The current drug treatment landscape for diabetes and perspectives for the future

The escalating global epidemic of type 2 diabetes mellitus has focused attention on the devastating consequences of protracted hyperglycemia. Early and effective intervention to control blood glucose is a fundamental principle of treatment guidelines, requiring assiduous use of current therapies. However, many patients do not achieve or maintain glycemic targets, emphasizing the need for further therapies. This narrative review assesses the available medicinal options to address hyperglycemia and the opportunities to develop novel agents.

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes

Aims : Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. Methods : We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. Results : Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. Conclusions : Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

The blood perfusion and NADH/FAD content combined analysis in patients with diabetes foot

Skin blood microcirculation and the metabolism activity of tissue were examined on the patients with type 2 diabetes. Laser Doppler flowmetry (LDF) with 1064 nm laser light source and fluorescence spectroscopy (FS) with excitation light of 365 nm and 450 nm have been used to monitor the blood perfusion and the content of coenzymes NADH and FAD. Concluding, the proposed combined LDF and tissue FS approach allows to identify the significant violations in the blood microcirculation and metabolic activity for type 2 diabetes patients.

The association between glycated haemoglobin levels and P100 visual evoked potentials in diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder which is characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. The long-term specific effects of DM include the development of retinopathy, nephropathy and neuropathy. Cardiac disease, peripheral arterial and cerebrovascular disease are also known to be linked with DM. Type 1 diabetes mellitus (T1DM) accounts for approximately 10% of all individuals with DM, and insulin therapy is the only available treatment. Type 2 diabetes mellitus (T2DM) accounts for 90% of all individuals with DM. Diet, exercise, oral hypoglycaemic agents and occasionally exogenous insulin are used to manage T2DM. The diagnosis of DM is made where the glycated haemoglobin (HbA1c) percentage is greater than 6.5%. Pattern-reversal visual evoked potential (PVEP) testing is an objective means of evaluating impulse conduction along the central nervous pathways. Increased peak time of the visual P100 waveform is an expression of structural damage at the level of myelinated optic nerve fibres. This was an observational cross sectional study. The participants were grouped into two phases. Phase 1, the control group, consisted of 30 healthy non-diabetic participants. Phase 2 comprised of 104 diabetic participants of whom 52 had an HbA1c greater than 10% (poorly controlled DM) and 52 whose HbA1c was 10% and less (moderately controlled DM). The aim of this study was to firstly observe the possible association between glycated haemoglobin levels and P100 peak time of pattern-reversal visual evoked potentials (PVEPs) in DM. Secondly, to assess whether the central nervous system (CNS) and in particular visual function is affected by type and/or duration of DM. The cut-off values to define P100 peak time delay was calculated as the mean P100 peak time plus 2.5 X standard deviations as measured for the non-diabetic control group, and were 110.64 ms for the right eye. The proportion of delayed P100 peak time amounted to 38.5% for both diabetic groups, thus the poorly controlled group (HbA1c > 10%) did not pose an increased risk for delayed P100 peak time, relative to the moderately controlled group (HbA1c ≤ 10%). The P100 PVEP results for this study, do however, reflect significant delay (p < 0.001) of the DM group as compared to the non-diabetic group; thus, subclincal neuropathy of the CNS occurs in 38.5% of cases. The duration of DM and type of DM had no influence on the P100 peak time measurements.

Medical advice, diabetes self-management, and health outcomes of a multi-ethnic population from the National Health and Nutrition Examination Survey 2007--2008

