Glucose Uptake In Insulin-sensitive Tissues Research Articles

Unique features of β-cell metabolism are lost in type 2 diabetes.

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

Fungal Depsidones Stimulate AKT-Dependent Glucose Uptake in 3T3-L1 Adipocytes.

Enhanced glucose uptake in insulin-sensitive tissues is one of the therapeutic strategies to ameliorate hyperglycemia and maintain glucose homeostasis in type 2 diabetes. This study disclosed the role of fungal depsidones in glucose uptake and the underlying mechanism in 3T3-L1 adipocytes. Depsidones, including nidulin, nornidulin, and unguinol, isolated from Aspergillus unguis, stimulate glucose uptake in adipocytes. Compared to the others, nidulin exhibited an upward trend in glucose uptake. The effect of nidulin was found to be dose- and time-dependent. Nidulin also enhanced insulin- and metformin-stimulated glucose uptake. Upregulation of GLUT4 expression and AKT and AMPK phosphorylation were observed with nidulin treatment. Blockage of AKT, but not AMPK, phosphorylation was largely accompanied by diminished glucose uptake. In agreement, nidulin triggered the translocation of GLUT4 to the plasma membrane. Importantly, nidulin elevated glucose uptake associated with increased AKT phosphorylation in insulin-resistant adipocytes. Taken together, nidulin could stimulate glucose uptake mainly through AKT-dependent GLUT4 translocation, serving as a seed compound in drug discovery for type 2 diabetes.

In Vitro Insulin Resistance Model: A Recent Update.

Insulin resistance, which affects insulin-sensitive tissues, including adipose tissues, skeletal muscle, and the liver, is the central pathophysiological mechanism underlying type 2 diabetes progression. Decreased glucose uptake in insulin-sensitive tissues disrupts insulin signaling pathways, particularly the PI3K/Akt pathway. An in vitro model is appropriate for studying the cellular and molecular mechanisms underlying insulin resistance because it is easy to maintain and the results can be easily reproduced. The application of cell-based models for exploring the pathogenesis of diabetes and insulin resistance as well as for developing drugs for these conditions is well known. However, a comprehensive review of in vitro insulin resistance models is lacking. Therefore, this review was conducted to provide a comprehensive overview and summary of the latest in vitro insulin resistance models, particularly 3T3-L1 (preadipocyte), C2C12 (skeletal muscle), and HepG2 (liver) cell lines induced with palmitic acid, high glucose, or chronic exposure to insulin.

Peripheral Dopamine Directly Acts on Insulin-Sensitive Tissues to Regulate Insulin Signaling and Metabolic Function

Dopamine is a key regulator of glucose metabolism in the central nervous system. However, dopamine is also present in the periphery and may have direct effects on insulin-sensitive tissues. Dopamine receptor 2 (D2R) agonist bromocriptine is a FDA-approved drug for type 2 diabetes. Herein, we explored the role of peripheral dopamine and its receptors in regulating glucose uptake and metabolism on insulin-sensitive tissues. Peripheral dopamine effect in [3H]2-deoxyglucose uptake in insulin-sensitive tissues was tested in vivo in rats. Direct effects on [3H]2-deoxyglucose uptake, insulin receptor phosphorylation, and regulation of metabolic function were tested ex vivo in the liver, soleus muscle, and white and brown adipose tissues. Bromocriptine and the antagonists domperidone, D2R antagonist, and haloperidol, antagonist of both dopamine receptor 1 (D1R) and D2R, were used to disclose dopamine receptors’ involvement.Peripheral dopamine increases glucose uptake in vivo. Ex vivo, only dopamine increased glucose uptake in the soleus, while bromocriptine increased it in the liver; the effects were reverted by haloperidol and domperidone, respectively. In adipose tissue, domperidone reverted dopamine- and bromocriptine-mediated potentiation of insulin-induced glucose uptake, but in turn increased the insulin receptor, Akt, AMPK, HSL, ACC, and ACL, phosphorylation. In the soleus muscle, AMPK-phosphorylation increased with bromocriptine and dopamine whose effects were suppressed by domperidone and haloperidol.In conclusion, peripheral dopamine stimulates glucose uptake with its receptors being differentially involved in glucose uptake in insulin-sensitive tissues. Dopamine also has a role in lipid metabolism in white adipose tissue. Altogether, these results suggest that peripheral modulation of the dopaminergic system should be further evaluated as a putative therapeutic approach for metabolic disorders.

Dopamine D2 receptor agonist, bromocriptine, remodels adipose tissue dopaminergic signalling and upregulates catabolic pathways, improving metabolic profile in type 2 diabetes

Background and objectivesThe therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue. MethodsThe expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle. ResultsPatients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed. ConclusionsBromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators.

