Metabolism of Storage Lipids and the Role of Lipid Droplets in the Yeast Schizosaccharomyces pombe

Storage lipids, triacylglycerols (TAG), and steryl esters (SE), are predominant constituents of lipid droplets (LD) in fungi. In several yeast species, metabolism of TAG and SE is linked to various cellular processes, including cell division, sporulation, apoptosis, response to stress, and lipotoxicity. In addition, TAG are an important source for the generation of value-added lipids for industrial and biomedical applications. The fission yeast Schizosaccharomyces pombe is a widely used unicellular eukaryotic model organism. It is a powerful tractable system used to study various aspects of eukaryotic cellular and molecular biology. However, the knowledge of S. pombe neutral lipids metabolism is quite limited. In this review, we summarize and discuss the current knowledge of the homeostasis of storage lipids and of the role of LD in the fission yeast S. pombe with the aim to stimulate research of lipid metabolism and its connection with other essential cellular processes. We also discuss the advantages and disadvantages of fission yeast in lipid biotechnology and recent achievements in the use of S. pombe in the biotechnological production of valuable lipid compounds.     

Metabolic Syndrome Affects Fatty Acid Composition of Plasma Lipids in Obese Prepubertal Children

The aim of the present study was to assess the plasma fatty acid composition of the total plasma lipids and lipid fractions in obese prepubertal children with and without metabolic syndrome (MS). Thirty-four obese prepubertal children were recruited: 17 who met MS criteria and 17 who did not; and twenty prepubertal children of normal weight. MS characteristics, insulin resistance (by homeostasis model assessment [HOMA-IR]), and plasma adiponectin (by radioimmunoassay) were recorded. Separation of lipid fractions was performed by liquid chromatography and the concentration of fatty acids in total plasma lipids and fractions was determined by gas-liquid chromatography. Concentrations of 16:1n-7, 16:1n-9, 18:3n-3, 22:6n-3, and n-3 PUFA in total plasma lipids (P < 0.05) and of 16:0, 16:1n-7, 18:1n-9, 18:2n-6, and n-6 PUFA in triacylglycerols (TG) (P < 0.05) were significantly higher in obese MS versus normal-weight children. Increased risk of MS was positively associated with plasma concentration of 16:1n-7 and negatively associated with proportion of 20:4n-6 (OR 2.76; P = 0.004; OR 0.56, P = 0.030, respectively). Saturated FA in TG were associated with HOMA-IR (R = 0.349, P = 0.017) and 22:5n-6 with adiponectin (R = 0.336, P = 0.05). In conclusion, increased concentrations of 16:1n-7 and decreased proportions of 20:4n-6 and 22:5n-6 in plasma lipids appear to be early markers of MS in children at prepubertal age.     

Metabolic Syndrome: Effects of n-3 PUFAs on a Model of Dyslipidemia,Insulin Resistance and Adiposity

Both genetic and environmental factors (e.g. nutrition, life style) contribute to the development of the plurimetabolic syndrome, which has a high prevalence in the world population. Dietary n-3 PUFAs specially those from marine oil (EPA and DHA) appear to play an important role against the adverse effects of this syndrome. The present work examined the effectiveness of fish oil (FO) in reversing or improving the dyslipidemia, insulin resistance and adiposity induced in rats by long-term feeding a sucrose-rich diet (SRD). We studied several metabolic and molecular mechanisms involved in both lipid and glucose metabolisms in different tissues (liver, skeletal muscle, fat pad) as well as insulin secretion patterns from perifused islets under the stimulation of different secretagogues. Dietary FO reverses dyslipidemia and improves insulin action and adiposity in the SRD fed rats. FO reduces adipocytes cell size and thus, the smaller adipocytes are more insulin sensitive and the release of fatty acids decreases. In muscle, FO normalizes both the oxidative and non-oxidative glucose pathways. Moreover, FO modifies the fatty acid composition of membrane phospholipids. In isolated β cells, lipid contents and glucose oxidation return to normal. All these effects could contribute to the normalization of glucose-stimulated insulin secretion and muscle insulin insensitivity.     

