The role of adipokines in beta-cell failure of type 2 diabetes

Beta-cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of beta-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, TNFa, resistin, visfatin, DPP-IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to beta-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines which act on the beta-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on beta-cells.

Dysregulated adipokines in the pathogenesis of type 2 diabetes and vascular disease

Obesity is commonly associated with type 2 diabetes and vascular disease. Changes in body composition in the obese state lead to a dysregulation of secretion of adipocyte-secreted hormones known as adipokines. Adipokines such as leptin and adiponectin are known to be involved in many physiological and pathological processes. Current knowledge suggests that adipokines provide potential therapeutic targets against type 2 diabetes and vascular disease.

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.

Patient adherence to medication requirements for therapy of type 2 diabetes

Type 2 diabetes is a complex, progressive endocrine and metabolical disease that typically requires substantial lifestyle changes and multiple medications to lower blood glucose, reduce cardiovascular risk and address comorbidities. Despite an extensive range of available and effective treatments, <50% of patients achieve a glycaemical target of HbA <7.0% and about two-thirds die of premature cardiovascular disease. Adherence to prescribed therapies is an important factor in the management of type 2 diabetes that is often overlooked. Inadequate adherence to oral antidiabetes agents, defined as collecting <80% of prescribed medication, is variously estimated to apply to between 36% and 93% of patients. All studies affirm that a significant proportion of type 2 diabetes patients exhibit poor adherence that will contribute to less than desired control. Identified factors that impede adherence include complex dosing regimens, clinical inertia, safety concerns, socioeconomic issues, ethnicity, patient education and beliefs, social support and polypharmacy. This review explores these factors and potential strategies to improve adherence in patients with type 2 diabetes. © 2011 Blackwell Publishing Ltd.

Expression profiling of type 2 diabetes susceptibility genes in the pancreatic islets, adipose tissue and liver of obese mice

Type 2 diabetes (T2D) is characterized by impaired beta cell function and insulin resistance. T2D susceptibility genes identified by Genome-wide association studies (GWAS) are likely to have roles in both impaired insulin secretion from the beta cell as well as insulin resistance. The aim of this study was to use gene expression profiling to assess the effect of the diabetic milieu on the expression of genes involved in both insulin secretion and insulin resistance. We measured the expression of 43 T2D susceptibility genes in the islets, adipose and liver of leptin-deficient Ob/Ob mice compared with Ob/+ littermates. The same panel of genes were also profiled in cultured rodent adipocytes, hepatocytes and beta cells in response to high glucose conditions, to distinguish expression effects due to elevated glycemia from those on the causal pathway to diabetes or induced by other factors in the diabetic microenviroment. We found widespread deregulation of these genes in tissues from Ob/Ob mice, with differential regulation of 23 genes in adipose, 18 genes in liver and one gene (Tcf7l2) in islets of diabetic animals (Ob/Ob) compared to control (Ob/+) animals. However, these expression changes were in most cases not noted in glucose-treated adipocyte, hepatocyte or beta cell lines, indicating that they may not be an effect of hyperglycemia alone. This study indicates that expression changes are apparent with diabetes in both the insulin producing beta cells, but also in peripheral tissues involved in insulin resistance. This suggests that incidence or progression of diabetic phenotypes in a mouse model of diabetes is driven by both secretory and peripheral defects. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York.

The hypocaloric diet in type 2 diabetes - déjà vu

Dietary modification is considered a cornerstone in the management of diabetes superimposed upon which are pharmacological therapies as required. The value of hypocaloric diets in reducing and eliminating glycosuria was extolled in the pre-insulin era. A common feature of the nutrient balance of these diets was restriction in the availability of carbohydrate. Herein we review the use of diet as therapy in the past and discuss the rationale for hypocaloric dietary management of type 2 diabetes in the 21st century, drawing comparisons with bariatric surgery and considering why weight loss is particularly difficult for overweight and obese individuals with type 2 diabetes. © SAGE Publications 2012.

Glycaemic control and cardiovascular outcome trials in type 2 diabetes

Large prospective trials designed to assess the relationship between metabolic control and CV outcomes in type 2 diabetes have entered a new phase of scrutiny due to strict requirements imposed by the FDA to assess new anti-diabetic agents. So what have we learned from recently completed trials and what do we expect to learn from on-going trials?

