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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti-inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors.
Curr Diabetes Rev 2015
PMID:Addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development. 2553 54

In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1/2 modulation.
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PMID:Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. 2554 Jun 23

Dapagliflozin is the first sodium-glucose co-transporter inhibitor developed. An extensive program covering all phases of clinical research showed us the efficacy and safety profile of the drug. Dapagliflozin and the other SGLT2 inhibitors are a new treatment alternative in patients with Type 2 diabetes either as monotherapy or combined with the hypoglycemic agents currently available and is approved in approximately 38 countries worldwide. This drug profile provides the necessary tools to assess the risks and benefits of this new molecule.
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PMID:Dapagliflozin: drug profile and its role in individualized treatment. 2556 Sep 82

Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.
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PMID:Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. 2561 7

The kidney plays an important role in gluconeogenesis during starvation. To clarify the anti-diabetic action of angiotensin receptor blockers, we examined the effects of telmisartan on the sodium-glucose co-transporters (SGLT) and the pathways of renal gluconeogenesis in streptozotocin-induced diabetes mellitus (DM) rats. At 4 weeks, the DM rats treated with/without telmisartan for 2 weeks and normal control rats were used for the study after a 24-hour fast. SGLT2 expressed on the brush border membrane of the proximal convoluted tubules increased in the DM rats, but decreased in the rats treated with telmisartan. The expression of restriction enzymes of gluconeogenesis, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased in the proximal tubules in the DM rats, whereas these enzymes decreased in the kidneys of the rats treated with telmisartan. The elevated cytoplasmic glucose-6-phosphate and glucose levels in the kidney of DM rats significantly decreased in those treated with telmisartan, whereas those levels in the liver did not show significant change. Meanwhile, the high plasma glucose levels in the DM rats during the intravenous insulin tolerance tests were ameliorated by telmisartan. The increased fasting plasma glucose levels after 24 hours of starvation in the DM rats thus returned to the control levels by telmisartan treatment. In conclusion, the increased renal SGLT2 expression, elevated renal gluconeogenesis enzymes and extent of insulin-resistance in the DM rats were ameliorated by telmisartan therapy, thus resulting in decreased plasma glucose levels after 24 hours of fasting.
Diabetes Metab Syndr Obes 2015
PMID:Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation. 2570 83

Diabetes risk increases exponentially with increasing BMI particularly if fat accumulates centrally and/or in the skeletal muscle, liver and other organs such as the pancreas. Those with diabetes and co-existing obesity, particularly if it is severe, are also at risk of other obesity-related conditions, such as cardiovascular disease, obstructive sleep apnoea, joint pain, many cancers and depression. In people with impaired glucose tolerance, modest weight loss can reduce the development of overt diabetes by 50% or more over four years. Once diabetes has developed weight loss can also be of benefit. Supporting patients to lose weight should be considered a key goal of diabetes care for all overweight and obese patients with type 2 diabetes. Increased physical activity improves insulin sensitivity and can help weight loss maintenance. Metformin is the first-line therapy and is generally considered weight neutral. Of the oral therapies available second line, DPP-IV inhibitors are weight neutral and the newer SGLT2 inhibitors can produce 2-3 kg of weight loss on average. Insulin often causes weight gain and patients should be counselled about this. Adjunctive treatment with metformin, SGLT2 inhibitors, DPP-IV inhibitors and GLP-1 analogues can help keep insulin doses lower and limit weight gain. Currently in the UK, obesity pharmacotherapy in type 2 diabetes is limited to orlistat which has been shown to improve glucose control. NICE recommends bariatric surgery as a clinically and cost effective option for obese patients with type 2 diabetes, particularly those with severe obesity. It typically results in 20-30% of body weight loss.
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PMID:Managing patients with type 2 diabetes and obesity. 2572 18

