Tiago G. Araújo

Hepatocyte Growth Factor Plays a Key Role in Insulin Resistance-Associated Compensatory Mechanisms

Insulin resistance is present in obesity and in type 2 diabetes and is associated with islet cell hyperplasia and hyperinsulinemia, but the driving forces behind this compensatory mechanism are incompletely understood. Previous data have suggested the involvement of an unknown circulating insulin resistance-related β-cell growth factor. In this context, looking for candidates to be a circulating factor, we realized that hepatocyte growth factor (HGF) is a strong candidate as a link between insulin resistance and increased mass of islets/hyperinsulinemia. Our approach aimed to show a possible cause-effect relationship between increase in circulating HGF levels and compensatory islet hyperplasia/hyperinsulinemia by showing the strength of the association, whether or not is a dose-dependent response, the temporality, consistency, plausibility, and reversibility of the association. In this regard, our data showed: 1) a strong and consistent correlation between HGF and the compensatory mechanism in three animal models of insulin resistance; 2) HGF increases β-cell mass in a dose-dependent manner; 3) blocking HGF shuts down the compensatory mechanisms; and 4) an increase in HGF levels seems to precede the compensatory response associated with insulin resistance, indicating that these events occur in a sequential mode. Additionally, blockages of HGF receptor (Met) worsen the impaired insulin-induced insulin signaling in liver of diet-induced obesity rats. Overall, our data indicate that HGF is a growth factor playing a key role in islet mass increase and hyperinsulinemia in diet-induced obesity rats and suggest that the HGF-Met axis may have a role on insulin signaling in the liver.

Diacerhein Improves Glucose Tolerance and Insulin Sensitivity in Mice on a High-Fat Diet

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.

Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet‐induced obese rats

It has become clear that exercise may be a useful therapy in the insulin resistance treatment, as it has anti‐inflammatory effects and improves insulin sensitivity. However, it remains uncertain whether exercise affects the adipocytes or infiltrated macrophages. Thus, the aim was to investigate the effects of acute exercise on the inflammatory status and insulin signaling of the white adipose tissue (WAT) fractions (stromal‐vascular fraction [SVF] and adipocytes).

Modulation of double-stranded RNA-activated protein kinase in insulin sensitive tissues of obese humans

Objective: The double‐stranded RNA‐dependent protein kinase (PKR) was recently implicated in regulating molecular integration of nutrient‐ and pathogen‐sensing pathways in obese mice. However, its modulation in human tissues in situations of insulin resistance has not been investigated. The present study was performed to first determine the tissue expression and phosphorylation levels of PKR in the liver, muscle, and adipose tissue in obese humans, and also the modulation of this protein in the adipose tissue of obese patients after bariatric surgery.

Insulin-Resistance-Associated Compensatory Mechanisms of Pancreatic Beta Cells: A Current Opinion