Obesity in the pathogenesis of type 2 diabetes

Obesity, and especially visceral adiposity, escalates the development of insulin resistance and type 2 diabetes. Excess adipose tissue contributes to a chronic increase in circulating fatty acids reducing the usage of glucose as a source of cellular energy. Excess fatty acids also result in increased deposition of fat in muscle and liver, and increased metabolites such as diacylglycerol and ceramide which activate isoforms of protein kinase C that impede cellular insulin signalling. Chronically raised lipid levels also impair islet beta cell function, acting in conjuction with insulin resistance to aggravate hyperglycaemia. The detrimental effects of several adipokines such as TNF, IL6 and RBP4, which are produced in excess by an increased adipose mass, and reduced production of adiponectin are further mechanisms through which obesity potentiates the development of type 2 diabetes. © 2011 The Author(s).

SGLT2 inhibitors:glucuretic treatment for type 2 diabetes

Sodium glucose co-transporter-2 (SGLT2) inhibitors offer a novel approach to treat diabetes by reducing hyperglycaemia via increased glucosuria. This approach reduces renal glucose reabsorption in the proximal renal tubules providing an insulin-independent mechanism to lower blood glucose. The glucuretics are advanced in clinical development and dapagliflozin has received most extensive study. Once daily dapaglifolozin as monotherapy or as add-on to metformin for 12-24 weeks in type 2 diabetic patients (baseline HbA 8-9%) reduced HbA by about 0.5-1%, accompanied by weight loss (2-3 kg) and without significant risk of hypoglycaemia. Dapagliflozin has reduced insulin requirement and improved glycaemic control without weight gain in insulin-treated patients. A mild osmotic diuresis associated with glucuretic therapy may account for a small increase in haematocrit (1-2%) and reduced blood pressure (2-5 mmHg). Dehydration and altered electrolyte balance have not been encountered. Urinary tract and genital infections increased in most studies with dapagliflozin, but were typically mild - resolving with selfmedication or standard intervention. Thus glucuretics provide a novel insulin-independent approach for control of hyperglycaemia which does not incur hypoglycaemia, promotes weight loss, may reduce blood pressure and offers compatibility with other glucose-lowering agents. © 2010 The Author(s).

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled 102-week trial

Background: Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.Methods: This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (=1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.Results: A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P

The efficacy and safety of imeglimin as add-on therapy in patientswith type 2 diabetes inadequately controlled with metformin monotherapy

OBJECTIVE - A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone. RESEARCH DESIGN AND METHODS - A total of 156 patients were randomized 1:1 to receive imeglimin (1,500mg twice a day) or placebo added to a stable dose of metformin (1,500-2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio. RESULTS - After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was 20.44% (P <0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (20.91 mg/dL and 27.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally welltolerated with a comparable safety profile to metformin-placebo. CONCLUSIONS - Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes. Copyright © 2013 by the American Diabetes Association.

Reduced postprandial proinsulinaemia and 32-33 split proinsulinaemia after a mixed meal in type 2 diabetic patients following sensitization to insulin with pioglitazone

Objective: Reduced insulin sensitivity associated with fasting hyperproinsulinaemia is common in type 2 diabetes. Proinsulinaemia is an established independent cardiovascular risk factor. The objective was to investigate fasting and postprandial release of insulin, proinsulin (PI) and 32-33 split proinsulin (SPI) before and after sensitization to insulin with pioglitazone compared to a group treated with glibenclamide. Design and patients: A randomized double-blind placebo-controlled trial. Twenty-two type 2 diabetic patients were recruited along with 10 normal subjects. After 4 weeks washout, patients received a mixed meal and were assigned to receive pioglitazone or glibenclamide for 20 weeks, after which patients received another identical test meal. The treatment regimes were designed to maintain glycaemic control (HbA1c) at pretreatment levels so that ß-cells received an equivalent glycaemic stimulus for both test meals. Measurements: Plasma insulin, PI, SPI and glucose concentrations were measured over an 8-h postprandial period. The output of PI and SPI was measured as the integrated postprandial response (area under the curve, AUC). Results: Pioglitazone treatment resulted in a significant reduction in fasting levels of PI and SPI compared to those of the controls. Postprandially, pioglitazone treatment had no effect on the insulin AUC response to the meal but significantly reduced the PI and SPI AUCs. Glibenclamide increased fasting insulin and the postprandial insulin AUC but had no effect on the PI and SPI AUCs. Conclusions: Sensitization to insulin with pioglitazone reduces the amount of insulin precursor species present in fasting and postprandially and may reduce cardiovascular risk. © 2007 The Authors.