Diabetes self-management, an essential component of diabetes care, includes weight control practices and requires guidance from providers. Minorities are likely to have less access to quality health care than White non-Hispanics (WNH) (American College of Physicians-American Society of Internal Medicine, 2000). Medical advice received and understood may differ by race/ethnicity as a consequence of the patient-provider communication process; and, may affect diabetes self-management. ^ This study examined the relationships among participants’ report of: (1) medical advice given; (2) diabetes self-management, and; (3) health outcomes for Mexican-Americans (MA) and Black non-Hispanics (BNH) as compared to WNH (reference group) using data available through the National Health and Nutrition Examination Survey (NHANES) for the years 2007–2008. This study was a secondary, single point analysis. Approximately 30 datasets were merged; and, the quality and integrity was assured by analysis of frequency, range and quartiles. The subjects were extracted based on the following inclusion criteria: belonging to either the MA, BNH or WNH categories; 21 years or older; responded yes to being diagnosed with diabetes. A final sample size of 654 adults [MA (131); BNH (223); WNH (300)] was used for the analyses. The findings revealed significant statistical differences in medical advice reported given. BNH [OR = 1.83 (1.16, 2.88), p = 0.013] were more likely than WNH to report being told to reduce fat or calories. Similarly, BNH [OR = 2.84 (1.45, 5.59), p = 0.005] were more likely than WNH to report that they were told to increase their physical activity. Mexican-Americans were less likely to self-monitor their blood glucose than WNH [OR = 2.70 (1.66, 4.38), p<0.001]. There were differences among ethnicities for reporting receiving recent diabetes education. Black, non-Hispanics were twice as likely to report receiving diabetes education than WNH [OR = 2.29 (1.36, 3.85), p = 0.004]. Medical advice reported given and ethnicity/race, together, predicted several health outcomes. Having recent diabetes education increased the likelihood of performing several diabetes self-management behaviors, independent of race. ^ These findings indicate a need for patient-provider communication and care to be assessed for effectiveness and, the importance of ongoing diabetes education for persons with diabetes.^

Television Watching, Diet Quality, and Physical Activity and Diabetes among Three Ethnicities in the United States

Diabetes is a world-wide epidemic associated with multiple environmental factors. Prolonged television viewing (TV) time has been related to increased risk of obesity and type 2 diabetes in several studies. TV viewing has been positively associated with cardiovascular disease risk factors, lower energy expenditure, over-eating high-calorie and high-fat foods. The objective of this study was to assess the associations of hours of TV viewing with dietary quality, obesity and physical activity for three ethnic minorities with and without type 2 diabetes. Diet quality and physical activity were inversely related to prolonged TV viewing. African Americans and participants with type 2 diabetes were more likely to watch more than 4 hours of TV per day as compared to their counterparts. Diet quality was inversely associated with physical activity level. Future studies are needed to establish the risk factors of prolonged TV watching in adult populations for the development of diabetes or diabetes-related complications. Although strategies to reduce TV watching have been proven effective among children, few trials have been conducted in adults. Intervention trials aimed at reducing TV viewing targeting people with type 2 diabetes may be beneficial to improve dietary quality and physical activity, which may reduce diabetes complications.

Serum Adiponectin and Ghrelin, Metabolic Syndrome and Diabetes Status in Cuban Americans

Purpose: Metabolic syndrome (MetS) is associated with the development of cardiovascular disease (CVD) and type 2 diabetes. Decreases in circulating adiponectin and ghrelin have been associated with MetS. Our primary aim was to evaluate the relationship of MetS with adiponectin and ghrelin for Cuban Americans with and without type 2 diabetes. Methods: Cross-sectional study of 367 adults, self identified as Cuban extraction and randomly recruited from a mailing list of Broward and Miami-Dade counties. Fasted whole blood for adiponectin (ADPN) was collected using K3EDTA tubes and measured by ELISA. Ghrelin was assayed with fasted blood plasma by Enzyme Immunometric Assay. MetS and 10-year risk for coronary heart disease (CHD) were determined using the ATP III criteria. Results: Adiponectin (F=51.8, R2 =0.21 p<0.001) and ghrelin (F=12.77, R 2 =0.06, p<0.001) differed by diabetes status (ANOVA) not age and gender. In stepwise linear regression models triglyceride levels ≥ 150 mg/dL negatively corresponded (coefficient = -0.23) with ghrelin levels for persons without diabetes (F=7.45, R2 =0.053, p=0.007); abdominal obesity and fasting plasma glucose predicted high sensitivity C-reactive protein (hs-CRP) for persons with and without diabetes (F=16.3, R2 = 0.144, p <0.001). Conclusion: Low ghrelin levels were associated with MetS regardless of diabetes status. High adiponectin levels were related to a low probability for those without diabetes only. There was a positive association of hs-CRP with BMI, MetS and number of MetS components.

