The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is ...highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin–angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.
The growing prevalence of metabolic syndrome (MetS) in the U.S. and even worldwide is becoming a serious health problem and economic burden. MetS has become a crucial risk factor for the development ...of type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD). The rising rates of CVD and diabetes, which are the two leading causes of death, simultaneously exist. To prevent the progression of MetS to diabetes and CVD, we have to understand how MetS occurs and how it progresses. Too many causative factors interact with each other, making the investigation and treatment of metabolic syndrome a very complex issue. Recently, a number of studies were conducted to investigate mechanisms and interventions of MetS, from different aspects. In this review, the proposed and demonstrated mechanisms of MetS pathogenesis are discussed and summarized. More importantly, different interventions are discussed, so that health practitioners can have a better understanding of the most recent research progress and have available references for their daily practice.
Insulin resistance is a major underlying mechanism responsible for the ‘metabolic syndrome’, which is also known as insulin resistance syndrome. The incidence of metabolic syndrome is increasing at ...an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies have demonstrated that insulin and its signaling cascade normally control cell growth, metabolism, and survival through the activation of MAPKs and activation of phosphatidylinositide-3-kinase (PI3K), in which the activation of PI3K associated with insulin receptor substrate 1 (IRS1) and IRS2 and subsequent Akt→Foxo1 phosphorylation cascade has a central role in the control of nutrient homeostasis and organ survival. The inactivation of Akt and activation of Foxo1, through the suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and overnutrition, may act as the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will probably provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the features of metabolic syndrome. Emphasis is placed on the role of IRS1, IRS2, and associated signaling pathways that are coupled to Akt and the forkhead/winged helix transcription factor Foxo1.
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ ...hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects.
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•Clinically relevant metformin dose improves liver mitochondrial respiration in obesity•Pharmacological metformin increases mitochondrial respiration and fission•Supra-pharmacological metformin inhibits mitochondrial activity by ADP reduction•AMPK is required for metformin suppression of liver glucose production
The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels.
Using electrolytic zero-valent iron-activated sodium hypochlorite (EZVI-NaClO) to pretreat sludge, the capillary suction time (CST) was utilized to evaluate sludge dewaterability. Ammonia nitrogen ...(NH4-N), dissolved phosphorus, and total phosphorus in the supernatant were used to analyze sludge disintegration. This approach aimed to evaluate the effectiveness of the pretreatment process and its impact on the sludge composition. The migration and transformation of extracellular polymeric substances (EPS), including dissolved EPS (S-EPS), loosely boundEPS, and tightly bound-EPS (TB-EPS), were analyzed by detecting protein and polysaccharide concentrations and three-dimensional fluorescence excitation-emission spectroscopy (3D-EEM). The sludge particle properties, including sludge viscosity and particle size, were also analyzed. The results suggested that the optimal pH value, NaClO dosage, current, and reaction time were 2, 100 mg/gDS (dry sludge), 0.2A, and 30 min, respectively, with a CST reduction of 43%. Protein and polysaccharide contents in TB-EPS were significantly reduced in the EZVI-NaClO group. Conversely, protein and polysaccharides contents in S-EPS increased, suggesting that EZVI-NaClO treatment could disrupt the EPS. Besides, the viscosity of the treated sludge decreased from 195.4 to 54.9 mPa·S, indicating that sludge fluidity became better. ZEVI-NaClO could enhance sludge dewaterability by destructing protein and polysaccharide structure and improving sludge hydrophobicity.
Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). ...However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-β1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-β1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-β1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-β1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-β1 signaling by chemical inhibitor of TGF-β1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-β1 signaling impairs metformin action on glycemic control, and suppression of TGF-β1 signaling could serve as part of combination therapy with metformin for T2D treatment.
Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted ...glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E
). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E
on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E
regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E
implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E
were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E
suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E
action on the suppression of gluconeogenesis. We further demonstrated that E
suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)α-phosphoinositide 3-kinase-Akt-Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E
in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERα can be a potential approach to modulate glucose metabolism and prevent diabetes.
Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a ...major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the
forkhead/winged helix
transcription factor Foxo1.
Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of ...insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. Here, we reviewed the effects of different components of macronutrients on insulin sensitivity and their underlying mechanisms, including fructose, dietary fiber, saturated and unsaturated fatty acids, and amino acids. Understanding the diet-gene interaction will help us to better uncover the molecular mechanisms of T2DM and promote the application of precision nutrition in practice by integrating multi-omics analysis.
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