Current Diabetes Reviews - Volume 12, Issue 3, 2016

Diabetes is a chronic and progressive syndrome commonly associated with several neuropsychiatric comorbities, of which depression is the most studied. The prevalence of depression is about two or three times higher in diabetic patients compared to the general population. It is believed that the diabetes - depression relation may be bidirectional, i.e., the depression can lead to diabetes and conversely diabetes could facilitate the emergence of depression. Depression is one of the most neglected symptoms in diabetic patients and is directly linked with lowering of quality of life. The treatment of depression in these patients is still quite ineffective and in many cases treatmentrefractory. Furthermore, some of the first choice drugs used to treat the depression affect the blood glucose control, aggravating the hyperglycemic state. These issues underscore the urgency in studies searching for new pharmacological targets for the treatment of depression associated with diabetes. For this, a better understanding of the pathophysiology that relates this comorbidity becomes critical. In this respect, this review will focus on some hypotheses that have been proposed to explain the mechanisms underlying depression associated with diabetes, highlighting the treatment options currently available and their limitations. Among these hypotheses, we will point out the hyperglycemia as a primary metabolic cause of the depression development, the involvement of the dysregulation of hypothalamic pituitary-adrenal (HPA) axis and of neurotransmitter systems, specially monoaminergic system. Besides, the role of oxidative stress, neuroinflammation and cell death, especially in hippocampus and prefrontal cortex, brain areas important for the mediation and modulation of emotional behavior will also be discussed. Finally, we will bring up the influence of the epigenetic regulation with respect to neuropsychiatric disorders.

Diabetic foot is one of the most common long term complications of diabetes. The risk of developing a foot ulcer is significantly increased when a patient presents with a callus. Callus develops due to various reasons, of which, the most important in people with diabetes is peripheral neuropathy. Motor neuropathy leads to deformity and sensory neuropathy causes lack of sensation, which results in persistent abnormal pressure on the foot. The cells of skin react to it by increasing keratinization and turns into a callus, which predisposes to foot ulceration. However, there is a lack of research in the field of callus. The link between hyperkeratosis, insulin and hyperglycaemia is not fully explored. There is also a lack of research on the relationship between genetic defects of hyperkeratosis, and the risk of developing a diabetic foot ulcer. There is scope for further research in this area, such as exploring whether development of callus is an individual risk factor, and whether glycaemic control or its treatment has any relationship with callus formation. The research around the genetic defects of hyperkeratosis may lead to identification of those, with diabetes, who may have increased risk of developing a foot ulcer.

Diabetes, both type 1 and type 2, is considered a chronic incurable disease. Complete cure would bring enormous benefits in terms of both the prevention of complications and reduction of the very high resulting social cost. Recent advances in the study of autoimmune mechanisms for type 1 and some non-medical therapeutic approaches for type 2 shed light on the pathophysiology and induce optimism concerning a possible cure in the not-too-distant future. This perspective highlights the main mechanisms involved in the pathophysiology of the two forms of diabetes, as the latest research has revealed, and the resulting possible therapeutic strategies that may be involved in obtaining a cure.

Individuals with type 2 diabetes (T2D) have poor glycemic control which contributes to cardiovascular disease and other diabetic comorbidities. The often relied upon measures of fasting glucose and glycosylated hemoglobin (HbA1c) do not accurately represent glycemic control because they do not reflect what occurs after meals and throughout the day in the free-living condition. An accumulating body of evidence now suggests that postprandial glucose fluctuations are more tightly correlated with microvascular and macrovascular morbidities and cardiovascular mortality than HbA1c or fasting glucose, stagnant measure of glycemia. Thus, effective therapies are needed which will improve not only HbA1c and fasting glucose, but also regulation of postprandial glycemia. Further, testing for glycemic control should employ a challenge that simulates the free-living condition to best determine how glucose is regulated after meals and throughout the day. Unlike medications, which generally have a poor effect at improving postprandial glucose, exercise is effective in reducing postprandial glycemic excursions in as little as a few days. However, how this is accomplished and the optimal prescription for reducing postprandial glycemic excursions and maintaining improvements in postprandial glycemic control have yet to be elucidated. Still further, the utility of a mixed meal test in providing the optimal challenge for detecting exercise-induced changes in postprandial glycemic control has value that warrants further investigation. Thus, the purpose of this review is to summarize the literature regarding exercise in treating postprandial glycemia in T2D and to review strengths and weaknesses in the current methodology for assessing changes in glycemic control.

