Showing papers in "Trends in Endocrinology and Metabolism in 2020"

Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host–Microbe Interplay

Abstract: Gut microbial metabolism is intimately coupled with host health and disease. Aromatic amino acid (AAA) catabolism by the gut microbiome yields numerous metabolites that may regulate immune, metabolic, and neuronal responses at local and distant sites. Such a chemical dialog between host cells and the gut microbiome is shaped by environmental cues, and may become dysregulated in gastrointestinal and systems diseases. Increasing knowledge of the bacterial pathway and signaling basis may shed additional light on metabolic host–microbiome crosstalk that remains untapped for drug discovery. Here, we update our understanding of microbial AAA metabolism and its impacts on host physiology and disease. We also consider open questions related to therapeutically mining these signaling metabolites and how recent concepts and tools may drive this area forward.

How May GIP Enhance the Therapeutic Efficacy of GLP-1?

Abstract: Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering.

Intersection of the Gut Microbiome and Circadian Rhythms in Metabolism.

Abstract: The gut microbiome and circadian rhythms (CRs) both exhibit unique influence on mammalian hosts and have been implicated in the context of many diseases, particularly metabolic disorders. It has become increasingly apparent that these systems also interact closely to alter host physiology and metabolism. However, the mechanisms that underlie these observations remain largely unknown. Recent findings have implicated microbially derived mediators as potential signals between the gut microbiome and host circadian clocks; two specific mediators are discussed in this review: short-chain fatty acids (SCFAs) and bile acids (BAs). Key gaps in knowledge and major challenges that remain in the circadian and microbiome fields are also discussed, including animal versus human models and the need for precise timed sample collection.

Chronic Diabetes Complications: The Need to Move beyond Classical Concepts.

Abstract: Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.

Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy

Abstract: The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B – the melatonin receptor gene – is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework – anchored in the dimension of 'time' – to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.

Mitochondria and T2D: Role of Autophagy, ER Stress, and Inflammasome

Abstract: Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.

The Immune System in Cushing’s Syndrome

Abstract: Cushing's syndrome (CS), or chronic hypercortisolism, induces a variety of alterations in the immune system, often leading to severe clinical complications such as sepsis and opportunistic infections. Prolonged exposure to high levels of glucocorticoids (GC), changes in the circadian rhythm, and the comorbidities associated therewith all combine to cause profound changes in the immune profile of affected patients. While traditionally associated with generalized immune suppression, such changes actually comprise a much more complex scenario, sharing traits with chronic inflammatory disorders. Persistently increased levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) and adipose tissue infiltration by immune cells lead to a chronic, nonresolving, inflammatory state. The combination of low-grade inflammation and selectively impaired immune response is thought to play a major role in the pathogenesis of clinical complications of CS, including diabetes, lipodystrophy, visceral adiposity, atherosclerosis, osteoporosis, and cognitive impairment. This dysregulation also explains rebound phenomena when CS is treated, involving new clinical complications sustained by an excessive immune response and autoimmunity. The aim of this review is to summarize the available evidence on the immune system in chronic hypercortisolism, while describing the main mechanisms of immune derangement and their role in the increased mortality and morbidity seen in this complex disease. A better understanding of immune system alterations in CS could help improve risk stratification, offer novel biomarkers, and provide the basis for more tailored therapies and post-remission follow-up.

Placenta Disrupted: Endocrine Disrupting Chemicals and Pregnancy

Abstract: Endocrine disrupting chemicals (EDCs) are chemicals that can interfere with normal endocrine signals. Human exposure to EDCs is particularly concerning during vulnerable periods of life, such as pregnancy. However, often overlooked is the effect that EDCs may pose to the placenta. The abundance of hormone receptors makes the placenta highly sensitive to EDCs. We have reviewed the most recent advances in our understanding of EDC exposures on the development and function of the placenta such as steroidogenesis, spiral artery remodeling, drug-transporter expression, implantation and cellular invasion, fusion, and proliferation. EDCs reviewed include those ubiquitous in the environment with available human biomonitoring data. This review also identifies critical gaps in knowledge to drive future research in the field.

Insights Into Mechanisms of GDF15 and Receptor GFRAL: Therapeutic Targets.

