Annona muricata L. peel extract inhibits carbohydrate metabolizing enzymes and reduces pancreatic β-cells, inflammation, and apoptosis via upregulation of PI3K/AKT genes

Abstract

Background and objective Annona muricata L. peel has been recognized for many ethnobotanical uses, including diabetes management. However, limited detailed scientific information about its mechanism of antidiabetic activity exists. The objective of this study was to evaluate the anti-diabetic properties of an aqueous extract of A. muricata peel (AEAMP) and its mechanism of action on alloxan-induced diabetic rats. Methods In vitro antidiabetic assays, such as α-amylase and α-glucosidase were analyzed on AEAMP. Alloxan monohydrate (150 mg/kg b.w) was used to induce diabetes in the rats. 150 mg/kg b.w positive control group doses of 6.67, 13.53, and 27.06 mg/kg were administered to 3 groups for twenty-one days. The positive control group was administered 30 mg/kg of metformin. The negative and normal control groups were administered distilled water. The fasting blood glucose, serum insulin, lipid profile, inflammatory cytokines, antioxidant markers, carbohydrate metabolizing enzymes, and liver glycogen were analyzed as well as PI3K/AKT and apoptotic markers PCNA and Bcl2 by RT-PCR. Results AEAMP inhibited α-amylase and α-glucosidase enzymes more effectively than acarbose. AEAMP reduced FBG levels, HOMA-IR, G6P, F-1,6-BP, MDA, TG, TC, AI, CRI, IL-6, TNF-α, and NF-κB in diabetic rats. Furthermore, in diabetic rats, AEAMP improved serum insulin levels, HOMA-β, hexokinase, CAT, GST, and HDL-c. Liver PI3K, liver PCNA and pancreas PCNA were not significantly different in untreated diabetic rats when compared to normal rats suggesting alloxan induction of diabetes did not downregulate the mRNA expression of these genes. AEAMP significantly up-regulated expression of AKT and Bcl2 in the liver and pancreatic tissue. It is interesting that luteolin and resorcinol were among the constituents of AEAMP. Conclusions AEAMP can improve β-cell dysfunction by upregulating liver AKT and pancreatic PI3K and AKT genes, inhibiting carbohydrate metabolizing enzymes and preventing apoptosis by upregulating liver and pancreatic Bcl2. However, the potential limitation of this study is the unavailability of equipment and techniques for collecting more data for the study.

Onopordum acanthium L. extract attenuates pancreatic β-Cells and cardiac inflammation in streptozocin-induced diabetic rats

“…In the liver, glucokinase is involved in the process of glucose store as glycogen. The effect of MEOAL on the inhibition α-glucosidase and α-amylase activity displayed to be concentration dependent indicating the potential activity of extract’s antidiabetic action [ 52 ]. Through in silico modelling six compounds in MEOAL are shown to bind to pancreatic alpha-amylase and glucokinase protein with Catechin, Kaempferol, and Epicatechin showing a highest binding affinities.…”

Hematological and Hypoglycemic Effects of Ethanolic Extract of Annona muricata Ripe Fruits Pulp on Streptozotocin-induced Diabetes in Rats: In vivo and In silico Studies

“…Studies have shown the effect of selected A. muricata active compounds (rutin, muricatocin A, anonaine, isolaureline, xylopine, and kaempferol 3-O-rutinoside) on inhibition of the Forkhead Box O1 (FOXO1) protein, and the results revealed that FOXO1 protein plays a crucial role in the proliferation process of pancreatic β-cells and inhibition of the FOXO1 protein activity in the nucleus will enhance insulin sensitivity [33,34]. Furthermore, a study has reported that an aqueous extract of A. muricata peel (AEAMP) inhibited α-amylase and α-glucosidase enzymes more effectively than acarbose, and that it improve β-cell dysfunction by upregulating liver AKT and pancreatic PI3K and AKT genes, and preventing apoptosis by upregulating liver and pancreatic Bcl2 [35].…”

Role of ceramides in diabetic foot ulcers (Review)

“…Another possible way to induce β-cell apoptosis is to inhibit the function of Akt, which is a serine/threonine kinase. First, it was shown that Akt could increase cellular proliferation, but that its inhibition could induce apoptosis ( 142 ). Second, Akt upregulates CDKN1B to trigger apoptosis while adversely regulating the transcriptional activity of FOXO1 ( 143 ).…”