In obesity and in most situations of insulin-resistance, β-cells compensate for this hormonal resistance for long periods of time by an increase in secretory capacity and in β-cell mass. In animal models of insulin-resistance there is islet hyperplasia (1–3) and very recently a clear correlation between BMI and β-cells mass was shown in humans (4). The driving forces that can contribute to the increased β-cell mass in insulin-resistant states are not completely understood. It is well-established that glucose itself is able to induce β-cell hyperplasia (3, 5). However in many situations of insulin-resistance the hyperplastic response comes prior to any change in circulating glucose levels, indicating that other factors independent of glucose may contribute to the islet hyperplasia. Among circulating hormones and/or growth factors such as growth hormone (GH), insulin-like growth factor I (IGF-I), prolactin, and placental lactogen were implicated in islet hyperplasia associated with insulin-resistance. However, some data does not support the contribution of these hormones in islet hyperplasia. For example, GH and IGF-I were not altered in diet-induced obesity (DIO) mice and most insulin-resistant animal models investigated were male, making prolactin and the placental lactogen improbable candidates. In the past 4 years a novel pathway involving a neural relay and two hormones – betatrophin and hepatocyte growth factor (HGF) – were implicated as an inter-organ communication system associated to the compensatory response of β cells in face of insulin-resistance (6–8). In this commentary we will focus on evidence showing the role of this novel pathway in islet hypertrophy associated with obesity and insulin-resistance. In a recent publication by Yi and collaborators (8), the authors identified betatrophin, a novel hormone that increases in insulin-resistant states and controls pancreatic β cell proliferation. This hormone was recognized through the infusion in mice of the insulin receptor antagonist (S961) able to induce insulin-resistance, and also provoke at a dose-dependent manner a dramatic pancreatic β cell proliferation. By microarray, they identified the hormone betatrophin from the liver and adipose tissue of these animals, which showed that it is able to induce beta cell proliferation. In addition, the authors also demonstrated that the betatrophin mRNA was increased in the liver from ob/ob and db/db mice (three to four-fold), as well as during the mice pregnancy (∼20-fold). As discussed below, HGF is a growth factor that plays a key role in regulation of islet mass increases along with hyperinsulinemia in animal models of insulin-resistance, therefore could also play a role, however, this possibility was not addressed by Yi et al. (8). Additional aspects of the work deserve further clarification, although Yi et al. showed a possible cause-effect relationship between betatrophin and an increase in pancreatic β cell proliferation in their approach, some aspects were not thoroughly clarified. For example, they did not demonstrate the correlation between circulating levels of betatrophin and the increase in islet mass; most of the experiments are in an artificial model of insulin-resistance, based on the use of an insulin receptor antagonist, and not in the traditional models of obesity and or insulin-resistance, mainly based on a diet-induced obesity (9, 10); and, the increase in mRNA of betatrophin is much higher in pregnancy than in ob/ob and db/db mice, but the increase in islet mass is usually higher in these genetic models compared to pregnancy (1, 11). In addition, the regulations of complex processes that are evolutionary conserved and/or adaptive traits, such as insulin-resistance is usually involve redundant mechanisms. In this regard, an important point we would like to emphasize is that the compensatory increase in islet cell mass and hyperinsulinemia is multifactorial and involves central nervous system (CNS) (7), and at least one more growth factor besides betatrophin, this one known as HGF, as we previously demonstrated (6). Imai and coworkers identified a neuronal relay, originating in the liver, which enhances both insulin secretion and pancreatic β-cell proliferation (7). They showed that blocking this neural relay in rodent obesity models led to an inhibition in pancreatic islet expansion during obesity development, presenting this inter-organ communication system to be physiologically involved in compensatory β-cell proliferation. This neuronal relay is connected with signaling pathways in the liver, since it is triggered by an increase in the phosphorylation of hepatic extracellular signal-regulated kinase (ERK), which is known to be activated in the liver of a murine obesity model (12). Thus, through an adenoviral gene transduction approach that promoted a liver-selective expression of a constitutively active mutant of mitogen-activated protein kinase/ERK kinase (MEK-1), they were able to induce insulin hypersecretion and β-cell proliferation. Moreover, they also demonstrated that these pancreatic effects of hepatic ERK activation were inhibited by splanchnic afferent blockade, pancreatic vagus dissection, or midbrain transection (7). Kahns group has consistently showed that circulating growth factors, probably produced by the liver, are also important in the connection between insulin-resistance and the increase in islet mass (1, 2). Also, our group recently published a study (6) that presented the HGF as one of the systemic liver-derived growth factors that plays a role in insulin-resistance compensatory mechanism through the liver-to-pancreas axis in the adaptive β cell growth response. The concept of the study, initially, was that since it is well-established that the HGF is a mesenchymal-derived pleiotropic cytokine that regulates cell proliferation, anti-apoptosis, motility, and morphogenesis, suggests that HGF may be a good candidate of circulating insulin-resistance-related β-cell growth factor. Moreover, HGF has at least four characteristics that suggest a pathophysiological link between insulin-resistance and islet hyperplasia/hyperinsulinemia: (1) HGF is mainly produced by the liver; (2) it is under the regulation of the ERK pathway; (3) HGF stimulates insulin secretion and increased islet mass both in vitro and in vivo; and (4) circulating levels are elevated in obesity associated-insulin-resistance. Based on this circumstantial evidence, we studied the role of HGF in insulin-resistance compensatory mechanisms. Our approach aimed to show a possible causal relationship between an increase in circulating HGF levels and compensatory islet hyperplasia/hiperinsulinemia. In this sense, we investigated the association in a dose-dependent, longitudinal approach. Our findings showed the following: (1) there is a strong and consistent correlation between HGF and the compensatory mechanism from β-cells in three animal models of insulin-resistance; (2) that HGF increases β-cell mass in a dose-dependent manner; (3) blocking HGF shuts down the compensatory mechanisms; and (4) an increase in HGF levels seems to precede the compensatory response associated with insulin-resistance, indicating that these events occur in a causal fashion. Additionally, blockages of HGF receptor (Met) worsen the already impaired insulin-induced insulin signaling in the liver of diet-induced obesity rats. In conclusion, it is important to emphasize that the recently described betatrophin is a hormone that has an important role in the connection between insulin-resistance and increased β-cell mass, but other growth factors such as HGF and also neural circuits certainly play an important role in this process (Figure ​(Figure1).1). The contribution of each of these factors in different situations of insulin-resistance, such as in pregnancy, obesity, and type 2 diabetes, deserves further investigation. Figure 1 Schematic representation of the effects of betatrophin and HGF hormones, as well as, neural circuits on islets in which these components together induce the compensatory response to insulin-resistance.