Abstract: Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily proteins. GDF15 acts as an inflammatory marker, and it plays a role in pathogenesis of tumors, ischemic diseases, metabolic disorders, and neurodegenerative processes. GDF15 is not normally expressed in the tissue; it is prominently induced following ‘injury’. GDF15 functions are critical for the regulation of endothelial adaptations after vascular damage. Recently, four research groups simultaneously identified glial-derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL) in the brain, an orphan receptor as the receptor for GDF15, signaling through the coreceptor RET. In this article, new aspects of the biology of GDF15 and receptor GFRAL, and their relationship with various pathologies, are commented on.

Role of Nitric Oxide in Insulin Secretion and Glucose Metabolism

Abstract: Nitric oxide (NO) contributes to carbohydrate metabolism and decreased NO bioavailability is involved in the development of type 2 diabetes mellitus (T2DM). NO donors may improve insulin signaling and glucose homeostasis in T2DM and insulin resistance (IR), suggesting the potential clinical importance of NO-based interventions. In this review, site-specific roles of the NO synthase (NOS)–NO pathway in carbohydrate metabolism are discussed. In addition, the metabolic effects of physiological low levels of NO produced by constitutive NOS (cNOS) versus pathological high levels of NO produced by inducible NOS (iNOS) in pancreatic β-cells, adipocytes, hepatocytes, and skeletal muscle cells are summarized. A better understanding of the NOS–NO system in the regulation of glucose homeostasis can hopefully facilitate the development of new treatments for T2DM.

Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation

Abstract: Methylglyoxal (MG) is a ubiquitous metabolite that spontaneously reacts with biopolymers forming advanced glycation end-products (AGEs). AGEs are strongly associated with aging-related diseases, including cancer, neurodegenerative diseases, and diabetes. As the formation of AGEs is nonenzymatic, the damage caused by MG and AGEs has been regarded as unspecific. This may have resulted in the field generally been regarded as unappealing by many researchers, as detailed mechanisms have been difficult to probe. However, accumulating evidence highlighting the importance of MG in human metabolism and disease, as well as data revealing how MG can elicit its signaling function via specific protein AGEs, could change the current mindset, accelerating the field to the forefront of future research.

Epigenetic Transgenerational Inheritance of Obesity Susceptibility.

Abstract: The prevalence of obesity and associated diseases has reached pandemic levels. Obesity is often associated with overnutrition and a sedentary lifestyle, but clearly other factors also increase the susceptibility of metabolic disease states. Ancestral and direct exposures to environmental toxicants and altered nutrition have been shown to increase susceptibility for obesity and metabolic dysregulation. Environmental insults can reprogram the epigenome of the germline (sperm and eggs), which transmits the susceptibility for disease to future generations through epigenetic transgenerational inheritance. In this review, we discuss current evidence and molecular mechanisms for epigenetic transgenerational inheritance of obesity susceptibility. Understanding ancestral environmental insults and epigenetic transgenerational impacts on future generations will be critical to fully understand the etiology of obesity and to develop preventative therapy options.

Polyphenols as Caloric Restriction Mimetics Regulating Mitochondrial Biogenesis and Mitophagy

Abstract: The tight coordination between mitochondrial biogenesis and mitophagy can be dysregulated during aging, critically influencing whole-body metabolism, health, and lifespan. To date, caloric restriction (CR) appears to be the most effective intervention strategy to improve mitochondrial turnover in aging organisms. The development of pharmacological mimetics of CR has gained attention as an attractive and potentially feasible approach to mimic the CR phenotype. Polyphenols, ubiquitously present in fruits and vegetables, have emerged as well-tolerated CR mimetics that target mitochondrial turnover. Here, we discuss the molecular mechanisms that orchestrate mitochondrial biogenesis and mitophagy, and we summarize the current knowledge of how CR promotes mitochondrial maintenance and to what extent different polyphenols may mimic CR and coordinate mitochondrial biogenesis and clearance.

The Diverse Functions of IMP2/IGF2BP2 in Metabolism.

