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the combination of insulin and GLP-1 analog

Helena W Rodbard
GLP-1 receptor agonists (GLP-1 RAs), introduced for clinical use in 2005, have excellent potency in reducing HbA1c and mean glucose, improving fasting plasma glucose, inducing weight loss or protecting against the weight gain associated with insulin therapy, reducing appetite, and delaying gastric emptying. Two of these medications, liraglutide and semaglutide, appear to have cardioprotective effects as reflected in cardiovascular outcomes studies. The GLP-1 RAs are associated with gastrointestinal side effects that tend to diminish over time...
June 5, 2018: Diabetes Technology & Therapeutics
Neil Skolnik, Debbie Hinnen, Yan Kiriakov, Melissa L Magwire, John R White
IN BRIEF Titratable fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist are new therapeutic options for people with type 2 diabetes. Two FRCs-insulin degludec/liraglutide and insulin glargine/lixisenatide-have been approved for use in the United States. The two components in these FRCs target different aspects of diabetes pathophysiology, working in a complementary manner to decrease blood glucose while mitigating the side effects associated with each component (hypoglycemia and weight gain with insulin and gastrointestinal side effects with GLP-1 receptor agonists)...
April 2018: Clinical Diabetes: a Publication of the American Diabetes Association
Lujin Wu, Ke Wang, Wei Wang, Zheng Wen, Peihua Wang, Lei Liu, Dao Wen Wang
Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks...
April 16, 2018: Aging Cell
Shinji Iwasaki, Teruki Hamada, Ikumi Chisaki, Tomohiro Andou, Noriyasu Sano, Atsutoshi Furuta, Nobuyuki Amano
In addition to their potent antidiabetic effects, glucagon-like peptide-1 (GLP-1) analogs lower body weight in humans. Hence, agonistic targeting of the GLP-1 receptor could be a valid approach to target obesity. However, quantitative analyses of the pharmacokinetic/pharmacodynamic (PK/PD) relationship between GLP-1 analogs and their antiobesity effect have not been reported in either animals or humans. Therefore, the present study was performed to establish a mechanism-based PK/PD model of GLP-1 receptor agonists using the GLP-1 analog exenatide for the development of promising new antiobesity drugs...
September 2017: Journal of Pharmacology and Experimental Therapeutics
Markolf Hanefeld, Denis Raccah, Louis Monnier
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with hyperglycemia, which can lead to serious vascular complications. Current treatment guidelines place particular emphasis on personalization of therapy. Within this guidance, the use of various second-line therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), is recommended under certain circumstances. Areas covered: Factors influencing glucose homeostasis, including gastric emptying and the associated cardiovascular (CV) risk when homeostasis is not maintained, are reviewed...
March 2017: Expert Opinion on Drug Metabolism & Toxicology
Allison L Brill, Jaclyn A Wisinski, Mark T Cadena, Mary F Thompson, Rachel J Fenske, Harpreet K Brar, Michael D Schaid, Renee L Pasker, Michelle E Kimple
A defining characteristic of type 1 diabetes mellitus (T1DM) pathophysiology is pancreatic β-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote β-cell replication and survival, thus reversing the loss of β-cell mass, while also preserving β-cell function, could lead to a real cure for T1DM. The α-subunit of the heterotrimeric Gz protein, Gαz, is a tonic negative regulator of adenylate cyclase and downstream cAMP production...
May 2016: Molecular Endocrinology
E M Varin, A Wojtusciszyn, C Broca, D Muller, M A Ravier, F Ceppo, E Renard, J-F Tanti, S Dalle
Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in β-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E β-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation...
