The effect and mechanism of metformin on peripheral neuropathy in type 1 diabetic rats / 药学学报

Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients, which often results in patients suffering from severe hyperalgesia and allodynia. Up to now, the clinical therapeutic effect of DPN is still unsatisfactory. Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades. Studies have shown that metformin can improve pain caused by DPN, but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN, and the mechanism for improving DPN are not clear. Therefore, the STZ-induced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN, and to preliminarily explore its mechanism in this study. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). After the model was established successfully, STZ diabetic rats were randomly divided into a model group and a metformin treatment group, and 10 normal SD rats were selected as the normal control group, and the rats were intragastrically administered for 12 weeks. The results showed that metformin significantly reduced blood glucose, glycosylated hemoglobin, food consumption and water consumption in STZ rats. Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold, prolonged the hot plate latency threshold, and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats. In addition, metformin increased the content of glutathione (GSH), enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced the content of malondialdehyde (MDA) in serum and sciatic nerve of STZ diabetic rats, as well as regulating the expression of genes related to oxidative stress in the sciatic nerve. Metformin obviously reduced the levels of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the serum in STZ rats, and inhibited the gene expression of these inflammatory factors in the sciatic nerve. In summary, metformin significantly increased nerve conduction velocity, improved sciatic nerve morphological abnormalities and pain in DPN rats, which may be related to its effect in improving oxidative stress and reducing inflammation.

Anti-diabetic effects of the fraction of alkaloids from Ramulus Mori, an innovative Sangzhi alkaloids as an α-glucosidase inhibitor / 药学学报

Sangzhi alkaloids (SZ-A) are derived from traditional Chinese medicine Ramulus Mori, serving well as an innovative antidiabetic drug, due to α-glucosidase inhibition. To evaluate the potency of glucosidase inhibitory effect of SZ-A, the enzyme-based screening platforms, including sucrase, maltase and amylase were established, and IC50 was calculated. The effects of SZ-A on postprandial blood glucose at a single dose, oral sucrose, starch and glucose loading were determined in normal ICR mice and alloxan-induced hyperglycemic mice. To confirm the anti-diabetic effects of SZ-A on glucose and lipid metabolism after long-term administration, the postprandial and fasting blood glucose, serum insulin, urinary glucose levels, glycosylated serum proteins and blood lipid levels were determined in high-fat fed C57 obese mice (pre-diabetic HFC57 mice) and diabetic rats induced by streptozotocin (STZ). The Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College approved all of the protocols for this research. We found that SZ-A exhibited a significant inhibitory effect on the sucrase and maltase. SZ-A showed no effect on amylase. In normal ICR mice and alloxan-induced hyperglycemic mice, SZ-A at a single dose significantly delayed and reduced the peak of blood glucose after sucrose or starch loading, but showed no effect on the increase of blood glucose after glucose loading. In STZ diabetic rats, SZ-A significantly reduced the postprandial or fasting blood glucose levels, glycosylated serum proteins and urinary glucose. SZ-A also reduced serum triglyceride (TG) and cholesterol (TC) levels after 3 weeks of treatment. SZ-A ameliorated the postprandial blood glucose or the fasting blood glucose elevation, and reduced the incidence of hyperglycemia in HFC57 mice. SZ-A decreased the basal insulin level, improved insulin sensitivity, and ameliorated glucose intolerance in pre-diabetic HFC57 mice. Our results indicated that SZ-A had a novel inhibitory activity on α-glucosidase, especially on disaccharidases. SZ-A at a single dose significantly reduced the peak of blood glucose elevation and delayed the increase of blood glucose in normal and diabetic mice after disaccharide and polysaccharide loading. Long-term SZ-A treatment improved glucose and lipid metabolic profiles by delaying carbohydrate absorption from the intestine and reduced the postprandial blood glucose levels in both pre-diabetic and diabetic animal models. Therefore, SZ-A application may display a beneficial role in preventing the development and complications of diabetes.

