Future glucose-lowering drugs for type 2 diabetes

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.

Management of type 2 diabetes:new and future developments in treatment

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11ß-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

The challenge of managing coexistent type 2 diabetes and obesity

The presence of obesity with type 2 diabetes increases morbidity and mortality from each condition. Excess adiposity accentuates insulin resistance and complicates the treatment of type 2 diabetes. Glucagon-like peptide 1 receptor agonists promote weight loss, whereas metformin, dipeptidyl peptidase 4 inhibitors, and a glucosidase inhibitors are typically weight neutral. The anabolic effects of increased insulin secretion and action restrict the benefits of treatment in obese patients. New treatments should ideally reduce hyperglycaemia and excess adiposity. Potential new treatments include analogues of intestinal and adipocyte hormones, inhibitors of renal glucose reabsorption and cellular glucocorticoid activation, and activators of cellular energy production.

Dietary antioxidant interventions in type 2 diabetes patients:a meta-analysis

An imbalance between reactive oxygen species (ROS) production and antioxidant scavenging has been implicated in type 2 diabetes. ROS are a byproduct in type 2 diabetes, generated during protein glycation and as a consequence of advanced glycation end-products-receptor binding; they impair insulin signalling pathways and induce cytotoxicity in pancreatic beta cells. Neutralisation of oxidants by increased antioxidant availability may mitigate these effects. Several human intervention studies have been undertaken to determine whether dietary antioxidants exert beneficial effects for type 2 diabetes patients. This paper describes a systematic review and meta-analysis of the effects of dietary supplementation with antioxidant vitamins C or E on (1) plasma glucose and insulin concentrations, as an indicator of the capacity for antioxidant to interfere with disease process and (2) on glycated haemoglobin A as a measure of antioxidant effects on posttranslational protein modification implicated in disease complications. Combined analysis of 14 studies that met inclusion criteria revealed that dietary antioxidant supplementation did not affect plasma glucose or insulin levels, suggesting that they could not interfere with the pathogenesis of insulin resistance. However, HbA levels were significantly reduced by antioxidant supplementation, suggesting that antioxidants may have some benefit in protecting against the complications of type 2 diabetes. © 2011 The Author(s).

New drugs for type 2 diabetes mellitus:what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulforylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women. Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagonlike peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on P cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety. In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Structure and regulation of type 2 transglutaminase in relation to its physiological functions and pathological roles

This chapter contains sections titled: Introduction Structure and Regulation Physiologic Functions of TG2 Disruption of TG2 Functions in Pathologic Conditions Perspectives for Pharmacologic Interventions Concluding Comments Acknowledgements References

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Nutritional supplementation for type 2 diabetes: a systematic review

The role of nutritional supplementation is of increasing interest with regard to ocular disease. Randomised controlled trials have demonstrated the effectiveness of supplementation for age-related macular degeneration, and formulations are now being developed for use by people with diabetes and diabetic retinopathy. The aim of this review was to synthesise the evidence for use of nutritional supplementation in type 2 diabetes. MEDLINE and EMBASE databases were searched using a systematic approach. Only double-masked randomised controlled trials were selected. A total of 50 trials were identified as suitable for inclusion. The potential role of alpha-lipoic acid, chromium, folic acid, isoflavones, magnesium, Pycnogenol®, selenium, vitamin C, vitamin E, and zinc in the treatment of type 2 diabetes is discussed. The review of trials identifies positive effects of these nutrients on various outcome measures relating to insulin resistance and cardiovascular factors. Chromium was the most studied supplement, accounting for 16 of the 50 trials. A majority of the trials found a positive effect of chromium on fasting plasma glucose. Isoflavones were found to have a positive effect on insulin resistance and cardiovascular outcome measures, but only when combined with soy proteins. Vitamin E is reported to reduce oxidative stress at levels of 200 mg day-1 or more.

Self monitoring of blood glucose in type 2 diabetes:Longitudinal qualitative study of patients' perspectives

Objective: To explore views of patients with type 2 diabetes about self monitoring of blood glucose over time. Design: Longitudinal, qualitative study. Setting: Primary and secondary care settings across Lothian, Scotland. Participants: 18 patients with type 2 diabetes. Main outcome measures: Results from repeat in-depth interviews with patients over four years after clinical diagnosis. Results: Analysis revealed three main themes - the role of health professionals, interpreting readings and managing high values, and the ongoing role of blood glucose self monitoring. Self monitoring decreased over time, and health professionals' behaviour seemed crucial in this: participants interpreted doctors' focus on levels of haemoglobin A1c, and lack of perceived interest in meter readings, as indicating that self monitoring was not worth continuing. Some participants saw readings as a proxy measure of good and bad behaviour - with women especially, chastising themselves when readings were high. Some participants continued to find readings difficult to interpret, with uncertainty about how to respond to high readings. Reassurance and habit were key reasons for continuing. There was little indication that participants were using self monitoring to effect and maintain behaviour change. Conclusions: Clinical uncertainty about the efficacy and role of blood glucose self monitoring in patients with type 2 diabetes is mirrored in patients' own accounts. Patients tended not to act on their self monitoring results, in part because of a lack of education about the appropriate response to readings. Health professionals should be explicit about whether and when such patients should self monitor and how they should interpret and act upon the results, especially high readings.