January 21, 2016: Cell Death & Disease
Wuquan Deng, Sheng Qiu, Gangyi Yang, Bing Chen
Glucagon-like peptide-1 (GLP-1) analogs, such as exenatide, have played an important role as antidiabetic medications in the treatment of type 2 diabetes (T2DM). Like most other hypoglycemic agents, exenatide has a number of actions, including lowering blood glucose, promoting weight loss, improving insulin resistance, and protecting islet β-cells. Although GLP-1 analogs, combined with other antidiabetic medications, have excellent performance in T2DM, some side effects and imperfections limit its use in clinical practice...
2015: Therapeutics and Clinical Risk Management
Elin V Johansson Boll, Linda M N K Ekström, Christophe M Courtin, Jan A Delcour, Anne C Nilsson, Inger M E Björck, Elin M Östman
PURPOSE: Specific combinations of dietary fiber (DF) have been observed to result in improved glucose tolerance at a subsequent standardized breakfast. Arabinoxylan oligosaccharides (AXOS) are considered as DF with prebiotic potential, but so far no studies have investigated their metabolic effects in humans. This randomized cross-over study evaluated the overnight impact of breads containing AXOS-rich wheat bran extract and resistant starch (RS, Hi-Maize), separately or combined, on glucose tolerance, related metabolic parameters and markers of gut fermentation in healthy subjects...
June 2016: European Journal of Nutrition
Belma Ascic Buturovic, Lejla Burnazovic Ristic, Alma Mujanovic Narancic
INTRODUCTION: Patient-oriented therapy represents a modern approach in the treatment of patients with diabetes, an approach which is supported in the most recent guidelines by the ADA and the European Association for the Study of Diabetes (EASD). The progressive nature of diabetes demands the introduction of insulin therapy much earlier in order to prevent the development of late complications of the disease. MATERIAL AND METHODS: The study included 30 patients who had been treated with long-acting insulin analogue and metformin in doses of 3 x 850 mg at least 6 months prior to study entry and in which a good glycaemic control had not been achieved, or with HbA1c > 7%...
October 2014: Medical Archives
Gerhard H Scholz, Holger Fleischmann
The combination of basal insulin and glucagon-like protein 1 receptor agonists (GLP-1 RAs) is a new intriguing therapeutic option for patients with type 2 diabetes. In our daily practice we abbreviate this therapeutic concept with the term BIT (basal insulin combined incretin mimetic therapy) in a certain analogy to BOT (basal insulin supported oral therapy). In most cases BIT is indeed an extension of BOT, if fasting, prandial or postprandial blood glucose values have not reached the target range. In our paper we discuss special features of combinations of short- or prandial-acting and long- or continuous-acting GLP-1 RAs like exenatide, lixisenatide and liraglutide with basal insulin in relation to different glycemic targets...
October 2014: Therapeutic Advances in Endocrinology and Metabolism
Kartikkumar Navinchandra Patel, Amit Arvind Joharapurkar, Vishal Patel, Samadhan Govind Kshirsagar, Rajesh Bahekar, Brijesh Kumar Srivastava, Mukul R Jain
Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant...
December 2014: Canadian Journal of Physiology and Pharmacology
Harumi Takahashi, Tadao Shibasaki, Jae-Hyung Park, Shihomi Hidaka, Toshimasa Takahashi, Aika Ono, Dae-Kyu Song, Susumu Seino
Incretin-related drugs and sulfonylureas are currently used worldwide for the treatment of type 2 diabetes. We recently found that Epac2A, a cAMP binding protein having guanine nucleotide exchange activity toward Rap, is a target of both incretin and sulfonylurea. This suggests the possibility of interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion. In this study, we examined the combinatorial effects of incretin and various sulfonylureas on insulin secretion and activation of Epac2A/Rap1 signaling...
April 2015: Diabetes
Bénédicte de Kalbermatten, Jaafar Jaafar, François R Jornayvaz, Jacques Philippe
Type 2 diabetes mellitus is a progressive and heterogeneous disease. The decrease in insulin secretion by pancreatic beta cells and the increase of glucagon secretion by pancreatic beta cells, are the two major pathophysiologic characteristics. The majority of type 2 diabetics will therefore require insulin in the evolution of their disease, with weight gain and hypoglycaemia as side effects. GLP-1 analogs are effective therapeutic alternatives due to their actions on glucagon and insulin secretion, on satiety and gastric emptying...