The Mighty Mitochondria Are Unifying Organelles and Metabolic Hubs in Multiple Organs of Obesity,Insulin Resistance,Metabolic Syndrome,and Type 2 Diabetes: An Observational Ultrastructure Study

Mitochondria (Mt) are essential cellular organelles for the production of energy and thermogenesis. Mt also serve a host of functions in addition to energy production, which include cell signaling, metabolism, cell death, and aging. Due to the central role of Mt in metabolism as metabolic hubs, there has been renewed interest in how Mt impact metabolic pathways and multiple pathologies. This review shares multiple observational ultrastructural findings in multiple cells and organs to depict aberrant mitochondrial (aMt) remodeling in pre-clinical rodent models. Further, it is intended to show how remodeling of Mt are associated with obesity, insulin resistance, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). Specifically, Mt remodeling in hypertensive and insulin-resistant lean models (Ren2 rat models), lean mice with streptozotocin-induced diabetes, obesity models including diet-induced obesity, genetic leptin-deficient ob/ob, and leptin receptor-deficient db/db diabetic mice are examined. Indeed, aMt dysfunction and damage have been implicated in multiple pathogenic diseases. Manipulation of Mt such as the induction of Mt biogenesis coupled with improvement of mitophagy machinery may be helpful to remove leaky damaged aMt in order to prevent the complications associated with the generation of superoxide-derived reactive oxygen species and the subsequent reactive species interactome. A better understanding of Mt remodeling may help to unlock many of the mysteries in obesity, insulin resistance, MetS, T2DM, and the associated complications of diabetic end-organ disease.     

Lipid Metabolism Is Dysregulated before,during and after Pregnancy in a Mouse Model of Gestational Diabetes

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.     

Effects of the Lipid Profile,Type 2 Diabetes and Medication on the Metabolic Syndrome—Associated Gut Microbiome

Metabolic syndrome (MetSyn) is a major health problem affecting approximately 25% of the worldwide population. Since the gut microbiota is highly connected to the host metabolism, several recent studies have emerged to characterize the role of the microbiome in MetSyn development and progression. To this end, our study aimed to identify the microbiome patterns which distinguish MetSyn from type 2 diabetes mellitus (T2DM). We performed 16S rRNA amplicon sequencing on a cohort of 70 individuals among which 40 were MetSyn patients. The microbiome of MetSyn patients was characterised by reduced diversity, loss of butyrate producers (Subdoligranulum, Butyricicoccus, Faecalibacterium prausnitzii) and enrichment in the relative abundance of fungal populations. We also show a link between the gut microbiome and lipid metabolism in MetSyn. Specifically, low-density lipoproteins (LDL) and high-density lipoproteins (HDL) display a positive effect on gut microbial diversity. When interrogating the signature of gut microbiota in a subgroup of patients harbouring both MetSyn and T2DM conditions, we observed a significant increase in taxa such as Bacteroides, Clostridiales, and Erysipelotrichaceae. This preliminary study shows for the first time that T2DM brings unique signatures of gut microbiota in MetSyn patients. We also highlight the impact of metformin treatment on the gut microbiota. Metformin administration was linked to changes in Prevotellaceae, Rickenellaceae, and Clostridiales. Further research focusing on the microbiome-metabolome patterns is needed to clarify the exact association of various gut microbial communities with the progression of T2DM and the occurrence of various complications in MetSyn patients.     

Triglyceride/High-Density Lipoprotein Cholesterol Ratio: A Clue to Metabolic Syndrome,Insulin Resistance,and Severe Atherosclerosis

High serum levels of triglycerides (Tg) and low levels of high-density lipoprotein cholesterol (HDL-C) are characteristic of the Metabolic Syndrome (MetS). We assessed the ratio of Tg to HDL-C as a way to identify MetS and insulin resistance. We also evaluated its association with severity of carotid atherosclerosis. Data were analyzed from three cohorts totaling 13,908 participants. MetS was defined according to the International Diabetes Federation criteria. Optimal cut-off for Tg/HDL-C ratio was obtained using Youden's index in receiver-operating characteristic (ROC) curve analyses. The risk of MetS and IR in those with a Tg/HDL-C ratio above the optimum cutoff was evaluated by logistic regression analysis. A Tg/HDL-C ratio above the optimal cutoff level significantly increased the odds ratio for MetS in the three cohorts (OR 6.00, 4.04, and 3.50, least in the healthy population), identified insulin resistance defined by the homeostatic model of insulin resistance (HOMA-IR) (p < 0.0001), and was strongly associated with atherosclerosis severity (p = 0.0001). Tg/HDL-C ratio identifies persons with MetS, insulin resistance, and severe atherosclerosis. It should be used more widely to identify patients at high risk. This is clinically important because insulin resistance is treatable.     

Pleiotropic Effects of APOB Variants on Lipid Profiles,Metabolic Syndrome,and the Risk of Diabetes Mellitus

Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype–phenotype analyses using APOB locus variants. Five APOB nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the APOB locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated APOB variants revealed significant association with prevalent DM (p = 0.0029 and 8.2 × 10⁻⁵, respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare APOB variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported APOB variants associated with the risk of DM through their associations with LDL cholesterol levels.     