Issues of cause and control in patient accounts of Type 2 diabetes

Patients experience considerable difficulties in making and sustaining health-related lifestyle changes. Many Type 2 diabetes patients struggle to follow disease risk-management advice even when they receive extensive information and support. Drawing on a qualitative study of patients with Type 2 diabetes, the paper uses discourse analysis to examine their accounts about disease causation and disease management, and the implications for how they respond to their condition and health services advice. As it is a multifactorial disease, biomedical discourse around Type 2 diabetes is complex. Patients are encouraged to grasp the complicated message that both cause and medical outcomes related to their condition are partly, but not wholly, within their control. Discursive constructions identified from respondent accounts indicate how these two messages are deployed variously by respondents when accounting for disease causation and management. While these constructions (identified in respondent accounts as 'Up to me' and 'Down to them') are a valuable resource for patients, equally they may be deployed in a selective and detrimental way. We conclude that clear messages from health professionals about effective disease management may help patients to position themselves more effectively in relation to their condition. More importantly, they might serve to hinder the availability of inappropriate and potentially harmful patient positions where patients either relinquish responsibility for disease management or reject all input from health professionals. © The Author 2005. Published by Oxford University Press. All rights reserved.

Taking the biscuit? A discursive approach to managing diet in type 2 diabetes

Adopting and maintaining a healthy diet is pivotal to diabetic regimens. Behavioural research has focused on strategies to modify/maintain healthy behaviours; thus 'compliance' and 'non-compliance' are operationalized by researchers. In contrast, discursive psychology focuses on the actions different accounts accomplish-in this case regarding diets. Using thematic discourse analysis, we examine dietary management talk in repeat-interviews with 40 newly diagnosed type 2 diabetes patients. Women in our study tended to construct dietary practices as an individual concern, while men presented food consumption as a family matter. Participants accounted for 'cheating' in complex ways that aim to accomplish, for instance, a compliant identity. Discursive psychology may facilitate fluidity in our understandings of dietary management, and challenge fixed notions of 'compliant' and 'non-compliant' diabetes patients. Copyright © 2005 SAGE Publications.

Diabetes service provision:a qualitative study of newly diagnosed Type 2 diabetes patients' experiences and views

Aims: To explore newly diagnosed Type 2 diabetes patients' views about Scottish diabetes services at a time when these services are undergoing a major reorganization. To provide recommendations to maximize opportunities brought by the devolvement of services from secondary to primary healthcare settings. Methods: Qualitative panel study with 40 patients newly diagnosed with Type 2 diabetes, recruited from hospital clinics and general practices in Lothian, Scotland. Patients were interviewed three times over 1 year. The study was informed by grounded theory, which involves concurrent data collection and analysis. Results: Patients were generally satisfied with diabetes services irrespective of the types of care received. Most wanted their future care/review to be based in general practice for reasons of convenience and accessibility, although they dis-liked it when appointments were scheduled for different days. Many said they lacked the knowledge/confidence to know how to manage their diabetes in particular situations, and needed access to healthcare professionals who could answer their questions promptly. Patients expressed a need for primary care professionals who had diabetes expertise, but who had more time and were more accessible than general practitioners. Patients who had encountered practice lead nurses for diabetes spoke particularly positively of these professionals. Conclusions: Nurses with diabetes training are particularly well placed to provide information and support to patients in primary care. Ideally, practices should run 'one-stop' diabetes clinics to provide structured care, with easily accessible dietetics, podiatry and retinopathy screening. Newly diagnosed patients may benefit from being made more aware of specific services provided by charitable organizations such as Diabetes UK. © 2005 Diabetes UK.

Lay perceptions of type 2 diabetes in Scotland:bringing health services back in

The growing prevalence of type 2 diabetes is placing Scottish health services under considerable strain. Consequently, diabetes services are undergoing a major process of reorganisation, including the devolvement of routine diabetes care/diabetic review from secondary to primary healthcare settings. This qualitative study was devised to explore newly diagnosed type 2 diabetes patients' perceptions of their disease and the health services they receive at a time when this restructuring of services is taking place. The sample comprised 40 patients resident in Lothian, Scotland, who had diverse experiences of services, some receiving GP-based care only, others having varying contact with hospital diabetes clinics. In-depth interviews were undertaken with patients, three times at six monthly intervals over 1 year, enabling their experiences to be tracked at critical junctures during the post-diagnostic period. Disease perceptions and health service delivery were found to be mutually informing and effecting. Not only did (different types of) health service delivery influence the ways in which patients thought about and self-managed their disease, over time patients' disease perceptions also informed their expectations of, and preferences for, diabetes services. We thus argue that there is a need for a reconceptualisation within the medical social sciences to take into account the context of healthcare and the economic/policy factors that inform health service delivery when looking at patients' disease perceptions. We also discuss the logistical and ethical challenges of drawing upon patients' perspectives, preferences and views in the design and delivery of future health services. © 2004 Elsevier Ltd. All rights reserved.

Diagnosis of type 2 diabetes:A qualitative analysis of patients' emotional reactions and views about information provision

Research about diagnosis of chronic illness indicates this is an emotional time for patients. Information provision is especially salient for diabetes management. Yet current orthodoxy suggests that too much information at the time of diagnosis is unhelpful for patients. In this study, we used in-depth interviews with 40 newly diagnosed type 2 diabetic (T2DM) patients in Scotland, to explore their emotional reactions about diagnosis, and their views about information provision at the time of diagnosis. Data were analysed using a thematic approach. Our results showed three main 'routes' to diagnosis: 'suspected diabetes' route; 'illness' route; and 'routine' route. Those within the 'routine' route described the most varied emotional reactions to their diagnosis. We found that most patients, irrespective of their route to diagnosis, wanted more information about diabetes management at the time of diagnosis. We suggest that practitioners would benefit from being sensitive to the route patients follow to diagnosis, and prompt, simple but detailed advice about T2DM management would be helpful for newly diagnosed patients. © 2004 Elsevier Ireland Ltd. All rights reserved.