Polyphenols and their effects on diabetes management: A review.

Background: Type 2 diabetes is a growing public health problem and is associated with increased morbidity and mortality. The worldwide prevalence of type 2 diabetes is rising. Polyphenols, such as flavonoids, phenolic acid, and stilbens, are a large and heterogeneous group of phytochemicals in plant-based foods. In this review, we aimed at assessing the studies on polyphenols and diabetes management. Methods: A literature search in the PubMed, EMBASE, Scopus, and ISI Web of Science databases was conducted to identify relevant studies published from 1986 to Jan 2017. Results: Several animal models and a limited number of human studies have revealed that polyphenols decrease hyperglycemia and improve acute insulin secretion and insulin sensitivity. The possible mechanisms include decrease in glucose absorption in the intestine, inhibition of carbohydrates digestion, stimulation of insulin secretion, modulation of glucose release from the liver, activation of insulin receptors and glucose uptake in insulin-sensitive tissues, modulation of intracellular signaling pathways, and gene expression. Conclusion: Growing evidence indicates that various dietary polyphenols may influence blood glucose at different levels and may also help control and prevent diabetes complication. However, we still need more clinical trials to determine the effects of polyphenols- rich foods, their effective dose, and mechanisms of their effects in managing diabetes.

Insulin Resistance and Mitochondrial Dysfunction.

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Link between the renin–angiotensin system and insulin resistance: Implications for cardiovascular disease

The incidence of metabolic syndrome is rapidly increasing in the United States and worldwide. The metabolic syndrome is a complex metabolic and vascular disorder that is associated with inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) in the cardiovascular (CV) system and increased CV morbidity and mortality. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes nitric oxide (NO) production in the endothelium and glucose uptake in insulin-sensitive tissues. Angiotensin (Ang) II inhibits insulin-mediated PI3K pathway activation, thereby impairing endothelial NO production and Glut-4 translocation in insulin-sensitive tissues, which results in vascular and systemic insulin resistance, respectively. On the other hand, Ang II enhances insulin-mediated activation of the mitogen-activated protein kinase (MAPK) pathway, which leads to vasoconstriction and pathologic vascular cellular growth. Therefore, the interaction of Ang II with insulin signaling is fully operative not only in insulin-sensitive tissues but also in CV tissues, thereby linking insulin resistance and CV disease. This notion is further supported by an increasing number of experimental and clinical studies indicating that pharmacological blockade of RAAS improves insulin sensitivity and endothelial function, as well as reduces the incidence of new-onset diabetes in high-risk patients with CV disease. This article reviews experimental and clinical data elucidating the physiological and pathophysiological role of the interaction between insulin and RAAS in the development of insulin resistance as well as CV disease.

Insulin Resistance Selectively Alters Cell‐Surface Glucose Transporters but not their Total Protein Expression in Equine Skeletal Muscle

Insulin resistance (IR) has been widely recognized in humans, and more recently in horses, but its underlying mechanisms are still not well understood. The translocation of glucose transporter 4 (GLUT4) to the cell surface is the limiting step for glucose uptake in insulin-sensitive tissues. Although the downstream signaling pathways regulating GLUT translocation are not well defined, AS160 recently has emerged as a potential key component. In addition, the role of GLUT12, one of the most recently identified insulin-sensitive GLUTs, during IR is unknown. We hypothesized that cell-surface GLUT will be decreased in muscle by an AS160-dependent pathway in horses with IR. Insulin-sensitive (IS) or IR mares (n = 5/group). Muscle biopsies were performed in mares classified as IS or IR based on results of an insulin-modified frequently sampled IV glucose tolerance test. By an exofacial bis-mannose photolabeled method, we specifically quantified active cell-surface GLUT4 and GLUT12 transporters. Total GLUT4 and GLUT12 and AS160 protein expression were measured by Western blots. IR decreased basal cell-surface GLUT4 expression (P= .027), but not GLUT12, by an AS160-independent pathway, without affecting total GLUT4 and GLUT12 content. Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group. IR induced defects in the skeletal muscle glucose transport pathway by decreasing active cell-surface GLUT4.

Atypical protein kinase C dysfunction and the metabolic syndrome

Atypical protein kinase C isoforms are crucial mediators of glucose uptake in insulin-sensitive tissues. In humans, decreased muscular atypical protein kinase C activity has been found in insulin-resistant states. In a recent report by Farese et al., a novel mouse model is described, featuring selective ablation of an atypical protein kinase C, protein kinase Clambda, in muscle. Phenotyping of these mice demonstrated systemic insulin resistance, reduced glucose tolerance, abdominal obesity and dyslipidemia, thus mimicking human metabolic syndrome. Intriguingly, therefore, atypical protein kinase Clambda deficiency might be sufficient to induce metabolic syndrome in mice.