Canagliflozin is a competitive, reversible, highly selective SGLT2 inhibitor and available in 100mg and 300mg as oral tablet form. Owing to this, it induced glucosuria and cause changes in glucose homeostasis without affecting insulin. This review addressed the efficacy and safety of canagliflozin in a specialized patients such as chronic kidney disease (stage III CKD), high risk cardiovascular patient and elderly population. Canagliflozin has reduced HbA1c in all the specialized population, albeit reduction is less as compared to the normal cohort. Additionally, canagliflozin causes reduction in body weight as well as in blood pressure. It was very well tolerated and did not produce significant adverse events compared to standard care (placebo) except genital mycotic infection due to glucosuria. In cardio vascular safety analysis, canagliflozin might be associated with increased incidence of major adverse cardiovascular plus (MACE plus) events in the initial period, which is of concern in a high- risk cardiovascular cohort. In patients with type 2 diabetes mellitus (T2 DM) and stage III CKD cohort, canagliflozin was well tolerated without much affecting eGFR and should be initiated with 100mg. Canagliflozin showed good safety profile in elderly population with T2DM without significantly affecting overall bone mineral density and bone resorption.

FoxO1, one of the most widely expressed sub-families of the winged helix forkhead factors, is biologically ‘omni-functional’ owing to its far-flung roles in metabolism, cell cycle, tissue differentiation and development and oxidative stress response. The knowledge of involvement of FoxO1 in metabolic disorders has long been there, but the potential target remained underutilized due to unavailability of specific and potent inhibitors. The review provides an insight into the role of FoxO1 in orchestrating metabolic diseases’ pathogenesis (including diabetes, its secondary complications and obesity) and compiles the literature on FoxO1 inhibitors. The emergence of various natural molecules and synthesized small molecules like AS1842856 as FoxO1 inhibitors urges us to think further and decide the future course of drug development for the management of metabolic disorders.

Diabetes mellitus (DM) and cancer are disorders of global importance. Multiple epidemiologic studies show that diabetic patients have an increased risk of developing cancer of different types. Myelodysplastic syndromes (MDS) are among the most common hematologic malignancies and include a heterogeneous group of hematopoietic neoplasms characterized by dysplastic changes, low blood counts, and an increased risk of progression to acute myeloid leukemia. Potential epigenetic and metabolic interferences between DM and MDS have been reported but are poorly understood. DM and MDS share some predisposing risk factors such as obesity. Patients with MDS and DM can experience worsening of diabetic control due to multiple factors that exacerbate hyperglycemia and insulin resistance such as stress, infections, adjunct drugs (e.g. steroids to control nausea), and others. In addition, accurate assessment of glucose control in diabetic patients who have MDS can be complicated. Alternatively, DM when associated with end-organ damage can complicate management of MDS, increase risks of complications, and limit the applicability of intensive therapeutic interventions. Here we review the current knowledge of the interactions between DM and MDS at the pathogenetic, clinical and epidemiologic levels, discuss how this knowledge could be used therapeutically to improve the outcome of patients affected by both conditions, and delineate important unmet needs that should be addressed in future research.

