SHIP2: an emerging target for the treatment of type 2 diabetes mellitus

With the rapid increase in the number of patients developing type 2 diabetes mellitus and the lack of optimal therapies, much focus has been placed on the insulin-signaling pathway in the discovery of novel drug targets. Phosphatidyl Inositol 3-Kinase (PI3K) is central to mediating insulin-s metabolic effects. PI3K catalyzes the generation of phosphatidyl inositol (3,4,5) triphosphate (PIP(3)). Inhibition of PI3K activity results in a blockade of insulin signaling including glucose uptake and glyocogen synthesis. Thus, PIP(3) is a critical mediator of insulin action. A family of phosphatidyl inositol phosphatases have been identified that counter-regulate PI3K activity by hydrolyzing PIP(3) to phosphatidyl inositol bisphosphate at either the 3' or 5' position of the inositol ring. Mice lacking one of these enzymes, Src-Homology Inositol Phosphatase-2 (SHIP2), demonstrate increased insulin sensitivity, suggesting that pharmacological inhibition of SHIP2 could alleviate insulin resistance. Recent studies demonstrate elevated SHIP2 expression is associated with insulin resistance in human patients. Comparing the studies on SHIP2 and other phosphatases suggests how inhibition of SHIP2 leads to increased insulin sensitivity without deleterious effects. This review focuses on the emergence of SHIP2 as a target in the insulin-signaling pathway for the treatment of type 2 diabetes.     

SGLT2抑制剂治疗糖尿病研究进展

近年来,钠-葡萄糖协同转运蛋白2(type 2 sodium glucose co-transporters,SGLT2)抑制剂作为一种新型的治疗糖尿病药物成为研究热点。SGLT2在肾近端小管葡萄糖重吸收中起着非常重要的作用;抑制肾脏SGLT2可以促进Ⅱ型糖尿病人尿糖的排泄,使其血糖恢复正常而不会有低血糖的风险。临床实验表明,SGLT2抑制剂对Ⅱ型糖尿病的治疗效果明显,且具有降低体重、无低血糖风险等优点,目前,许多SGLT2抑制剂已经进入临床评价后期。     

Omarigliptin for the treatment of type 2 diabetes mellitus

Introduction: The estimated global prevalence of diabetes mellitus for adults aged 20-70 in 2015 was 415 million with approximately 90% of diagnosed cases being Type 2 diabetes mellitus (T2DM). Improvements in lifestyle and effective therapies are key to management but due to the progressive nature of T2DM, pharmacotherapy is typically required. Whilst the initial therapy will usually be with metformin, thereafter treatment should be individualised, with consideration of several different second line options. These include the dipeptidyl peptidase-4 (DPP-4) inhibitors, of which omarigliptin is the second once weekly version.

Areas covered: The paper summarises key pharmoacodynamic and pharmacokinetic features and reviews the efficacy and safety trial data of omarigliptin, a once-weekly DPP-4 inhibitor.

Expert opinion: Omarigliptin results in a significant improvement in glycaemia with an effective once weekly pharmacokinetic profile and low risk of drug-drug interactions. It has equivalent efficacy to existing once daily DPP-4 inhibitors and shares a similar side effect profile. It is weight neutral with a significantly lower risk of hypoglycaemia compared with sulphonylureas. Adherence to prescribed medication is poor in patients with T2DM. Once weekly omarigliptin is a welcomed addition to the therapeutic armoury but whether it will improve compliance remains to be seen.     

Glucagon like peptides-1 modulators as newer target for diabetes

Diabetes mellitus (DM) has been recognized as a growing world-wide epidemic by many health advocacy groups including the World Health Organization (WHO). DM affects about 6% of the North American population. A recent report estimated that 8.2% of adult population worldwide has impaired glucose tolerance. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. In many cases monotherapy gradually fails to improve blood glucose control and combination therapy is employed. The long-term success of these treatments varies substantially. Thus, there is an imperative need for novel therapeutic approaches for glycemic control that can complement existing therapies and possibly attempt to preserve normal physiological response to meal intake. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. Glucoregulatory actions of GLP-1 include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, Dipeptidyl Peptidase-IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential antidiabetic agents. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 modulators.     

糖尿病新靶点药物的研发进展

当前糖尿病临床治疗的热点是改善胰岛素抵抗、防止胰岛β-细胞衰竭.现就过氧化酶体增殖激活受体(PPAR)类药物、抑制糖异生促进外围组织对糖的摄取与利用的药物、胰高血糖素抑制剂等一些新的作用靶点糖尿病药物的研发进展及其在糖尿病治疗药物中的地位与前景进行讨论.     

