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Authored  by Pushparajah Thavarajah

Abstract

Global diabetes and obesity prevalence continue to rise. There are no signs that these rising rates will come to a halt with current food production and consumption practices. Therefore, modifications to current food system are urgently needed. This article addresses the existing food problem(s), changes needed, and short-term food solutions to reduce diabetes and obesity.

Introduction

Globally, the number of people with diabetes has risen to 314 million or doubled in two decades. Among them 1.6 million die direct result of diabetes, and another 2.2 million deaths because of high blood glucose levels [1]. Although many factors responsible for diabetes, overweight and obesity are major ones. To date, worldwide obesity has tripled since 1975, and more than one third above 18 years are overweight. Among young, over 340 million children and adolescents are overweight or obese [2]. There are no signs that current diabetes and overweight/obesity rates to decline making many more to suffer.

To solve these problems, diabetes and obesity prevention is focused on two main areas: reduce of calorie or sugar focused diets and increase in physical activity levels. Although these are essential for prevention, their impacts had been rather limited despite efforts by those program participants. Why we continue to see rise of these two epidemics? This article will briefly discuss present food production and consumption failures, and provide short term food solutions to reduce diabetes and obesity prevalence.

Discussion

The current food production, processing, and distribution is economically efficient or at its best as never seen before in human history to provide greatest caloric content for a unit cost. This system works because it continues to maximize calorie content by using sugars and oils as primary food ingredients. Those two food ingredients are nonperishable; hence, calories in them could be stored, and distributed to majority of world populations at affordable prices. In the past, calorie dense foods prevented hunger and famine. They may be still needed when natural disaster or in a military conflict prevents food supplies. However, continue to maximize only calorie comes at a greater human health costs.

To address diabetes and obesity health costs, scientific reports, interest groups, and governments time to time highlight the negative effects on sole calorie based diets. Food industry responds to these pressures, and consumer demands. Perhaps more than anything, those calorie reductions by cutting sugar and fat levels are economically favorable to produce when no other added costs to have same product profiles. This pattern of only calorie focused global food supply and demand will continue; hence, no attention to all other essential nutrients for greater human health.

Every human requires 50 plus nutrients on daily basis for healthy living. Foods that fail to provide these nutrients results in severe energy and micronutrient malnutrition. Emerging economies with larger populations (e.g. China and India) will have the greatest malnutrition burdens. Among different population groups; women and young children will face major nutritional challenges because of additional nutrient requirements for reproduction and growth. Abundance of calorie dense foods devoid any other nutrients, and continue to consume those will drive both overweigh/obesity and micronutrient malnutrition rates to much higher levels. Including the US more than one third of global population is deficient in one or more mineral and vitamin micronutrients. Micronutrient deficiency, a cause and a compounding factor, could make existing health problems worse.

Energy and micronutrient malnutrition issues, over supply of calorie and under supply of micronutrients will continue to gain worldwide attentions because those malnutrition effects are visible. However, there is a hidden, and often neglected, perhaps most important factor in human health- gut bacteria. Simply, there are hundreds of more live bacteria than human cells in digestive tract working harder and harder. They determine how we use what we eat. Recent gut micro biome studies show their indispensable role on human health. For example, lean individuals have diverse range of bacteria to keep them lean, while obese have less diverse or relatively few species. The type and number of bacteria, their actions of what we eat, metabolites they release, and how they control what get absorbed in to the body may have roles in causing type 2 diabetes and other diseases. What are the foods that could control body weights and promote human health beneficial bacteria? Will they easily fit in to today’s calorie focused food system?

Prebiotic foods, more specifically prebiotic carbohydrates, promote human health beneficial bacterial growth and their diversity. By incorporating prebiotic carbohydrates in to foods, for example resistant starch- a type of starch not breaking down to glucose by human digestive enzymes, can promote human health beneficial bacterial diversity and growth. Resistant starch is low caloric and provides the same sensory properties just like starch. Their production levels could be increased using the same cost parameters as of regular starch. They can easily replace part of starch to reduce calorie intakes, develop healthier gut bacteria, and increase micronutrients absorption. Besides resistant starches, there are other prebiotic carbohydrates: sugar alcohols, insulin and large number of low-and nondigestible carbohydrates. These carbohydrates also could provide same gut health benefits while providing sweetness to foods. Therefore, by producing these prebiotic carbohydrates in abundance, including them in commonly eaten foods, and providing at affordable prices may be food solutions to reduce diabetes and obesity.

Conclusion

Novel foods based on reduced caloric densities and prebiotic effects may be short term solution to reduce diabetes and obesity burdens. Certainly, prebiotic carbohydrates could replace most or all readily digestible carbohydrates in our foods, and may well fit in to the present food-economic system to provide greater human nutritional value.

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Authored by Jeff C Huffman

Abstract

Positive psychological characteristics such as optimism, positive affect, gratitude, and related constructs may play an important role in health. In patients with type 2 diabetes (T2D), positive psychological constructs have been associated with superior medical outcomes, including better glucose control and lower mortality rates. The beneficial effects of positive psychological states in T2D are most likely mediated through health behaviors such as increased physical activity and adherence to a healthier diet. Furthermore, numerous studies with non-diabetic populations have shown that performing various positive psychological exercises (e.g., writing gratitude letters, performing acts of kindness) have led to greater well-being. Compared to other available treatments, these activities are simple and involve constructs that have been associated with superior adherence and diabetes-related outcomes. However, there has been minimal research on the use of positive psychological interventions in T2D, though small studies of related interventions have been linked to improvements in positive affect and, in some cases, greater health behavior adherence and lower blood sugar. Continued work is needed to ascertain whether positive psychology interventions can truly impact functioning, blood sugar, and overall health in this key population.

Keywords: Diabetes; Positive psychology; Well-being; Positive affect; Positive psychology intervention; Optimism

Introduction

Psychological distress and negative affective disorders are common in patients with type 2 diabetes (T2D). A substantial proportion of patients with T2D have clinical depression [1] and even those who do not meet full diagnostic criteria for a depressive disorder have substantial distress that can impede self-care, functioning across multiple domains (e.g., occupational, personal), and quality of life [2]. Psychological states may also significantly impact health behavior and clinical outcomes in patients with T2D [3]. Negative psychological syndromes such as depression and anxiety have been consistently associated with poor outcomes in patients with T2D [4-6]. For example, depression is associated with impaired glucose control [7], functional disability [8], end-organ complications [7], and mortality [7,9,10], and distress itself is associated with lower levels of treatment adherence [2].

On the other hand, positive psychological characteristics- optimism, positive affect, gratitude, and related constructs-may also play an important role in medical outcomes. These positive psychological constructs are not simply the flip-side of depression [11,12], e.g., it is possible that a depressed individual may be optimistic about the future whereas a non-depressed individual may conversely have low levels of optimism. Prior work has found that these constructs have been linked to superior health outcomes including healthier diet, increased physical activity, and lower rates of mortality across various medical conditions [13-15]. Furthermore, the connections between positive psychological constructs and health have been independent of sociodemographic factors, medical characteristics, and the adverse effects of depression and anxiety [13,15]. Nonetheless, there has been less focus on the promotion of positive psychological well-being in T2D individuals.

Specifically related to T2D, positive psychological constructs have been associated with numerous beneficial outcomes [3,16-18]. For example, in a large epidemiologic study, measures of psychological well-being, including emotional vitality and life satisfaction, were prospectively linked with the prevention of T2D [19]. Among patients who have developed T2D, positive psychological attributes are related to superior outcomes. For instance, overall well-being is correlated with better glucose control [20]. Likewise, resilience has been associated with lower levels of hemoglobin A1c, and such resilience has been shown to buffer the effects of psychological distress on blood sugar [21]. Finally, positive affect has been prospectively and independently linked to lower mortality among those with T2D [22].

Though the relationship of positive psychological constructs and health outcomes is not fully understood, the beneficial effects of positive psychological states are most likely mediated through health behaviors. Positive states in some studies have been directly associated with favorable effects on physiology in T2D (e.g., reduced sympathetic hyperactivity, decreased levels of proinflammatory biomarkers, and decreased hypothalamicpituitary- adrenal axis hyperactivity) [3,16-18]. However, most evidence that links positive states to superior outcomes does so via increased adherence to health behaviors [16-18]. For example, in T2D patients, positive affect and optimism have been prospectively linked to greater physical activity, healthier diet, and reduced smoking, even after controlling for baseline behavior and relevant covariates [22]. Such improvements in health behavior may be caused by easier initiation of physical activity, greater confidence in meeting diet and activity goals, and more vitality/energy to engage in self-management when experiencing positive mood [23].

An important question is whether positive psychological well-being is inherent or whether it can be modified. There is by now a substantial literature on so-called positive psychology (PP) interventions and their efficacy in improving psychological well-being. PP interventions use exercises (e.g., gratitude letters, acts of kindness, personal strengths), completed in a systematic manner, to boost optimism, positive affect, and resilience. In healthy participants, PP exercises have consistently increased well-being and decreased depression in studies of over 5000 participants [24]. More recently, trials in patients with coronary heart disease, hypertension, and HIV have found that such programs have had beneficial effects on well-being, depression, and in some cases, health behaviors [25-29].

PP interventions have several potential advantages to other treatment programs, particularly when considering individuals with T2D. First, as opposed to treatments that are applied only to patients with clinical depression or other psychiatric disorders, PP interventions are instead designed to increase positive psychological well-being across a variety of different populations, including those considered to be psychiatrically healthy [30]. This should make the PP intervention more applicable to individuals with T2D who may experience a range of psychiatric symptoms. PP also differs from somewhat-related mindfulnessbased stress reduction and self-efficacy interventions [31-33] in that it: (a) specifically targets constructs-positive affect and optimism-linked to superior adherence and outcomes in T2D [3], (b) utilizes validated PP exercises found to be effective across dozens of studies [24], and (c) is simple for patients and does not require the substantial provider training needed for most other interventions.

