Novel glucose-lowering peptides with potential to treat diabetes via an insulin-independent mechanism-of-action

SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD) the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD.

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Emi2-mediated Inhibition of E2-substrate Ubiquitin Transfer by the Anaphase-promoting Complex/Cyclosome through a D-Box–independent Mechanism

Molecular Biology of the Cell ◽

10.1091/mbc.e09-08-0708 ◽

2010 ◽

Vol 21 (15) ◽

pp. 2589-2597 ◽

Cited By ~ 14

Author(s):

Wanli Tang ◽

Judy Qiju Wu ◽

Chen Chen ◽

Chih-Sheng Yang ◽

Jessie Yanxiang Guo ◽

...

Keyword(s):

Oocyte Maturation ◽

Mechanism Of Action ◽

Substrate Binding ◽

Zinc Binding ◽

Anaphase Promoting Complex ◽

Binding Region ◽

Independent Mechanism ◽

Interesting Possibility ◽

Vertebrate Eggs

Vertebrate eggs are arrested at Metaphase II by Emi2, the meiotic anaphase-promoting complex/cyclosome (APC/C) inhibitor. Although the importance of Emi2 during oocyte maturation has been widely recognized and its regulation extensively studied, its mechanism of action remained elusive. Many APC/C inhibitors have been reported to act as pseudosubstrates, inhibiting the APC/C by preventing substrate binding. Here we show that a previously identified zinc-binding region is critical for the function of Emi2, whereas the D-box is largely dispensable. We further demonstrate that instead of acting through a “pseudosubstrate” mechanism as previously hypothesized, Emi2 can inhibit Cdc20-dependent activation of the APC/C substoichiometrically, blocking ubiquitin transfer from the ubiquitin-charged E2 to the substrate. These findings provide a novel mechanism of APC/C inhibition wherein the final step of ubiquitin transfer is targeted and raise the interesting possibility that APC/C is inhibited by Emi2 in a catalytic manner.

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3-Deazaadenosine. S-adenosylhomocysteine hydrolase-independent mechanism of action in mouse lymphocytes.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)43575-7 ◽

1984 ◽

Vol 259 (2) ◽

pp. 1122-1126

Author(s):

T P Zimmerman ◽

M Iannone ◽

G Wolberg

Keyword(s):

Mechanism Of Action ◽

Adenosylhomocysteine Hydrolase ◽

Independent Mechanism ◽

Mouse Lymphocytes

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Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitus

Diabetes Mellitus ◽

10.14341/dm8216 ◽

2016 ◽

Vol 19 (6) ◽

pp. 494-510 ◽

Cited By ~ 2

Author(s):

Vladimir V. Salukhov ◽

Tatiana Y. Demidova

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Mechanism Of Action ◽

Glucose Lowering ◽

Long Duration ◽

Increased Risk ◽

Urinary Glucose ◽

Cv Disease

Patients with type 2 diabetes mellitus have an increased risk of cardiovascular (CV) complications. Although hyperglycaemia contributes to the pathogenesis of atherosclerosis and heart failure in these patients, glucose-lowering strategies did not have a significant effect on reducing CV risk, particularly in patients with a long duration of type 2 diabetes mellitus and prevalent CV disease (CVD). Sodium-glucose linked transporter-2 (SGLT2) inhibitors are a new class of anti-hyperglycaemic medications that increase glycaemic control via insulin-dependent mechanism of action associated with increased urinary glucose excretion.In this review, we present an analysis of the Empa-Reg Outcomes investigation, focussed on assessing the CV safety of empagliflozin, an inhibitor of SGLT2. We discuss the impressive results of trials that provide evidence on the cardiac and renal properties of empagliflozin. We present and analyse the current hypothesis on the mechanism of action of glucose-lowering medication, which has such a severe and complex impact on outcomes in patients with type 2 diabetes at high CV risk.

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