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Saint Helens, United Kingdom

Wong J.,Diabetes Center | Wong J.,University of Sydney
Diabetes and Vascular Disease Research | Year: 2013

Since the initial discovery of Angiotensin converting enzyme inhibitors (ACEI) in the 1960s and the launch of Captopril as the first available for clinical use in the 1970s, there now exist three other classes of drugs that block the renin angiotensin aldosterone system (RAAS): the angiotensin II receptor blockers (ARB), aldosterone antagonists (AA) and direct renin inhibitors (DRI). With the proven efficacy of RAAS blockers as monotherapy in many arenas there has been considerable interest in the use of dual therapy combinations of these medications that target different points in the pathway. By potentially offering a more complete RAAS blockade with a commensurate enhanced clinical effect, the strong biological rationale for dual therapy has led to it being embraced by clinicians as a treatment option, for hypertension and nephroprotection in particular. However, the initial enthusiasm for this treatment has been tempered by the recent results from several large trials such as ONTARGET and ALTITUDE, which do not support a specific dual therapy approach. In contrast, there is supportive evidence for dual blockade of specific combinations in selected patient groups and data are lacking for others. In the wake of this complex contemporary evidence, the conundrum now faced by clinicians committed to individualised care is, for which patients dual therapy could still be of benefit. This review examines for the practising clinician the current 'state of play' for dual blockade of various combinations and a perspective on its use in cardio-renal disease and diabetic complications. © The Author(s) 2013.

Song S.H.,Diabetes Center
Advances in Experimental Medicine and Biology | Year: 2013

Type 2 diabetes mellitus (a disease normally appears in the post 40 age group people) now seems to emerging in young adults at the level of global epidemic driven by the increasing burden of obesity. Evidence is accumulating to suggest that this young diabet iccohort is an aggressive phenotype which leads to the premature development of complications that not only have impact on the quality of life but also unfavourably influence the long term outcome, raising the possibility of a serious public health challenge in the next few decades. This chapter reviews the current understanding of the phenomenon of T2DM in the young adults and discusses the clinical challen ges in managing this high risk group. © 2012 Landes Bioscience and Springer Science+Business Media.

Schofield C.J.,Diabetes Center | Sutherland C.,University of Dundee
Diabetic Medicine | Year: 2012

For many years, the development of insulin resistance has been seen as the core defect responsible for the development of Type2 diabetes. However, despite extensive research, the initial factors responsible for insulin resistance development have not been elucidated. If insulin resistance can be overcome by enhanced insulin secretion, then hyperglycaemia will never develop. Therefore, a β-cell defect is clearly required for the development of diabetes. There is a wealth of evidence to suggest that disorders in insulin secretion can lead to the development of decreased insulin sensitivity. In this review, we describe the potential initiating defects in Type 2 diabetes, normal pulsatile insulin secretion and the effects that disordered secretion may have on both β-cell function and hepatic insulin sensitivity. We go on to examine evidence from physiological and epidemiological studies describing β-cell dysfunction in the development of insulin resistance. Finally, we describe how disordered insulin secretion may cause intracellular insulin resistance and the implications this concept has for diabetes therapy. In summary, disordered insulin secretion may contribute to development of insulin resistance and hence represent an initiating factor in the progression to Type 2 diabetes. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Candido R.,Diabetes Center
Current Opinion in Nephrology and Hypertension | Year: 2014

PURPOSE OF REVIEW: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine belonging to the TNF superfamily. TRAIL may modulate cell survival and proliferation through interaction with two different receptors, TRAIL-R1 and TRAIL-R2. The actions of TRAIL are regulated by three decoy receptors, TRAIL-R3, TRAIL-R4 and osteoprotegerin (OPG). There is evidence that both TRAIL and OPG are expressed by renal cells. The OPG/TRAIL axis has been recently linked to the pathogenesis of renal damage and, in particular, diabetic nephropathy. RECENT FINDINGS: In patients with kidney diseases, serum TRAIL and OPG levels are increased in parallel and are significantly associated with each other. In diabetic nephropathy, the renal expression of TRAIL and OPG is elevated, and in tubular cells proinflammatory cytokines enhance TRAIL expression. Additionally, a high-glucose microenvironment sensitizes tubular cells to apoptosis induced by TRAIL, whereas OPG counteracts the actions of TRAIL in cultured cells. SUMMARY: It seems that the expression and levels of TRAIL and OPG at serum and kidney levels are crucial for the pathogenesis of kidney diseases, and in particular diabetic nephropathy. Although further studies are necessary to clarify the exact role of the OPG/TRAIL axis in the kidney, this system seems to hold promise to provide therapeutic approaches for the management of renal damage. VIDEO ABSTRACT AVAILABLE: See the Video Supplementary Digital Content 1 (http://links.lww.com/CONH/A5). © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Barnett A.H.,Diabetes Center
Advances in Therapy | Year: 2013

Introduction: Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy. Methods: A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included "insulin combination therapy," "add-on therapy diabetes," "dipeptidyl peptidase-4 (DPP-4) inhibitors," "glucagon-like peptide-1 (GLP-1) receptor agonist," "sodium-glucose cotransporter 2 (SGLT2) inhibitors", "insulin metformin," "insulin sulfonylurea," and "insulin thiazolidinedione." Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed. Results: Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight. Conclusion: GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies. © 2013 Springer Healthcare.

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