Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-β (TGF-β) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease.
Alzheimer’s disease is a neurodegenerative disorder leading to dementia. Scientific efforts in the last decade focused mainly on understanding pathophysiology of disease and possible pharmacological approach to alleviate cognitive decline symptoms. Amyloid cascade hypothesis though criticized, remains the leading hypothesis to understand pathogenic mechanisms of cognitive decline. Intriguingly, changes of metabolic activity of cortical neurons are associated with reduced or absent sensitivity to insulin in Alzheimer’s disease brain. Insulin is a multipotent hormone regulating, not only glucose levels, but also cell survival and synaptic plasticity mechanisms of neurons. Replacement of insulin might represent a new strategic approach to counteract neurodegeneration. Here we review most of the available data regarding relationship between Alzheimer’s disease and insulin and propose new direction to deepen our understanding about insulin involvement in the pathogenesis of Alzheimer’s dementia.
Aim
Although it is now well established that the deleterious effects of chronic hyperglycaemia (i.e., glucose toxicity) play an important role in the progressive impairment of insulin secretion and sensitivity, the two major actors of the pathogenesis of type 2 diabetes mellitus, the precise biochemical and molecular mechanisms responsible for the defects induced by glucose toxicity still remain to be defined.
Data synthesis
here we will briefly report on convincing evidence that glucose toxicity acts through oxidative stress, modifications in the exosamine pathway, protein kinase C and others. After inducing or contributing to the genesis of type 2 diabetes, these same mechanisms are considered responsible for the appearance and worsening of diabetic specific microvascular complications, while its role in increasing the risk of cardiovascular diseases is less clear. Recent intervention studies (ADVANCE, ACCORD, VADT), conducted to evaluate the effects of strict glycaemic control, apparently failed to demonstrate an effect of glucose toxicity on cardiovascular diseases, at least in secondary prevention or when diabetes is present for a prolonged time. The re-examination, 20 years later, of the population studied in the UKPDS study, however, clearly demonstrated that the earliest is the strict glycaemic control reached, the lowest is the incidence of cardiovascular diseases observed, including myocardial infarction.
Conclusion
The acquaintance of the role of glucose toxicity should strongly influence the usual therapeutic choices and glycaemic targets where the reduced or absent risk of hypoglycaemia, durability of action, and data on prolonged safety should be the preferred characteristics of the drug of choice in the treatment of type 2 diabetes mellitus.
Background & aims
Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS.
Methods
We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS.
Results
Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not.
Conclusions
Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity.
Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS.
Methods
We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS.
Results
Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not.
Conclusions
Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity.
We read with interest the article by Kayaniyil et al. (1) that supplied elegant data suggesting that 25-hydroxyvitamin D [25(OH)D] is related to insulin resistance and β-cell function in a large population at high risk for type 2 diabetes and/or metabolic syndrome, thus concluding that 25(OH)D may be an independent risk factor for diabetes. We have, however, some concerns.
First, the studied population was mainly composed of obese subjects (the mean BMI was 30.5 kg/m2). Clearly, within a population with such a high BMI, the major variable influencing insulin sensitivity is fat mass. An increased fat mass (within the same BMI) could determine both the reduced insulin sensitivity and 25(OH)D. The two variables therefore correlate, but are not causally related. In our recently published article (2), we approached this important question by comparing two groups of obese subjects matched by BMI but different in terms of insulin sensitivity: no differences in 25(OH)D concentrations could be found, suggesting that the adipose tissue is its reservoir. Kayaniyil et al. themselves reported a weaker correlation in their obese (BMI >30 kg/m2) subpopulation but, unfortunately, they did not provide data on body composition.
Second, although the correlation within the high risk (for diabetes) population is intriguing, a control population is missing. In particular, it is not reported whether the studied population has lower 25(OH)D concentration than an hypothetical control cohort. If this was not the case, the working hypothesis fails. How could normal 25(OH)D determine insulin resistance?
Third, if 25(OH)D is involved in the pathogenesis of type 2 diabetes, one would expect that a supplementation of calcitriol or its analogues would ameliorate the glucose metabolism. This was not the case either in insulin-resistant diabetic patients (3) or in healthy subjects (4).