Abstract: The human insulin-like growth factor 2 (IGF2) mRNA binding protein family (IMPs/IGF2BPs) is involved in a spectrum of biological processes, including development, tumorigenesis, and stemness. IMPs play a major role in post-transcriptional regulation of RNAs through the ribonucleoprotein complex (RNP). They have emerged as direct mammalian target of rapamycin (mTOR) substrates that coordinate nutrient stimulation and RNA life cycle control. IMP2 is a human type 2 diabetes (T2D) gene associated with impaired insulin secretion. Recently, using murine models, the substantial progress in understanding disease mechanisms has highlighted the significance of IMP2 in metabolism. This new knowledge may have the potential for therapeutic benefit.

Inositols in Polycystic Ovary Syndrome: An Overview on the Advances.

Abstract: This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and d-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle-stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. Moreover, MI enhances the effect of metformin and clomiphene on the fertility of PCOS women seeking pregnancy. As impaired intestinal transport may lead to unsuccessful inositol treatment, we also discuss new data on the use of alpha-lactalbumin to boost inositol absorption. Overall, the physiological activities of MI and DCI dictate the dosages and timing of inositol supplementation in the treatment of PCOS.

Pros and Cons of Chaperone-Mediated Autophagy in Cancer Biology

Abstract: Autophagy contributes to cellular quality control and energetics through lysosomal breakdown and recycling of essential cellular components. Chaperone-mediated autophagy (CMA) adds to these autophagic functions the ability to timely and selectively degrade single tagged proteins to terminate their cellular function and, in this way, participate in the regulation of multiple cellular processes. Many cancer cells upregulate CMA for protumorigenic and prosurvival purposes. However, growing evidence supports a physiological role for CMA in limiting malignant transformation. Understanding the mechanisms behind this functional switch of CMA from antioncogenic to pro-oncogenic is fundamental for targeting CMA in cancer treatment. We summarize current understanding of CMA functions in cancer biology and discuss the basis for its context-dependent dual role in oncogenesis.

Blood Microbiota and Circulating Microbial Metabolites in Diabetes and Cardiovascular Disease

Abstract: Diabetes and cardiovascular disease (CVD) have evolved as the leading cause of mortality and morbidity worldwide. In addition to traditional risk factors, recent studies have established that the human microbiota, particularly gut bacteria, plays a role in the development of diabetes and CVD. Although the presence of microbes in blood has been known for centuries, mounting evidence in this metagenomic era provides new insights into the role of the blood microbiota in the pathogenesis of non-infectious diseases such as diabetes and CVD. We highlight the origin and physiology of the blood microbiota and circulating microbial metabolites in relation to the etiology and progression of diabetes and CVD. We also discuss translational perspectives targeting the blood microbiota in the diagnosis and treatment of diabetes and CVD.

Dyslipidemia in Type 1 Diabetes: A Masked Danger.

Abstract: Type 1 diabetes (T1D) patients show lipid disorders which are likely to play a role in their increased cardiovascular (CV) disease risk. Quantitative abnormalities of lipoproteins are noted in T1D with poor glycemic control. In T1D with optimal glycemic control, triglycerides and LDL-cholesterol are normal or slightly decreased whereas HDL-cholesterol is normal or slightly increased. T1D patients, even with good glycemic control, show several qualitative and functional abnormalities of lipoproteins that are potentially atherogenic. An association between these abnormalities and CV disease risk has been reported in recent studies. Although the mechanisms underlying T1D dyslipidemia remain unclear, the subcutaneous route of insulin administration, that is responsible for peripheral hyperinsulinemia, is likely to be an important factor.

Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity.

Abstract: Ghrelin and the growth hormone secretagogue receptor 1a (GHS-R1a) are important targets for disorders related to energy balance and metabolic regulation. Pharmacological control of ghrelin signaling is a promising avenue to address health issues involving appetite, weight gain, obesity, and related metabolic disorders, and may be an option for patients suffering from wasting conditions like cachexia. In this review, we summarize recent developments in the biochemistry of ghrelin and GHS-R1a signaling. These include unravelling the enzymatic transformations that generate active ghrelin and the discovery of multiple proteins that interact with ghrelin and GHS-R1a to regulate signaling. Furthermore, we propose that harnessing these processes will lead to highly selective treatments to address obesity, diabetes, and other metabolism-linked disorders.