Exploring the role of sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus

For the last 30 years, sulfonylureas have been the mainstay of treatment for patients with non-insulin-dependent diabetes mellitus (NIDDM). They offered patients an alternative to using insulin to lower their blood glucose. One of the advantages of these agents was that they could be taken orally as opposed to insulin, which required multiple daily injections. In addition, they are tolerable, with few side effects, and they cause less hypoglycemia than does insulin. In the past year, new agents (metformin and acarbose) have been introduced into the market and have offered practitioners an alternative to the traditional sulfonylureas. The sulfonylureas are still valuable agents in the treatment of NIDDM. Their efficacy is unsurpassed by any other oral medications. They possess the best tolerability profile of all oral agents on the market, and they possess very few contraindications or drug interactions. The sulfonylureas should still be considered first-line agents for NIDDM. Metformin and acarbose are agents that may benefit a specific patient population, but sulfonylureas are agents that can benefit most patients.     

Association between the membrane transporter proteins and type 2 diabetes mellitus

ABSTRACT

Introduction: The prevalence rate of diabetes is increasing day by day and the current scenario of the available agents for its treatment has given rise to stimulation in the search for new therapeutic targets and agents. Therefore the present review will examine the role of membrane composition in the pathophysiology of Type 2 Diabetes and the possible therapeutic approaches for this.

Areas covered: Glucose transporter proteins (GLUTs) are integral membrane proteins which are responsible for facilitated glucose transport over the plasma membrane into cells. Thus, this chapter is an attempt to interpret the co-relation between membrane transporter proteins and lipid molecules of cell membrane and their implications in type 2 diabetes mellitus. The relationship between the composition controlled flexibility of the membrane in the insertion of GLUTs into cell membrane as well as its fusion with the membrane is the focus of this chapter.

Expert opinion: There is increasing data on the central role of phospholipid composition toward T2DM. Plasma membrane lipid composition plays a key role in maintaining the machinery for insulin-independent GLUT insertion into the membrane as well as insulin-dependent GLUT4 containing vesicles. As a therapeutic option, the designing of new chemical entities should be aimed to decrease saturated fatty acids of lipid bilayer phospholipids to target type 2 diabetes mellitus.     

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Introduction: Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential.

Areas covered: This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart.

Expert opinion: SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.     

广东籍2型糖尿病患者1型葡萄糖转运蛋白基因多态性的研究

目的探讨1型葡萄糖转运蛋白(GLUT1)基因多态性与广东籍2型糖尿病遗传易感性的关系。方法应用聚合酶链反应(PCR)技术对73例广东籍2型糖尿病患者和102名健康人(NT)GLUT1基因多态性进行检测。结果GLUT1基因多态性XbaⅠ(+/+)型、XbaⅠ(+/-)型、XbaⅠ(-/-)型在正常人群和广东籍2型DM患者中的分布频率有一定差异,但无统计学意义(P>0.05)。结论GLUT1基因多态性可能与广东籍2型DM患者的遗传易感性无关。     

Canagliflozin:治疗2型糖尿病的新型钠-葡萄糖共转运体2抑制剂

钠-葡萄糖共转运体2(SGLT2)是近年来新发现的2型糖尿病治疗靶点。抑制SGLT2可减少肾脏葡萄糖的重吸收,增加尿糖排出,从而降低血糖。Canagliflozin是SGLT2抑制剂,可结合饮食控制和运动来改善成人2型糖尿病的血糖。Canagliflozin的推荐剂量为100 mg,口服,每日1次。临床试验表明canagliflozin治疗2型糖尿病安全有效,耐受性好。     

钠-葡萄糖共转运蛋白2抑制剂治疗2型糖尿病的临床研究进展

2 型糖尿病是一种以胰岛素分泌缺陷、胰岛素抵抗或者两者并存所致的高血糖为特征的慢性代谢性疾病。早期血糖控制不佳可以促进微血管并发症的进展,以及大血管风险的发生。虽然有众多的降糖药物在临床使用,但只有约50%的患者能实现血糖控制,传统药物仍存在某些不足,因此,需要开发具有新机制的治疗药物。钠-葡萄糖共转运蛋白2（SGLT2）是近年来发现的具有全新作用机制的一个糖尿病治疗靶点。SGLT2 抑制剂通过抑制肾脏近端小管对葡萄糖的重吸收来增加尿中葡萄糖的排泄而达到控制血糖的目的,其独立于葡萄糖依赖的胰岛素途径,能使低血糖发生风险降低。临床试验数据表明,SGLT2 抑制剂单药治疗和与传统降糖药物联合治疗均可以有效地控制血糖,并改善胰岛素抵抗,同时也有降血压和减少体质量作用。尽管后续的研究显示了SGLT2 抑制剂具有良好的耐受性,该类药物在临床上报道的意想不到的风险仍需要大量和长期的临床数据证实。     

钠葡萄糖转运子2研究进展

钠葡萄糖转运子2(sodium-dependent glucose transporters,SGLT2)是一种主要表达于肾脏近曲小管的低亲和力转运蛋白,在肾脏葡萄糖的重吸收中有着重要的作用。SGLT2竞争性抑制药可增加尿糖排泄、能量消耗,从而可以有效地降低血糖,成为糖尿病治疗的又一个靶点。随着研究的深入,不断有新型的SGLT2抑制药问世。本文就SGLT家族的生物学特性、各种SGLT2抑制药的特点、临床疗效、安全性及在糖尿病治疗中的应用前景进行探讨。     

The treatment of type 1 diabetes mellitus with agents approved for type 2 diabetes mellitus

Introduction: The management of type 1 diabetes remains a challenge for clinicians. Current practice is to administer insulin analogues to best mimic normal physiological insulin profiles. However, despite our best efforts the majority of individuals with type 1 diabetes continue to suffer from suboptimal glucose control, significant hypoglycemia and microvascular tissue complications of the disease. There is thus a significant unmet need in the treatment of T1DM to obtain better glycemic control.