Despite the potential benefits of an intervention that could promote well-being, reduce distress, and improve self-care in T2D patients, there has been limited study of PP interventions in this patient population. However, results to date have yielded encouraging findings. For example, an online positive affect intervention for T2D patients led to improvements in positive affect and depression, although no significant changes in diabetes-specific efficacy or in health behaviors were found [34]. A related resilience-focused intervention for T2D patients was, however, associated with improvements in HDL cholesterol and fasting blood sugar in a small controlled trial [35], and a one-arm pilot study of a PP intervention also found substantial improvements in psychological outcomes and self-reported health behavior adherence [36].

In the context of these promising but mixed results in T2D patients, there is still a question about whether such PP interventions alone are enough to result in changes in selfcare and outcomes, or whether they are better combined with existing behavioral interventions. In the case of the latter scenario, the well-being component would presumably promote motivation, self-efficacy, and optimism, which would allow for greater engagement in the intervention. It is also still unknown how PP interventions compare to other behavioral interventions that have been tested in this population targeting self-efficacy or stress management, which have been shown to affect diabetesrelated distress [37,38] and, less consistently, health outcomes [39-42]. Given the clear associations between well-being and outcomes in T2D, along with the promising effects of initial PPbased studies, continued work in this area is needed to ascertain whether well-being interventions can truly impact function, blood sugar, and overall health in this key population.

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Authored by Julia Peinado Onsurbe 

Abstract

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased rapidly, paralleling the epidemic of type 2 diabetes mellitus (T2DM) and obesity leading to cardiovascular disease (CVD). It has been demonstrated that NAFLD is strongly associated with atherosclerosis [1]. With recently gained knowledge, it now appears that NAFLD might induce insulin resistance, dyslipidaemia, oxidative stress, inflammation, and fluctuation of the adipokines associated with atherosclerosis [1]. The association between NAFLD and atheromatosis in obese patients with or without T2DM has been controversial. It could be that liver disease participates in the origin of atheromatous plaques.

Excess liver fat is extremely common, and the prevalence of NAFLD has been increasing mainly because of the increased prevalence of obesity. The prevalence increases to 57% in obese subjects, 70% in diabetic subjects and 90% in morbidly obese people. Patients with NAFLD are at increased risk for cardio-metabolic complications, such as CVD and T2DM. Bariatric surgery corrects improves the steatosis, T2DM [2,3] and cardiovascular risk factors, and it reduces long-term cardiovascular events.

It is possible that a higher degree of liver disease indicates further progression of atheroma, but that finding could occur given that, due to a certain degree of liver injury, bariatric surgery is notable to improve or reverse vascular lesions [4].

Keywords: Steatosis; Atherosclerosis; Liver; Obesity; Diabetes; Cardiovascular disease

Abbreviations: NAFLD: Non-Alcoholic Fatty Liver Disease; T2DM: Type 2 Diabetes Mellitus; FFA: Free Fatty Acids; ROS: Reactive Oxygen Species; PUFA: Polyunsaturated Fatty Acids; VV: Vasa Vasorum

Introduction

Non-alcoholic fatty liver disease (NAFLD)

Excess liver fat is extremely common, and the prevalence of NAFLD has been increasing rapidly, paralleling the epidemic of type 2 diabetes mellitus (T2DM) and obesity leading to cardiovascular disease (CVD). It has been demonstrated that NAFLD is strongly associated with atherosclerosis [1]. Simple hepatic steatosis has been shown to be associated with marked silent carotid atherosclerosis [5]. The prevalence increases to 57% in obese subjects, 70% in diabetic subjects and 90% in morbidly obese people [6,7].

Increased hepatocyte triglyceride formation could play a protective role to prevent hepatocytes from FFA-induced damage. These toxic effects induced by FFA and other derived metabolites is known as lipotoxicity [8]. One important mediator of lipotoxicity is the over-production of reactive oxygen species (ROS). When ROS production exceeds the antioxidant capacity, it leads to oxidative stress. Numerous studies have demonstrated that oxidative stress is elevated in NAFLD patients [9]. Despite the powerful anti-oxidant capacity of the liver, excessive FFA oxidation in the steatotic hepatocytes could cause substantial oxidative stress [10].

Oxidative stress can cause mitochondrial injury by causing the reaction of ROS with polyunsaturated fatty acids (PUFAs) at the mitochondrial membrane. Insulin resistance (IR) plays a central role in these processes by allowing for the excessive flow of fatty acids from adipose tissue and also by impairing peripheral glucose disposal. Peroxisome proliferator-activated receptor a (PPAR-a) is a key transcription factor regulating the expression of genes involved in mitochondrial, peroxisomal and microsomal FFA oxidation [11]. Hepatocyte injury, a characteristic of NAFLD, which manifests as ballooning, is produced by the abnormal distribution of intermediate filaments induced by oxidative stress. This reaction is mediated by the Wnt/beta-catenin pathway. These ROS attack and react with PUFAs (polyunsaturated fattyacids) present at themitochondrial membranes, so ROS damage mitochondrial DNA and cause mitochondrial dysfunction. Apoptosis can be initiated by dysfunction almitochondria via the Wnt/beta-catenin pathway, and it is also the main mechanism of death in NASH, promoting the progression from simple steatosis to NASH.

Kupffer cells play a key role in liver inflammation [12], regulated by the balance of pro-inflammatory M1 Kupffer cells and anti-inflammatory M2 Kupffer cells [13]. Imbalanced M1/M2 phenotypic Kupffer cells have emerged as a central mechanism underlying steatohepatitis. Kupffer cells are exposed to various substances and they function to sense and remove pathogens and dangerous molecules via pattern recognition receptors (PRRs). The PRRs comprise at least two families of sensing proteins: the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs). Both NLRs and TLRs detect danger signals, including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs are pathogens originating from gut-derived microorganisms, while DAMPs include molecules endogenously released from stressed or injured hepatocytes. TLRs recognize bacterial products derived from gut microbiota, such as lipopolysaccharide (LPS, also known as endotoxin) and peptidoglycan. Kupffer cells are the primary sensors of PAMPs and DAMPs as well, and TLR and NLR receptors have emerged as important mediators of Kupffer cell activation [14].

Atheromatous processes

The vasa vasorum (VV) are blood vessels that extend from the adventitia of large vessels and irrigate their walls. Its primary mission is to provide nutrients and oxygen to the layers that cannot penetrate the blood vessel lumen. One of the earliest changes that can be observed in the atheromatous process is the proliferation of VV in the adventitia [15]. The hypoxia is the main stimulus of intimal neovascularization by perpendicular adventitial vessels [16]. Hypoxia of the vessel wall, either by injury or by increasing demand, is the main factor inducing neoangiogenesis [17]. A correlation was shown between the density of the VV and the progression of atherosclerotic plaque [18]. Neovascularization and endothelial dysfunction are the initial phenomena of atheromatosis, while increased IMT and appearance of the plaque occur later.

Endothelial injury

Theendothelial injury process begins with the molecular responses of transcription factors induced by hypoxia (HIF, hypoxia inducing factor) [19], where in the increase in low density lipoprotein [20] and reduced nitric oxide (NO, mainvasodilator) initiate a cascade of endothelial activation, recruitment of inflammatory cells, production of reactive oxygen species(ROS) and monocyte infiltration, the direct migration of which is mediated by monocytechemo attractant protein(MCP-1) [21]. The LDL are subjected to oxidative modification, resulting in a highly oxidized and aggregated lipoprotein called oxLDL, which is among the more atherogenic forms of LDL [22]. OxLDL stimulates the inflammatory signalling by endothelial cells, releasing chemotactic proteins, such as MCP1, and growth factors, such as monocyte colony-stimulating factor (MCSF), which facilitate the recruitment of monocytes by the arterial wall, a process mediated by the selectins [23]. oxLDL also promotes monocyte differentiation into the macrophages that convert oxLDL into lipid-laden foam cells, which are cells with the hallmark of atherosclerosis [22]. oxLDL is recognized by the scavenger receptor (landfill) macrophages SR-A and SRB-1 or CD36 (scavenger receptor-A and B, respectively). In nondiabetic subjects, sCD36 (soluble CD36) was significantly associated with IR indices, carotid atherosclerosis and fatty liver. However, prospective studies are needed to further evaluate the role of sCD36 in the inter-relationship among atherosclerosis, fatty liver and insulin resistance [24].

Activated macrophages express cytokines, such as TNF-a, and IL-1 beta (Interleukin-1 beta), which stimulate endothelial cells to express adhesion proteins, such as VCAM-1 and ICAM-1 (vascular-1 molecules and adhesion intercellular-1, respectively). ICAM-1 plays an important role in the recruitment of immune cells during the progression of plaque, and it was positively correlated with HOMA-IR (homeostasis model of resistance insulin), BMI (body mass index), leptin, and adiponectin and negatively correlated with high density lipoprotein (HDL) cholesterol [25]. Moreover, ICAM-1 is induced as a result of the binding of angiotensin-2 to its receptor, promoting the release of ROS and endothelin-1 by endothelial cells [26]. Other molecules involved in pathophysiology of the plaque are VEGF [26], PAI-1 and adiponectin [27].

It is well established that IR is the primary factor underlying hepatic steatosis. IR is present in almost all NAFLD patients [28]. Fat accumulation in the liver is associated with oxidative stress and lipid peroxidation. Furthermore, NAFLD subjects have increased secretion of inflammatory marker and plasma glucose and decreased HDL concentrations. The consequence of this physiological dysfunction is an increased risk for the development of diabetes and atherosclerosis and an increased risk of coronary artery disease [29].