Anti-diabetes effects and mechanisms of a Chinese herbal medicine preparation JQ-R in diabetic KKAy mice and in vitro / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effects and mechanisms by which JQ-R regulated the glucose metabolism and improves insulin sensitivity in diabetic KKAy mice and insulin-resistant L6 myotubes. JQ-R is a mixture of refined extracts from Coptis chinensis, Astragalus membranaceus and Lonicera japonica, three major herbs of JinQi-JiangTang tablet. METHODS Diabetic KKAy mice were adminis-tered JQ-R (100 mg·kg-1or 200 mg·kg-1BW) for 10 weeks. Levels of fasting plasma glucose, lipids, insulin and hemoglobin A1c were monitored.Systemic insulin sensitivity was quantified using the eugly-cemic clamp.The effect of JQ-R on the expressions of the enzymes involved in insulin signaling,oxidative stress and inflammation(Akt,NFκB,IΚBα, JNK, Erk, p38 MAPK) were measured in L6 insulin-resis-tant myotubes. RESULTS JQ-R showed beneficial effects on glucose homeostasis and insulin sensi-tivity in diabetic KKAy mice after 10 weeks treatment. JQ-R also ameliorated the plasma lipid profiles. Moreover,JQ-R can directly reverse the decreased activity of SOD and increased MDA levels as well as activity of iNOS in insulin resistant L6 cell induced with palmitic acid(PA).The expressions of phos-phorylation of NF-κB p65,IκBα,JNK1/2 and Erk1/2 were also decreased after JQ-R treatment.It was also shown that the insulin-stimulated glucose uptake increased significantly after JQ-R treatment,with upregulated expression of phosphorylation of Akt. CONCLUSION JQ-R ameliorated the glucose and lipid metabolism and insulin sensitivity in diabetic KKAy mice. In vitro treatment with JQ-R directly enhanced insulin stimulated glucose uptake in insulin resistant myotubes with improved insulin signal-ling and inflammatory response and oxidative stress state.

Advances in diabetic animal models and its application in the traditional Chinese medicine research / 药学学报

The high and continuing soaring incidence of diabetes may become a huge obstacle to China's development. The antidiabetic drug development is one way to solve the problem. Animal model is a powerful tool for drug development. This paper compares and analyzes the three kinds of animal models for antidiabetic drug development in replicating principle, methods and characteristic, then summarized the application in the research of traditional Chinese medicine. At the same time, the analysis of the market, application and clinical advantages of hypoglycemic medicine from traditional Chinese medicine, is given in this paper, based on the literature analysis. From the point of the clinic advantage embodiment and new drug development, this paper will provide advisory and assistance support for the anti-diabetic fighting with traditional Chinese medicine.

Effect of Mudan Granule on islets beta cell function in monosodium glutamate induced obese mice with insulin resistance: an experimental study / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of Mudan Granule (MD) on the glucose metabolism and beta cell function in monosodium glutamate (MSG) induced obese mice with insulin resistance (IR).</p><p><b>METHODS</b>MSG obese mice were induced by subcutaneous injecting MSG (4 g/kg for 7 successive days in neonatal ICR mice). Forty MSG mice with IR features were recruited and divided into four groups according to body weight, fasting blood glucose, triglyceride (TG), total cholesterol (TC), and the percentage of blood glucose decreased within 40 min in the IR test, i.e., the model group (Con), the low dose MD group, the high dose MD group, and the Metformin group (Met). Besides, another 10 ICR mice were recruited as the normal control group (Nor). The water solvent of 2.5 g/kg MD or 5 g/kg MD was respectively administered to mice in the low dose MD group and the high dose MD group. Metformin hydrochloride was given to mice in the Met group at 0.2 g/kg body weight. Equal dose solvent distilled water was administered to mice in the Nor group and the Con group by gastrogavage, once per day. All medication was lasted for 15 weeks. Insulin tolerance test (ITT) and oral glucose tolerance test (OGTT) were performed after 6 weeks of treatment. Beta cell function was assessed by hyperglycemic clamp technique. The morphological changes in the pancreas were evaluated by hematoxylin-eosin (HE) staining. Changes of iNOS, NF-kappaB p65, and p-NF-kappaB p65 in the pancreas were tested.</p><p><b>RESULTS</b>Compared with the Nor group, the blood glucose level, AUC, and fasting blood insulin, ONOO-contents, iNOS activities, and the expression of iNOS, NF-kappaB p65 subunit, pNF-kappaB p65 subunit obviously increased; decreased percentage of blood glucose within 40 min in ITT, glucose infusion rate (GIR), Clamp 1 min insulin, and Max-Insulin obviously decreased in the Con group (P < 0.05, P < 0.01). Compared with the Con group, the aforesaid indices could be improved in the Met group (P < 0.05, P < 0.01). In the low dose MD group, AUC, iNOS activities, and the expression of iNOS and p-NF-kappaB p65 subunit obviously decreased; percentage of blood glucose within 40 min in ITT and GIR obviously increased (P < 0.05, P < 0.01). In the high dose MD group, AUC, ONOO-contents, iNOS activities, and the expression of iNOS, NF-kappaB p65 subunit, and p-NF-KB p65 subunit obviously decreased; percentage of blood glucose within 40 min in ITT, Max-Insulin, and GIR obviously increased (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>MD could significantly improve IR and functional disorder of 3 cells in MSG obese mice, which might be associated with lowering inflammatory reaction in the pancreas.</p>