Diabetes mellitus is a common and growing problem worldwide, especially in the elderly population imposing a huge economic burden for individuals and healthcare services. The purpose of this narrative review was to summarize the current state of knowledge about the relationship between diabetes and important geriatric syndromes, physical function measures, and gait variables. Studies pertaining to the topics were identified through on-line search of databases. Seniors with diabetes are more likely to experience falls, depression, and frailty. Furthermore, in older patients, diabetes has been associated with disability, including basic and instrumental activities of daily living, and with poorer performance on objective measures of physical function, such as sit-to-stand test, handgrip strength, Timed Up and Go (TUG) test, and Short Physical Performance Battery (SPPB). Diabetic seniors also have an altered gait pattern characterized by lower velocity and stride length, and higher step width, stance time, double support time, and stride length variability compared to non-diabetic seniors. Little is known about fear of falling in older adults with diabetes. The relationship between these outcomes and diabetes in older people is still outstanding and merits further investigation.

There is increasing interest in how exposure to environmental substances can contribute to the onset of Type II diabetes mellitus (T2DM). Impaired insulin release is a hallmark of type I diabetes mellitus and is involved in the progression of T2DM. Both epidemiological and experimental studies show that exposure to the environmental pollutant cadmium (Cd), is associated with hyperglycemia, T2DM and reduced serum insulin. The goal of this review is to examine likely mechanisms of action of Cd-induced dysglycemia based on experimental studies in the literature and from the most recent findings in the Edwards lab. The primary focus of this review will examine how Cd may cause islet dysfunction and subsequent impaired insulin release. Recent findings in the Edwards lab indicate that Cd causes timedependent and statistically significant changes in fasting leptin, Glucose-dependent Insulinotropic Polypeptide (GIP) and pancreas polypeptide hormone levels in a subchronic animal model of Cd-induced hyperglycemia. This review summarizes the most likely cellular mechanisms by which the ubiquitous environmental contaminant Cd disrupts glucose homeostasis. While individual cellular effects of Cd are reviewed it is likely that no one single mechanism is involved, rather multiple mechanisms exist and work synergistically resulting in islet dysfunction and ultimately dysglycemia.

Diabetes mellitus is characterized by loss of glucose homeostasis; altered metabolism of glucose, proteins and lipids. Although a number of effective allopathic medicines are currently available for treatment and management of diabetes, but prevalence of side effects and higher cost poses a big challenge to the goal of pharmacotherapy. Herbs are mine of medicinal agents that are found to be efficacious, cost effective and safe in preventing diabetes and a number of plants have been used in management or treatment of diabetes. Modern pharmacopoeia has a healthy number of plant derived medicines and a large number of medicines from allopathic system are derived from the plant sources. This review aims to assess currently available preclinical and clinical knowledge of medicinal herbs intended for the management of diabetes and their mode of action.

Background/Aim: Diabetes mellitus (DM) is a considerable systemic metabolic disorder to exhibit various metabolic and cardiovascular disorders, mainly hyperglycemia. Our study aims to evaluate oxidative stress markers in DM patients and to determine the clinical correlates affecting the investigational parameters. Methodology: To evaluate oxidative stress, the following parameters were included: tri-glycerides(TG), total cholesterol, low density lipoprotein cholesterol(LDL), oxidized LDL cholesterol(Ox LDL), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px) and plasminogen activator inhibitor(PAI) which were measured at single observation point. Patient clinical and demographic data were taken from registered medication profiles from the Outpatient Department. Results: The diabetic subjects have significantly high measured values of endocrine(p<0.01), metabolic(p<0.01) and antioxidant parameters(p<0.05), and have significant higher values of TG(3.69±1.27 vs 1.79±0.84 mmol/L, p< 0.01), Ox LDL(85.37±19.1 vs 77.11±26.64 mmol/L, p<0.05) and SOD enzyme activity(918.78 ± 145.39 vs 880.08±149.52 U/g Hb, p<0.05) compared to the controls. A significant negative correlation was found between Ox LDL and HbA1c(r = -0.6782, p < 0.001) among diabetic subjects. Conclusion: Elevated Ox-LDL, SOD and GSH-Px are associated with the diabetic patients. However, oxidative stress threshold values also showed high oxidative activity markers among controls. Clinical variables showed predictive information on oxidative activity among diabetes patients.