Uterine Luminal Epithelium as the Transient Gateway for Embryo Implantation

Abstract: The uterine luminal epithelium (LE) is the first maternal contact for an implanting embryo. Intrauterine fluid resorption, cessation of LE proliferation and apoptosis, and LE structural changes are prerequisites for establishing transient uterine receptivity for embryo implantation. Vesicle trafficking in the LE and receptor-mediated paracrine and autocrine mechanisms are crucial both for LE preparation and LE communications with the embryo and stroma during the initiation of embryo implantation. This review mainly covers recent in vivo studies in LE of mouse models from 0.5 days post-coitus (D0.5) to ∼D4 20 h when the trophoblasts pass through the LE layer for embryo implantation. The review is organized into three interconnected sections: preimplantation LE preparation for embryo attachment, embryo–LE communications, and LE–stroma communications.

Cardiovascular Manifestations and Mechanisms in Patients with COVID-19.

Abstract: Coronavirus disease 2019 (COVID-19) patients with pre-existing cardiovascular disease (CVD) or with cardiovascular complications have a higher risk of mortality. The main cardiovascular complications of COVID-19 include acute cardiac injury, acute myocardial infarction (AMI), myocarditis, arrhythmia, heart failure, shock, and venous thromboembolism (VTE)/pulmonary embolism (PE). COVID-19 can cause cardiovascular complications or deterioration of coexisting CVD through direct or indirect mechanisms, including viral toxicity, dysregulation of the renin–angiotensin–aldosterone system (RAAS), endothelial cell damage and thromboinflammation, cytokine storm, and oxygen supply–demand mismatch. We systematically review cardiovascular manifestations, histopathology, and mechanisms of COVID-19, to help to formulate future research goals and facilitate the development of therapeutic management strategies.

Time for a New Perspective on Prolactin in Metabolism.

Abstract: The pituitary hormone prolactin (PRL) regulates a variety of functions beyond reproduction. The association between physiological (pregnancy) and pathological (prolactinoma) hyperprolactinemia and metabolic alterations led to the concept of this hormone being diabetogenic. However, large cohort clinical studies have recently shown that low circulating PRL levels are associated with metabolic disease and represent a risk factor for type 2 diabetes (T2D), whereas high PRL levels are beneficial. Moreover, PRL acts on the pancreas, liver, adipose tissue, and hypothalamus to maintain and promote metabolic homeostasis. By integrating basic and clinical evidence, we hypothesize that upregulation of PRL levels is a mechanism to maintain metabolic homeostasis and, thus, propose that the range of PRL levels considered physiological should be expanded to higher values.

Sexual Dimorphism of Coronavirus 19 Morbidity and Lethality.

Abstract: The recent coronavirus disease 2019 (COVID-19) pandemic showed a different severity in the disease between males and females. Men have been becoming severely ill at a higher rate than women. These data along with an age-dependent disease susceptibility and mortality in the elderly suggest that sex hormones are the main factors in determining the clinical course of the infection. The differences in aging males versus females and the role of sex hormones in key phenotypes of COVID-19 infection are described in this review. Recommendations based on a dimorphic approach for males and females suggest a sex-specific management the disease.

Mineralocorticoid Receptors in Metabolic Syndrome: From Physiology to Disease.

Abstract: Over the past decade, several studies have shown that activity of extra-renal mineralocorticoid receptors (MR) regulates vascular tone, adipogenesis, adipose tissue function, and cardiomyocyte contraction. In mice, abnormal activation of MR in the vasculature and in adipose tissue favors the occurrence of several components of the metabolic syndrome (MetS), such as hypertension, obesity, and glucose intolerance. Accordingly, high levels of aldosterone are associated with obesity and MetS in humans, suggesting that altered activation of aldosterone-MR system in extra-renal tissues leads to profound metabolic dysfunctions. In this context, in addition to the classical indications for heart failure and hypertension, MR antagonists (MRAs) nowadays represent a promising approach to tackle cardiovascular and metabolic disorders occurring in the MetS.

Integrating Hunger with Rival Motivations.

Abstract: Motivated behaviors have fascinated neuroscientists and ethologists for decades due to their necessity for organism survival. Motivations guide behavioral choice through an intricate synthesis of internal state detection, external stimulus exposure, and learned associations. One critical motivation, hunger, provides an accessible example for understanding purposeful behavior. Neuroscientists commonly focus research efforts on neural circuits underlying individual motivations, sacrificing ethological relevance for tight experimental control. This restrictive focus deprives the field of a more nuanced understanding of the unified nervous system in weighing multiple motivations simultaneously and choosing, moment-to-moment, optimal behaviors for survival. Here, we explore the reciprocal interplay between hunger, encoded via hypothalamic neurons marked by the expression of Agouti-related peptide, and alternative need-based motivational systems.

