Showing papers on "Insulin resistance published in 2016"

Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association

Abstract: The adoption and maintenance of physical activity are critical foci for blood glucose management and overall health in individuals with diabetes and prediabetes. Recommendations and precautions vary depending on individual characteristics and health status. In this Position Statement, we provide a clinically oriented review and evidence-based recommendations regarding physical activity and exercise in people with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and prediabetes. Physical activity includes all movement that increases energy use, whereas exercise is planned, structured physical activity. Exercise improves blood glucose control in type 2 diabetes, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being (1,2). Regular exercise may prevent or delay type 2 diabetes development (3). Regular exercise also has considerable health benefits for people with type 1 diabetes (e.g., improved cardiovascular fitness, muscle strength, insulin sensitivity, etc.) (4). The challenges related to blood glucose management vary with diabetes type, activity type, and presence of diabetes-related complications (5,6). Physical activity and exercise recommendations, therefore, should be tailored to meet the specific needs of each individual. Physical activity recommendations and precautions may vary by diabetes type. The primary types of diabetes are type 1 and type 2. Type 1 diabetes (5%–10% of cases) results from cellular-mediated autoimmune destruction of the pancreatic β-cells, producing insulin deficiency (7). Although it can occur at any age, β-cell destruction rates vary, typically occurring more rapidly in youth than in adults. Type 2 diabetes (90%–95% of cases) results from a progressive loss of insulin secretion, usually also with insulin resistance. Gestational diabetes mellitus occurs during pregnancy, with screening typically occurring at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. Prediabetes is diagnosed when blood glucose levels are above the normal range but not high enough to be classified as …

Human gut microbes impact host serum metabolome and insulin sensitivity

Abstract: Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome

Abstract: Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient-gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.

Abstract: Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

Abstract: Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Abstract: BackgroundPatients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. MethodsIn this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. ResultsBy 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group...

Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial.

Abstract: Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n=30 in each group) treating with either milk (control group) or a mixture of probiotic (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum (2×109 CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (-5.03%±3.00), the probiotic treated (+27.90%±8.07) patients showed a significant improvement in the MMSE score (P<0.001). In addition, changes in plasma malondialdehyde (-22.01%±4.84 vs. +2.67%±3.86 µmol/L, P<0.001), serum high-sensitivity C-reactive protein (-17.61%±3.70 vs. +45.26%±3.50 µg/mL, P<0.001), homeostasis model of assessment-estimated insulin resistance (+28.84%±13.34 vs.+76.95%±24.60, P=0.002), Beta cell function (+3.45%±10.91 vs. +75.62%±23.18, P=0.001), serum triglycerides (-20.29%±4.49 vs. -0.16%±5.24 mg/dL, P=0.003) and quantitative insulin sensitivity check index (-1.83±1.26 vs. -4.66±1.70, P=0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose and other lipid profiles. Overall, the current study demonstrated that probiotic consumption for 12 weeks positively affects cognitive function and some metabolic statuses in the AD patients.

Molecular mechanisms of ROS production and oxidative stress in diabetes.

Abstract: Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of excessive levels of ROS is the modification of the structure and function of cellular proteins and lipids, leading to cellular dysfunction including impaired energy metabolism, altered cell signalling and cell cycle control, impaired cell transport mechanisms and overall dysfunctional biological activity, immune activation and inflammation. Nutritional stress, such as that caused by excess high-fat and/or carbohydrate diets, promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation and decreased antioxidant status. In obesity, chronic oxidative stress and associated inflammation are the underlying factors that lead to the development of pathologies such as insulin resistance, dysregulated pathways of metabolism, diabetes and cardiovascular disease through impaired signalling and metabolism resulting in dysfunction to insulin secretion, insulin action and immune responses. However, exercise may counter excessive levels of oxidative stress and thus improve metabolic and inflammatory outcomes. In the present article, we review the cellular and molecular origins and significance of ROS production, the molecular targets and responses describing how oxidative stress affects cell function including mechanisms of insulin secretion and action, from the point of view of possible application of novel diabetic therapies based on redox regulation.

Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy

Abstract: Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.

Insulin resistance and sarcopenia: mechanistic links between common co-morbidities.

Abstract: Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of 'sarcopenic obesity' (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed.

Targeting adipose tissue in the treatment of obesity-associated diabetes

Abstract: Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.

Sugar consumption, metabolic disease and obesity: The state of the controversy.

Abstract: The impact of sugar consumption on health continues to be a controversial topic. The objective of this review is to discuss the evidence and lack of evidence that allows the controversy to continue, and why resolution of the controversy is important. There are plausible mechanisms and research evidence that supports the suggestion that consumption of excess sugar promotes the development of cardiovascular disease (CVD) and type 2 diabetes (T2DM) both directly and indirectly. The direct pathway involves the unregulated hepatic uptake and metabolism of fructose, leading to liver lipid accumulation, dyslipidemia, decreased insulin sensitivity and increased uric acid levels. The epidemiological data suggest that these direct effects of fructose are pertinent to the consumption of the fructose-containing sugars, sucrose and high fructose corn syrup (HFCS), which are the predominant added sugars. Consumption of added sugar is associated with development and/or prevalence of fatty liver, dyslipidemia, insulin resistance, hyperuricemia, CVD and T2DM, often independent of body weight gain or total energy intake. There are diet intervention studies in which human subjects exhibited increased circulating lipids and decreased insulin sensitivity when consuming high sugar compared with control diets. Most recently, our group has reported that supplementing the ad libitum diets of young adults with beverages containing 0%, 10%, 17.5% or 25% of daily energy requirement (Ereq) as HFCS increased lipid/lipoprotein risk factors for CVD and uric acid in a dose-response manner. However, un-confounded studies conducted in healthy humans under a controlled, energy-balanced diet protocol that enables determination of the effects of sugar with diets that do not allow for body weight gain are lacking. Furthermore, recent reports conclude that there are no adverse effects of consuming beverages containing up to 30% Ereq sucrose or HFCS, and the conclusions from several meta-analyses suggest that fructose has no specific adverse effects relative to any other carbohydrate. Consumption of excess sugar may also promote the development of CVD and T2DM indirectly by causing increased body weight and fat gain, but this is also a topic of controversy. Mechanistically, it is plausible that fructose consumption causes increased energy intake and reduced energy expenditure due to its failure to stimulate leptin production. Functional magnetic resonance imaging (fMRI) of the brain demonstrates that the brain responds differently to fructose or fructose-containing sugars compared with glucose or aspartame. Some epidemiological studies show that sugar consumption is associated with body weight gain, and there are intervention studies in which consumption of ad libitum high-sugar diets promoted increased body weight gain compared with consumption of ad libitum low- sugar diets. However, there are no studies in which energy intake and weight gain were compared in subjects consuming high or low sugar, blinded, ad libitum diets formulated to ensure both groups consumed a comparable macronutrient distribution and the same amounts of fiber. There is also little data to determine whether the form in which added sugar is consumed, as beverage or as solid food, affects its potential to promote weight gain. It will be very challenging to obtain the funding to conduct the clinical diet studies needed to address these evidence gaps, especially at the levels of added sugar that are commonly consumed. Yet, filling these evidence gaps may be necessary for supporting the policy changes that will help to turn the food environment into one that does not promote the development of obesity and metabolic disease.

Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance.

Abstract: Obesity and insulin resistance are the major predisposing factors to comorbidities, such as Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. The prevalence of obesity is still increasing worldwide and now affects a large number of individuals. Here, we review the role of the gut microbiota in the pathophysiology of insulin resistance/obesity. The human intestine is colonized by ∼100 trillion bacteria, which constitute the gut microbiota. Studies have shown that lean and overweight rodents and humans may present differences in the composition of their intestinal flora. Over the past 10 years, data from different sources have established a causal link between the intestinal microbiota and obesity/insulin resistance. It is important to emphasize that diet-induced obesity promotes insulin resistance by mechanisms independent and dependent on gut microbiota. In this review, we present several mechanisms that contribute to explaining the link between intestinal flora and insulin resistance/obesity. The LPS from intestinal flora bacteria can induce a chronic subclinical inflammatory process and obesity, leading to insulin resistance through activation of TLR4. The reduction in circulating SCFA may also have an essential role in the installation of reduced insulin sensitivity and obesity. Other mechanisms include effects of bile acids, branched-chain amino acids (BCAA), and some other lesser-known factors. In the near future, this area should open new therapeutic avenues for obesity/insulin resistance and its comorbidities.

