Compared to liver, bile duct and skeletal muscle garlic (versus normal saline) only enhances pancreas insulin m-RNA transcription that corresponds to islets cellular plasticity and local and circulating hyperinsulinemia in diabetic rats

Background: Garlic aqueous extract (GE) augments insulin circulating concentration in streptozotocin-induced type-1 diabetes mellitus (STZ-DM) rat model. Objective: This study investigated at 4 stages in a time-line fashion whether modifications in insulin m-RNA transcription occur, and if they do, are they related to accumulative changes in insulin - serum and tissue concentrations and immunohistochemical (IHC) localizations and plasticities as part of the GE-induced insulinogenic mechanism(s) in the pancreas, liver, bile duct and gastrocnemius skeletal muscle (GSM) of STZ-DM rats. Method: The body weight, food and water intake, urine output, fasting blood glucose (FBG), serum insulin (SI), in addition to tissues insulin concentrations, IHC localizations and numerical intensities and m-RNA transcriptions were investigated before (basal level = BL) and after 1, 4 and 8 weeks of oral treatment in normal rats given normal saline (NR-NS), diabetic rats given normal saline (DR-NS) and diabetic rats given GE (DR-GE). The readings collected were compared using two-way ANOVA with LSD post-hoc test (IBM SPSS - V.22) and differences were considered significant when P <0.05.Results: Compared to NR-NS, DR-NS showed typical diabetic biophysical symptoms in addition to significant accumulative increases in FBG and reductions in SI, which corresponded positively with reductions in pancreatic insulin IHC localization and numerical intensity and m-RNA transcription. Conversely, and in comparison to DR-NS, DR-GE showed amelioration of diabetic biophysical symptoms, in addition to significant accumulative decreases in FBG and increases in SI, which corresponded positively with increases in pancreatic insulin IHC localization and numerical intensity and m-RNA transcription. The liver, bile duct and GSM did not show any changes in the targeted parameters (or indicators of insulin synthesis: proinsulin or C-peptide) in response to GE treatment. Conclusion: GE induced increases in circulating insulin concentration could have been due to increases in pancreas insulin concentrations as a result of an enhancement in islets cellular plasticity and m-RNA transcription. Accordingly, garlic insulinogenic action could be partly due to modification of pancreas genetic expression.

Importance of the route of insulin delivery to its control of glucose metabolism

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

Diabetes and Rheumatology

Diabetes mellitus (DM) is a chronic disease characterized by persistent hyperglycaemia that happens as a result of a pancreatic insulin deficiency and/or insulin resistance. Its morbidity and mortality are primarily related to the resultant microvascular and macrovascular complications. Its prevalence has grown widely, which will result in higher rates of diabetic complications including rheumatic manifestations.

Antidiabetes of Combination of Fractionated-extracts of Andrographispaniculata and Centellaasiatica in Neonatal Streptozotocin-induced Diabetic Rats

Many medicinal plants are widely grown in South- and Southeast Asia countries. Some of them are traditionally used for treatment of diabetes mellitus such as Andrographispaniculata and Centellaasiatica. In the study, we provided fractionated-extracts of A. paniculata and C. asiatica to increase the concentration of their active compounds and eliminate unexpected substances. The aim of the study was to evaluate the antidiabetes effect of the combination of their fractionated-extracts in male neonatal streptozotocin (STZ)-induced diabetic rats. In the study, diabetes was injected intraperitoneally 90mg.kg-1 BWSTZ to two day-old rats. At the age of three months, the rats were administered with the combination of both fractionated-extracts for 14 consecutive days. We evaluated antidiabetes with parameters of blood glucose levels, morphology of pancreatic islet, β-cell density as well as immunohistochemical pancreatic insulin. The levels of MDA, SOD and GPx were also determined about oxidative stress change after treatment with the combination. In the study, the combination succeeded to lower the blood glucose level in neonatal STZ-induced diabetic rats. Inline with fact, improvement of rat pancreatic islets and β cells density, as well as moderate restoration of pancreatic insulin, were observed after treatment with the combination. The substance could decrease the level of MDA, and increase the levels of SOD and GPx. In conclusion, the combination of fractionated-extracts of A. paniculata and C. asiatica exhibited potential antidiabetic effect to its antioxidative effect in male neonatal STZ-induced diabetes rats.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.