Obesity/Metabolic Syndrome and Diabetes Mellitus on Peri-implantitis.

Abstract: Literature has reported that up to 50% of dental implants may be affected by peri-implantitis, a bacteria-induced chronic inflammatory process, which promotes osteoclast-mediated bone resorption and inhibits bone formation, leading to progressive bone loss around implants Current evidence points toward an increased risk for the development of peri-implantitis in both obesity/metabolic syndrome (MetS) and diabetes mellitus (DM) conditions relative to the healthy population Currently, there is no effective treatment for peri-implantitis and the 50% prevalence in MetS and DM, along with its predicted increase in the worldwide population, presents a major concern in implant dentistry as hyperglycemic conditions are associated with bone-healing impairment; this may be through dysfunction of osteocalcin-induced glucose metabolism The MetS/DM proinflammatory systemic condition and altered immune/microbiome response affect both catabolic and anabolic events of bone-healing that include increased osteoclastogenesis and compromised osteoblast activity, which could be explained by the dysfunction of insulin receptor that led to activation of signals related with osteoblast differentiation Furthermore, chronic hyperglycemia along with associated micro- and macro-vascular ailments leads to delayed/impaired wound healing due to activation of pathways that are particularly important in initiating events linked to inflammation, oxidative stress, and cell apoptosis; this may be through deactivation of AKT/PKB protein, which possesses a pivotal role in drive survival and eNOS signaling This review presents an overview of the local and systemic mechanisms synergistically affecting bone-healing impairment in MetS/DM individuals, as well as a rationale for hierarchical animal model selection, in an effort to characterize peri-implantitis disease and treatment

Maternal Lifestyle Interventions: Targeting Preconception Health

Abstract: About one-third of women of reproductive age are obese, predisposing both mother and baby to unfavourable pregnancy outcomes and initiating an intergenerational cycle of chronic metabolic disorders. Here we summarise recent research on the influence of maternal metabolic health on offspring susceptibility to future cardiometabolic diseases. Current primary lifestyle approaches (i.e., diet and exercise interventions) to halt the succession of inherited and epigenetic metabolic abnormalities have met with limited success due to late implementation, poor adherence, and/or generic guidelines. In our opinion, such interventions must commence prior to conception to improve both maternal and child health outcomes, with new approaches urgently needed to increase adherence to primary lifestyle changes among reproductive-age women.

Metabolic Signatures of Distinct Endothelial Phenotypes

Abstract: Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during vessel sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings.

Intestinal Organoids: A Tool for Modelling Diet-Microbiome-Host Interactions.

Abstract: Dietary patterns, microbiome dysbiosis, and gut microbial metabolites (GMMs) have a pivotal role in the homeostasis of intestinal epithelial cells and in disease progression, such as that of colorectal cancer (CRC). Although GMMs and microorganisms have crucial roles in many biological activities, models for deciphering diet–microbiome–host relationships are largely limited to animal models. Thus, intestinal organoids (IOs) have provided unprecedented opportunities for the generation of in vitro platforms with the sufficient level of complexity to model physiological and pathological diet–microbiome–host conditions. Overall, IO responses to GMM metabolites and microorganisms can provide new insights into the mechanisms by which those agents may prevent or trigger diseases, significantly extending our knowledge of diet–microbiome–host interactions.

What Is GLP-1 Really Doing in Obesity?

Abstract: Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released in response to meal ingestion and enhances insulin secretion from pancreatic β cells. In several human studies, GLP-1 secretory responses to oral glucose load or a meal were decreased in subjects with obesity, glucose intolerance, or diabetes compared with those in healthy subjects. However, the results of meta-analysis and cohort studies do not necessarily support this concept. Results from animal studies are also inconsistent; in multiple studies, GLP-1 secretory responses to a meal were repeatedly higher in diet-induced obese rats than in control rats. Thus, the postprandial GLP-1 response is not necessarily decreased but rather enhanced during obesity development, which is likely to play a protective role against glucose intolerance.