Sodium-dependent glucose cotransporters (SGLTs) play an important role in glucose reabsorption in the kidney and have been identified as promising targets to treat diabetes. Because of the side effects like glucose and galactose malabsorption by targeting SGLT1, highly selective SGLT2 inhibitors are more promising in the treatment of diabetes. To understand the mechanism of selectivity, we conducted selectivity-based three-dimensional quantitative structure-activity relationship studies to highlight the structure requirements for highly selective SGLT2 inhibitors. The best comparative molecular field analysis and comparative molecular similarity indices analysis models showed the noncross-validated coefficient (r(2) ) of 0.967 and 0.943, respectively. The predicted correlation coefficients (r(2) pred ) of 0.974 and 0.938 validated the reliability and predictability of these models. Besides, homology models of SGLT2 and SGLT1 were also constructed to investigate the selective mechanism from structure-based perspective. Molecular dynamics simulation and binding free energy calculation were performed on the systems of a potent and selective compound interacting with SGLT2 and SGLT1 to compare the different binding modes. The simulation results showed that the stretch of the methylthio group on Met241 had an essential effect on the different binding modes between SGLT1 and SGLT2, which was consistent with the three-dimensional quantitative structure-activity relationship analysis. Hydrogen bond analysis and binding free energy calculation revealed that SGLT2 binding complex was more stable and favorable than SGLT1 complex, which was highly correlated with the experimental results. Our obtained results give useful information for the investigation of the inhibitors' selectivity between SGLT2 and SGLT1 and will help for further development of highly selective SGLT2 inhibitors.
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PMID:A selectivity study of sodium-dependent glucose cotransporter 2/sodium-dependent glucose cotransporter 1 inhibitors by molecular modeling. 2575 71

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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PMID:Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease. 2578 81

The objective of this study was to investigate how physiological, pharmacological, and pathological conditions that alter sodium reabsorption (TNa) in the proximal tubule affect oxygen consumption (QO2 ) and Na(+) transport efficiency (TNa/QO2 ). To do so, we expanded a mathematical model of solute transport in the proximal tubule of the rat kidney. The model represents compliant S1, S2, and S3 segments and accounts for their specific apical and basolateral transporters. Sodium is reabsorbed transcellularly, via apical Na(+)/H(+) exchangers (NHE) and Na(+)-glucose (SGLT) cotransporters, and paracellularly. Our results suggest that TNa/QO2 is 80% higher in S3 than in S1-S2 segments, due to the greater contribution of the passive paracellular pathway to TNa in the former segment. Inhibition of NHE or Na-K-ATPase reduced TNa and QO2 , as well as Na(+) transport efficiency. SGLT2 inhibition also reduced proximal tubular TNa but increased QO2 ; these effects were relatively more pronounced in the S3 vs. the S1-S2 segments. Diabetes increased TNa and QO2 and reduced TNa/QO2 , owing mostly to hyperfiltration. Since SGLT2 inhibition lowers diabetic hyperfiltration, the net effect on TNa, QO2 , and Na(+) transport efficiency in the proximal tubule will largely depend on the individual extent to which glomerular filtration rate is lowered.
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PMID:Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. 2585 13

It has been known for centuries that the kidneys play a role in glucose homeostasis, yet the underlying tubular mechanisms have only been recently identified by studying patients with familial glucosuria. These insights have lead to the commercialization of a novel class of oral antidiabetic agents named gliflozines. Gliflozines induce renal glucosuria by blocking the Na-glucose cotransporter SGLT2, localized in the proximal tubule, and allow a reduction of 0.5 to 1% of glycated hemoglobin. They also diminish proximal sodium reabsorption, and reduce the glomerular hyperfiltration that is often seen in the early stages of diabetes. Preliminary data suggest that they may decrease blood pressure and have renoprotective effects. This article provides an overview of the role of kidneys in glucose homeostasis and the renal effects of SGLT2-inhibitors.
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PMID:[Renal aspects of sodium glucose cotransporter 2 inhibitors]. 2589 56


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