Substituted benzoxazinones as potent positive allosteric AMPA receptor modulators: part II

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzoxazinone derivatives with good to very good in vitro activity as positive allosteric AMPAR modulators was synthesized and evaluated. The appropriate substituent choice on the benzoxazinone fragment improved the affinity towards the AMPA receptor significantly in comparison to our lead molecule CX614.     

Autophagy and adipogenesis: Implications in obesity and type II diabetes

Obesity is a direct result of the accumulation of white adipose tissue (WAT). In this study, the role of autophagy in the differentiation of white adipose tissue was studied by deleting the autophagy-related 7 (atg7) gene from adipose tissue in mice. This deletion results in a striking phenotype at the cellular, tissue, and whole-organism levels. Adipose tissue deposits in the mutant mice are much smaller in mass than those observed in their wild-type counterparts, and mutant adipocytes exhibit unusual morphological characteristics including multilocular lipid droplets and greatly increased numbers of mitochondria. The knockout mice are noticeably slimmer than their wild-type littermates, despite parity in food and water consumption. The mutant mice also exhibit higher basal physical activity levels and an array of metabolic changes revealed through blood tests. Most importantly, these mice show resistance to high-fat diet-induced obesity and markedly increased sensitivity to insulin. These findings establish a new function for autophagy and provide a new model system for use in the search for treatments for obesity and type II diabetes.     

Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes

Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two G-protein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.     

Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes

The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.     

MicroRNAs and type 2 diabetes/obesity

MicroRNAs belong to a newly identified class of small non-coding RNAs that have been widely implicated in the fine-tuning of many physiological processes such as the pathogenesis of type 2 diabetes(T2D) and obesity.Microarray studies have highlighted an altered profile of miRNA expression in insulin target tissues in diabetic and obese models.Emerging evidences suggest that miRNAs play significant roles in insulin production,secretion and actions,as well as in diverse aspects of glucose homeostasis and adipocyte differentiation. The identification of tissue-specific miRNAs implicated in T2D and obesity might be useful for the future development of effective strategies for early diagnosis and therapeutic intervention of obesity-related medical complications.     

Intestinal endotoxin as a trigger of type 1 diabetes mellitus

The blood serum level of intestinal flora endotoxin was studied in 45 children and adolescents aged 3–17 years with type 1 diabetes mellitus. In all the patients the endotoxin levels 2.89 ± 0.33 EU/ml) were significantly elevated compared to the control group (0.4 ± 0.03 EU/ml). A higher level of endotoxin at the disease onset (3.93 ± 0.79 EU/ml) compared to that in children afflicted with diabetes for more than two years (2.37 ± 0.27 EU/ml) gives evidence of the involvement of endotoxin in the initiation of the disease.     

PCK1 and PCK2 as candidate diabetes and obesity genes

The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO₂. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2–3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129–135). The purpose of this review is to further explore these possibilities.     

潜在的防治肥胖及糖尿病靶标——DGAT

二酰基甘油酰基转移酶(DGAT)是甘油三酯(TG)合成的关键酶,催化TG合成的最后一步。DGAT有两种亚型:DGAT1和DGAT2。DGAT1缺陷的小鼠对胰岛素和瘦素的敏感性增加且可以抵抗饮食诱导的肥胖;DGAT2功能下调可明显降低肥胖小鼠肝脏TG含量,改善脂肪肝的形成。DGAT抑制剂可改善动物模型的高脂血症和脂肪肝。因此,DGAT有可能成为防治肥胖、糖尿病等代谢性疾病的新的药物靶标。该文详细阐述了DGAT的生理功能研究及其抑制剂的研究进展。     

Mesenchymal stem cell-based therapy for the treatment of type 1 diabetes mellitus

The pathophysiology of Type 1 diabetes (T1D) appears largely related to an innate defect in the immune system culminating in a loss of self tolerance and destruction of the insulin producing β-cells. Currently, there is no definitive cure for diabetes. Insulin injection does not mimic the precise regulation of β-cells on glucose homeostasis, leading long term to the development of complications. Other therapeutic approaches therefore, are necessary and cell therapy is thought to be a possible approach. In this sense, mesenchymal stem cells (MSCs) can offer a promising possibility that deserves to be explored. MSCs are multipotent non-hematopoietic progenitor cells. Their therapeutic potentials have recently been brought into the spotlights of many fields of research. Although the regenerative capabilities of MSCs have been a driving force to initiate studies testing their therapeutic effectiveness, their immunomodulatory properties have been equally exciting. MSCs possess specific immunomodulatory properties that would appear capable of disabling immune dysregulation that leads to β-cell destruction in T1D. Furthermore, MSCs can be sequentially cultured in specially defined conditions and their differentiation extends toward the β-cell phenotype and the formation of insulin producing cells (IPCs). To date, the role of MSCs in T1D remains completely unexplored. We herein summarize multiple strategies that have been proposed and tested for its potential therapeutic benefit for T1D.     