Both diabetes and IR cause a combination of endothelial dysfunctions, which can diminish the anti-atherogenic role of the vascular endothelium [30]. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction might be a critical early target for preventing atherosclerosis and cardiovascular disease. The biochemical or cellular links between elevated blood glucose levels and vascular lesions remain incompletely understood.

Molecular mechanisms

MicroRNAs (miRNAs) have emerged as a new class of gene regulators, recent studies of which have emphasized that they play a crucial role in atherosclerosis [15]. miRNAs have also been associated with oxidative stress, inflammation, insulin signalling, apoptosis and angiogenesis related to obesity. All of these processes contribute to the development of T2DM and atherosclerosis and therefore are associated with cardiovascular disorders [31]. Recent studies have reported that the miRNAs released by cells have endothelial anti-atherogenic properties, similar to those that increase vascular areas when the laminar flow is high or that decrease when the flow is low or abnormal, such as miRNA-10a [32], the miRNA-19 [33] or miRNA-143/-145 [34]. Other studies have reported pro-atherogenic roles for miRNA-712 [35] and miRNA-92a [36].

Studies of human NAFLD have identified approximately 44 miRNAs dysregulated in the NAFLD liver [37]. Several miRNAs have been identified as playing key roles in the development of steatosis and its progression to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma [38]. Overexpression of miR-185 resulted in increased insulin receptor substrate-2 (IRS-2) expression, improved insulin sensitivity and reduced steatosis [39]. The predicted targets of miR-122 include genes regulating cholesterol and lipid metabolism, proteasomal protein degradation, cell adhesion and extracellular matrix biology [40]. In addition to miR-122, several miRNAs have been associated with the pathogenesis of NAFLD. Cheung and colleagues found that miR-21 was heavily upregulated in the livers of patients with steatohepatitis [41].

Atheromatosis, NAFLD and endothelial changes may be reversible Bigornia et al. [42] demonstrated that reversing endothelial dysfunction at 12 months of weight loss was a more important metabolic change than the degree of weight loss. Mavri et al. [43] observed similar results in obese subjects submitted to a diet and found an improvement in endothelial dysfunction at one week after initiating the diet. Recently, decreased IMT was found after gastric bypass only in obese patients with T2DM but not in patients with impaired glucose tolerance [44]. Currently, we have several non-invasive techniques that allow us to assess endothelial dysfunction and adventitious arterial blood, more specifically VV, including the study of arterial tone in peripheral beds with EndoPAT and examining the density of the VV in the adventitia with carotid ultrasound echography after contrast administration (microbubbles of hexafluoride sulphur). The use of micro bubbles allows us to study the vascular structures that these compounds leave in the bloodstream and thus allows for the visualization of VV [45].

All this finding showed that relatively early atherosclerotic changes might be reversible if it is explored with more sensitive measuring methods than IMT, presumably by measuring more development and obtaining early results.

Acknowledgement

This work was supported by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (ISCIII) (PI11/01159 and PI15/00190 to JP-O PI15/00332 to JAB-F) and the FEDER Funds of the EU (Fondo Europeo de Desarrollo Regional: “Una manera de hacer Europa”). English grammar and language have been corrected by American Journal Experts (www.journalexperts. com).

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Authored by Kanwaljit Chopra

Abstract

Insulin resistance (IR) is an important link between obesity and post obesity complications varying from diabetes mellitus to neurological insults such as cognitive dysfunction and Alzheimer's disease. Currently available high calorific diet induced preclinical models mimic clinical pathologies of various metabolic disorders but they are highly time consuming. Zymosan a well-known inflammagen has recently been used to induce reversible IR conditions in rodent models. Though, the insulin resistance lasts as long as zymosan is injected to animals, but the pathogenesis that resembles to that of obesity, IR and metabolic syndrome. However, high fat or high carbohydrate diet could be used in combination with zymosan to develop a novel animal model of IR where both inducers act synergistically to exert their primary actions. The combination of these two approaches may help in development of a robust experimental model of IR and post IR complications within a very short duration. Such preclinical models will help the researchers to better understand the pathological evolution of long term metabolic disruptions like metabolic syndrome and others.

Keywords:    Zymosan; Insulin resistance; High fat diet; High carbohydrate diet; Diabetes; Obesity; animal model; Metabolic syndrome; Metabolic complications  

Abbrevations:   AKT: Protein Kinase B; CD 14: Cluster of Differentiation 14; GSK 3: Glycogen Synthase Kinase-3; HFCS: High Fructose Corn Syrup; HFD: High Fat Diet; IL: Interleukin; IR: Insulin Resistance; IRS 1: Insulin Receptor Substrate 1; JAK: Janus Kinase; LTB4: Leuko Triene B4; MIP: Macrophage Inflammatory Protein; NFKB: Nuclear Factor Kappa Light Chain Enhancer of Activated B Cells; PI3K: Phosphor Inositide 3-Kinase; PMNs: Poly Morph Nuclear Cells; ROS: Reactive Oxygen Species; STAT: Signal Transducer and Activator of Transcription; T2DM: Type 2 Diabetes Mellitus; TLR: Toll Like Receptor

    Introduction

Insulin is the major pancreatic hormone that regulates the glucose homeostasis in our body. The pathological state in which the production of insulin is decreased, mostly due to beta cell destruction is known as insulin deficiency whereas the situation in which insulin secretion is normal and muscle cells are unable to respond to the systemically available insulin is referred to as insulin insensitivity or insulin resistance (IR) [1]. In such resistant states, the body cells fail to take up the glucose from blood stream and this leads to elevated blood sugar levels, referred to as hyperglycemia. IR is a primary pathological result of obesity and hypertriglyceridemia [2] that leads to a wide range of secondary complications such as type 2 diabetes (T2DM) [3], metabolic syndrome (Syndrome X) [4,5], cardiovascular events [6,7], stroke [8] including recently discovered link between hypertriglyceridemia, insulin resistance, altered brain glucose homeostasis, Alzheimer's disease [9,10] and cognitive dysfunctions [11-13]. The pathophysiology of insulin resistance is very complex with number of known etiologies, most of which are diet or nutrition related. Over-nutrition or obesity triggered inflammation in adipose tissue [7,14], altered lipid metabolism resulting in hypertriglyceridemia [15] and distorted gastrointestinal microbiota (dysbiosis) [16-18] and all of the contributing factors are interrelated at variable degrees to rise to the final state of IR. The complexity and multi factorial etiologies of IR sum up to make it very hard to replicate and develop a heterogeneous animal model for the purpose of understanding the pathogenesis of IR and its secondary complications and pharmacological screening of chemical entities. Hence the new chemical entities need to be screened in more than one animal models of IR to determine their safety and efficacy. Currently, a number of preclinical testing systems including transgenic models are available for the purpose of IR research. Among various available models of IR, diet-induced animal models are affordable, extensively studied and utilized for the research purposes [19]. Diet-induced animal models involve the use of high calorie containing food sources such as fats (vegetable oil and animal fat consisting high amounts of saturated fats) [20,21], fructose corn syrup [22,23] and sucrose [24] alone or in combination [25,26] to induce IR. Though, these dietary animal models induce the disease with similar pathophysiological mechanisms to that of clinical cases, the development of pathological hallmarks of IR takes 12-24 weeks of time which makes these models tedious and cumbersome to use [25,27].

Zymosan a glucan with repeating glucose units connected by β-1, 3-glycosidic link ages is an insoluble powder prepared from cell wall from Saccharomyces cerevisiae,consisting of protein-carbohydrate complexes [28]. Zymosan is an inflammagen majorly used as a pharmacological tool to develop animal models of rheumatoid arthritis [29], acute peritonitis, multiple organ failure [30] and IR [31]. Zymosan exerts its inflammatory actions by stimulating macrophages via TLR-2 Receptors and neutronphil infiltration through various activated cytokines and chemokiness. Zymosan stimulated TLR-2 associates with TLR-6 and CD-14 cells, initiating the activation of macrophages [28]. Furthermore, zymosan acts directly by binding to Dectin-2 a phagocytic receptor which is expressed on the surface of macrophages and dendritic cells. Recognition of zymosan by Dectin-2 besides the activation of TLR-2 and TLR-6 augments the immune response that leads to inflammation [32]. Zymosan causes neutrophil infiltration to the site of action by stimulating the production of Leukotriene B4 (LTB4), a chemotactic agent responsible for the recruitment of various chemokines and cytokines like IL-1α, IL- 15, IL-18, TNF-α, IL-8, MIP-1 α and MIP-2 [33,34]. Zymosan also exerts its action by other minor mechanisms that play a key role in inducing inflammation, which includes-systemic hypotension, increasing plasma nitric oxide levels, increasing cycloxygenase activity, increasing exudates formation and excessive reactive oxygen species (ROS) production by formation of activated polymorphonuclear(PMN)cells [30].

Being an inflammagen, Zymosan has become one of the potential tools for disease animal modelingwhere inflammation has major role to play to mimic the similar pathophysiology as that of humans. With varying dose, zymosan has been used to develop various preclinical disease models. The disease models include rheumatoid arthritis induced in wistar rats by injecting in rear knee joint at a dose of 1mg suspended in 50μL of sterile normal saline [29], multiple organ failure by administering intraperitoneally (i.p.) to rats at a dose of 500mg/kg [30] and acute peritonitis by i.p. injection to Balb/C Mice at a dose of 0.5mL from a zymosan stock solution of 2mg/mL [35].

