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 (E₂). 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 E₂ 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 E₂ regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E₂ implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E₂ were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E₂ suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E₂ action on the suppression of gluconeogenesis. We further demonstrated that E₂ 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 E₂ 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.

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.

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.

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.

Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes mellitus (T2D). The pancreatic hormone glucagon increases, and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A (PKA)-dependent phosphorylation of Foxo1 at Ser276. Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in control of Foxo1 bioactivity and associated metabolic diseases.

Ginsenoside Rg2 is one of the specific ginsenosides in red ginseng, and has been reported to exhibit protective effects against neurotoxicity and memory impairment, and also inhibition of hepatic glucose production. However, the effect of Rg2 on the prevention of obesity has not been investigated. In this study, we evaluated the anti-obesity and anti-adipogenic effects of Rg2 in high-fat diet-induced obese mice (HFD mice) and 3T3-L1 preadipocytes. Oral administration of Rg2 (10 mg kg⁻¹) to HFD mice significantly decreased body weight gain, total triglycerides, and free fatty acid levels. In 3T3-L1 preadipocytes, Rg2 (80 μM) inhibited adipocyte differentiation and reduced the accumulation of intracellular lipids. Quantitative PCR and western blot analysis revealed that Rg2 decreased the expression levels of adipogenic transcription factors (PPARγ, C/EBPα, and SREBP1-c), and then regulated target genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Rg2 significantly promoted AMP-activated protein kinase (AMPK) both in vivo and in vitro, which is known to suppress adipogenesis. It was also found that pretreating with compound C, a typical inhibitor of AMPK, attenuated the inhibitory effect of Rg2 on AMPK phosphorylation. These findings suggested that Rg2-induced activation of AMPK leads to a decrease in the expression of adipogenic transcription factors, and suppression of adipogenesis in vivo and in vitro. Hence, Rg2 has the potential for the development of healthy foods and the prevention of obesity.