Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus

Rivista: Nature medicine

Autori: Kiechl S, Wittmann J, Giaccari A, Knoflach M, Willeit P, Bozec A, Moschen AR, Muscogiuri G, Sorice GP, Kireva T, Summerer M, Wirtz S, Luther J, Mielenz D, Billmeier U, Egger G, Mayr A, Oberhollenzer F, Kronenberg F, Orthofer M, Penninger JM, Meigs JB, Bonora E, Tilg H, Willeit J, Schett G.

Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P< 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.

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Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney

Rivista: Am J Physiol Cell Physiol

Autori: Mariappan MM, DeSilva K, Sorice GP, Muscogiuri G, Jimenez F, Ahuja S, Barnes JL, Choudhury GG, Musi N, DeFronzo R, Kasinath BS

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.

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Insulin and the Future Treatment of Alzheimer’s Disease

Rivista: CNS & Neurological Disorders - Drug Targets

Autori: Semprini R, Koch G, Belli L, Lorenzo FD, Ragonese M, Manenti G, Sorice GP, Martorana A

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.

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Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes – mechanisms and potentials for treatment

Rivista: Nutrition, Metabolism & Cardiovascular Diseases

Autori: Giaccari A, Sorice G, Muscogiuri G

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.

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Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause-effect in PCOS?

Rivista: Clinical Nutrition

Autori: Muscogiuri G, Policola C, Prioletta A, Sorice G, Mezza T, Lassandro A, Della Casa S, Pontecorvi A, Giaccari A

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.

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Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes

Rivista: Diabetes Care

Autori: Muscogiuri G, Sorice GP, Prioletta A, Policola C, Della Casa S, Pontecorvi A, Giaccari A

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.

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Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives

Rivista: Nutrition, Metabolism & Cardiovascular Diseases

Autori: Muscogiuri G, Sorice GP, Ajjan R, Mezza T, Pilz S, Prioletta A, Scragg R, Volpe SL, Witham MD, Giaccari A

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.

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Vitamin D Deficiency: A New Risk Factor for Type 2 Diabetes?

Rivista: Ann Nutr Metab

Autori: Mezza T, Muscogiuri G, Sorice GP, Prioletta A, Salomone E, Pontecorvi A, Giaccari A

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.

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Will vitamin D reduce insulin resistance? Still a long way to go

Rivista: American Journal of Clinical Nutrition

Autori: Muscogiuri G, Sorice GP, Prioletta A, Policola C, Della Casa S, Pontecorvi A, Giaccari A

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.

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The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship?

Rivista: Clin Endocrinol

Autori: Muscogiuri G, Sorice GP, Prioletta A, Mezza T, Cipolla C, Salomone E, Giaccari A, Pontecorvi A, Della Casa S

Context  Adrenal incidentalomas (AI) have often been associated with a high prevalence of insulin resistance (IR) and cardiovascular risk factors, although direct measurement of insulin sensitivity (IS) has never been carried out.

Objective  We aimed to investigate whether the morphological and hormonal features of AI correlate with the presence and severity of IR, using the hyperinsulinaemic euglycaemic clamp (HEC).

Design and Measurements  Forty patients with AI (22 women) with a mean age of 58·5 ± 11·1 years underwent hormonal and morphological evaluation. Nineteen patients with AI without known history of diabetes mellitus (DM) or impaired glucose tolerance (IGT) and 17 matched controls underwent oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp (HEC).

Results  Diabetes mellitus was observed in 13 patients (33%), while three (8%) had IGT. Thirty-one of the AI were nonfunctioning (82·5%), whereas two (5%) secreted cortisol (Cushing’s syndrome) and seven (12·5%) showed subclinical secretion of cortisol. The 19 patients with nonfunctioning AI were more insulin resistant than controls (glucose up-take: 4·58 ± 1·80 vs 5·85 ± 2·48 mg/kg/min respectively; P = 0·01); IS was inversely related to the mass size (r = −0·57; P = 0·04), free urinary cortisol (r = −0·68; P = 0·01), serum cortisol after 1-mg dexamethasone suppression (−0·65; P = 0·02) and percentage of trunk fat mass (−0·77; P = 0·02) and directly related to serum adreno cortico tropic hormone (ACTH) (r = 0·62; P = 0·03). After performing multivariate regression, the mass size was found to be the most powerful predictor of IR.

Conclusion  Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.

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