Advances of the mechanism study on berberine in the control of blood glucose and lipid as well as metabolism disorders / 药学学报

Berberine, an isoquinoline alkaloid isolated from some Chinese medicinal herbs such as Coptidis rhizoma, has been used for the treatment of diarrhea and other gastrointestinal infections as an antibacterial drug in Chinese medicine. In recent years, it was reported to have beneficial effects on the metabolism disorders states of diabetes. The mechanisms involve many aspects of the diabetes, including regulating the blood cholesterol and triglyceride, lowering blood glucose, ameliorating the insulin resistant state and influencing the function of the pancreatic beta cell.

A novel cell model targeted on GLP-1 receptor for application to anti-diabetic candidates screening / 药学学报

The aim of this project is to establish a GLP-1 signaling pathway targeted cell model, for screening the new class of GLP-1 receptor agonists as anti-diabetic candidates. Firstly construct a recombined plasmid with multi-copied specific response element (RIP-CRE) regulated by GLP-1 signaling pathway and E-GFP reporter gene. Transient transfect this recombined plasmid into islet cell NIT-1, then detect the responsibility of transfected cell to GLP-1 analogue, Exendin 4. For secondly, use stable transfection and monocloning cell culture to obtain a GLP-1 signaling-specific cell line. It indicates that this cell model can response to Exendin 4, which response can be completely inhibited by GLP-1 receptor antagonist, Exendin 9-39, further showing GLP-1 receptor specific activity with a cAMP-PKA-independently mechanism. Establishment of this novel cell model can be used in high-throughput drug screening of peptides or small molecular GLP-1 analogues.

Experimental treatment of complications in alloxan diabetic rats with alpha-glucosidase inhibitor from the Chinese medicinal herb ramulus mori / 药学学报

<p><b>AIM</b>To assess the effects of the alpha-glucosidase inhibitor Sangzhi (Ramulus mori, SZ) on the relief of diabetic symptoms of hyperglycemia and the prevention of its late complications in alloxan diabetic rats with high-calorie chow.</p><p><b>METHODS</b>The aqueous extract of Sangzhi was given orally to alloxan diabetic rats for 15 days. The hyperglycemic symptoms were observed. The blood glucose, lipid levels and the nephrotic representations were measured.</p><p><b>RESULTS</b>When alloxan diabetic rats on high-calorie chow were treated with SZ, the hyperglycemic symptoms were improved, the blood lipid levels were improved, the ratio of kidney over body weight and the blood N-acetyl-beta-D-glucosaminidase (NAG) activity were lowered. The degree of renal pathological changes was significantly reduced.</p><p><b>CONCLUSION</b>SZ may be useful for treating diabetes and its complications.</p>