Venkat N. Vangaveti

Free fatty acid receptors: emerging targets for treatment of diabetes and its complications

Fatty acids (FAs) are important as metabolic substrates and as structural components of biological membranes. However, they also function as signalling molecules. Recently, a series of G protein-coupled receptors (GPRs) for FAs has been described and characterized. These receptors have differing specificities for FAs of differing chain length and degree of saturation, for FA derivatives such as oleoylethanolamide, and for oxidized FAs. They are a critical component of the body’s nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of diabetes and its complications. Agonists of the long-chain free fatty acid receptors FFAR1 and GPR119 act as insulin secretagogues, both directly and by increasing incretins. Although, drugs acting at short-chain FFA receptors (FFAR2 and FFAR3) have not yet been developed, they are attractive targets as they regulate nutrient balance through effects in the intestine and adipose tissue. These include regulation of the secretion of cholecystokinin, peptide YY and leptin. Finally, GPR132 is a receptor for oxidized FAs, which may be a sensor of lipid overload and oxidative stress, and which is involved in atherosclerosis. Regulation of its signalling pathways with drugs may decrease the macrovascular risk experienced by diabetic patients. In summary, FA receptors are emerging drug targets that are involved in the regulation of nutrient status and carbohydrate tolerance, and modulators of these receptors may well figure prominently in the next generation of antidiabetic drugs.

Disease burden evaluation of fall-related events in the elderly due to hypoglycemia and other diabetic complications: a clinical review

A hypoglycemia-induced fall is common in older persons with diabetes. The etiology of falls in this population is usually multifactorial, and includes microvascular and macrovascular complications and age-related comorbidities, with hypoglycemia being one of the major precipitating causes. In this review, we systematically searched the literature that was available up to March 31, 2014 from MEDLINE/PubMed, Embase, and Google Scholar using the following terms: hypoglycemia; insulin; diabetic complications; and falls in elderly. Hypoglycemia, defined as blood glucose <4.0 mmol/L (70 mg/dL) requiring external assistance, occurs in one-third of elderly diabetics on glucose-lowering therapies. It represents a major barrier to the treatment of diabetes, particularly in the elderly population. Patients who experience hypoglycemia are at a high risk for adverse outcomes, including falls leading to bone fracture, seizures, cognitive dysfunction, and prolonged hospital stays. An increase in mortality has been observed in patients who experience any one of these events. Paradoxically, rational insulin therapy, dosed according to a patient’s clinical status and the results of home blood glucose monitoring, so as to achieve and maintain recommended glycemic goals, can be an effective method for the prevention of hypoglycemia and falls in the elderly. Contingencies, such as clinician-directed hypoglycemia treatment protocols that guide the immediate treatment of hypoglycemia, help to limit both the duration and severity of the event. Older diabetic patients with or without underlying renal insufficiency or other severe illnesses represent groups that are at high risk for hypoglycemia-induced falls and, therefore, require lower insulin dosages. In this review, the risk factors of falls associated with hypoglycemia in elderly diabetics were highlighted and management plans were suggested. A target hemoglobin A1c level between 7% and 8% seems to be more appropriate for this population. In addition, the first-choice drugs should have good safety profiles and have the lowest probability of causing hypoglycemia – such as metformin (in the absence of significant renal impairment) and incretin enhancers – while other therapies that may cause more frequent hypoglycemia should be avoided.

Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.

Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo-​octadecadienoic acid (PubChem CID: 3083831), 13-oxo-​octadecadienoic acid (PubChem CID: 4163990), 9,10-epoxy-12-octadecenoate (PubChem CID: 5283018), 12,13-epoxy-9-keto-10- trans -octadecenoic acid (PubChem CID: 53394018), Pioglitazone (PubChem CID: 4829).

