Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.

The angiogenic properties of human amniotic membrane stem cells are enhanced in gestational diabetes and associate with fetal adiposity

Background An environment of gestational diabetes mellitus (GDM) can modify the phenotype of stem cell populations differentially according to their placental localization, which can be useful to study the consequences for the fetus. We sought to explore the effect of intrauterine GDM exposure on the angiogenic properties of human amniotic membrane stem cells (hAMSCs). Methods We comprehensively characterized the angiogenic phenotype of hAMSCs isolated from 14 patients with GDM and 14 controls with normal glucose tolerance (NGT). Maternal and fetal parameters were also recorded. Hyperglycemia, hyperinsulinemia and palmitic acid were used to in vitro mimic a GDM-like pathology. Pharmacological and genetic inhibition of protein function was used to investigate the molecular pathways underlying the angiogenic properties of hAMSCs isolated from women with GDM. Results Capillary tube formation assays revealed that GDM-hAMSCs produced a significantly higher number of nodes (P = 0.004), junctions (P = 0.002) and meshes (P < 0.001) than equivalent NGT-hAMSCs, concomitant with an increase in the gene/protein expression of FGFR2, TGFBR1, SERPINE1 and VEGFA. These latter changes were recapitulated in NGT-hAMSCs exposed to GDM-like conditions. Inhibition of the protein product of SERPINE1 (plasminogen activator inhibitor 1, PAI-1) suppressed the angiogenic properties of GDM-hAMSCs. Correlation analyses revealed that cord blood insulin levels in offspring strongly correlated with the number of nodes (r = 0.860; P = 0.001), junctions (r = 0.853; P = 0.002) and meshes (r = 0.816; P = 0.004) in tube formation assays. Finally, FGFR2 levels correlated positively with placental weight (r = 0.586; P = 0.028) and neonatal adiposity (r = 0.496; P = 0.014). Conclusions GDM exposure contributes to the angiogenic abilities of hAMSCs, which are further related to increased cord blood insulin and fetal adiposity. PAI-1 emerges as a potential key player of GDM-induced angiogenesis.

The role of maternal diet on offspring hyperinsulinaemia and adiposity after birth: a systematic review of randomised controlled trials

In utero diet may be directly related to the risk of fetal hyperinsulinaemia and offspring metabolic health. This review examines the relationship between maternal dietary exposures and sub-clinical fetal hyperinsulinaemia and neonatal adiposity. Articles were identified in MEDLINE, Web of Science, Cochrane Controlled Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, SCOPUS, and SPORTDiscus (September 2019–March 2021) using the preferred reporting items for systematic reviews and meta-analyses guidelines. PROSPERO registration ID CRD42020146453. Studies were selected by two independent reviewers. Randomised controlled trials (RCT) involving a dietary intervention with pregnant women (healthy pregnancy, gestational diabetes mellitus and obesity) and reporting fetal cord-blood insulin, c-peptide, glucose or adiposity estimates were included. One author extracted all information on main study characteristics and outcomes. Risk of bias was assessed using the Cochrane Collaboration’s bias risk assessment tool. A total of 733 articles were identified. Fourteen articles from 11 RCTs (3614 participants) were included. Studies reviewed showed no specific effect of maternal diet on neonatal cord blood insulin, c-peptide or glucose levels. Infants born to mothers who followed a low glycaemic load (GL) had lower skin fold thickness compared to controls. Interventions that provided individualised nutrition counselling to women with obesity or previous infant born > 4 kg were also associated with lower adiposity. The studies reviewed suggest that lifestyle-based dietary interventions to improve glycaemia (low GL) have a protective effect against excess adiposity. Future studies should incorporate multi-modal interventions with dietary counselling to support lifestyle changes throughout gestation and include assessments of maternal insulin resistance at recruitment.

The effect of vitamin K1 on VEGF levels in chick embryos with type 1 diabetes and Diabetic Retinopathy induced by streptozotocin

Objective: Hyperglycemia caused by Diabetes Mellitus (DM) is associated with long-term dysfunction such as diabetic retinopathy (DRP). The most effective growth factor in the development of DRP is the vascular endothelial growth factor (VEGF). Vitamin K1 reduces hyperglycemia and prevents the development of DM. In this study, we aimed to create streptozotocin (STZ) induced DM and DRP in chick embryos and to show whether vitamin K1 can prevent early-stage DRP by measuring VEGF levels. Material and Methods: The 140 specific pathogen-free (SPF) fertilized chicken eggs were used in this study. Three different STZ doses were administered to 120 SPF eggs for an induced DM model. Three different vitamin K1 doses were administered in each STZ dose group. On the 12th day and 18th day the remaining 20 SPF eggs were separated as control groups. On the 18th-day, blood glucose, blood insulin and VEGF levels were measured. Results: 0.45 mg/egg STZ dose (STZ3) was determined as the optimal/ideal dose for the DM model. When the group-administered STZ3 and vitamin K1 were evaluated among themselves; it was determined that there were significant changes in blood glucose, blood insulin, VEGF levels of the STZ3+K1-3 group compared to the STZ3+K1-1 and STZ3+K1-2 groups (p<0.05). Conclusion: Vitamin K1 increases blood insulin levels and decreases blood glucose levels. When hyperglycemia reduces, the VEGF levels reduce. Vitamin K1 protects from DRP by reducing VEGF levels.