Chlorella modulates insulin signaling pathway and prevents high-fat diet-induced insulin resistance in mice

AIMS The search for natural agents that minimize obesity-associated disorders is receiving special attention. In this regard, the present study aimed to evaluate the prophylactic effect of Chlorella vulgaris (CV) on body weight, lipid profile, blood glucose and insulin signaling in liver, skeletal muscle and adipose tissue of diet-induced obese mice. MAIN METHODS Balb/C mice were fed either with standard rodent chow diet or high-fat diet (HFD) and received concomitant treatment with CV for 12 consecutive weeks. Triglyceride, free fatty acid, total cholesterol and fractions of cholesterol were measured using commercial assay. Insulin and leptin levels were determined by enzyme-linked immunosorbent assay (ELISA). Insulin and glucose tolerance tests were performed. The expression and phosphorylation of IRβ, IRS-1 and Akt were determined by Western blot analyses. KEY FINDINGS Herein we demonstrate for the first time in the literature that prevention by CV of high-fat diet-induced insulin resistance in obese mice, as shown by increased glucose and insulin tolerance, is in part due to the improvement in the insulin signaling pathway at its main target tissues, by increasing the phosphorylation levels of proteins such as IR, IRS-1 and Akt. In parallel, the lower phosphorylation levels of IRS-1(ser307) were observed in obese mice. We also found that CV administration prevents high-fat diet-induced dyslipidemia by reducing triglyceride, cholesterol and free fatty acid levels. SIGNIFICANCE We propose that the modulatory effect of CV treatment preventing the deleterious effects induced by high-fat diet is a good indicator for its use as a prophylactic-therapeutic agent against obesity-related complications.

Augmented β-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.

Characterization of the Antidiabetic Role of Parkinsonia aculeata (Caesalpineaceae)

This paper reports the characterization of the antidiabetic role of a hydroethanolic extract from Parkinsonia aerial parts (HEPA), in normal and alloxan-induced diabetic rats, treated with HEPA (125 and 250 mg/kg; p.o.). Oral glucose tolerance test, acute oral toxicity test and preliminary phytochemical analyses were performed. The diabetic rats treated with HEPA showed a significant reduction in serum and urinary glucose, urinary urea and triglyceride levels, as compared to the diabetic untreated group. However, in the normal treated groups, a significant reduction was found only in serum triglyceride levels. In all treated diabetic groups, an improvement in hepatic glycogen was observed, as well as a decrease in liquid intake and urinary volume, and an enhancement in the weight of skeletal muscles (soleus and extensor digitorum longus), kidneys and epididymal adipose tissue. Nevertheless, body and liver weights were ameliorated only in the diabetic group treated with HEPA (250 mg/kg). Moreover, oral glucose tolerance was higher in animals treated with HEPA, while results also showed that HEPA could be considered toxicologically safe. Phytochemical analysis revealed the presence of tanins, flavonoids and steroids in HEPA. In conclusion, P. aculeata presents an antidiabetic activity and other beneficial effects that ameliorate diabetes and associated complications.

Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice

Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.

The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes

In obesity, insulin resistance (IR) and diabetes, there are proteins and hormones that may lead to the discovery of promising biomarkers and treatments for these metabolic disorders. For example, these molecules may impair the insulin signaling pathway or provide protection against IR. Thus, identifying proteins that are upregulated in IR states is relevant to the diagnosis and treatment of the associated disorders. It is becoming clear that hepatocyte growth factor (HGF) is an important component of the pathophysiology of IR, with increased levels in most common IR conditions, including obesity. HGF has a role in the metabolic flux of glucose in different insulin sensitive cell types; plays a key role in β-cell homeostasis; and is capable of modulating the inflammatory response. In this review, we discuss how, and to what extent HGF contributes to IR and diabetes pathophysiology, as well as its role in cancer which is more prevalent in obesity and diabetes. Based on the current literature and knowledge, it is clear that HGF plays a central role in these metabolic disorders. Thus, HGF levels could be employed as a biomarker for disease status/progression, and HGF/c-Met signaling pathway modulators could effectively regulate IR and treat diabetes.