Genetic and molecular basis of diabetic foot ulcers: Clinical review

Diabetic Foot Ulcers (DFUs) are major complications associated with diabetes and often correlate with peripheral neuropathy, trauma and peripheral vascular disease. It is necessary to understand the molecular and genetic basis of diabetic foot ulcers in order to tailor patient centred care towards particular patient groups. This review aimed to evaluate whether current literature was indicative of an underlying molecular and genetic basis for DFUs and to discuss clinical applications. From a molecular perspective, wound healing is a process that transpires following breach of the skin barrier and is usually mediated by growth factors and cytokines released by specialised cells activated by the immune response, including fibroblasts, endothelial cells, phagocytes, platelets and keratinocytes. Growth factors and cytokines are fundamental in the organisation of the molecular processes involved in making cutaneous wound healing possible. There is a significant role for single nucleotide polymorphism (SNPs) in the fluctuation of these growth factors and cytokines in DFUs. Furthermore, recent evidence suggests a key role for epigenetic mechanisms such as DNA methylation from long standing hyperglycemia and non-coding RNAs in the complex interplay between genes and the environment. Genetic factors and ethnicity can also play a significant role in the development of diabetic neuropathy leading to DFUs. Clinically, interventions which have improved outcomes for people with DFUs or those at risk of DFUs include some systemic therapeutic drug interventions which improve microvascular blood flow, surgical interventions, human growth factors, and hyperbaric oxygen therapy, negative pressure wound therapy, skin replacement or shockwave therapy and the use of topical treatments. Future treatment modalities including stem cell and gene therapies are promising in the therapeutic approach to prevent the progression of chronic diabetic complications.

Prevalence and Risk Factors for Diabetic Lower Limb Amputation: A Clinic-Based Case Control Study

Objective. The aim of the study was to evaluate the prevalence of and risk factors for lower limb amputation in a specialist foot clinic-based setting. Methods. A retrospective quantitative study was conducted, using clinical and biochemical profiles of diabetic foot patients attending the High Risk Foot Clinic at The Townsville Hospital, Australia, between January 1, 2011, and December 31, 2013. Results. The total study sample included 129 subjects, comprising 81 males and 48 females with M : F ratio of 1.7 : 1. Twenty-three subjects were Indigenous Australians, representing 17.8% of the study population. The average age of the cohort was 63.4 years ± 14.1 years [CI 90.98–65.89]. Lower limb amputation was identified as a common and significant outcome (n = 44), occurring in 34.1%, more commonly amongst the Indigenous Australians (56.5% versus 29.2%; p = 0.94, OR 0.94). Risk factors most closely associated with amputation included diabetic retinopathy (p = 0.00, OR 4.4), coronary artery bypass graft (CABG) surgery (p = 0.01, OR 4.1), Charcots arthropathy (p = 0.01, OR 2.9), and Indigenous ethnicity (p = 0.01, OR 3.4). Although average serum creatinine, corrected calcium, and glycosylated haemoglobin A1c (Hba1c) levels were higher amongst amputees they were statistically insignificant. Conclusions. Lower limb amputation is a common outcome and linked to ethnicity and neurovascular diabetic complications amongst subjects with diabetic foot ulcer. Further research is needed to identify why risk of lower limb amputation seems to differ according to ethnicity.

Rheumatoid Arthritis Referrals and Rheumatologist Scarcity: A Prioritization Tool

To assess whether applying the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for rheumatoid arthritis (RA) to primary care referrals improved triage decisions and reduced waiting times, and to determine the sensitivity and specificity of this strategy.