Type 2 Diabetes Mellitus: A Pathophysiologic Perspective

Type 2 Diabetes Mellitus (T2DM) is characterized by chronically elevated blood glucose (hyperglycemia) and elevated blood insulin (hyperinsulinemia). When the blood glucose concentration is 100 milligrams/deciliter the bloodstream of an average adult contains about 5–10 grams of glucose. Carbohydrate-restricted diets have been used effectively to treat obesity and T2DM for over 100 years, and their effectiveness may simply be due to lowering the dietary contribution to glucose and insulin levels, which then leads to improvements in hyperglycemia and hyperinsulinemia. Treatments for T2DM that lead to improvements in glycemic control and reductions in blood insulin levels are sensible based on this pathophysiologic perspective. In this article, a pathophysiological argument for using carbohydrate restriction to treat T2DM will be made.

An algorithm mimicking pancreas pulsatile behavior improves artificial pancreas performance

Background: Artificial pancreas design using subcutaneous insulin infusion without pre-meal feed-forward boluses often induces an over-response leading to hypoglycemia due to the increase of blood insulin concentration sustained in time. The objective of this work was to create an algorithm for controlling the function of insulin pumps in closed-loop systems to improve blood glucose management in type 1 diabetic patients by mimicking the pulsatile behaviour of the pancreas. Methods: A controller tuned in a pulsatile way promotes damped oscillations of blood insulin concentration injected through an insulin pump. We tested it in a simulated environment, using nine ‘in silica’ subjects. The control algorithm is founded on feedback linearization where through a change of variables, the nonlinear system turns into an equivalent linear system, suitable for implementing through a PID controller. We compared the results obtained ‘in silica’ with the volume injected by an insulin pump controlled by this algorithm. Results: The use of this algorithm resulted in a pulsatile control of postprandial blood glucose concentration, avoiding hypoglycaemic episodes. The results obtained ‘in silica’ were replicated in a real pump ‘in vitro’. Conclusions: With this proposed linear system, an appropriate control input can be designed. The controller works with a damped pulsatile pattern making the insulin infusion from the pump and blood insulin concentration pulsatile. This operational would improve the performance of an artificial pancreas.

Short-Term Calorie Restriction Maintains Plasma Insulin Concentrations along with a Reduction in Hepatic Insulin-Degrading Enzyme Levels in db/db Mice

Maintaining blood insulin levels is important for patients with diabetes because insulin secretion capacity declines with the development of the disease. Calorie restriction (CR) is effective for the improvement of glucose tolerance, but it is not clear whether CR can maintain insulin levels in the late stage of diabetes. We examined the effect of CR on whole-body glucose tolerance and fasting blood insulin concentrations in the late stage of diabetes. Male db/db mice were subjected to either a standard laboratory diet ad libitum for 3 weeks (dbdb group) or 40% CR (dbdb+CR group). CR significantly decreased body mass and epididymal fat weight. Glucose tolerance and fasting glucose levels were significantly improved with 3-week CR. Fasting insulin concentrations were decreased in the dbdb group but were maintained in the dbdb+CR group. CR significantly reduced insulin-degrading enzyme (IDE) levels in the liver, and hepatic IDE levels were significantly positively and negatively correlated with plasma glucose concentrations (area under the curve) after glucose administration and after fasting insulin concentrations, respectively. Therefore, 3-week CR maintained blood insulin levels and improved glucose tolerance with decreased hepatic IDE levels in an animal model of late-stage diabetes.

Dietary Modified Cassava Chip and Corn Seed: Effect on Growth Performance, Rumen Production, and Blood glucose and Insulin in Early Fattening Beef Bulls

Effects of feeding modified cassava chip and corn seed as energy source inclusion in diet were investigated on growth performance, rumen fermentation, and blood metabolites in early fattening bulls. Thirty-six 1-year-old Charolais crossbred bulls with initial weight 270 ± 50 kg were randomly assigned into 6 groups with different experimental rations as cassava-based concentrates including non-modified cassava chip (Cass-Con), with 15 % of alkaline-treated cassava chip (Cass-Alkaline), with 15 % of steam-treated cassava chip (Cass-Steam) and corn-based concentrates including non-modified corn seed (Corn-Con), with 15 % of alkaline-treated corn seed (Corn-Alkaline), and with 15 % of steam-treated corn seed (Corn-Steam), according to completely randomized design (CRD). Results showed that feed intake and digestibility were not significantly different among treatments, while digestible dry matter and organic matter intake of Cass-Steam and Corn-Alkaline were higher than those of the other diets (P < 0.05). Ruminal pH post-feeding was highest in Corn-Alkaline and lowest in Cass-Con (P < 0.05). Blood glucose was similar among treatments. However, blood insulin at 4 h post-feeding was higher in Cass-Steam, Corn-Alkaline, and Corn-Steam than in the others. Blood insulin in bulls fed corn-based concentrate was higher than in bulls fed cassava-based concentrate (P < 0.01). Body weight gain and average daily gain were significantly higher (P < 0.05), while feed conversion ratio was lower in Cass-Steam, Corn-Alkaline, and Corn-Steam as compared with in Cass-Con, Cass-Alkaline and Corn-Con. Results indicated that using a modified energy source can improve growth performance in early fattening beef bulls. An appropriate method to modify cassava chip was steam method, while alkaline method for corn seed was superior.