Till date, there has been only one study published over the use of zymosanto induce reversible IR in preclinical setting. Mice were injected with zymosan viai p. Route at a dose of 100mg/kg once a week for four consecutive weeks. Inflammation driven ROS production is the mechanism involved in zymosan induced IR. Zymosan causes inflammation through activation of macrophages via stimulation of TLR-2 and TLR-6, Activation of PMN cells to escalate the intracellular ROS production. In this model of IR, zymosan injection has also been held responsible for the reduced expression of various protein markers involved in insulin signaling like IRS-1, PI3-Kinase, phosphorylated GSK-3 and Akt [31].The main aim of this review is to highlight the importance of need of accelerated new animal model to study insulin resistance and associated secondary complications of IR.

    Discussion

Feeding laboratory animals adlibitum with high calorific diets take a minimum time of 12 weeks to reach the IR state whereas a study carried out by Wang et al. [31] suggest that zymosan could successfully induce IR within just 1/3 of the time that is taken by high calorific diet to create the same situation. The only limitation of this model is that the IR is reversible and animals have returned to their normal state within 4 weeks after withdrawal of zymosan administration. Meanwhile, we hypothesize that the combinatorial use of high calorific diet and zymosan can cut short the time duration to induce IR. The use of zymosan with high calorific diet will be rational, as both of these disease inducing agents act through the analogous inflammatory pathways. Zymosan and high calorific diet acts on toll like receptors (TLRs) present on cell membrane to initiate the release of inflammatory cytokines which in turn leads to the activation of NF-k Band JAK-STAT pathways that desensitize insulin receptors towards insulin and leads to surge in unutilized levels of insulin in systemic circulation, can also be termed as insulin resistance [28,36-38].\

    Conclusions & Prospective

A. Insulin resistance is considered as a major mediating and facilitating factor for the development of secondary metabolic complications associated with consumption of high calorific or cafeteria or junk food. With an aim of developing a new, less time consuming and clinically relevant animal model to study and understand the pathology of various metabolic complications in which IR plays a vital role.

B. Inflammation is the common mechanism through which the high calorific diets and zymosan induce IR and their combined use shall exert a synergistic effect towards rapid onset of insulin resistant state than traditional models. This hypothesis can be adapted and utilized by the researchers working in the fields of IR, obesity, T2DM, metabolic syndrome and cognitive dysfunction associated with metabolic complications.

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Authored by Leila Ben Amor

Abstract

Objective: To describe clinical factors associated with SGA-induced weight gain induced by long-term second generation antipsychotic (SGA) treatment in children and adolescents.

Methods: A 24-month retrospective study conducted between November 2005 and June 2013. 147 antipsychotic-naive patients were selected [mean age 12.8; (95% CI 9.8 to 15.9)] and treated with an SGA (risperidone, olanzapine, quetiapine and aripiprazole) for up to 24 months. Weight and height were measured and BMI (body mass index) z-scores were calculated at baseline, 1, 3, 6, 12 and 24 months. Linear mixed-model analysis was used to compare weight, BMI and BMI z-score changes of the SGA treatment with the repeated factor being the time relative to baseline at 1, 3, 6, 12 and 24 months.

Results: After 24 months of SGA treatment, mean weight increased significantly by 12.8 kg (95% CI 10.4 to 15.0) and BMI z-score by 0.44 (95% CI 0.21 to 0.68). Incidence of overweight/obesity was 22.6% and significant BMI z-score increase over 0.5 was 9.4%. Older age (p=0.001), male sex (p=0.002) and diagnosis of mood disorder (p=0.0004) were associated with a significant increase in weight gain. Lower baseline BMI z-score (p<0.0001) and presence of mood disorder (p=0.011) had a significant impact on BMI z-score augmentation.

Conclusion: Older age, male sex, lower baseline BMI z-score and diagnosis of mood disorder were associated to more pronounce SGA- induced weight gain.

Keywords: Second generation antipsychotics; Weight gain; Children; Adolescents

    Introduction

Second generation antipsychotics (SGAs), which are medications used to treat a variety of psychiatric disorders, are associated with weight gain, obesity, and increased cardiovascular risk in children, adolescents as well as in adult populations [1-3]. A source of concern is increasing evidence suggesting a greater or exigenic effect of SGAs in youth compared to adults [3-8], especially considering childhood obesity adversely affects nearly every organ system, causing substantial morbidity and mortality in adulthood [9].

Multiple factors have been associated with SGA-induced cardio-metabolic side effects, such as SGA type, dose, treatment duration, previous exposure or SGA polypharmacy, subject's age, sex or illness-related factors , but there is little consensus over their respective effects [2,3,5,6,10,11]. Among SGAs, olanzapine and clozapine are associated with the most important weight gain risk, followed by quetiapine and risperidone, and finally by aripiprazole and ziprasidone which have the lowest risk [3,12]. The findings of some, but not all, studies suggest that women have a greater vulnerability to antipsychotic-induced weight gain that men [2,3]. Evidence in the antipsychotic-drug- naive pediatric population suggest a dose-dependent effect of risperidone on weight gain and lipid profiles as well as dose dependent effect of olanzapine on serum lipids and blood glucose levels [13]. The impact of the treatment duration on the weight gain remains a subject of debate as some studies showed an attenuation of the weight gain over time with a plateau around 6 or 12 months [1,14-18], whereas others demonstrated a continuous weight increase over time [19-21]. Anyhow, data on the long term metabolic effects of antipsychotics in pediatric populations are scarce [3]. The heterogeneous results regarding moderating variables could be explained in part by the different methodologies and study samples found across studies.

The aim of this study is to describe clinical factors associated with the SGA-induced weight and increase in BMI z-score in antipsychotic-naive children and adolescents, in the "real- life" clinical setting. We hypothesize that older age, female sex, lower baseline BMI z-score and polypharmacy other than with psychostimulants will be associated with more important weight gain, in accordance with actual literature [2,3,6,7].

    Subjects and Methods

Study design

The medical charts of the inpatients and outpatients from the "Second-Generation Antipsychotic Monitoring Program" at Hotel-Dieu de Levis Hospital (Quebec, Canada) between November 2005 and June 2013 were retrospectively reviewed. The population in the area deserved by the department of child psychiatry is almost exclusively of French-Canadian origin. All study procedures were reviewed and approved by the local ethics and research committee (CER-1213-018).

Study subjects

The inclusion criteria for the study subjects were being under 18 years old, having no previous history of antipsychotic treatment and having received treatment with an SGA for at least one month during the study. The exclusion criteria included preexisting dyslipidemia, diabetes or receiving medications for metabolic conditions. For each patient, we gathered information for age, sex, psychiatric diagnoses, SGA treatment (total dose/ day, duration of use), other medications (total dose/day, duration of use), height and weight. The height and weight were measured at baseline, 1, 3, 6, 12 and 24 months by a nurse. Diagnoses were made by a child psychiatrist in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) criteria. Clinical data was collected from the chart notes. The main diagnosis was considered the one for which the SGA was prescribed. In many cases, more than one main diagnosis was recorded because SGAs were used to treat symptoms common to many diagnostics, such as disruptive behavior and ADHD. The other medications given in adjunct with the SGA were grouped in four categories: psychostimulants (amphetamine-based, methylphenidate-based), atomoxetine (to more accurately discriminate the potential metabolic impact with psychostimulants), antidepressants (bupropion, citalopram, fluvoxamine, sertraline, venlafaxine) and mood stabilizers (carbamazepine, lithium, valproic acid).

Treatment

The patients received SGAs (olanzapine, risperidone, quetiapine or aripiprazole) in monotherapy (the same SGA was prescribed from the beginning to the end of the period of the follow-up) or in polytherapy (switched from one SGA to another or used a combination of two SGAs, with the second SGA added between 0.5 and 24 months).

Measures

The variables studied were weight, BMI-calculated as weight (kg)/height squared(m2)-and standardized BMI z-score- calculated using the children's BMI percentile-for-age calculator from the Children's Nutrition Research Center, Baylor College of medicine website (http://www.bcm.edu/cnrc--- apps/ bodycomp/bmiz2.html). The exact day of weight measurement was not always available in the charts; therefore, we calculated the BMI z-scores as if the patients were always weighed on the first day of the month to minimize the measurement bias. The BMI z-score represents the BMI adjusted for age and sex, thus considering the weight gain attributable to the growth process. It allows the comparison between the BMI of children and adolescents of the same age and sex [22]. Overweight was defined as BMI z-scores between the 85th and 95th percentile and obesity as BMI z-scores greater than or equal to the 95th percentile [23]. The doses of each SGA were converted in chlorpromazine equivalents [24].

    Statistical Analysis

The statistical analysis included all the patients with data available at baseline and at least at one follow-up assessment time. The characteristics of the sample are presented as means (95% CI) for the continuous variables and as frequencies or percentages for the categorical variables. We assessed changes secondary to SGA treatment in continuous outcomes using the linear mixed model with repeated measures. The repeated factor was the time relative to baseline at 1, 3, 6, 12 and 24 months. Since the measures were collected from retrospective chart review, they reflect ‘real-life’ clinical situations not always strictly respecting follow-up time intervals. We averaged data for plus or minus one month interval (for example, the third month corresponds to data from the second to the fourth months).

Incidence was calculated as the proportion of new-onset metabolic complications at each time point divided by the number of patients with available data. For each outcome, we adjusted for age and sex plus other medications associated with SGA or primary psychiatric diagnosis, thus yielding two different analyses. Summary statistics are presented as adjusted means of change over time (95% CI). All analyses were made using SAS 9.3 (SAS Institute Inc., North Carolina, USA). The threshold for statistical significance was set at p<0.05.