Non-traumatic lower limb amputation in patients with end-stage renal failure on dialysis: an Australian perspective

Abstract Background: End-stage renal failure (ESRF) and dialysis have been identified as a risk factor for lower limb amputations (LLAs). High rate of ESRF amongst the Australian population has been reported, however till date no study has been published identifying magnitude and risk factors of LLA in subjects on renal dialysis. Objective: The study aims to document trends in the prevalence and identify risk factors of non-traumatic LLA in Australian patients on dialysis. Methods: A retrospective review of all patients (218) who attended the regional dialysis center between 1st January 2009 and 31st December 2013 was conducted. Demographic, clinical and biochemical data were analyzed. Results: We identified a high prevalence of 13.3% of LLAs amongst Australian patients with ESRF on dialysis at our center. The associated risk factors were the presence of diabetes (OR 1.67 [1.49–1.88] p < 0.001), history of foot ulceration (OR 81 [18.20–360.48] p < 0.001), peripheral arterial disease (OR 31.29 [9.02–108.56] p < 0.001), peripheral neuropathy (OR 31.29 [9.02–108.56] p < 0.001), foot deformity (OR 23.62 [5.82–95.93] p < 0.001), retinopathy (OR 6.08 [2.64–14.02] p < 0.001), dyslipidemia (OR 4.6 [1.05–20.05] p= 0.049) and indigenous background (OR 3.39 [1.38–8.33] p= 0.01). 75% of the amputees had aboriginal heritage. We also identified higher HbA1c and CRP levels as well as low serum albumin, hemoglobin and vitamin D levels to have a strong association with LLAs (p < 0.05). Conclusion: There is high prevalence of LLAs amongst Australian indigenous patients with diabetes on dialysis in North Queensland. Other strongly associated risk factors include history of foot ulceration, foot deformity and peripheral neuropathy as well as high HbA1c levels and low serum albumin levels.

Emerging Therapeutic Potential of Nanoparticles in Pancreatic Cancer: A Systematic Review of Clinical Trials

Pancreatic cancer is an aggressive disease with a five year survival rate of less than 5%, which is associated with late presentation. In recent years, research into nanomedicine and the use of nanoparticles as therapeutic agents for cancers has increased. This article describes the latest developments in the use of nanoparticles, and evaluates the risks and benefits of nanoparticles as an emerging therapy for pancreatic cancer. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses checklist was used. Studies were extracted by searching the Embase, MEDLINE, SCOPUS, Web of Science, and Cochrane Library databases from inception to 18 March 2016 with no language restrictions. Clinical trials involving the use of nanoparticles as a therapeutic or prognostic option in patients with pancreatic cancer were considered. Selected studies were evaluated using the Jadad score for randomised control trials and the Therapy CA Worksheet for intervention studies. Of the 210 articles found, 10 clinical trials including one randomised control trial and nine phase I/II clinical trials met the inclusion criteria and were analysed. These studies demonstrated that nanoparticles can be used in conjunction with chemotherapeutic agents increasing their efficacy whilst reducing their toxicity. Increased efficacy of treatment with nanoparticles may improve the clinical outcomes and quality of life in patients with pancreatic cancer, although the long-term side effects are yet to be defined. The study registration number is CRD42015020009.

The vitamin K-dependent Gla proteins and risk of type 2 diabetes.

[Extract] Recently Haase et al [1] reported that maternal low-protein diet in rats was associated with decreased beta cell mass and decreased expression of growth arrest specific protein 6 (GAS6) in islets of Langerhans, and that incubation of neonatal islets with GAS6 enhanced beta cell proliferation. Low beta cell mass early in life is associated with increased future risk of type 2 diabetes. Consistent with a protective effect of GAS6, the c.834+7G>A polymorphism is associated with type 2 diabetes risk in humans [2]. The AA phenotype is associated with higher levels of GAS6, lower glucose levels, and decreased diabetes risk. Currently used drugs affecting the incretin axis have stimulated interest in therapeutic approaches that either preserve or enhance beta cell mass or function, and GAS6 (secreted by alpha cells) is, therefore, an attractive therapeutic target.

A prospective comparison of times to presentation and treatment of regional and remote head and neck patients in North Queensland, Australia

This study aims to examine differences between outer regional (OR) and remote/very remote (RVR) patients in northern Queensland, Australia in the times taken to receive various aspects of head and neck cancer management.