As we (2) and others (5) reported, 25(OH)D concentration mainly reflects body fat mass; the reduction of fat mass, rather than vitamin D supplementation, is the main road for the prevention and treatment of insulin resistance and diabetes.
Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.
Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity.
We read with interest the article by Alvarez et al, which aimed to investigate the relations of circulating 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations with direct measurements of insulin sensitivity, after robust measures of body composition and fat distribution were accounted for. We would like to express our opinion and a different interpretation of the data provided by authors, with the hope that other points for discussion are brought up.
In a very recent publication, Alvarez et al provided novel findings suggesting that dietary vitamin D is independently associated with insulin sensitivity in African Americans (AAs) but not in European Americans (EAs). Interestingly, the 2 groups were identical for hepatic insulin sensitivity [homeostatic model assessment (HOMA)], whereas Si, a method for measuring insulin sensitivity that encompasses both hepatic and peripheral tissues, was lower in AAs, therefore suggesting a pivotal role for insulin resistance in skeletal muscle [especially in the presence of identical body mass index (BMI)] in correlation with 25(OH)D. In the present article, the authors suggest that 25(OH)D and PTH concentrations are independently associated with whole-body insulin sensitivity and suggest that these variables may influence insulin sensitivity through independent mechanisms. In fact, multiple linear regression analysis indicated that 25(OH)D and PTH concentrations were independently related to Si after adjustment for age, race, and intraabdominal adipose tissue. It is well known, however, that adipose tissue is the natural reservoir for lipo-soluble 25(OH)D. The higher BMI and the higher subcutaneous fat content found in AAs (although the latter difference was not statistically significant) could therefore explain the differences in 25(OH)D concentration, as well as in HOMA index, found by the authors.
Abstract
Introduction
The purpose of this study was to determine whether single-fiber conduction velocity (SF-CV) of a small number of axons increases sensitivity for identification of motor nerve conduction alterations in patients with diabetes.
Methods
Twenty-one consecutive diabetic patients in good metabolic control were studied. For each patient, conventional (C-CV) and SF-CV results were correlated with the presence of neuropathic symptoms.
Results
Nine of 21 patients reported symptoms suggestive of mild nerve impairment. Three patients had abnormal sural nerve CV, 1 of whom also had abnormal motor nerve conduction. Eighteen patients had normal findings on conventional tests, 3 of whom had slowing of SF-CV.
Conclusions
SF-CV is able to detect mild myelin damage with higher sensitivity than conventional tests. The use of SF-CV may be a helpful tool in the early identification of diabetic polyneuropathy, and it may be useful for tailoring an approach to diabetic polyneuropathy. Muscle Nerve, 2011
Metabolic syndrome is a cluster of risk factors that predispose to major cardiovascular diseases, liver steatosis and fibrosis, as well as reduced renal function. Metabolic syndrome and its early hepatic manifestation, non-alcoholic fatty liver disease, are prevalent both among the general population and in pre- and posttransplantation settings. Because indications for solid-organ transplantation are gradually increasing, attention should focus on the incidence of metabolic syndrome among transplanted patients, defined as posttransplant metabolic syndrome (PTMS). Subjects with worse metabolic profiles with two or more criteria of the syndrome show lower survival rates and greater co-morbidities.
However, it is still unclear whether the pathophysiology of posttransplantation metabolic syndrome differ from that of the general population and may be determined by the primary disease affecting the liver or kidney, or amplified or altered by the immunosuppressive treatment, as it has already been established that corticosteroids and calcineurin inhibitors cause metabolic disarrangements. Although there is controversy regarding the definition and the impact of PTMS on overall survival rates following transplantation, these patients are at increased risk for cardiovascular morbidity and mortality. Early recognition, prevention, and treatment of these conditions may impact long-term survival after transplantation. Thus, even if metabolic syndrome in transplant patients remains an unclear definition, an insulin resistance is present in these patients. The treatment of this condition represents a health problem that requires intervention by clinicians before and after transplantation.