Lipid transfers to HDL are diminished in long-term bedridden patients: association with low HDL-cholesterol and increased inflammatory markers

Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long‐term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 ± 36 vs 160 ± 43, p = 0.005), LDL (124 ± 3 vs 96 ± 33 p = 0.003) and HDL‐cholesterol (45 ± 10 vs 36 ± 13, p = 0.008), apolipoprotein A‐I (134 ± 20 vs 111 ± 24, p = 0.001) and oxidized LDL (53 ± 13 vs 43 ± 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL‐cholesterol levels. Concentrations of IL‐1β, IL‐6, IL‐8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL‐cholesterol, apolipoprotein A‐I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition.     

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.     

Gut-Microbial Metabolites,Probiotics and Their Roles in Type 2 Diabetes

Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.     

Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile,Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum

Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.     

Acrylamide and Potential Risk of Diabetes Mellitus: Effects on Human Population,Glucose Metabolism and Beta-Cell Toxicity

Diabetes mellitus is a frequent endocrine disorder characterized by hyperglycemia. Acrylamide (AA) is food contaminant formed during the high-temperature processing of food rich in carbohydrates and low in proteins. Recent human epidemiological studies have shown a potential association between AA exposure and the prevalence of diabetes in the general population. In male rats, AA treatment promoted pancreatic islet remodeling, which was determined by alpha-cell expansion and beta-cell reduction, while in female rats AA caused hyperglycemia and histopathological changes in pancreatic islets. In vitro and in vivo rodent model systems have revealed that AA induces oxidative stress in beta cells and that AA impairs glucose metabolism and the insulin signaling pathway. Animal studies have shown that diabetic rodents are more sensitive to acrylamide and that AA aggravates the diabetic state. In this review, we provide an overview of human epidemiological studies that examined the relation between AA exposure and glucose disorders. In addition, the effects of AA treatment on pancreatic islet structure, beta-cell function and glucose metabolism in animal models are comprehensively analyzed with an emphasis on sex-related responses. Furthermore, oxidative stress as a putative mechanism of AA-induced toxicity in beta cells is explored. Finally, we discuss the effects of AA on diabetics in a rodent model system.     

The Obscure Effect of Tribulus terrestris Saponins Plus Inulin on Liver Morphology,Liver Fatty Acids,Plasma Glucose,and Lipid Profile in SD Rats with and without Induced Type 2 Diabetes Mellitus

Diabetes is a predictor of nonalcoholic fatty liver disease (NAFLD). There are data suggesting that Tribulus terrestris (TT) saponins act as antidiabetic agents and protect against NAFLD. The effect of saponins may be increased by fermentable fibers such as inulin. The aim of the present study was to investigate the influence of TT saponins and TT saponins plus inulin on the plasma lipid profile and liver fatty acids of rats with induced diabetes mellitus type 2 (T2DM). The study was performed on 36 male Sprague–Dawley rats divided into two main groups: control and diabetic. Animals of the diabetic (DM) group were fed a high-fat diet and injected with streptozotocin (low doses). Animals of the control group (nDM) were on a regular diet and were injected with buffer. After the injections, the animals were split into subgroups: three non-diabetic (nDM): (i) control (c-C); (ii) saponin-treated rats (C-Sap); (iii) rats treated with saponins + inulin (C-Sap + IN), and three diabetic subgroups (DM): (iv) control (c-DM); (v) saponin-treated rats (DM-Sap); (vi) rats treated with saponins + inulin (DM-Sap + IN). Liver fatty acids were extracted and analyzed by gas chromatography, and plasma glucose and lipids were measured. The study showed significant changes in liver morphology, liver fatty acids, plasma lipid profile, and plasma glucose. In summary, supplementation with TT saponins or saponins with inulin for one month decreased the level of steatosis in rats with induced type 2 diabetes. Moreover, there were favorable effects on the plasma lipid profile in the rats. However, additional supplementation with inulin had a negative effect on liver morphology (with a microvesicular type of steatosis) in the non-diabetes group. Moreover, supplementation with inulin had a negative effect on plasma glucose in both diabetic and non-diabetic rats. These data show that a diet enriched with fermentable fibers reveals different effects in different organisms, and not all sources and forms of fiber are beneficial to health.     