Television Watching, Diet Quality, Physical Activity and Diabetes Among Three Ethnicities in the United States

Diabetes is a world-wide epidemic associated with multiple environmental factors. Prolonged television viewing (TV) time has been related to increased risk of obesity and type 2 diabetes in several studies. TV viewing has been positively associated with cardiovascular disease risk factors, lower energy expenditure, over-eating high-calorie and high-fat foods. The objective of this study was to assess the associations of hours of TV viewing with dietary quality, obesity and physical activity for three ethnic minorities with and without type 2 diabetes. Diet quality and physical activity were inversely related to prolonged TV viewing. African Americans and participants with type 2 diabetes were more likely to watch more than 4 hours of TV per day as compared to their counterparts. Diet quality was inversely associated with physical activity level. Future studies are needed to establish the risk factors of prolonged TV watching in adult populations for the development of diabetes or diabetes-related complications. Although strategies to reduce TV watching have been proven effective among children, few trials have been conducted in adults. Intervention trials aimed at reducing TV viewing targeting people with type 2 diabetes may be beneficial to improve dietary quality and physical activity, which may reduce diabetes complications.

Acculturation and Diabetes Self-management of Cuban Americans: Is Age a Protective Factor?

Migration to the United States has been linked to obesity and poor diet quality. We investigated the relationship among diabetes self-management, diet, age and acculturation factors for 182 Cuban-Americans (Females = 110, Males = 72) with type 2 diabetes recruited from a randomized mailing list in South Florida. Inadequate glycemic control (β = 0.257), BMI (β = 0.251), total fat intake (β = 0.251), and smoking (β = 0.200), were positively associated, while understanding of overall diabetes care (β = -0.165), was negatively associated with migration (N = 162, adj.R2 = 0.286, F = 14.65, p < 0.001). These associations suggest that effective diabetes education targeting acculturation issues is lacking.

Diabetes Self Management: Are Cuban Americans Receiving Quality Health Care?

Objectives: We investigated the relationship among factors predicting inadequate glucose control among 182 Cuban-American adults (Females=110, Males=72) with type 2 diabetes mellitus (CAA). Study Design: Cross-sectional study of CAA from a randomized mailing list in two counties of South Florida Methods: Fasted blood parameters and anthropometric measures were collected during the study. BMI was calculated (kg/ m2). Characteristics and diabetes care of CAA were self-reported Participants were screened by trained interviewers for heritage and diabetes status (inclusion criteria: self-reported having type 2 diabetes; age  35 years, male and female; not pregnant or lactating; no thyroid disorders; no major psychiatric disorders). Participants signed informed consent form. Statistical analyses used SPSS and included descriptive statistic, multiple logistic and ordinal logistic regression models, where all CI 95%. Results: Eighty-eight percent of CAA had BMI of ≥ 25 kg/ m2. Only 54% reported having a diet prescribed/told to schedule meals. We found CAA told to schedule meals were 3.62 more likely to plan meals (1.81, 7.26), p<0.001) and given a prescribed diet, controlling for age, corresponded with following a meal plan OR 4.43 (2.52, 7.79, p<0.001). The overall relationship for HbA1c < 8.5 to following a meal plan was OR 9.34 (2.84, 30.7. p<0.001). Conclusions: The advantage of having a medical professional prescribe a diet seems to be an important environmental support factor in this sample’s diabetes care, since obesity rates are well above the national average. Nearly half CAA are not given dietary guidance, yet our results indicate CAA may improve glycemic control by receiving dietary instructions.