    Results

Figure 1 A total of 147 patients treated for the first time with an SGA between November 2005 and June 2013 were included in the study. One hundred sixteen (78.9%) of them received an SGA in monotherapy and 31 (21.1%) received an SGA polytherapy (20 subjects switched SGAs and 11 received a combination of two SGAs). Subjects were almost exclusively French Canadian. The category 'Other' primary psychiatric diagnosis included personality disorder, mental retardation, pervasive developmental disorder and obsessive-compulsive disorder.

Further data presented originates from the analysis controlling for age, sex and co-medications Table 1. The other analysis (controlling for age, sex and primary diagnosis) yielded similar results. After 24 months of SGA treatment, mean weight increased significantly by 12.8 kg (95% CI 10.4-15.0, p< 0.0001) and BMI z-score increased by 0.44 (95% CI 0.21-0.68, p= 0.0002).

Incidence of newly developed conditions is considerable as 22.6% of subjects became overweight or obese and 42.9% had a significant BMI z-score increase over 0.5 after two years of treatment. Table 2 Compared to younger age, older age was associated with a superior mean gain weight of 0.38 kg (p=0.001). Males gained a mean of 1.89 kg more than females (p=0.002) and subjects with a mood disorder, a mean 2.49 kg extra compared to the absence of mood disorder (p=0.0004). A lower baseline BMI z-score (p<0.0001) and the presence of mood disorder (p=0.011) had a significant impact on BMI z-score augmentation.

    Discussion

In this retrospective study, older patients, males, those with a lower baseline BMI z-score and subjects with a primary diagnosis of mood disorder had a significantly more pronounced weight gain and BMI z-score increase after up to 24 months of SGA therapy. Clinical characteristics as older age and lower baseline BMI z-score have already been associated with an increased SGA-induced weight gain in children and adolescents [10,25]. In adults, even if low baseline BMI has frequently been associated with greater antipsychotic-induced weight gain, controversy still exist over this potential influence as this might be due-at least partially-to a regression to the mean effect and not to an underlying biological factor [2,26].

Counter to our hypothesis, female sex [10] and concomitant use of mood stabilizers [7] were not associated with a more important weight gain. An unexpected finding was male sex being significantly associated with more weight gain that female sex. In agreement with our study (in which most subjects were treated with risperidone), Saklad et al. [27] found that male sex was associated with a more pronounced weight gain in youth treated with risperidone [27]. Another study analyzing metabolic changes in youth treated with risperidone showed no association between sex, age or baseline BMI and the SGA- induced weight gain [28], although this might be due to their small sample size (37 subjects compared to 147 in our study). Our subjects treated for mood disorder with SGAs had a significantly more pronounced weight gain and BMI z-score increase. We found only one short-term study comparing SGA-induced weight gain between bipolar, psychotic and non-psychotic disorders in children and adolescents, which failed to demonstrate an association between mood disorders and weight gain [29]. In our study, the association of mood disorders with a more important weight gain could be explained -at least partially- by the metabolic risk conferred by a more severe pathology, as individuals with psychosis and bipolar disorder appear to have higher baseline metabolic risk than the general population [30].

Although mood stabilizers such as lithium and valproate have been associated with mild weight gain [7,31], we did not find an association between the concomitant use of mood stabilizers with SGAs and more important weight or BMI z-score increase. Only a tendency was found, possibly due to our study's relatively small sample size.

    Limitations

The results of this study should be interpreted in consideration of its limitations. Due to the naturalistic design, the metabolic monitoring at 12 and 24 months was relatively low, which limited data available for the analyses and influenced the statistical power of our results. Also, all four SGAs (risperidone, olanzapine, quetiapine, aripiprazole) were regrouped thus preventing us from evaluating their respective effects-however not enough subjects were available to analyze each molecule separately. Additionally, 'a confounding by indication’ bias should be considered when interpreting the results, as physicians might have prescribed a specific SGA depending on the baseline weight of the patient [6]. Moreover, given the variability of SGA doses in the clinical sample, we were unable to adjust the statistical analyses for the SGA chlorpromazine-equivalent dose. Finally, the homogeneity of the population sample analyzed in our study can limit the generalizability of the results.

    Strengths

Aside from being a limitation, the genetic homogeneity of our sample confers an asset, as with the subjects being almost exclusively French Canadian the differences attributable to ethnic genetic diversity are limited. Also, our recruitment was restricted to an antipsychotic-naive population, leading to more accurate conclusions about the first exposure to SGAs. Finally, this is one of the few long-term studies of metabolic complications in children and adolescents informing on weight gain and clinical factors associated with SGA use in drug-naive populations.

    Conclusion

In summary, we described that older age, lower baseline BMI z-score, male sex and primary diagnosis of mood disorder were associated with more pronounced SGA-induced weight gain, on one hand consolidating previous findings, and on the other eliciting more possible factors implicated in the vulnerability to SGA-induced weight gain: male sex and mood disorder. This information is valuable as it provides insight for physicians about clinical characteristics of patients having increased vulnerability of weight gain when treated with an SGA.

Clinicians should carefully monitor metabolic side effects as they were related not only to physical health complications but also to mental health problems, psychosocial dysfunction and poor treatment adherence [2,32]. Long-term prospective studies with larger sample sizes and control groups are needed to investigate the predictive factors of metabolic complications induced by SGAs.

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Authored by Ricardo Alexandre Fernandes Ferro

Abstract

Background: Erectile dysfunction (ED) is a mistreated and neglected complication that affects 35%-75% of males with type 2 diabetes (T2DM) leading to worsening quality of life and interpersonal relations. Males with T2DM develop ED 5-10 years earlier than non-diabetics.

Methods: This was a prospective, longitudinal and observational study including 50 consecutive male patients with T2DM and a body mass index (BMI) <35Kg/m2 who underwent laparoscopic ileal interposition associated to sleeve gastrectomy (II-SG).

Objectives: Observe the ED prevalence before and after 12 months of II-SG evaluated by a questionnaire. Evaluate global sexual function 12 months after the procedure and compare with initial parameters. Analyze if diabetes duration was an interfering factor in sexual function improvement 12 months after the surgery.

Results: Mean age was 54.4 years (37-69). Mean diabetes duration was 12, 1 years (05-23 years). Mean HbAlc was 8, 8 % (7, 5-10, 5%). After 12 months, we observed a significant improvement in glycemic control, dyslipidemia, blood pressure and a reduction in the use of insulin and anti-diabetic agents (p<0.05). Erectile dysfunction, sexual intercourse satisfaction, orgasmic function, sexual desire and overall sexual life satisfaction were improved (p<0.05). ED prevalence was 78% before and 46% after the procedure. More than 15 years of diagnosis was a bad predictor for ED improvement.

Conclusion: Ileal Interposition associated to sleeve gastrectomy, significantly improved erectile function, satisfaction with sexual intercourse, orgasmic function, sexual desire and sexual life of patients with type 2 diabetes 1 year after the surgery.

Keywords:  Erectile and sexual dysfunction; Type 2 diabetes; Ileal interposition

Abbreviations:  ED: Erectile Dysfunction; T2DM: Type 2 Diabetes; BMI: Body Mass Index; II-SG: Ileal Interposition Associated to Sleeve Gastrectomy; HbA1c: Glycated Hemoglobin; ADA: American Diabetes Association; IIEF: International Index of Erectile Function Questionnaire; IBM: International Business Machines; SPSS: Statistical Package for Social Sciences

    Introduction

Diabetes mellitus type 2 (T2DM) is a chronic metabolic disorder with a dramatically increasing prevalence. T2DM stems from a progressive insulin secretory defect on the background of insulin resistance. Prolonged insufficient metabolic control with constantly elevated HbA1c levels inevitably leads to complications, most commonly to diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and macrovascular problems [1].

Modern anti-glycemic agents and life style modifications can lead to metabolic control, but a long-lasting effect still needs to be proven. Erectile dysfunction is a chronic complication presented in a wide range (35-75%) in T2DM male patients, usually 5-10 years earlier than non-diabetic males [2]. Relaxation of the smooth muscles of the venous (cavernous) sinusoids is the final erection mechanism and having sinusoids endothelium integrity is vital for the process. On the other hand, endothelium injury is present in the vast majority organic causes of ED [3]. Obesity, dyslipidemia and diabetes are independent risk factors for cardiovascular disease and also constitute major risk factors for ED, where sinusoids endothelium injury is an indicative of developing atherosclerosis [4]. In the very obese patient with type 2 diabetes, bariatric surgery appears to be a treatment modality that is both highly effective and increasingly attractive [5]. On the other hand, in the most frequent kind of type 2 diabetes, i.e., the hyperglycaemia surfacing after the fourth decade of life in moderately obese subjects, is a progressive disease, and resolution, whether spontaneous or by treatment, is rare. This discrepancy in outcome is irrefutable and unaccounted for [6].

One potential explanation is that the hyperglycaemia of morbid obesity has a different pathogenesis from the hyperglycaemia of the moderately obese or lean diabetic. Another possibility is that bariatric surgery per se interferes with glucose metabolism in ways that none of the other antidiabetic treatments does. The available evidence, if limited and non- homogeneous, suggests that at least some of the antidiabetic effect of bariatric surgery may be independent of the induced weight loss [7].

De Paula et al. had shown that in type 2 diabetic patients with a BMI below 35 kg/m2, ileal interposition associated to sleeve gastrectomy (II-SG) is an effective, safe and long-lasting procedure reaching normal levels of blood glucose, HbAlc, lipid profile and blood pressure in 86% of patients without any anti-diabetic agents [8,9]. In this prospective, longitudinal and observational study we observed the ED prevalence before and after 12 months of II-SG evaluated by a questionnaire, evaluate global sexual function 12 months after the procedure and compare with initial parameters and analyze if diabetes duration was an interfering factor in sexual function improvement 12 months after the surgery.