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

Abstract: Rationale:The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. Objective:Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. Methods and Results:In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α–dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/β activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammato...

Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.

Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered.

Dietary Advanced Glycation End Products and Their Potential Role in Cardiometabolic Disease in Children.

Abstract: The rising incidence of obesity and metabolic diseases such as diabetes mellitus and cardiovascular disease in adolescents and young adults is of grave concern. Recent studies favor a role of lifestyle factors over genetics in the perpetuation of inflammation, insulin resistance and oxidative stress, which are pathophysiologic processes common to the above diseases; furthermore, the importance of dietary factors in addition to calories and physical activity in these processes is being increasingly recognized. Advanced glycation end products (AGEs) belong to a category of dietary oxidants which have been implicated in the pathogenesis of inflammation, oxidative stress, insulin resistance, β-cell failure and endothelial dysfunction. This paper reviews the studies of AGEs with a focus on their role in cardiometabolic disease in children. A Medline search was performed using the key words 'childhood obesity', 'metabolic syndrome' and 'advanced glycation end products'. Articles published in English between 1975 and 2015 and their references were reviewed. While most studies were performed in adults, a few studies also demonstrated a role of AGEs in obesity and associated cardiometabolic comorbidities in the younger population. Available evidence suggests an involvement of AGEs in the pathogenesis of adiposity and β-cell failure in children. Potential areas for further research to investigate underlying mechanisms are proposed.

Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective

Abstract: Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between ‘insulin-sensitive’ and ‘insulin-insensitive’ diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms ‘insulin-dependent’ (indicating undetectable insulin levels) and ‘non-insulin-dependent’ (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with ‘insulin-dependent’ diabetes. At the same time, new experimental techniques allowing measurement of insulin ‘impedance’ showed a reduced peripheral effect of insulin in subjects with ‘non-insulin-dependent’ diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions ‘type I’ and ‘type II’ diabetes were introduced to replace the former ‘insulin-dependent’ and ‘non-insulin-dependent’ terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in ‘type II’ diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between ‘type I’ and ‘type II’ diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple ‘glucocentric’ view could result in a better patient phenotyping and therapeutic approach.

Polyphenols and Glycemic Control

Abstract: Growing evidence from animal studies supports the anti-diabetic properties of some dietary polyphenols, suggesting that dietary polyphenols could be one dietary therapy for the prevention and management of Type 2 diabetes. This review aims to address the potential mechanisms of action of dietary polyphenols in the regulation of glucose homeostasis and insulin sensitivity based on in vitro and in vivo studies, and to provide a comprehensive overview of the anti-diabetic effects of commonly consumed dietary polyphenols including polyphenol-rich mixed diets, tea and coffee, chocolate and cocoa, cinnamon, grape, pomegranate, red wine, berries and olive oil, with a focus on human clinical trials. Dietary polyphenols may inhibit α-amylase and α-glucosidase, inhibit glucose absorption in the intestine by sodium-dependent glucose transporter 1 (SGLT1), stimulate insulin secretion and reduce hepatic glucose output. Polyphenols may also enhance insulin-dependent glucose uptake, activate 5′ adenosine monophosphate-activated protein kinase (AMPK), modify the microbiome and have anti-inflammatory effects. However, human epidemiological and intervention studies have shown inconsistent results. Further intervention studies are essential to clarify the conflicting findings and confirm or refute the anti-diabetic effects of dietary polyphenols.

A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance

Abstract: Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

A clinical perspective of obesity, metabolic syndrome and cardiovascular disease.

Abstract: The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.

Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans

Abstract: Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

Abstract: The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.