Optimization of peptide-based polyagonists for treatment of diabetes and obesity

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PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes

Neuromedin U (NMU) is an endogenous peptide, whose role in the regulation of feeding and energy homeostasis is well documented. Two NMU receptors have been identified: NMUR1, expressed primarily in the periphery, and NMUR2, expressed predominantly in the brain. We recently demonstrated that acute peripheral administration of NMU exerts potent but acute anorectic activity and can improve glucose homeostasis, with both actions mediated by NMUR1. Here, we describe the development of a metabolically stable analog of NMU, based on derivatization of the native peptide with high molecular weight poly(ethylene) glycol (PEG) ('PEGylation'). PEG size, site of attachment, and conjugation chemistry were optimized, to yield an analog which displays robust and long-lasting anorectic activity and significant glucose-lowering activity in vivo. Studies in NMU receptor-deficient mice showed that PEG-NMU displays an expanded pharmacological profile, with the ability to engage NMUR2 in addition to NMUR1. In light of these data, PEGylated derivatives of NMU represent promising candidates for the treatment of obesity and diabetes.     

Phenylalanine derivatives as GPR142 agonists for the treatment of Type II diabetes

GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.     

Hematopoietic stem cell transplantation for the treatment of autoimmunity in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic b cells. While there is no current cure, recent work in the field of allogeneic hematopoietic stem cell transplantation (HSCT) and the induction of mixed chimerism, a state in which multilineage hematopoietic populations of both recipient and donor co-exist, has demonstrated that it is possible to provide protection from disease onset, as well as reverse the autoimmune state in spontaneously diabetic mice. Furthermore, the establishment of mixed chimerism induces donor-specific tolerance, providing the potential to normalize glucose regulation via pancreatic islet transplantation without the requirement of life-long immunosuppression. Current studies are aimed at understanding the mechanisms involved in both the reversal of autoimmunity and the induction of tolerance, with the aim of moving this promising approach to curing T1D into the clinic.     

Novel AGLP-1 albumin fusion protein as a long-lasting agent for type 2 diabetes

Glucagon like peptide-1 (GLP-1) regulates glucose mediated-insulin secretion, nutrient accumulation, and β-cell growth. Despite the potential therapeutic usage for type 2 diabetes (T2D), GLP-1 has a short half-life in vivo (t_1/2 ＜2 min). In an attempt to prolong half-life, GLP-1 fusion proteins were genetically engineered: GLP-1 human serum albumin fusion (GLP-1/HSA), AGLP-1/HSA which has an additional alanine at the N-terminus of GLP-1, and AGLP-1-L/HSA, in which a peptide linker is inserted between AGLP-1 and HSA. Recombinant fusion proteins secreted from the Chinese Hamster Ovary-K1 (CHO-K1) cell line were purified with high purity (＞96%). AGLP-1 fusion protein was resistant against the dipeptidyl peptidase-IV (DPP-IV). The fusion proteins activated cAMP-mediated signaling in rat insulinoma INS-1 cells. Furthermore, a C57BL/6N mice pharmacodynamics study exhibited that AGLP-1-L/HSA effectively reduced blood glucose level compared to AGLP-1/HSA. [BMB Reports 2013; 46(12): 606-610]     

New developments in the treatment and monitoring of type 1 diabetes mellitus

In recent years, insulin analogues are the benefits of the use in functional intensive insulin therapy for the treatment of diabetes. Shortacting insulin (lispro, aspart and glulisine) and long-acting insulin (glargine and detemir) have been developed for the management of diabetes. Short-acting insulin analogues are an alternative to regular human insulin before meals. These new short-acting insulin analogues show more rapid onset of activity and a shorter duration of action. As a result of these pharmacokinetic differences, an improved postprandial glycemic control is achieved, without increasing the risk of hypoglycemia. In addition, these insulin analogues can be administered immediately before a meal. The long-acting insulin analogues provide basal insulin levels for 24 h when administered once (glargine) or two (detemir) daily. Compared with previous intermediate- or long-acting conventional insulin, these insulins shows a flat profile of plasma insulin levels . The use of these long-acting insulin analogues appears to be associated with a reduced incidence of hypoglycemia, especially at night. The availability of these new insulin analogues has the potential to significantly improve long-term control over blood glucose in diabetic patients. In recent years more and more frequently the method of multiple daily injections (MDI) of insulin is being replaced by the method of continuous subcutaneous insulin infusion (CSII). It is the most physiological way to administer insulin. In recent years treatment with insulin pumps has been used more frequently in the pediatric patients and in the treatment of diabetes in pregnancy. Use of continuous glucose monitoring systems enables detection of glycemia fluctuations unrevealed by selfmonitoring of blood glucose, such as night hypoglycemias and early postprandial hyperglycemias. Real-time systems allow to reduce HbA1c levels and limit number of excursions. Non-invasive glucose measurement devices are introduced. Fully automated continuous glucose monitoring systems integrated with insulin pumps operating in closed-loop model, requiring no patient assistance, are still being researched. Commercially available systems operate in open-loop model, where the patient has to decide on administration and dose of insulin.     

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.