaning (PW). There were significant (P≥0.05) differences in plasma leptin concentration during 1st parity. The highest value of plasma leptin concentration was recorded by the PW group at mating. Also, there were significant differences in plasma insulin and T3 hormones concentrations of doe rabbits. The highest value of plasma insulin concentration was recorded by the PW group at mating in 1st parity and the highest value of plasma T3 hormone concentration was recorded for the PS group at mating. While there were insignificant differences during 2nd parity in T3 hormone concentration in rabbits, the differences of plasma glucose and triglyceride concentrations of doe rabbits during 1st parity and 2nd parity were significant. However, the highest significant value of plasma glucose concentration was recorded by the PW group at mating. On the other hand, there were insignificant differences in plasma urea concentration of doe rabbits during 1st parity and 2nd parity. Finally, no significant effects were observed on comet length, head diameter, tail length, or DNA % tail.

Dapagliflozin, metformin, monotherapy or both in patients with metabolic syndrome

The present study evaluated the effects of dapagliflozin, a SGLT2 inhibitor, or dapagliflozin plus metformin versus metformin monotherapy in patients with metabolic syndrome. This study included patients who admitted in Jiangxi Provincial People’s Hospital from January 1, 2017 to December 31, 2019 and were diagnosed with metabolic syndrome. A total of 248 participants were randomly assigned to divide into three groups: dapagliflozin group; metformin group; dapagliflozin in combined with metformin group. Dapagliflozin group and metformin group were associated with similar improvements in components of metabolic syndrome. Relative to dapagliflozin or metformin monotherapy, dapagliflozin combined with metformin provided greater improvements in components of metabolic syndrome. So did HOMA-IR scores, fasting plasma insulin and inflammatory indicators (hsCRP, PMN/HDL-C and Monocytes/HDL-C). Dapagliflozin improved all components of metabolic syndrome in patients with metabolic syndrome. Furthermore, dapagliflozin combined with metformin showed more meaningful improvements in any of components of metabolic syndrome than dapagliflozin or metformin monotherapy.

Comparison of aspartame- and sugar-sweetened soft drinks on postprandial metabolism

Aim: We compared the impact of artificially- and sugar-sweetened beverages co-ingested with a mixed meal on postprandial fat and carbohydrate oxidation, blood glucose, and plasma insulin and triglyceride concentrations. Methods: Eight college-aged, healthy males completed three randomly assigned trials, which consisted of a mixed macronutrient meal test with 20oz of Diet-Coke (AS), Coca-Cola (NS), or water (CON). One week separated each trial and each participant served as his own control. Resting energy expenditure (REE) via indirect calorimetry, blood pressure, and blood samples were obtained immediately before, 5, 10, 30, 60, 120, and 180 min after meal and beverage ingestion. A two-way (treatment × time) repeated-measures ANOVA was conducted to assess REE, fat and carbohydrate oxidation rates, blood glucose, and plasma insulin and triglyceride concentrations. Results: There was a significant main effect of treatment on total fat oxidation (P = 0.006), fat oxidation was significantly higher after AS (P = 0.006) and CON (P = 0.001) compared to following NS. There was a significant main effect of treatment on total carbohydrate oxidation (P = 0.005), carbohydrate oxidation was significantly lower after AS (P = 0.014) and CON (P = 0.001) compared to following NS. Plasma insulin concentration AUC was significantly lower after AS (P = 0.019) and trended lower in CON (P = 0.054) compared to following NS. Conclusion: Ingestion of a mixed meal with an artificially-sweetened beverage does not impact postprandial metabolism, whereas a sugar-sweetened beverage suppresses fat oxidation and increases carbohydrate oxidation compared to artificially-sweetened beverage and water.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration–time curve to the last quantifiable concentration (INS-AUClast), area under the GIR–time curve during the clamp (GIR-AUC0–10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94–1.05) for INS-Cmax and 1.02 (90% CI 1.00–1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93–1.06) for GIR-AUC0–10 h and 1.01 (95% CI 0.95–1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80–1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Metabolic and production parameters of dairy cows with different dry period lengths and parities