Screening for albuminuria in diabetes:the need to do more

Aims: To reassess the utilisation rate of urinary albumin to creatinine ratio (ACR) screening in our centre; and the rate of repeat testing, where appropriate. To look at risk factors for albuminuria in our outpatient population. Methods: All patients attending one of our two weekly diabetes outpatient clinics in 2011–2012 were enrolled in this study. Demographic and relevant clinical data were extracted from electronic care records and analysed using SPSS 21. Results: Our study cohort comprised 998 people (51.4% men;59.6% White, 30.5% Southeast Asian, 9.9% Afro-Caribbean),most of whom had Type 2 diabetes (82.6%). The ACR testing rate in our centre was 62.8% (2012–2013 data; previously 62.4%). The incidence of initial albuminuria was 32.2% in women vs42.8% in men. Just 48.7% of patients (44.4% of women, 51.8% of men) with initial albuminuria were retested: 36.4% of women and 19.7% of men with initial albuminuria had no evidence of this on follow-up. Logistic regression modelling confirmed an association of high systolic blood pressure with albuminuria [odds ratio1.92 (1.01–3.70 in women, 1.08–3.57 in men)]. Treatment with anangiotens in converting enzyme inhibitor (ACEi) or angiotens in 2 receptor blocker (A2RB) was negatively associated with albuminuria in men [odds ratio 0.42 (0.20–0.89)], but not in women. Conclusions: A relatively high, albeit suboptimal, albuminuria screening rate in our outpatient population has been sustained.High systolic blood pressure was confirmed as a risk factor foralbuminuria. The incidence of albuminuria was higher in men, who had a lower rate of negative repeat testing and appeared to benefit more from ACEi/A2RB therapy. More rigorous screening for albuminuria is warranted to identify at-risk individuals.

The Genetic Landscape of Renal Complications in Type 1 Diabetes

Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% ( p=6x10-3 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index ( p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation ( p=1.1×10-4 ). Pathway analysis implicated ascorbate and aldarate metabolism ( p=9×10-6), and pentose and glucuronate interconversions ( p=3×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.  

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.

Effect of implementation of a preconception counselling resource for women with diabetes: A population based study

Aim To evaluate the effect of regional implementation of a preconception counselling resource into routine diabetes care on pregnancy planning indicators. Methods A preconception counselling DVD was distributed to women by diabetes care teams and general practices. Subsequently, in a prospective population-based study, pregnancy planning indicators were evaluated. The post-DVD cohort (n = 135), including a viewed-DVD subgroup (n = 58), were compared with an historical cohort (pre-DVD, n = 114). Primary outcome was HbA1c at first diabetes-antenatal visit. Secondary outcomes included preconception folic acid consumption, planned pregnancy and HbA1c recorded in the 6 months preconception. Results Mean first visit HbA1c was lower post-DVD vs. pre-DVD: 7.5% vs. 7.8% [58.4 vs. 61.8 mmol/mol]; p = 0.12), although not statistically significant. 53% and 20% of women with type 1 and 2 diabetes, respectively, viewed the DVD. The viewed-DVD subgroup were significantly more likely to have lower first visit HbA1c: 6.9% vs. 7.8% [52.1 vs. 61.8 mmol/mol], P < 0.001; planned pregnancy (88% vs. 59%, P < 0.001); taken folic acid preconception (81% vs. 43%, P = 0.001); and had HbA1c recorded preconception (88% vs. 53%, P < 0.001) than the pre-DVD cohort. Conclusions Implementation of a preconception counselling resource was associated with improved pregnancy planning indicators. Women with type 2 diabetes are difficult to reach. Greater awareness within primary care of the importance of preconception counselling among this population is needed.

NHS Diabetes Prevention Programme (NHS DPP) non-diabetic hyperglycaemia

Non-diabetic hyperglycaemia, also known as pre-diabetes or impaired glucose regulation, refers to raised blood glucose levels, but not in the diabetic range.  People with non-diabetic hyperglycaemia are at increased risk of developing Type 2 diabetes. They are also at increased risk of other cardiovascular conditions.  The spreadsheet outlines the number of people in every local authority who are estimated as having non-diabetic hyperglycaemia.