    Methods

This was a prospective, longitudinal and observational study with a mean follow up of 12 months designed to evaluate ED in T2DM patients.

Study population

The study included 50 consecutive male patients with type 2 diabetes (diagnosed according to the revised ADA criteria) and a body mass index (BMI) <35kg/m2, who underwent laparoscopic ileal interposition associated to sleeve gastrectomy (II-SG). Mean age was 54.4 years (37-69). Smoking was present in 12% of the patients. Mean diabetes duration was 12, 1 years (05-25 years). Patients were invited to participate the study and respond a questionnaire in the pre- and postoperative period. All subjects gave written informed consent to the study, and the protocol was approved by the ethics committee of the hospital and referenced by the consolidated note from Plataforma Brasil/Ministério da Saúde.

Surgical procedure

The surgical procedure was performed by laparoscopy. II- SG started with division of the jejunum 20cm bellow the Treitz ligament using a linear stapler. An ileal segment of 200cm was removed 30cm proximally to the ileocecal valve, and interposed peristaltically up into the jejunum. The anastomoses were performed functionally side by side. The intestinal measurements were performed with traction along the antimesenteric border using a 10cm atraumatic gasper. The sleeve gastrectomy was performed after devascularization of the greater curvature using the ultrasonic scalpel. A 36-French Fouchet orogastric calibration tube was placed along the lesser curvature toward the pylorus. The gastric resection was performed starting at the antrum and continuing up to the angle of His using a linear stapler; the staple line was covered by an invaginating suture [10].

Inclusion criteria : All subjects had had type 2 diabetes for at least 3 years but none had had major upper abdominal surgery; active sexual life in the last four weeks preceding the procedure; hbA1c above 7% in the last three months; documentation of HbA1c exceeding 7.5% for at least 3 months; stable weight, defined as no significant change (>3%) over the 3 months before enrollment; evidence of stable treatment with oral hypoglycemic therapy or insulin for at least 12 months; BMI less than 35 kg/ m2.

Exclusion criteria : Elderly patients (>70years); Type 1 diabetes (Positive anti GAD and anti-IA-2 auto-antibodies); previous major upper abdominal surgery; pregnancy; malignant or debilitating diseases; severe pulmonary or cardiac diseases, severe renal disease (glomerular filtration rate <30ml/min); use of appetite suppressant medication, eating disorder such as bulimia or binge eating; obesity due to any other endocrine disorder; users of penile prosthesis; use of PDE5 inhibitor medication or any other kind of ED treatment in the last 4 weeks before the procedure; hormonal replacement therapy with testosterone or any other medication that interferes in the steroid hormone laboratory dosage in the last three months before the surgery.

Questionnaire: A standardized questionnaire was applied in 56 T2DM patients in the preoperative period and in 50 after 12 months of follow-up. In 6 patients, we were unable to apply the questionnaire in the appropriate period. This was a discreet procedure conducted by the same investigator in the day before the surgery and after 12 months when a clinical and laboratory evaluation were performed. The International Index of Erectile Function Questionnaire (IIEF) was used to classify the sexual dysfunction level [11].

    Statistical Analysis

All analyses were performed using the International Business Machines (IBM) Statistical Package for Social Sciences (SPSS) Advanced Statistics version 17.084. Some results were analyzed based on their frequency distribution. The chi-square test (x2) with Yates correction in contingency tables was used to analyze associations between two variables. When the sample size was too small, resulting in expected values lower than five in one or more blanks, we applied the Fisher's exact test. P values are two-sided and p<0.05 was accepted as statistically significant. Analysis of variance was used to compare means and the Kruskal-Wallis test for comparison of medians.

To analyze the effects of the surgical procedure were employed variables change before and after the procedure, using the McNemar test. For running the test, two conditions must be satisfied: the measurement scale needs to be nominal and with two measures. Another condition to be satisfied is data independence and parity, in other words, data must belong to the same individual, in this study represented by the patient before and after surgery, each patient being independent of each other, so the conditions for the test were met.

To analyze the IIEF variables preoperatively and 12 months later the nonparametric Wilcoxon test was used. In order to reach a significance of 95%, the minimum number of patients enrolled were 21. This means that the number collected from 56 patients before and 50 patients later caters perfectly for scientific and statistical analysis. To quantify the reliability degree between some preoperative and postoperative assessments Kappa coefficient was employed. Kappa values vary depending on the degree of concordance.

Kappa values Degree of concordance

0-0, 20 Weak

0, 21-0, 40 Considerable

0, 41-0, 60 Moderate

0, 61-0, 80 Substantial

0, 81-1, 00 Almost complete

    Results

In this prospective, longitudinal observational study, 50 male with T2DM were evaluated pre and 12 month post Ileal interposition associated with sleeve gastrectomy, showing significant improvement in Erection hardness grading scale (EHGS) and International Index of Erectile Function (IIEF). Before the procedure all patients used antidiabetic oral drugs and/or insulin. However, after 12 months, it was restricted to only 10% of them. The same reduction was observed in relation to the use of antihypertensive drugs (p<0.05). All procedures were performed laparoscopically, and there was no mortality. Preoperatively, dyslipidemia was diagnosed in 91.6% of the patients. Arterial hypertension was observed in 75%, nephropathy in 33.3%, retinopathy in 20.8%, neuropathy in 33.3% and coronary artery disease in 33.3% of the patients.

There was a significant decrease (p<0.05) in serum total cholesterol, LDL- cholesterol, triglycerides, fasting glucose, postprandial glucose, hemoglobin A1c, insulin, HOMA-IR and microalbuminuria. The variables creatinine clearance and serum HDL- cholesterol showed significant increase (p <0.05).

Evaluation of erectile function before and 12 months after surgery

Erection hardness grading scale (EHGS) provides evaluation of penile rigidity using a four-grade scale, where score of 1 indicates that the penis is larger than normal, but not hard; 2 means the penis is hard, but not hard enough for penetration, 3 means the penis is hard enough for penetration but not completely hard, and 4 indicates that the penis is completely hard and fully rigid. Before surgery, 22% of patients were able to make vaginal penetration (EHGS 3-4). After 12 months of operation, this number increase to 54% (p<0,05). Before the operation, 34% of patients were scale-graded as 1 and after the intervention this rate decreased to 14% (p <0,05). After 12 months of operation, the number of patients scale-graded 3 doubled and tripled in grade 4. In both cases the differences were significant (p<0.05). Such observations can be translated by the IIEF.

Evaluating the data of the International Index of Erectile Function Questionnaire obtained in the study, it was concluded that there was an improvement in erectile function score given by the erection, when comparing the results observed in the pre-and postoperative II-SG. This difference was significant (p <0.05). The same was found regarding satisfaction with sexual intercourse, the orgasmic function, sexual desire and overall sexual experience.

Assessment of satisfaction with sexual intercourse before and 12 months after surgery

24% of patients had satisfactory level before the operation, with scores less than 10. This rate increased to 62% in the evaluation performed 12 months after surgery (p<0.01).

Evaluation of orgasmic function before and 12 months after surgery

The orgasmic function before and after surgery showed significant improvement (p<0.05), with 50% of patients reporting maximum score postoperatively, while only 6% reached initially.

Evaluation of sexual desire before and 12 months after surgery

While only 26% of patients had satisfactory sexual desire (score less than seven) before the intervention, 96% of them reached these levels in the analysis 12 months after the procedure (p<0 .001).

Assessment of overall satisfaction with the sexual act of the couple before and 12 months after surgery

Regarding overall satisfaction with sexual intercourse the couple, initially 32% of patients had adequate index of satisfaction (score equal to or above seven). After 12 months, 62% of them reached adequate levels of satisfaction (p<0.05).

Evaluation of the total international index of erectile function score before and 12 months after surgery

The IIEF score can range from 5 to 75 points. We observed a significant improvement. Before the operation, 32% of patients scored 30 points. In the second evaluation, the figure was 6% (p<0.01). On the other hand, 40% of patients had a score equal to or greater than 40 in the preoperative evaluation and this index increased to 74% after 12 months of operation (p<0.05).

Correlation of chronological parameters and laboratory with the spheres of sexual function before and 12 months after surgery

Correlating diabetes duration with improved sexual function 12 months after surgery shows that patients who did not had significant improvement in the IIEF and EHGS parameters were those who had more time to diagnosis (more than 180 months). These bad-responder group includes 10% of the patients who maintained the use of antidiabetic medication 12 months after surgery. Among the 25 patients with scores below 10 in the requirement satisfaction with sexual intercourse after 12 months of II-SG were all those more than 15 years of diabetes diagnosis. The same can be said for orgasmic function, sexual desire and overall satisfaction with sexual intercourse.

    Discussion

In this report of 12 months follow-up of 50 consecutive type 2 diabetic patients with BMI<35 submitted to laparoscopic ileal interposition associated with a sleeve gastrectomy, we showed that 89.9% had HbA1c below 7% without antidiabetic medication. Using IIEF we evaluated the five main spheres of human sexual function, namely, erectile function, satisfaction with sexual intercourse, orgasmic function, sexual desire and overall satisfaction with sexual function. IIEF has been used widely and universally by medical literature and it becomes possible to compare the results of this study with other published or which may be realized [12].