Emerging role of protein kinase B/Akt signaling in pancreatic β-cell mass and function

The serine-threonine kinase Akt also known as protein kinase B is one of the most studied molecules. In addition to the important role in carcinogenesis, Akt is a major regulator of carbohydrate metabolism. Akt mediates insulin-dependent glucose uptake in insulin-sensitive tissues. Recent evidence underscores the importance of Akt for regulation of β-cell mass and function. This review summarizes current findings concerning the molecular mechanisms, downstream signaling pathways, and critical components involved in regulation of β-cell mass and function by Akt. The results of these observations suggest that elucidation of critical downstream effectors of this signaling pathway could generate promising molecules as a potential target to induce proliferation and survival of β-cells.

Insulin Resistance and Hypertension

Insulin resistance refers to the reduction in insulin-mediated glucose uptake in insulin-sensitive tissues, specifically in skeletal muscle. As a compensatory response, hyperinsulinemia ensues to maintain normal blood glucose levels. In epidemiological studies, fasting insulin level is commonly used as a surrogate marker of insulin resistance. In normoglycemic subjects, fasting insulin correlated well with whole-body glucose uptake ( r =−0.68) as measured by the “gold standard” euglycemic hyperinsulinemic clamp method, although the correlation was lower in individuals with impaired glucose tolerance or type 2 diabetes mellitus.1 Although fasting insulin is a reasonable measure of insulin resistance, it is potentially confounded by variability in insulin secretion. Thus, the indexes derived from fasting insulin and glucose, such as the Homeostasis Model Assessment (HOMA),2 the Quantitative Insulin Sensitivity Check Index (QUICKI),3 and the insulin sensitivity index (ISI) developed by Gutt and coworkers,4 have been more widely used to assess insulin resistance in clinical and population-based studies. See p 1719 Although the role of insulin resistance in the pathophysiology of type 2 diabetes mellitus is well accepted, the relationship between insulin resistance and blood pressure remains controversial. Nearly 40 years ago, Welborn and colleagues5 observed that nondiabetic patients with essential hypertension had significantly higher plasma insulin concentrations than did normotensive individuals. This positive relationship has been confirmed in several longitudinal studies, but the results are not entirely consistent. In some studies, the association between hyperinsulinemia and incident hypertension disappeared after adjustment for body mass index (BMI), suggesting that the association is confounded or mediated through obesity. Therefore, the causal role of insulin resistance/compensatory hyperinsulinemia in the development of hypertension continues to be debated. As reported in this issue of Circulation , Arnlov and colleagues6 investigated the relationship between insulin sensitivity, using ISI, and the 4-year incidence of hypertension and blood …

Tyramine stimulates glucose uptake in insulin-sensitive tissues in vitro and in vivo via its oxidation by amine oxidases.

Tyramine and benzylamine have been described as stimulators of glucose transport in adipocytes. This effect is dependent on amine oxidation by monoamine oxidase (MAO) or semicarbazide-sensitive amine oxidase (SSAO) and on the subsequent hydrogen peroxide formation as already demonstrated by blockade with oxidase inhibitors or antioxidants and potentiation with vanadate. In this work, we extended these observations to skeletal muscle and cardiac myocytes using in vitro and in vivo approaches. Tissue distribution studies showed that substantial extrahepatic peripheral MAO activities exist in kidney and gut, but also in insulin-sensitive tissues: heart, adipose tissue, and skeletal muscles. SSAO activity is also widely distributed and present at a lower level than MAO, except in fat depots where both oxidases were equally involved in tyramine oxidation. When tested in vitro at millimolar doses, tyramine caused a large stimulation of glucose transport in rat adipocytes and in skeletal and cardiac muscles. In vivo administration of tyramine (4 mg/kg i.p.) lowered the hyperglycemic responses to a glucose challenge in control and in streptozotocin-treated rats. This positive effect on glucose disposal was obtained without vanadate and was abolished by SSAO and MAO inhibitors. Tyramine increased hexose uptake in vivo in insulin-sensitive tissues, whereas it induced only transient effects on plasma insulin or cardiovascular parameters. In conclusion, activation of the amine oxidases present in insulin-sensitive tissues induces insulin-like effects, readily detectable in vitro, and increasing peripheral glucose utilization in vivo.