tance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/ resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. glucose clamp; quantitative insulin sensitivity check index; minimal model; homeostatis model assessment INSULIN IS AN ESSENTIAL PEPTIDE HORMONE whose metabolic actions maintain whole body glucose homeostasis and promote efficient glucose utilization (3). Insulin stimulates increased glucose disposal in skeletal muscle and adipose tissue, whereas it inhibits gluconeogenesis in liver to help regulate glucose homeostasis. In addition to these classical insulin target tissues, there are many other important physiological targets of insulin, including the brain, pancreatic ␤-cells, heart, and vascular endothelium, that help to coordinate and couple metabolic and cardiovascular homeostasis under healthy conditions (3,54,72,79). Insulin has concentration-dependent saturable actions to increase whole body glucose disposal. The maximal effect of insulin defines "insulin responsiveness," whereas the insulin concentration required for a half-maximal response defines "insulin sensitivity" (Fig. 1A).Insulin resistance is typically defined as decreased sensitivity or responsiveness to metabolic actions of insulin, such as insulin-mediated glucose d...

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing substantial morbidity and mortality. Older age and presence of diabetes mellitus, hypertension, and obesity significantly increases the risk for hospitalization and death in COVID-19 patients. In this Perspective, informed by the studies on SARS-CoV-2, Middle East respiratory syndrome (MERS-CoV), and the current literature on SARS-CoV-2, we discuss potential mechanisms by which diabetes modulates the host-viral interactions and host-immune responses. We hope to highlight gaps in knowledge that require further studies pertinent to COVID-19 in patients with diabetes.

Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption.

Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.

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Both osteoporosis and cardiovascular disease (CVD) are major public health problems leading to increased morbidity and mortality. Although traditionally viewed as separate disease entities that increase in prevalence with aging, accumulating evidence indicates that there are similar pathophysiological mechanisms underlying both diseases. In addition to menopause and advanced age, other risk factors for CVD such as dyslipidemia, oxidative stress, inflammation, hyperhomocystinemia, hypertension, and diabetes have also been associated with increased risk of low bone mineral density (LBMD). Elevated LDL and low HDL cholesterol are associated with LBMD, altered lipid metabolism is associated with both bone remodeling and the atherosclerotic process, which might explain, in part, the co-existence of osteoporosis and atherosclerosis in patients with dyslipidemia. Similarly, inflammation plays a pivotal role in both atherosclerosis and osteoporosis. Elevated plasma homocysteine levels are associated with both CVD and osteoporosis. Nitric oxide (NO), in addition to its known atheroprotective effects, appears to also play a role in osteoblast function and bone turnover. Supporting this notion, in a small randomized controlled trial, nitroglycerine (an NO donor) was found to be as effective as estrogen in preventing bone loss in women with surgical menopause. Statins, agents that reduce atherogenesis, also stimulate bone formation. Furthermore, bis- phosphonates, used in the treatment of osteoporosis, have been shown to inhibit atherogenesis. Intravenous bisphosphonate therapy significantly decreases serum LDL and increases HDL in postmenopausal women The exciting possibilities of newer pharmacological agents that effectively treat both osteoporosis and CVD hold considerable promise. However, it is important to emphasize that the current evidence linking both of these diseases is far from conclusive. Therefore, additional research is necessary to further characterize the relationship between these two common illnesses.

SynopsisEndothelial dysfunction and insulin resistance are frequently co-morbid states. Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways that stimulate production of nitric oxide from vascular endothelium. This helps to couple metabolic and hemodynamic homeostasis under healthy conditions. In pathological states, shared causal factors including glucotoxicity, lipotoxicity, and inflammation selectively impair PI3K-dependent insulin signaling pathways that contribute to reciprocal relationships between insulin resistance and endothelial dysfunction. We discuss implications of pathway-selective insulin resistance in vascular endothelium, interactions between endothelial dysfunction and insulin resistance, and therapeutic interventions that may simultaneously improve both metabolic and cardiovascular physiology in insulin-resistant conditions. KeywordsNitric Oxide; Insulin Resistance; Endothelial Dysfunction; Metabolic Syndrome IntroductionInsulin resistance plays a major patho-physiological role in type 2 diabetes and is tightly associated with major public health problems including obesity, hypertension, coronary artery disease, dyslipidemias, and a cluster of metabolic and cardiovascular abnormalities that define the metabolic syndrome [1,2]. A global epidemic of obesity is driving the increased incidence and prevalence of insulin resistance and its cardiovascular complications [3]. Insulin regulates glucose homeostasis by promoting glucose disposal in skeletal muscle and adipose tissue and inhibiting gluconeogenesis in liver [4]. In addition to these classical insulin target tissues, insulin has important physiological functions in the brain, pancreatic beta cells, heart, and vascular endothelium that help coordinate and couple metabolic and cardiovascular homeostasis under healthy conditions [5]. For example, vasodilator actions of insulin to stimulate production of nitric oxide (NO) from vascular endothelium lead to increased blood *Corresponding author for proof and reprints: Michael J. Quon, MD, PhD, Chief, Diabetes Unit, NCCAM, NIH, 9 Memorial Drive, Building 9, Room 1N-105 MSC 0920, Bethesda, MD 20892-0920, Tel: (301) Fax: (301) 402-1679, Email: quonm@nih.gov. Coauthors addresses: Ranganath Muniyappa, MD, PhD, Diabetes Unit, NCCAM, NIH, 10 Center Drive, 10-CRC, Room 4-1741, Bethesda, MD 20892-1632, Tel: (301) Fax: (301) 480 3159, Email: muniyapr@mail.nih.gov Micaela Iantorno, MD, Diabetes Unit, NCCAM, NIH, 9 Memorial Drive, Building 9, Room 1N-105 MSC 0920, Bethesda, MD 20892-0920, Tel: (301) Fax: (301) 402-1679, Email: iantornm@mail.nih.gov Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be...