In this study, the prevalence of ED in T2DM was 78% applying the IIEF. According to Ferrini & cols, it is estimated that by the time a man is in his 40's, he has about a 40% chance of having some form of ED and this prevalence increases about 10% per decade thereafter [13]. There was no significant reduction in BMI before and after the surgical procedure, which reinforces the thesis that the weight loss is not the main mechanism in metabolic improvement observed in T2DM patients undergoing procedures such as ileal interposition [14]. The metabolic results found in this study are in agreement with other previously published papers using the same technique- Ileal Interposition associated with Sleeve Gastrectomy [15,16]. Before surgery, all patients used oral antidiabetic drugs and/or exogenous insulin, and even then, all had HbA1c above 7%. So, they were outside the therapeutic goal (HbA1c<7%) established by recognized international organizations. Twelve months after surgery, 90% of patients had HbA1c below 7% without the use of any antidiabetic medication. Midterm results of this procedure shown similar results and we hypothesized that sustained weight loss associated with better insulin sensitivity and continuous after-meal GLP-1 secretion may be the reason [17].

T2DM patients normally have decreased HDL-cholesterol, elevated triglycerides and LDL-cholesterol. After 12 months of surgery we observed normalization of HDL-cholesterol, LDL-cholesterol and triglycerides, with a significant difference compared to preoperative period. The obtained control of dyslipidemia in patients of the current study may have contributed to the improvement in sexual function [18]. It reinforces the data of several authors demonstrating that lipemic control is extremely important for endothelial dysfunction improvement, including erectile dysfunction. Dyslipidemia leads to a decreased production of nitric oxide (NO) and/or decreased NO dependent muscle relaxation. This may explain why even young dyslipidemic individuals have a higher prevalence of ED [19].

In this study, we were able to show 78% of patients with inability to vaginal penetration (EHGS 1 and 2) before surgery. After 12 months, 46% of patients still EHGS 1 and 2. Analyzing EHGS and IIEF compiled data we observed a significant difference between the findings pre- and postoperatively (p<0.05) in all spheres of sexuality analyzed by the test, i.e., erectile function, satisfaction with sexual intercourse, orgasmic function, sexual desire and overall satisfaction with sex life. Patients with uncontrolled DM present with lower rates of NO intracavernous synthesis. It is possible that the metabolic control obtained by II-SG may have improved NO synthesis and thereby favored erectile function. One of the weaknesses of this study is that we were unable to access this data. The number of patients and time of follow-up also account for [20].

Even though there has been no significant reduction in BMI, the observed weight loss, especially abdominal/visceral fat, may have contributed to the improvement in sexual function. Visceral fat can convert testosterone hormone (predominantly male) in estradiol hormone (predominantly female) and the first is essential for all sexual spheres. It is known that plasma concentration of testosterone is inversely proportional to BMI and DM2 patients may show a reduction in free testosterone [21]. Patients who did not show significant improvement in some spheres were precisely those who had diabetes duration over 15 years. These patients probably had micro and macrovascular irreversible injuries. Thus, even with the improvement of virtually all metabolic parameters following II-SG, these patients did not achieve the degree of improvement in all sexual spheres experienced by those with shorter disease.

Normal sexual function requires complex interaction between vascular, neurologic, hormonal and psychological systems [22]. It is possible that, in addition to metabolic control provided by the surgical procedure, other factors may contribute to the improvement in the sexual life of these patients. After II-SG most of them do not require everyday measurements of blood glucose, antidiabetic, antihypertensive and lipid lowering medications. This improves quality of life, triggers more willingness to work capacity, to sexual activity and physical activity.

    Conclusion

The incidence of erectile dysfunction in patients with type 2 diabetes mellitus was 78% before surgery and 46% after 12 months. After 12 months postoperatively, significant improvement in erectile function, satisfaction with sexual intercourse, orgasmic function, sexual desire and sexual life of patients were seen.

Patients with diabetes duration over 15 years had lower responses in controlling diabetes mellitus and sexual dysfunction.

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Authored by:  Xiaoqi Xie*

Introduction

Gliomas which originated from glial cells and made up 80% of all primary CNS tumors in the United States were classified as “low grade” (WHO grades I and II) and “high grade” (WHO grades III and IV) according to histopathologic changes [1,2]. High-grade gliomas (HGGs) are related with poor prognosis and consist of anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma; WHO grade III) and glioblastomas (GBMs; WHO grade IV). The current standard therapy for newly diagnosed GBMs involves maximal safe resection followed by radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) [3-5]. Despite optimal therapy, the median time-to-tumor progression (mTTP) for patients with newly diagnosed GBMs is approximately 6.9 months and these tumors unavoidably relapse with a median overall survival (mOS) of only 15 months [3]. However, the treatment of anaplastic gliomas is abroad controversial topics in neuro-oncology. By above therapy, anaplastic gliomas achieves a mTTP of about 1.2 to 2.6 years and a mOS of 2 to 7 years [4,6,7].

Compared with anaplastic oligodendroglioma, treatment of the anaplastic astrocytoma has been less optimistic. This tumor is more resistant to therapy and patients have a shorter mOS of only 2 to 3 years. In the United States, most oncologists treat anaplastic astrocytoma patients with maximal safe resection followed by field radiotherapy with concurrent and adjuvant chemotherapy (temozolomide), same to the regimen now deemed as the standard of care for GBMs [3]. Moreover, all HGGs nearly recur and survival following disease progression is doomed to be approximately 6 months for GBMs and 10 months for anaplastic gliomas [8,9]. Treatment options for recurrent HGGs include re-resection, chemotherapy, or re-irradiation. But, the optimal treatment strategies for recurrent HGGs are still unknown and the randomized control trials which contrast active intervention and determine standard therapy are absent. We herein report the case of a recurrent anaplastic astrocytoma patient with the long-term progression free survival (PFS) after the combination of radiation therapy with concurrent chemotherapy of nimotuzumab and temozolomide followed adjuvant temozolomide.

Case Report

We present the unique case of a 33-year-old gentleman who initially presented with a several days history of headaches behind the right brain, with associated “vomiting”. There were no complaints of numbness, weakness, or any visual changes. Physical examination of the patient revealed that he had a depressed superficial reflex in the right limbs and positive pyramidal tract signs. A MRI scan at that time revealed a large, irregularly enhancing mass in the right frontal lobe that was associated with marked edema, bleeding and mass effect. These symptoms relieved with the treatment of dehydration to reduce intracranial pressure. Following the consultation with a neurosurgeon and discussing the probability of a brain tumor and therapeutic regimen, the patient experienced a right frontal lobe Lobectomy in local hospital in October 2008. The final pathology was anaplastic astrocytoma (WHO grade III).

The patient recovered well from surgery, and his headaches were resolved. Adjuvant treatment options were explained to him and included radiotherapy plus concomitant and adjuvant Temozolomide. But the patient refused further therapy. In April 2009, a follow-up CT scan revealed local recurrence in the operative bed (Figures 1-3). And the patient was treated in West China Hospital. The pathology department in West China Hospital held a pathological consultation with tumor section in local hospital and diagnosed anaplastic astrocytoma (WHO grade III) containing a few of oligodendroglioma ingredients with histopathologic changes of partial necrosis, mitotic activity and endothelial cell proliferation (Figure 4). KRAS mutation was detected in codon 12 and codon 13 and the DNA repair enzyme O6-methylguanine- DNA methyltransferase (MGMT) promoter methylation was positive. Chromosomal 1p and 19q co-deletion was detected by FISH (Figures 5&6). Isocitrate dehydrogenase 1 mutation (codon 132) was detected by PCR and Sanger sequencing and Isocitrate dehydrogenase 2 (codon 172) was wild type (Figures 7&8).

Starting on May 22, 2009, the patient underwent whole brain radiotherapy to a dose of 4000 cGy and local lesion radiotherapy to a dose of 6000 cGy (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks) with concurrent combined chemotherapy of intravenous nimotuzumab (100 mg every 1 weeks) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks followed by six cycles of adjuvant temozolomide (150 mg per square meter for 5 days during each 28-day cycle). Treatment was generally well tolerated, and the adverse events were nausea, vomiting and hematologic toxicities, which all of them were classified as mild. Following his radiotherapy and chemotherapy, he was followed clinically as well as with surveillance MRI scans at regular intervals. The follow-up MRI scan in 3 months after radiotherapy were as follows (Figure 2). The latest MRI scan revealed no recurrence in May 31, 2016 (Figure 3). Until now, the patient is still alive with a long-term progression free survival lasting seven years. And the survival following the initial diagnosis is up to eight years.

Discussion

A high rate of local recurrences has been observed after multi-disciplinary therapy in high-grade gliomas (HGGs) patients.10 Important variables predicting longer survival include oligodendroglial cell line, extent of resection, and younger age (<50 years) [11]. Moreover, gliomas with the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, chromosomal 1p and 19q co-deletion or isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations is associated with a better prognosis [12-15]. In this patient, the chromosomal 1p and 19q co-deletion was detected by FISH; and the MGMT promoter methylation was positive and Isocitrate dehydrogenase 1 was mutation type, which was one of the reason of long-term progression free survival (PFS). PFS is associated with overall survival (OS) and has become a marker for evaluating the efficacy of treatments in recurrent HGGs patients. The 6-month PFS (PFS6) for recurrent GBM ranges from 9 to 21% [8,9,16], while PFS6 for anaplastic gliomas have ranged from 37 to 48% [17,18]. In our report, the patient still does not progress with a long-term PFS lasting seven years. Although the prognosis of recurrence HGGs patients is invariably poor, it is vital just as this case to improve the quality of life and prolong survival by multimodal therapy.

Therapy options for recurrent HGGs are limited and may include surgery, re-irradiation, chemotherapy and targeted therapies. For recurrent HGGs patients which were subjected to clinical deterioration on account of mass effect, surgery might be one of option. But, until now, no prospective researches demonstrate that re-surgery can improve the survival for recurrent HGGs patients. Moreover, due to the application of targeted therapies, a fewer proportion of recurrent HGGs patients are going through diagnostic or therapeutic re-surgery.

