Engineered glucagon-like peptide-1-producing hepatocytes lower plasma glucose levels in mice

2009 ◽  
Vol 296 (4) ◽  
pp. E936-E944 ◽  
Author(s):  
Michael J. Riedel ◽  
Corinna Wai Kwan Lee ◽  
Timothy J. Kieffer
Keyword(s):  
Type 2 Diabetes ◽  
Gene Therapy ◽  
Plasma Glucose ◽  
Glucose Levels ◽  
Dpp Iv ◽  
Adenoviral Delivery ◽  
Glucagon Like Peptide ◽  
Novel Strategy

Glucagon-like peptide (GLP)-1 is an incretin hormone with well-characterized antidiabetic properties, including glucose-dependent stimulation of insulin secretion and enhancement of β-cell mass. GLP-1 agonists have recently been developed and are now in clinical use for the treatment of type 2 diabetes. Rapid degradation of GLP-1 by enzymes including dipeptidyl-peptidase (DPP)-IV and neutral endopeptidase (NEP) 24.11, along with renal clearance, contribute to a short biological half-life, necessitating frequent injections to maintain therapeutic efficacy. Gene therapy may represent a promising alternative approach for achieving long-term increases in endogenous release of GLP-1. We have developed a novel strategy for glucose-regulated production of GLP-1 in hepatocytes by expressing a DPP-IV-resistant GLP-1 peptide in hepatocytes under control of the liver-type pyruvate kinase promoter. Adenoviral delivery of this construct to hepatocytes in vitro resulted in production and secretion of bioactive GLP-1 as measured by a luciferase-based bioassay developed to detect the NH2-terminally modified GLP-1 peptide engineered for this study. Transplantation of encapsulated hepatocytes into CD-1 mice resulted in an increase in plasma GLP-1 levels that was accompanied by a significant reduction in fasting plasma glucose levels. The results from this study demonstrate that a gene therapy approach designed to induce GLP-1 production in hepatocytes may represent a novel strategy for long-term secretion of bioactive GLP-1 for the treatment of type 2 diabetes.

Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors

2015 ◽  
Vol 93 (7) ◽  
pp. 721-729
Author(s):  
R. Abu Khalaf ◽  
Z. Jarekji ◽  
T. Al-Qirim ◽  
D. Sabbah ◽  
G. Shattat
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Inhibitory Polypeptide ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Glucose Levels ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Circulating Levels

Inhibition of dipeptidyl peptidase-IV (DPP-IV) prevents the inactivation of gastric inhibitory polypeptide (GIP) and glucagon-like peptide–1 (GLP-1). This increases circulating levels of active GLP-1 and GIP and stimulates insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. In this study, pharmacophore modeling and docking experiments were carried out and a series of eight novel 2-ethoxy-6,9-disubstituted acridines (13, 15, and 17a–17f) have been designed and synthesized. Then, these compounds were evaluated for their ability to inhibit DPP-IV. Most of the synthesized compounds were proven to have anti-DPP-IV activity where compound 17b displayed the best activity of 43.8% inhibition at 30 μmol/L concentration. Results of this work might be helpful for further optimization to develop more potent DPP-IV inhibitors.

scholarly journals N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

2004 ◽  
Vol 180 (3) ◽  
pp. 379-388 ◽  
Author(s):  
BD Green ◽  
MH Mooney ◽  
VA Gault ◽  
N Irwin ◽  
CJ Bailey ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Plasma Glucose ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.

Effect of High ß-Glucan Barley on Postprandial Plasma Glucose Levels in Subjects with Normal Glucose Tolerance and Patients with Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 772-P
Author(s):  
MARIKO HIGA ◽  
AYANA HASHIMOTO ◽  
MOE HAYASAKA ◽  
MAI HIJIKATA ◽  
AYAMI UEDA ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Normal Glucose Tolerance ◽  
Postprandial Plasma Glucose ◽  
Glucose Levels ◽  
Normal Glucose

scholarly journals Association between fasting insulin and C-reactive protein among adults without diabetes using a two-part model: NHANES 2005–2010

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amanda L. Missel ◽  
Laura R. Saslow ◽  
Dina H. Griauzde ◽  
Donna Marvicsin ◽  
Ananda Sen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Waist Circumference ◽  
Low Grade ◽  
Fasting Insulin ◽  
C Reactive Protein ◽  
Glucose Levels ◽  
Reactive Protein ◽  
Part Model

Abstract Introduction Chronic inflammation is associated with the development, progression and long-term complications of type 2 diabetes. Hyperglycemia is associated with chronic low-grade inflammation, and thus has become the focus of many screening and treatment recommendations. We hypothesize that insulin may also be associated with inflammation and may be an additional factor to consider in screening and treatment. Methods This study used National Health and Nutrition Examination Survey data from 2005 to 2010 to analyze the association between fasting insulin and C-reactive protein (CRP). A two-part model was used due to the high number of values reported as 0.1 mg/L. Two models were analyzed, both with and without the addition of waist circumference to other covariates in the model. Results The final sample included 4527 adults with a mean age of 43.31 years. In the first model, higher fasting insulin was associated with increased odds of CRP > 0.1 mg/L (OR = 1.02, p < .001) and with higher CRP (β = 0.03, p < .001). In the adjusted model, including waist circumference as a covariate, higher fasting insulin was not associated with CRP > 0.1 mg/L (OR = 1.00, p = .307) but the association between higher fasting insulin and higher continuous CRP remained significant (β = 0.01, p = .012). Conclusion This study found that higher fasting insulin is associated with higher CRP. These results suggest that treatment approaches that simultaneously decrease insulin levels as well as glucose levels may provide additive anti-inflammatory effects, and therefore may improve long-term outcomes for adults with type 2 diabetes.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

1998 ◽  
Vol 95 (3) ◽  
pp. 325-329 ◽  
Author(s):  
Jeannie F. TODD ◽  
C. Mark B. EDWARDS ◽  
Mohammad A. GHATEI ◽  
Hugh M. MATHER ◽  
Stephen R. BLOOM
Keyword(s):  
Type 2 Diabetes ◽  
Glycaemic Control ◽  
Plasma Glucose ◽  
Test Meal ◽  
Insulin Response ◽  
Standard Test ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Response

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia. 2.To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period. 3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0–240 ;min: GLP-1 start of treatment, 196±141 ;mmol·min-1·l-1; saline start of treatment, 469±124 ;mmol·min-1·l-1; F = 16.4, P< 0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 ;min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period. 4.We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.

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