Type-2 TOPSIS:a group decision problem when ideal values are not extreme endpoints

In the traditional TOPSIS, the ideal solutions are assumed to be located at the endpoints of the data interval. However, not all performance attributes possess ideal values at the endpoints. We termed performance attributes that have ideal values at extreme points as Type-1 attributes. Type-2 attributes however possess ideal values somewhere within the data interval instead of being at the extreme end points. This provides a preference ranking problem when all attributes are computed and assumed to be of the Type-1 nature. To overcome this issue, we propose a new Fuzzy DEA method for computing the ideal values and distance function of Type-2 attributes in a TOPSIS methodology. Our method allows Type-1 and Type-2 attributes to be included in an evaluation system without compromising the ranking quality. The efficacy of the proposed model is illustrated with a vendor evaluation case for a high-tech investment decision making exercise. A comparison analysis with the traditional TOPSIS is also presented. © 2012 Springer Science+Business Media B.V.

Illness perceptions, beliefs and prevention of Type 2 Diabetes among British Pakistani mothers and young British Pakistani women

The prevalence rates of type2 diabetes mellitus (T2DM) continues to rise among British Pakistanis. The aim of this project was to explore T2DM perceptions and any preventative intentions among British Pakistani women and to discover whether they are doing anything to prevent the onset in themselves and their families. Initially a systematic review was conducted to investigate 20 existing prevention interventions and to assess their effectiveness (n=12,419). Mixed methods approach was adopted and three studies were conducted. The first study consisted of two focus groups with T2DM mothers (n=8) and three focus groups with non-T2DM mothers (n=17). The second study consisted of four focus groups young British Pakistani females (n=11). All focus groups were transcribed verbatim and analysed using thematic analysis. Following these a quantitative study was undertaken comprising of a questionnaire survey; 12 prevention-perception items (derived from the qualitative data) and the Illness-Perception Questionnaire Revised (IPQ-R) using participants from the same populations: T2DM mothers (n=41), non-T2DM mother (n=47) and young women (n=42). Results were analysed using multiple/hierarchical regression. The systematic review highlighted that the most effective prevention programmes focussed on behaviour and lifestyle with a combination of support and education to participants. The research studies demonstrated that T2DM was seen as an older person’s disease to be dealt with if/when it happens. T2DM mothers demonstrated knowledge and prevention understanding. There were non-significant relationships between prevention perceptions and T2DM illness perceptions across all three groups. The finding of this thesis emphasised that lifestyle interventions are crucial to aiding T2DM preventions as a good healthy diet and regular physical activity are the key components to T2DM prevention, and the importance of personal experience in perceived severity and lay-beliefs regarding T2DM and on family/cultural influences in British-Pakistanis. The findings of this project can be used to design culturally specific interventions towards preventing T2DM in the British Pakistani community.

Individualized glycaemic targets and pharmacotherapy in type 2 diabetes

The Global Partnership for Effective Diabetes Management, established to provide practical guidance to improve patient outcomes in diabetes, has developed and modified recommendations to improve glycaemic control in type 2 diabetes. The Global Partnership advocates an individualized therapeutic approach and, as part of the process to customize therapy, has previously identified specific type 2 diabetes patient subgroups that require special consideration. This article builds on earlier publications, expanding the scope of practical guidance to include newly diagnosed individuals with complications and women with diabetes in pregnancy. Good glycaemic control remains the cornerstone of managing type 2 diabetes, and plays a vital role in preventing or delaying the onset and progression of diabetic complications. Individualizing therapeutic goals and treatments to meet glycaemic targets safely and without delay remains paramount, in addition to a wider programme of care to reduce cardiovascular risk factors and improve patient outcomes. © The Author(s) 2013.