Background: Diabetes mellitus (DM) and coronary heart disease (CHD) are in a complex medical status which are closely associated and generally coexist. Many relationships of DM & CHD are well-known but their precise nature still remains unknown. Objectives: The present report aims to derive an appropriate probabilistic model between DM & CHD, and also to identify their risk factors, based on a data set of 366 African Americans in rural Virginia, USA. Method: Both the positive responses glycosylated hemoglobin and total cholesterol are identified as non-constant variance. Thus, they may be modeled by joint log-normal or gamma models, where both the mean and variance are modeled by using two interlinked models for the mean and the variance, based on the observed data and gamma deviance. Results: Statistical significant causal factors, namely, total cholesterol (chol) (P=0.002), hdl-c (P=0.082), interaction effect of tchol & hdl-c (P=0.032), stabilized glucose (stb.gl) (P=0.000), postprandial time when labs were drawn (tim.pn) (P=0.024), interaction effect of stb.gl & tim.pn (P=0.008), age (P=2e-7), height (P=0.029), interaction effect of age & height (P=0.003), waist (P=0.014), location (P=0.016), sex (P=0.007), frame of study (P=2e-4), have been identified as the determinants of DM (based on glycosylated hemoglobin (HbA1c)). Identified statistical significant factors for CHD (based on tchol) are interaction effect of hdl-c and ratio of tchol & hdl-c (P=0.000), HbA1c (P=0.045), tim.pn (P=0.020), interaction effect of HbA1c & tim.pn (P=0.019), stb.gl (P=0.016), age (P=0.037), location (P=0.070), sex (P=0.005), height (P=0.002), interaction effect of height and tim.pn (P=0.007), first diastolic blood pressure (bp.1d) (P=2e-4), interaction effect of bp.1d & first systolic blood pressure (bp.1s) (P=0.084). Conclusion: It has been established herein that the DM marker HbA1c is closely related with the CHD risk factors, so the diabetic patients should be care on CHD.

Untreated or sub-clinical hypothyroidism is associated with insulin resistance, obesity, adverse effects on cardiovascular system, hypertension and in turn risk of nephropathy. However, these changes are reversible with thyroxine replacement therapy (TRT). Current research studied 4235 diabetic patients, divided into two groups, those with clinical hypothyroidism /on TRT, compared to those without thyroid disease or undiagnosed. BMI, blood pressure, creatinine, urine microalbumin and spot urine protein levels were compared between these two groups. Study finding demonstrated that for hypothyroid cases, BMI was higher (32.2 ± 7.44 versus 29.4 ± 5.7; p < 0.0001), serum creatinine was on lower levels (0.75 ± 0.27 versus 1.0 ± 0.74; p = 0.001), systolic BP was on lower side (123.7 ± 15.9 versus 128.13 ± 16.8; p= 0.015); spot urine microalbumin was on lower side (52.58 ± 71.65; versus 87.77 ± 140.86; p=0.010) and spot urine protein had lower levels (25.3 ± 38.3 versus 44.28 ± 123.58; p < 0.0001). Current research also demonstrated that Pearson's x2 and odds/protective odds for hypothyroidism (on TRT) was strongly associated with obesity (p <0.0001; odds ratio 2.28, 95% CI 1.47 to 3.56). However, they were protected from HTN (p= 0.272; protective odds ratio 1.28, 95%CI 0.824 to 1.98), nephropathy (p=0.386; protective odds 1.36, 95% CI 0.861 to 2.14) and chronic renal disease (p= 0.112; protective odds 3.42, 95% CI 0.83 to 14.13). In conclusion, TRT itself has protective effects on cardiovascular and renal system. Hence, thyroid screening is essential among diabetics to detect sub clinical or clinical hypothyroidism.