DA-JC1 improves circadian rhythm disorder induced by amyloid β-protein 31-35 / 中华神经科杂志

Objective To observe the effect of DA-JC1 on the circadian rhythm disorder in C57BL/6 mice and the abnormal expression of period1 in HT22 cells induced by amyloid β-protein 31-35 (Aβ31-35).Methods (1) The six-eight weeks old C57BL/6 male mice were selected for wheelrunning behavior experiment.Then we analyzed the effect of DA-JC1 on the circadian rhythm disorder induced by Aβ31-35.(2) HT22 mouse hippocampal cells were adopted as the research objects.Cells were divided into vehicle group,Aβ31-35 group,pre-DA-JC1 group and DA-JC1 group (n =4 respectively) by random number table method.Cell viability was assessed by methylthiazolyldiphenyl-tetrazolium bromide cytotoxicity assay.Real-time quantitative PCR was used to detect the expression of clock gene period1,and Western blotting was applied to examine the expression of period1 protein at circadian time (CT) 12.Results (1) Compared with the vehicle group ((23.54 ± 0.07) h),the circadian rhythm of mice in the Aβ31-35 group was disturbed which exhibited significantly longer free running period ((23.80 ± 0.06) h,t=0.265,P=0.010),whereas the disruption was significantly relieved with pre-treatment of DA-JC1 ((23.61 ± 0.06) h,t =0.193,P =0.047).(2) Compared with the vehicle group (100.0％ ± 3.6％),5 μmol/L Aβ31-35 decreased the cell viability significantly (78.7％ ± 3.4％,t =12.393,P =0.005),and DA-JC1 can reduce the toxicity of Aβ31-35 in HT22 cells (89.2％ ± 2.3％,t =9.748,P =0.048).(3) Compared with the vehicle group (period1 gene:1.00 ± 0.09;period1 protein:1.01 ± 0.07),abnormal rhythmic expression of period1 was induced by Aβ31-35 in HT22 cells which significantly decreased at CT12 (period1 gene:0.58 ± 0.04,t =0.419,P =0.001;period1 protein:0.74 ± 0.07,t =0.221,P =0.007) while DA-JC1 pre-treatment can reverse the abnormal expression (period1 gene:0.79 ±0.11,t =0.279,P=0.024;period1 protein:0.99 ±0.05,t=0.226,P=0.009).Conclusion DA-JC1 improves the circadian rhythm disorder induced by Aβ31-35 in C57BL/6 mice and improves the abnormal expression of period1 induced by Aβ31-35 in HT22 cells.

Glucose-dependent insulinotropic polypeptide in diabetes and obesity / 中华内分泌代谢杂志

[Summary] Glucose-dependent insulinotropic polypeptide ( GIP) is known to promote the release of insulin fromβcells, but this function suffers from a defect in obese patients. More and more evidences suggest that GIP is the bridge between a high-fat diet, obesity, insulin resistance, and type 2 diabetes. With the deepening of research in GIP in type 2 diabetes and obesity, GIP may provide new ideas for the treatment of type 2 diabetes and obesity.

Dipeptidyl Peptidase-4 Inhibitor / 대한내과학회지

Recent advances in incretin biology have led to the development of a new class of oral anti-diabetic drugs. To date, there are two known incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), of which the former is a more important therapeutic target for type 2 diabetes. GLP-1 is secreted by intestinal L-cells in response to oral nutrient intake, and it stimulates insulin secretion and suppresses glucagon secretion in a glucose-dependent manner. However, both GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), a multifunctional type II transmembrane glycoprotein. Thus, several DPP-4 inhibitors with different pharmacologic features are now available and can be used either as monotherapy or in combination with other anti-diabetic agents for the treatment of type 2 diabetes. In both therapeutic regimens, DPP-4 inhibitors have been shown to reduce hemoglobin A1c levels by approximately 0.5-0.8%. In clinical trials, DPP-4 inhibitors were generally well-tolerated, posed a low risk of hypoglycemia, and did not increase body weight. Despite some reports of a possible increased risk of pancreatitis with GLP-1 receptor agonists and DPP-4 inhibitors, no causal associations have been found. Recent randomized controlled clinical trials have shown that DPP-4 inhibitors did not increase or decrease the rates of major adverse cardiovascular events in patients with type 2 diabetes at high risk of cardiovascular disease, even though this class of anti-diabetic agents had various salutary effects in many studies involving animals or healthy and diabetic humans. Additional studies will be required to resolve these disparate conclusions.

Progress in the studies on extra-islet effects of incretin / 中华内分泌代谢杂志

Incretin is defined as an intestinal hormone released in response to nutrient ingestion, which potentiates the glucose-induced insulin response. In human body, the incretin's effect is mainly induced by two peptide hormones, glucagon-like peptide-I (GLP-I)and glucose-dependent insulinotropic polypeptide (GIP). In order to fully evaluate the clinical advantages of novel agents based on incretin, this review introduces the islet actions of incretin in brief, and mainly focuses on the extra-islet effect of incretin.

Insulin Secretion and Incretin Hormone Concentration in Women with Previous Gestational Diabetes Mellitus

BACKGROUND: We examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) on insulin secretion in women with previous gestational diabetes (pGDM). METHODS: A 75-g oral glucose tolerance test (OGTT) was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured. RESULTS: Among 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT) and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT. CONCLUSION: GLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes.

The Incretins and Pancreatic beta-Cells: Use of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide to Cure Type 2 Diabetes Mellitus / 당뇨병

Type 2 diabetes mellitus (T2DM) is increasing in prevalence worldwide. The complications associated with T2DM result in increased mortality and financial cost for those affected. T2DM has long been known to be associated with insulin resistance in peripheral tissues and a relative degree of insulin deficiency. However, the concept that insulin secretion and insulin sensitivity are not linked through a hyperbolic relationship in T2DM has continuously been demonstrated in many clinical trials. Thus, in order to prevent and treat T2DM, it is necessary to identify the substance(s) that will improve the function and survival of the pancreatic beta-cells in both normal and pathologic conditions, so that production and secretion of insulin can be enhanced. Incretin hormones, such as glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), have been shown to lower the postprandial and fasting glucose and the glycated hemoglobin levels, suppress the elevated glucagon level, and stimulate glucose-dependent insulin synthesis and secretion. In this report, we will review the biological actions and mechanisms associated with the actions of incretin hormones, GLP-1 and GIP, on beta-cell health and compare the differences between GLP-1 and GIP.

The Incretins and Pancreatic beta-Cells: Use of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide to Cure Type 2 Diabetes Mellitus / 당뇨병

Type 2 diabetes mellitus (T2DM) is increasing in prevalence worldwide. The complications associated with T2DM result in increased mortality and financial cost for those affected. T2DM has long been known to be associated with insulin resistance in peripheral tissues and a relative degree of insulin deficiency. However, the concept that insulin secretion and insulin sensitivity are not linked through a hyperbolic relationship in T2DM has continuously been demonstrated in many clinical trials. Thus, in order to prevent and treat T2DM, it is necessary to identify the substance(s) that will improve the function and survival of the pancreatic beta-cells in both normal and pathologic conditions, so that production and secretion of insulin can be enhanced. Incretin hormones, such as glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), have been shown to lower the postprandial and fasting glucose and the glycated hemoglobin levels, suppress the elevated glucagon level, and stimulate glucose-dependent insulin synthesis and secretion. In this report, we will review the biological actions and mechanisms associated with the actions of incretin hormones, GLP-1 and GIP, on beta-cell health and compare the differences between GLP-1 and GIP.