For HGGs patients, primary therapy most involves adjuvant radiotherapy with the maximum tolerated dose. The dose limitation of healthy brain tissue and the short duration between initial radiation therapy and recurrence confined the use of reirradiation therapy for recurrent HGGs with conventional external beam radiotherapy, which may have an influence on patient’s quality of life. However, Romanelli et al’ s research that evaluated the efficacy of stereotactic radiosurgery (SRS) in recurrent glioma have indicated median OS from 7.5 to 30 months after treatment [19]. And in Mahajan’s research [20], recurrent GBM patients treated with SRS achieved a longer median OS compared with untreated patients [20]. Hypofractionated stereotactic irradiation might be another choice for recurrent glioma. According to Fogh, et al. [21] research, the median OS after re-irradiation with a hypofractionated protocol (3.5 Gy per fraction up to a median dose of 35 Gy) over a 2-week period was 11 months. In this case, because patient did not receive any further treatment after surgery, conventional external beam radiotherapy (whole brain radiotherapy to a dose of 4000 cGy and local lesion radiotherapy to a dose of 6000 cGy) plus concomitant and adjuvant Temozolomide were recommended to him and the progression free survival after irradiation was seven years.

The efficacy of chemotherapy in recurrent HGGs was limited. And many chemotherapeutic agents, including single agents and combination chemotherapy agents, have been used to treat recurrent HGGs [22,23]. Temozolomide, PCV and bevacizumab are some of the treatment choice according to several researches [24-27]. Temozolomide was evaluated in recurrent HGGs before becoming the first line chemotherapy for glioma. The recurrent anaplastic glioma patients that were treated with single-agent TMZ showed a 35% response rate and PFS6 of 46% [28]. Bevacizumab has been authorized by FDA as the treatment of recurrent GBMs [29]. Moreover, Nimotuzumab is a humanized monoclonal antibody which binds the extracellular domain of epidermal growth factor receptor (EGFR) and blocks EGFR signal pathway activation [30]. And the efficacy of nimotuzumab in HGGs is depended on the combination of nimotuzumab with radiochemotherapy or radiotherapy. Solomon et al. [31] research has illustrated the median survival time of the combination of nimotuzumab with radiotherapy was 12.4 months or 27.0 months for patients with GBM or anaplastic astrocytoma patients. In our case, the chemotherapy agents were the concurrent combined chemotherapy of intravenous nimotuzumab and oral temozolomide for 6 weeks followed by six cycles of adjuvant temozolomide. And the efficacy was surprising. Thus, nimotuzumab might be one of the chemotherapy choice and more randomized clinical trials need to be done to clarify the efficacy of nimotuzumab.

Conclusion

Authored by Joan C Lo

Abstract

Purpose: The prevalence of prediabetes or diabetes was examined by race/ethnicity, weight and health behaviors among children with obesity to identify metabolic disparities and modifiable behaviors prior to adulthood.

Methods: Data were examined from 2296 children with obesity aged 10-17 years who were identified at well-child visits in 2012-2013, completed a questionnaire pertaining to dietary and lifestyle behaviors (including juice or sugar-sweetened beverage intake and exercise frequency) and had fasting glucose or hemoglobin A1C measured within 1 year of their visit. Obesity was classified as moderate or severe and glycemic status was examined using standard laboratory criteria for prediabetes and diabetes.

Results: Of 2296 children (mean age 13 years, 21% non-Hispanic white), the prevalence of prediabetes or diabetes was 33.1% overall, 9.6% among 2049 children by fasting glucose alone, and 43.2% among 1548 by hemoglobin A1C alone. The prevalence of prediabetes or diabetes varied substantially by race/ethnicity and increased with severity of obesity, but did not differ by exercise level or consumption of sugar sweetened beverage or juice.

Conclusion: One in three children with obesity had prediabetes or diabetes based on laboratory findings. The prevalence of prediabetes or diabetes increased with obesity severity and varied by race/ethnicity. Future studies should examine racial/ethnic differences in glycemic status, including variation by fasting glucose and hemoglobin A1C among these high risk children.

Keywords:  Prediabetes; Adolescence; Body mass index; Obesity

Abbreviations:  HbA1C: Hemoglobin A1C; OR: Odds Ratio

    Introduction

Approximately 20.6% of U.S. adolescents aged 12-19 years are obese, an increase of nearly2-fold within the past 20 years [1]. The prevalence of prediabetes and diabetes has also increased among U.S. adolescents, based on fasting glucose levels [2] and/or hemoglobin A1C [3]. These conditions elevate the risk of cardiovascular disease in adulthood, although data from diverse pediatric populations receiving health care remain limited. In this study, we examined the prevalence of prediabetes and diabetes and associated health behaviors among northern California children with obesity to characterize their metabolic risk and identify modifiable behaviors prior to adulthood.

    Methods

The source cohort included 4856 children aged 10-17 years with body mass index>95th percentile identified at well- child visits from 2012-2013 for Kaiser Permanente Northern California's Get Healthy Action Plan, a pediatric clinic-based weight program that assessed all children with elevated BMI at participating pediatric clinics [4]. Parents or teens were asked to complete a questionnaire about dietary and lifestyle behaviors, including juice or sugar-sweetened beverage (SSB) intake and exercise frequency. The study was approved by the Kaiser Permanente Northern California Institutional Review Board and the requirement for informed consent was waived due to the nature of the study. For these analyses, we examined data from the 2296 children with fasting glucose and/or HbAlC measured within 1 year of their visit. A fasting glucose of 100-125mg/dL or HbAlc of 5.7-6.4% defined prediabetes and higher values were considered diabetes range. Moderate and severe obesity were defined by a body mass index 100-119% and ≥120% of the 95th percentile, respectively. Subgroups were compared using the chi-square test, with a p-value criterion of <0.05 for statistical significance (SAS 9.4, Cary NC).

    Results

Among 2296 children (mean age 13.1±2.2 years), 69.6% were age 10-14 years old. The cohort was extremely diverse, with 21.4% non-Hispanic white, 11.8% black, 46.1% Hispanic, 13.5% Asian/Pacific Islander and 7.2% other/unknown race. There were 761 (33.1%) individuals who met laboratory criteria for prediabetes (N=731, 31.8%) or diabetes (N=30, 1.3%), with a prevalence of9.6% among 2049 children by fasting glucose alone and 43.2% among 1548 children by HbA1C alone (with measurements). Notably, among the 1301 children with both tests obtained anytime within 1 year of the visit, 12.0% and 43.7% had prediabetes or diabetes by fasting glucose and HbA1C, respectively, with a prevalence of 46.2% by either test criteria.

Using data from fasting glucose, HbA1C or both to classify glycemic status, the prevalence of prediabetes or diabetes varied by race/ethnicity and was highest for black (47.6%) and Asian (39.7%) children followed by Hispanic (33.3%) and white children (21.8%, p<0.05). Prediabetes or diabetes prevalence was also was higher for moderate (28.3%) versus severe obesity (38.8% p<0.001; Table 1). Black (adjusted odds ratio, OR 3.1, 95% confidence interval CI 2.2-4.2), Asian (OR 2.5, 95% CI 1.8-3.4) and Hispanic (OR 1.8, 95% CI 1.4-2.3) children had a higher odds of prediabetes or diabetes than white children after accounting for age, sex and body mass index. Exercise and sugar sweetened beverage or juice intake did not differ significantly by prediabetes or diabetes status (T-able), with notably high proportions of children with (60.5%) and without (57.6%) prediabetes or diabetes consuming at least 2 sugar sweetened beverage/juice drinks per day.

*Row percentage among N=2296 with either fasting glucose (N=2049) or Hemoglobin A1c (N=1548) values.

**Among 2264 and 2235 respondents reporting sugar sweetened beverage (SSB)/juice intake and exercise level (for at least 60 minutes, excluding school physical education), respectively

    Discussion

In a diverse population of children aged 10-17 years with obesity, 1 in 3 met criteria for prediabetes or diabetes, with only 1.3% in the diabetes range. The prevalence of prediabetes or diabetes also increased with obesity severity but did not differ by certain health behaviors. Our prediabetes estimate of 31.8% is higher than that reported for U.S. adolescents [5], as expected for an ethnically-diverse pediatric obesity cohort, but our observed prevalence based on fasting glucose compared to HbA1C criteria differs from national estimates [2]. Tester et al. [6] similarly reported a higher prediabetes prevalence using HbA1C (31.6%) compared to fasting glucose level (7.8%) in 1356 northern California children with obesity aged 2-19 years (36.0% and9.4% for adolescents, respectively). Whether differences in laboratory procedures or assays, selection for obesity, and ethnic or pediatric variation in the predictive value of HbA1C and fasting glucose thresholds contribute to these findings is unclear [7-9]. In this study, we combined findings from both fasting glucose and HbA1C to classify prediabetes and diabetes. However, future studies should also examine the extent to which race/ethnicity contributes to variation in glycemic status among children with obesity.

In summary, we observed a high prevalence of prediabetes or diabetes among children with obesity. While our data are cross-sectional and focus on a diverse community-based pediatric cohort in the healthcare setting, these findings also provide implications for population management. The much higher prevalence of prediabetes identified by HbA1C in our study and the limited sensitivity and predictive value of HbA1C thresholds and/or correlation with fasting glucose reported in other pediatric studies [7,9,10] underscore the need to determine the optimal screening test criteria for metabolic risk in children with obesity. In the meantime, continued efforts toward behavioral targets for weight reduction and improved glucose homeostasis are paramount to promoting prevention of metabolic disease in adulthood.

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