Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: The metformin, glucagon-like peptide-1 receptor agonist, and insulin (MGI) approach.
ABSTRACT The prevalence of type 2 diabetes mellitus (T2DM) is rising in association with an increase in obesity rates. Current treatment options for patients with T2DM include lifestyle modifications and numerous antidiabetic medications. Despite the availability of effective and well-tolerated treatments, many patients do not achieve recommended glycemic targets. Lack of efficacy is complicated by the wide range of available agents and little specificity in treatment guidelines, thus challenging clinicians to understand the relative benefits and risks of individual options for each patient. In this article, lifestyle intervention strategies and current antidiabetic agents are evaluated for their efficacy, safety, and weight-loss potential. Because of the heterogeneous and progressive nature of T2DM, physicians should advocate approaches that emphasize weight management, limit the risk of hypoglycemia and adverse events, and focus on the core pathophysiologic defects in patients with T2DM. A healthy, plant-based diet that is low in saturated fat and refined carbohydrates but high in whole grains, vegetables, legumes, and fruits, coupled with resistance and aerobic exercise regimens, are recommended for patients with T2DM. When necessary, drug intervention, described in this article as the MGI (metformin, glucagon-like peptide-1 receptor agonist, and insulin) approach, should begin with metformin and progress to the early addition of glucagon-like peptide-1 receptor agonists because of their weight loss potential and ability to target multiple pathophysiologic defects in patients with T2DM. For most patients, treatments that induce weight gain and hypoglycemia should be avoided. Long-acting insulin should be initiated if glycemic control is not achieved with metformin and glucagon-like peptide-1 receptor agonist combination therapy, focusing on long-acting insulin analogs that induce the least weight gain and have the lowest hypoglycemic risk. Ultimately, a patient-centered treatment approach that addresses the core pathologies of T2DM and obesity will not only increase overall efficacy and the likelihood that a patient adheres to treatment, but may also improve a patient's mental well-being and quality of life.
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ABSTRACT: Regulation of balance between lipid accumulation and energy consumption is a critical step for the maintenance of energy homeostasis. Here, we show that Panax red ginseng extract treatments increased energy expenditures and prevented mice from diet induced obesity. Panax red ginseng extracts strongly activated Hormone Specific Lipase (HSL) via Protein Kinase A (PKA). Since activation of HSL induces lipolysis in WAT and fatty acid oxidation in brown adipose tissue (BAT), these results suggest that Panax red ginseng extracts prevent HFD induced obesity by regulating lipid mobilization.Biochemical and Biophysical Research Communications 04/2014; DOI:10.1016/j.bbrc.2014.04.056 · 2.28 Impact Factor
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ABSTRACT: Aim:GPR119 is a G protein-coupled receptor (GPCR) that is highly expressed in pancreatic β-cells and intestinal L-cells and facilitates glucose-stimulated insulin secretion (GSIS). GPR119 may represent a novel target for the treatment of metabolic disorders. Here, we sought to identify novel small-molecule GPR119 agonists.Methods:A cell-based high-throughput screening assay was established using HEK293 cells stably expressing GPR119 and pCRE-luc reporter plasmid (HEK293/GPR119/pCRE-luc). A compound library composed of 1440 compounds was screened. Mouse β-cell line MIN-6 and isolated mouse islets were used to evaluate the effects of candidate compounds on GSIS in vitro.Results:Three compounds with novel structures (ZSY-04, -06, and -13) were found to activate GPR119-mediated signaling and to induce GPR119 desensitization. The EC50 values of ZSY-04, -06, and -13 in stimulating intracellular cAMP accumulation in HEK293/GPR119 cells were 2.758, 3.046, and 0.778 μmol/L, respectively. Furthermore, all three compounds displayed high selectivity for GPR119, and did not activate other 9 GPCRs tested. Moreover, all three compounds significantly increased GSIS in both MIN-6 mouse β-cells and isolated mouse islets at concentration of 10 μmol/L.Conclusion:Three novel small-molecule GPR119 agonists (ZSY-04, -06, and -13) with high receptor selectivity and capacity to induce GSIS in vitro were discovered. These compounds are potential candidates to be structurally optimized into drugs for the treatment of type 2 diabetes.Acta Pharmacologica Sinica 03/2014; DOI:10.1038/aps.2014.8 · 2.35 Impact Factor
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ABSTRACT: Type 2 diabetes mellitus (T2DM) is a growing public health problem with significant lifetime health care costs. The majority of Americans do not achieve minimal targets for exercise, and individuals with T2DM typically engage in less exercise than the general adult population. However, those patients with T2DM who are sufficiently self-motivated to manage their condition have the potential to reverse diabetes and prevent its complications through behavioral and pharmacologic interventions. Marked improvements are possible through increased awareness and selection of healthy eating options, a willingness to incorporate vigorous exercise into their lifestyle, and the use of newer medications that essentially eliminate the risk of hypoglycemia while facilitating weight loss and the achievement of ideal glucose targets. For self-motivated patients, daily aerobic activity of 45 to 60 minutes per day may be a suitable target. For those who have cardiovascular clearance, high-intensity interval training accomplishes high levels of cardiometabolic fitness with shorter training periods by alternating moderate and intense exertion. Suitable medications that have a low risk of hypoglycemia during exercise include metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose linked transporter-2 inhibitors. Specific daily caloric goals and incorporation of a mainly plant-based diet should be considered as a primary target for diabetes management. Self-management is important to achieving diabetes treatment goals, and mobile applications can be useful tools to support lifestyle changes in patients with T2DM.The Physician and sportsmedicine 11/2014; 42(4):49-59. DOI:10.3810/psm.2014.11.2091 · 1.49 Impact Factor