To assess the effects of dry period (DP) length on metabolic, reproductive, and productive parameters, second- (SP) and third- (TP) parity cows were assigned to a traditional (9 weeks, T) or short (5 weeks, S) DP, obtaining four subgroups: second-parity cows with traditional (SPT = 8) and short (SPS = 8) DP, third-parity cows with traditional (TPT = 8) and short (TPS = 10) DP. Plasma insulin-like growth factor-I (IGF-I) and non-esterified fatty acid (NEFA) levels were assessed from 5 weeks before to 14 weeks after parturition. IGF-I concentrations were affected by parity (P < 0.05) and by the interaction of time and DP length (P < 0.01). NEFA levels were affected only by time (P < 0.01). S DP cows showed a shorter interval between calving and ovarian cyclicity resumption (P < 0.01) and a higher milk yield (P < 0.01) and fat and protein corrected milk (P < 0.01) compared with T DP cows. Decreased milk protein content was found in the SPS group compared to the SPT (P < 0.05) and the TPS (P < 0.05) group. In conclusion, a short DP length does not affect reproductive performances, except for hastening the resumption of ovarian cyclicity. A short DP appears to increase milk production and is associated with higher IGF-I levels both in the prepartum and the postpartum period.

Novel Triterpenoids from Cassia fistula Stem Bark Depreciates STZ-Induced Detrimental Changes in IRS-1/Akt-Mediated Insulin Signaling Mechanisms in Type-1 Diabetic Rats

Here, we identified the mechanisms of action of antidiabetic activity of novel compounds isolated from Cassia fistula stem bark in STZ-diabetic animals. Novel triterpenoid compounds (C1, C2 and C3) were treated to STZ-administered diabetic animals at a concentration of 20mg/kg body weight orally for 60 days to assess their effects on plasma glucose, plasma insulin/C-peptide, serum lipid markers and the enzymes of carbohydrate metabolism, glucose oxidation and insulin signaling molecules. Oral administration of novel triterpenoid compounds to STZ-diabetic animals significantly decreased (p < 0.05) the plasma glucose concentration on the 7th, 15th, 30th, 45th and 60th daysin a duration-dependent manner (p < 0.05). Plasma insulin (p < 0.0001)/C-peptide (p < 0.0006), tissue glycogen (p < 0.0034), glycogen phosphorylase (p < 0.005), glucose 6-phosphatase (p < 0.0001) and lipid markers were significantly increased (p < 0.0001) in diabetic rats, whereas glucokinase (p < 0.0047), glycogen synthase (p < 0.003), glucose oxidation (p < 0.001), GLUT4 mRNA (p < 0.0463), GLUT4 protein (p < 0.0475) and the insulin-signaling molecules IR mRNA (p < 0.0195), IR protein (p < 0.0001), IRS-1 mRNA (p < 0.0478), p-IRS-1Tyr612 (p < 0.0185), Akt mRNA (p < 0.0394), p–AktSer473 (p < 0.0162), GLUT4 mRNA (p < 0.0463) and GLUT4 (p < 0.0475) were decreased in the gastrocnemius muscle. In silico analysis of C1–C3 with IRK and PPAR-γ protein coincided with in vivo findings. C1–C3 possessed promising antidiabetic activity by regulating insulin signaling mechanisms and carbohydrate metabolic enzymes.

Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities

Rett syndrome (RTT) is a neurodevelopmental disorder with X-linked dominant inheritance caused mainly by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The effects of various Mecp2 mutations have been extensively assessed in mouse models, but none adequately mimic the symptoms and pathological changes of RTT. In this study, we assessed the effects of Mecp2 gene deletion on female rats (Mecp2+/−) and found severe impairments in social behavior [at 8 weeks (w), 12 w, and 23 w of age], motor function [at 16 w and 26 w], and spatial cognition [at 29 w] as well as lower plasma insulin-like growth factor (but not brain-derived neurotrophic factor) and markedly reduced acetylcholine (30%–50%) in multiple brain regions compared to female Mecp2+/+ rats [at 29 w]. Alternatively, changes in brain monoamine levels were relatively small, in contrast to reports on mouse Mecp2 mutants. Female Mecp2-deficient rats express phenotypes resembling RTT and so may provide a robust model for future research on RTT pathobiology and treatment.