Apolipoprotein CIII (ApoCIII), a small protein that resides on the surface of lipoprotein particles, is a key regulator of triglyceride metabolism. The inhibition of lipoprotein lipase (LPL), the increased assembly and secretion of very low-density lipoproteins (VLDL) and the decreased reuptake of triglyceride-rich lipoproteins (TRLs) by the liver are mechanisms associating elevated serum ApoCIII levels and hypertriglyceridemia. ApoCIII concentration is high in individuals with diabetes mellitus indicating a possible positive correlation with impairment of glucose metabolism. The aim of this review (based on a Pubmed search until August 2018) is to present the possible mechanisms linking ApoCIII and deterioration of carbohydrate homeostasis. ApoCIII enhances pancreatic β-cells apoptosis via an increase of the cytoplasmic Ca2+ levels in the insulin producing cells. In addition, overexpression of ApoCIII enhances non-alcoholic fatty liver disease and exacerbates inflammatory pathways in skeletal muscles, affecting insulin signaling and thereby inducing insulin resistance. Moreover, recent studies reveal a possible mechanism of body weight increase and glucose production through a potential ApoCIII-induced LPL inhibition in the hypothalamus. Also, the presence of ApoCIII on the surface of high-density lipoprotein particles is associated with impairment of their antiglycemic and atheroprotective properties. Modulating ApoCIII may be a potent therapeutic approach to manage hypertriglyceridemia and improve carbohydrate metabolism.

Regular physical activity increases lifespan for those with type 1 diabetes. However, disease-related barriers may deter children from exercise and affect their fitness. This study examined the safety of the Cooper test concerning diabetes-related acute complications in children with type 1 diabetes and their fitness. Blood glucose was recorded before and 0, 30, 60 min after the test. The covered distances were transformed to z-scores based on the national charts. Body mass index, body fat percentage and glycated hemoglobin were measured. The run was completed by 80 individuals (45% boys, age 13.6±2.1 years; diabetes duration 6.3±3.5 years). During the follow-up 11 children reached glucose alert values (3-3.9 mmol/L), 3 presented clinically significant hypoglycemia (<3 mmol/L), none experienced severe hypoglycemia. The covered distance was 1914±298 m, not significantly different from the reference population (z-score -0.12±0.71 vs 0, p=0.12). The study participants were more overweight than general pediatric population in terms of body mass index (z-score 0.48±0.94 vs 0, p<0.001) and body fat percentage (z-score: 0.37±0.85 vs 0, p<0.001). In conclusion, the Cooper test can be safely used in children with diabetes to assess their physical capacity. Youth with type 1 diabetes present fitness similar to healthy children but exhibit increased body mass index and adiposity.

Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to exert beneficial effects against insulin resistance (IR) and type 2 diabetes. Combined oral contraceptive (COC) treatment is associated with impaired glucose and lipid metabolism but the mechanisms are elusive. We therefore, hypothesized that DPP-4 inhibition ameliorates COC-induced glucose dysregulation and hepatic triglyceride (TG) accumulation through adenosine deaminase (ADA) /xanthine oxidase (XO) /uric acid-dependent pathway. Female Wistar rats received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel; po) with or without DPP-4 inhibitor (sitagliptin; 100 mg/kg; po) for 8 weeks (n = 6/group). Glucose dysmetabolism was assessed by elevated fasting blood glucose, impaired oral glucose tolerance test and homeostatic model assessment of IR. Treatment with COC led to increased plasma fasting glucose, triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, IR and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic TG, TG/HDL-cholesterol ratio, malondialdehyde, uric acid (plasma; 25.2 ± 0.6 mg/dl; hepatic 128.9 ± 8.0 mg/100 mg tissue), lactate dehydrogenase, DPP-4, ADA and XO (plasma;10.5 ± 1.1 U/L; hepatic 21.2 ± 1.4 U/g protein) activities. Likewise, COC led to reduction in nitric oxide level. However, DPP-4 inhibition significantly ameliorated these alterations induced by COC treatment through suppression of uric acid (plasma; 15.1 ± 1.0 mg/dl, hepatic; 75.6 ± 5.0 mg/100 mg tissue), XO (plasma; 4.1 ± 0.9 U/L, hepatic; 8.7 ± 0.4 U/g protein), ADA and DPP-4 activities suggesting their involvement in glucose dysregulation and hepatic TG accumulation induced by COC treatment. Therefore, DPP-4 inhibition would impact positively on cardiometabolic disorders, at least in part, through XO, ADA and uric acid suppression.

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).