小檗碱对高脂血症兔脂代谢及肝脏LDLR和SR-B1基因表达的影响

目的研究小檗碱(Berberine,Ber)对高脂血症兔脂代谢及肝脏低密度脂蛋白受体(Low density lipoprotein re-ceptor,LDLR)和B类1型清道夫受体(Scavenger receptor B1,SR-B1)基因表达的影响。方法取新西兰大耳白兔40只,以基础饲料喂养1周后,随机选取8只为普通饲料组(ND),继续以基础饲料喂养;其余32只以高脂饲料喂养;复制高脂血症兔模型。建模8周后,将模型动物随机分为4组:高脂饲料组(HFD)、高脂饲料+非诺贝特组(FD)、高脂饲料+低剂量Ber干预组(BLD)组和高脂饲料+高剂量Ber干预组(BHD),继续喂养8周,采用全自动生化分析仪测定兔血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)的含量;观察肝脏组织病理学变化;实时荧光定量PCR法检测肝脏组织LDLR和SR-B1基因表达的变化。结果 HFD组TC、TG和LDL-C的表达水平较ND组明显升高(P<0.01),肝脏发生中度脂肪变性和水样变性的病理学改变,而经Ber干预后,血清中TC、TG和LDL-C的表达的水平较HFD组显著降低(P<0.01),且肝细胞脂肪变性和水样变性程度较HFD组有所减轻;HFD组LDLR和SR-B1基因mRNA的表达水平明显低于ND组(P<0.01),经Ber干预后,LDLR和SR-B1基因mRNA的表达水平则较HFD组明显上调(P<0.01)。结论 Ber具有明显的调血脂作用,其作用机制可能是通过上调肝脏LDLR和SR-B1基因的表达,进而抑制肝脏中胆固醇的合成。     

Cardiac Autonomic Neuropathy: A Progressive Consequence of Chronic Low-Grade Inflammation in Type 2 Diabetes and Related Metabolic Disorders

Cardiac autonomic neuropathy (CAN) is one of the earliest complications of type 2 diabetes (T2D), presenting a silent cause of cardiovascular morbidity and mortality. Recent research relates the pathogenesis of cardiovascular disease in T2D to an ensuing chronic, low-grade proinflammatory and pro-oxidative environment, being the hallmark of the metabolic syndrome. Metabolic inflammation emerges as adipose tissue inflammatory changes extending systemically, on the advent of hyperglycemia, to reach central regions of the brain. In light of changes in glucose and insulin homeostasis, dysbiosis or alteration of the gut microbiome (GM) emerges, further contributing to inflammatory processes through increased gut and blood–brain barrier permeability. Interestingly, studies reveal that the determinants of oxidative stress and inflammation progression exist at the crossroad of CAN manifestations, dictating their evolution along the natural course of T2D development. Indeed, sympathetic and parasympathetic deterioration was shown to correlate with markers of adipose, vascular, and systemic inflammation. Additionally, evidence points out that dysbiosis could promote a sympatho-excitatory state through differentially affecting the secretion of hormones and neuromodulators, such as norepinephrine, serotonin, and γ-aminobutyric acid, and acting along the renin–angiotensin–aldosterone axis. Emerging neuronal inflammation and concomitant autophagic defects in brainstem nuclei were described as possible underlying mechanisms of CAN in experimental models of metabolic syndrome and T2D. Drugs with anti-inflammatory characteristics provide potential avenues for targeting pathways involved in CAN initiation and progression. The aim of this review is to delineate the etiology of CAN in the context of a metabolic disorder characterized by elevated oxidative and inflammatory load.     

Alzheimer’s Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer’s disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-β accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.     

Hyperinsulinemia and Its Pivotal Role in Aging,Obesity, Type 2 Diabetes,Cardiovascular Disease and Cancer

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.     

Visceral Adipose Tissue Displays Unique Metabolomic Fingerprints in Obesity,Pre-Diabetes and Type 2 Diabetes

Visceral adipose tissue (VAT) metabolic profiling harbors the potential to disentangle molecular changes underlying obesity-related dysglycemia. In this study, the VAT exometabolome of subjects with obesity and different glycemic statuses are analyzed. The subjects (n = 19) are divided into groups according to body mass index and glycemic status: subjects with obesity and euglycemia (Ob+NGT, n = 5), subjects with obesity and pre-diabetes (Ob+Pre-T2D, n = 5), subjects with obesity and type 2 diabetes under metformin treatment (Ob+T2D, n = 5) and subjects without obesity and with euglycemia (Non-Ob, n = 4), used as controls. VATs are incubated in culture media and extracellular metabolite content is determined by proton nuclear magnetic resonance (¹H-NMR). Glucose consumption is not different between the groups. Pyruvate and pyroglutamate consumption are significantly lower in all groups of subjects with obesity compared to Non-Ob, and significantly lower in Ob+Pre-T2D as compared to Ob+NGT. In contrast, isoleucine consumption is significantly higher in all groups of subjects with obesity, particularly in Ob+Pre-T2D, compared to Non-Ob. Acetate production is also significantly lower in Ob+Pre-T2D compared to Non-Ob. In sum, the VAT metabolic fingerprint is associated with pre-diabetes and characterized by higher isoleucine consumption, accompanied by lower acetate production and pyruvate and pyroglutamate consumption. We propose that glucose metabolism follows different fates within the VAT, depending on the individuals’ health status.