Teresa Mezza

Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell–to–α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes.

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

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.

MECHANISMS IN ENDOCRINOLOGY: Vitamin D as a potential contributor in endocrine health and disease

OBJECTIVE It has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases, such as hyperparathyroidism, type 1 diabetes (T1DM), type 2 diabetes (T2DM), autoimmune thyroid diseases, Addisons disease and polycystic ovary syndrome (PCOS). In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases. METHODS Narrative overview of the literature synthesizing the current evidence retrieved from searches of computerized databases, hand searches and authoritative texts. RESULTS Evidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships have been reported not only between blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also with risk of T1DM, T2DM, and PCOS. There is less evidence for an association with Addisons disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of T2DM, but the available evidence is not consistent. CONCLUSIONS Although observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Ongoing randomized controlled trials are expected to provide insights into the efficacy and safety of vitamin D in the management of endocrine disease.

Vitamin D deficiency: a new risk factor for type 2 diabetes?

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.

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

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.

IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity.

Obesity elicits immune cell infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since interleukin (IL)-21 plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Treg differentiation/activity, we hypothesized that it could play a role in obesity-induced insulin resistance. We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (WT) mice and in stromal vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers. Interestingly, a larger infiltration of Treg cells was seen in the adipose tissue of IL-21 knockout (KO) mice compared with WT animals fed both normal diet and HFD. In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by a higher induction of interferon regulatory factor 4 (IRF4), a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state.

High‐normal tsh values in obesity: Is it insulin resistance or adipose tissue's guilt?

Clinical evidences reported subclinical alterations of thyroid function in obesity, although the relationship between thyroid status and obesity remains unclear. We cross‐sectionally investigated the influence of metabolic features on hypothalamic–pituitary–thyroid axis in obesity.

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

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.

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and age-dependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

In anorexia nervosa, even a small increase in abdominal fat is responsible for the appearance of insulin resistance

Context  The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients’ body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment.