Objective:

2

To investigate the effects of Clean-DM1 (C-DM1)

a polyherbal formulation of

Radix Scrophulariae

Radix Astragali

Rhizoma Atractylodis

and

Radix Salviae

Miltiorrhizae

on high-fat diet (HFD)-induced diabetes mice.

Methods:

2

The information about active components of C-DM1 extract and molecular mechanism was obtained from network pharmacology analysis. Main compounds of C-DM1 extract by high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis were conducted for quality control. For

in vivo

study

mice were induced diabetes by HFD for 12 weeks. The mice in the normal group (Nor) were maintained with a regular diet and treated with saline by gavage. The HFD model mice were randomly divided into 3 groups

including a HFD diabetic model group

a C-DM1 extract-administered group (C-DM1

500 mg/kg)

and metformin-administered groups (Met

500 mg/kg)

8 mice in each group. Food intake

body weight (BW)

and fasting blood glucose (FBG) levels were recorded weekly for 4 weeks. After 4 weeks of treatment

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

blood glucose

low-density lipoprotein cholesterol (LDL-C) were determined using an automated clinical chemistry analyzer

and homeostatic model for assessing insulin resistance (HOMA-IR) levels and oral glucose tolerance test (OGTT) were detected. The histopathological changes of liver and pancreatic tissues were observed by hematoxylin-eosin staining. Insulin receptor substrate (IRS)/phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT) and adenosine 5'-monophosphate-activated protein kinase (AMPK) expressions in liver and pancreas tissues were detected by Western blot analysis.

Results:

2

HPLC-MS identified dihydroisotanshinone

dihydroisotanshinone Ⅰ

cryptotanshinone

harpagoside

and atractyloside A in C-DM1 extract. The administration of C-DM1 extract significantly decreased body weight

calorie intake

and the levels of blood glucose and insulin in the diabetic mice (

P

<

0.05 or

P

<

0.01). The C-DM1 extract administration improved the impaired glucose tolerance and insulin resistance in the diabetic mice and significantly decreased the levels of LDL-C

ALT and AST (

P

<

0.01). The C-DM1 extract inhibited the histopathological changes of fatty liver and hyperplasia of pancreatic islets in the diabetic mice. The C-DM1 extract significantly increased the phosphorylation of IRS

AKT

and AMPK and the expression of PI3K in pancreas and liver tissues (

P

<

0.05 or

P

<

0.01)

which was consistent with the analysis results of network pharmacology.

Conclusion:

2

C-DM1 extract improved diabetes symptoms in long-term HFD-induced mice by regulation of IRS/PI3K/AKT and AMPK expressions in pancreas and liver tissues

suggesting that C-DM1 formulation may help prevent the progression of T2DM.