Areas covered: We discuss the use of α-glucosidase inhibitors, dipeptidyl-peptidase inhibitors, glucagon-like peptide 1 agonists, biguanides, thiazolidinediones and sodium glucose co-transporter 2 inhibitors in individuals with T1DM.

Expert opinion: Non-insulin therapies present a unique and exciting adjunctive treatment for individuals with type 1 diabetes. Although data are scarce, the classes of medications discussed help to lower glucose, decrease glycemic excursions and in some cases improve body weight, along with allowing dose reductions in total daily insulin. Glucagon-like peptide 1 agonists and sodium glucose co-transporter 2 inhibitors, in particular, have been demonstrated to provide clinical improvements in individuals with T1DM and we feel their use can be explored in obese, insulin-resistant patients with T1DM, those with frequent and significant glycemic excursions or individuals with persistently elevated hemoglobin A1c.     

DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.     

Metformin extended release for the treatment of Type 2 diabetes mellitus

Metformin extended release (ER) (Glumetza?, Depomed, Inc.) is a recently approved formulation that provides effective and well-tolerated glycaemic control with once-daily dosing. Metformin ER has similar bioavailability to conventional immediate-release (IR) formulations. In controlled clinical trials, metformin ER provided effective glycaemic control for 24 weeks when administered either as monotherapy or in combination with sulfonylurea. Good glycaemic control was maintained for an additional 24 weeks during an open-label extension study. Once-daily dosing with metformin ER 1500 mg/day was as effective as twice-daily dosing with metformin IR at the same total daily dose. Metformin ER was well tolerated at doses of 1500 or 2000 mg/day, with no increase in the frequency or severity of adverse events at the higher dose.     

Metformin extended release for the treatment of type 2 diabetes mellitus

Metformin extended release (ER) (Glumetza, Depomed, Inc.) is a recently approved formulation that provides effective and well-tolerated glycaemic control with once-daily dosing. Metformin ER has similar bioavailability to conventional immediate-release (IR) formulations. In controlled clinical trials, metformin ER provided effective glycaemic control for 24 weeks when administered either as monotherapy or in combination with sulfonylurea. Good glycaemic control was maintained for an additional 24 weeks during an open-label extension study. Once-daily dosing with metformin ER 1500 mg/day was as effective as twice-daily dosing with metformin IR at the same total daily dose. Metformin ER was well tolerated at doses of 1500 or 2000 mg/day, with no increase in the frequency or severity of adverse events at the higher dose.     

Empagliflozin,a sodium glucose co-transporter 2 inhibitor,in the treatment of type 1 diabetes

Introduction: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM.

Areas covered: Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM.

Expert opinion: Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.     

糖化血红蛋白达标的2型糖尿病患者血糖波动与尿白蛋白/肌酐的关系探讨

目的 探讨糖化血红蛋白（HbA1c）达标的2型糖尿病患者血糖波动与尿白蛋白/尿肌酐（UACR）的关系。方法 选择合肥市第二人民医院2010年8月至2016年3月收治的2型糖尿病患者（HbA1c<7.0%）107例,根据UACR结果分为正常组21例（NUA组）和升高组86例（MUA组）。动态血糖监测系统（CGMS）对受试者进行连续72 h的血糖监测,计算出平均血糖（MBG）和平均血糖波动幅度（MAGE）,同时检测血肌酐（Scr）、谷丙转氨酶（ALT）,测量血压和计算体质指数（BMI）。结果 MUA组MAGE显著高于NUA组,差异有统计学意义（P<0.05）。MAGE与年龄、病程、Scr、UACR呈中度相关（P<0.05）,与收缩压、舒张压、BMI、ALT呈低度相关（P<0.05）。结论 血糖控制达标的2型糖尿病患者尿白蛋白排泄增加与血糖波动有关。     

Glucagon as a target for the treatment of Type 2 diabetes

Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeu-tic agents to target glucagon action as a treatment for Type 2 diabe-tes.     

Challenges for the treatment of diabetes mellitus

The present review summarizes the existing literature data regarding the development of newer categories of antidiabetic agents, their mechanism of action and their clinical importance. In this paper, a review of the recent patents for the treatment of diabetes will be presented. In recent years significant achievements have been done, including the development of SGLT2 inhibitors, glucokinase activators as well as the role of free fatty acids and bile acid metabolism in the treatment of diabetes are reviewed.