June 4, 2014: Revue Médicale Suisse
Irl B Hirsch, Doron Schneider, Aaron King, William H Polonsky, Timothy S Reid, Jay Shubrook, Carol A Verderese, Jeffrey Wallace, Matthew C Riddle
New models of health care delivery that emphasize patient-centered care affirm the need for alternatives to add-on prandial insulin therapy when optimized basal insulin fails to maintain glycemic control in patients with type 2 diabetes mellitus. Regimens that are easy to teach, convenient, and flexible generally improve the outlook for long-term success. Our review reconsiders traditional barriers to insulin intensification in primary care and provides an illustration of how the benefits and drawbacks of > 1 choice of action--specifically, adding rapid-acting insulin or a short-acting glucagon-like peptide-1 analog--can be weighed by the patient and provider together to determine the best next treatment step that balances efficacy, safety, and adherence to therapy...
May 2014: Postgraduate Medicine
Etie S Moghissi
Patients with long-standing type 2 diabetes mellitus (T2DM) can be clinically challenging for physicians to treat because these patients often lack sufficient β-cell function to respond to some oral glucose-lowering agents, may have profound comorbidities, and may have renal impairment that limits the use of traditional agents. These complications, in addition to older age, also increase the risk of hypoglycemia, which can be a major barrier to treatment success. Individualizing treatment targets to balance the benefits of glycemic control with risks of hypoglycemia is the first step to successfully treating these patients...
May 2014: Journal of the American Osteopathic Association
Shu Meguro, Toshihide Kawai, Tomohiro Matsuhashi, Motoaki Sano, Keiichi Fukuda, Hiroshi Itoh, Yoshihiko Suzuki
Introduction. Treatment with a glucagon-like peptide 1 (GLP-1) analog fails in some patients due to rebound hyperglycemia caused by tachyphylaxis (GLP-1 tachyphylaxis). We investigated the efficacy of basal-supported oral therapy (BOT) with insulin glargine and sitagliptin for counteracting GLP-1 tachyphylaxis. Materials and Methods. The subjects were 12 men and 3 women aged 59.9 ± 10.0 years who had been treated with GLP-1 analogs. All of them had developed rebound hyperglycemia caused by GLP-1 tachyphylaxis...
2014: International Journal of Endocrinology
John Gerich
Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections...
December 4, 2013: International Journal of General Medicine
Helena W Rodbard
The ADA/EASD and AACE guidelines emphasize the importance of individualizing treatment to best meet each patient's situation. Metformin remains the preferred choice as initial therapy for most patients. The 2009 AACE algorithm elevated the role of incretin-based therapies (GLP-1R agonists and DPP-4 inhibitors) relative to previous algorithms and this has been endorsed by subsequent algorithms and guidelines. The incretin-based therapies and insulin therapy should be considered with very high priority. Either incretin-based therapy or insulin therapy can be used as monotherapy or in combination with other agents...
December 2013: Journal of Family Practice
Tae Jung Oh, Ji Yon Shin, Gyeong Hoon Kang, Kyong Soo Park, Young Min Cho
Metformin has been reported to increase the expression of the glucagon-like peptide-1 (GLP-1) receptor in pancreatic beta cells in a peroxisome proliferator-activated receptor (PPAR)-α-dependent manner. We investigated whether a PPARα agonist, fenofibrate, exhibits an additive or synergistic effect on glucose metabolism, independent of its lipid-lowering effect, when added to metformin. Non-obese diabetic Goto-Kakizaki (GK) rats were divided into four groups and treated for 28 days with metformin, fenofibrate, metformin plus fenofibrate or vehicle...
2013: Experimental & Molecular Medicine
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