Identification of Novel Type 2 Diabetes Candidate Genes Involved in the Crosstalk between the Mitochondrial and the Insulin Signaling Systems

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein–protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10⁻⁵). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.     

The involvement of microRNAs in Type 2 diabetes

T2D (Type 2 diabetes mellitus) is a major health issue that has reached epidemic status worldwide. T2D is a progressive metabolic disorder characterized by reduced insulin sensitivity, insulin resistance and pancreatic β-cell dysfunction. Improper treatment of TD2 can lead to severe complications such as heart disease, stroke, kidney failure, blindness and nerve damage. The aetiology and molecular mechanisms of T2D are not fully understood, but compelling evidence points to a link between T2D, obesity, dyslipidaemia and insulin resistance. Although T2D seems to be strongly linked to environmental factors such as nutrition and lifestyle, studies have shown that genetic factors, such as polymorphisms associated with metabolic genes, imprinting, fetal programming and miRNA (microRNA) expression, could also contribute to the development of this disease. miRNAs are small 22-25-nt-long untranslated RNAs that negatively regulate the translation of mRNAs. miRNAs are involved in a large number of biological functions such as development, metabolism, immunity and diseases such as cancer, cardiovascular diseases and diabetes. The present review examines the various miRNAs that have been identified as being potentially involved in T2D, focusing on the insulin-sensitive organs: white adipose tissue, liver, skeletal muscle and the insulin-producing pancreatic β-cells.     

Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes

The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.     

Increased Aβ production prompts the onset of glucose intolerance and insulin resistance

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.     

Oxymatrine ameliorates insulin resistance in rats with type 2 diabetes by regulating the expression of KSRP,PETN, and AKT in the liver

Insulin resistance plays a key role in the development and progression of type 2 diabetes mellitus (T2DM). Recent studies found that insulin resistance was associated with the dysfunction of KH-type splicing regulatory protein (KSRP) expression and AKT pathway, and that oxymatrine possesses an antidiabetic effect. The aim of the present study was to investigate whether the protection of oxymatrine against T2DM was associated with the modulation of the KSRP expression and AKT pathway. Sprague-Dawley rats were fed a high-fat diet and injected with streptozotocin intraperitoneally to induce T2DM, which led to an increase in blood glucose levels and insulin resistance, and a decrease in insulin sensitivity and glycogen synthesis concomitant with KSRP downregulation, PTEN upregulation, and AKT phosphorylation deficiency. The administration of oxymatrine decreased blood glucose levels and insulin resistance, increased insulin sensitivity, and improved glycogen synthesis in the liver of T2DM rats, through a reversal in the expression of KSRP, PTEN, and AKT. On the basis of these observations, we concluded that oxymatrine can protect T2DM rats from insulin resistance through the regulation of the KSRP, PETN, and AKT expression in the liver.     

Genetic predisposition to type 2 diabetes is associated with impaired insulin secretion but does not modify insulin resistance or secretion in response to an intervention to lower dietary saturated fat

Genome-wide association studies have identified SNPs reproducibly associated with type 2 diabetes (T2D). We examined the effect of genetic predisposition to T2D on insulin sensitivity and secretion using detailed phenotyping in overweight individuals with no diagnosis of T2D. Furthermore, we investigated whether this genetic predisposition modifies the responses in beta-cell function and insulin sensitivity to a 24-week dietary intervention. We genotyped 25 T2D-associated SNPs in 377 white participants from the RISCK study. Participants underwent an IVGTT prior to and following a dietary intervention that aimed to lower saturated fat intake by replacement with monounsaturated fat or carbohydrate. We composed a genetic predisposition score (T2D-GPS) by summing the T2D risk-increasing alleles of the 25 SNPs and tested for association with insulin secretion and sensitivity at baseline, and with the change in response to the dietary intervention. At baseline, a higher T2D-GPS was associated with lower acute insulin secretion (AIRg 4% lower/risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si). T2D-GPS did not modify changes in insulin secretion, insulin sensitivity or the disposition index in response to the dietary interventions to lower saturated fat. Participants genetically predisposed to T2D have an impaired ability to compensate for peripheral insulin resistance with insulin secretion at baseline, but this does not modify the response to a reduction in dietary saturated fat through iso-energetic replacement with carbohydrate or monounsaturated fat.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-012-0284-8) contains supplementary material, which is available to authorized users.     

SOCS and diabetes—ups and downs of a turbulent relationship

Diabetes mellitus is one of the most emerging diseases threatening the present world. Thus, intensive investigations are carried out to better understand the mechanisms occurring in type 1 (T1D) and 2 (T2D) diabetes, and to elaborate more potent methods to fight the disease. In this aspect, the suppressors of cytokine signalling (SOCS) are one of the most studied factors of recent years. SOCS proteins have been discovered as cytokine pathway inhibitors; however, presently, their influence seems wider. Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β‐cell failure and eventually T1D and T2D. They are also involved in complications related with diabetes, such as retinopathy, nephropathy and cardiomyopathy. In T1D, SOCS proteins regulate β‐cell mass, mediate resistance to damaging factors and improve pancreatic islet graft survival. Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. However, not all of the present data are consistent, and thus, further studies are required. Finally, for several pharmacologically active substances of importance regarding the treatment of diabetes, SOCS‐modulating properties have already been described. Here, we review the findings of SOCS–diabetes relations of the last decade. Copyright © 2013 John Wiley & Sons, Ltd.     

Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice

We previously reported that ubiquitin-specific protease (USP) 2 in macrophages down-regulates genes associated with metabolic diseases, suggesting a putative anti-diabetic role for USP2 in macrophages. In this study, we evaluate this role at both cellular and individual levels. Isolated macrophages forcibly expressing Usp2a, a longer splicing variant of USP2, failed to modulate the insulin sensitivity of 3T3-L1 adipocytes. Similarly, macrophage-selective overexpression of Usp2a in mice (Usp2a transgenic mice) had a negligible effect on insulin sensitivity relative to wild type littermates following a three-month high-fat diet. However, Usp2a transgenic mice exhibited fewer M1 macrophages in their mesenteric adipose tissue. Following a six-month high-fat diet, Usp2a transgenic mice exhibited a retarded progression of insulin resistance in their skeletal muscle and liver, and an improvement in insulin sensitivity at an individual level. Although conditioned media from Usp2a-overexpressing macrophages did not directly affect the insulin sensitivity of C2C12 myotubes compared to media from control macrophages, they did increase the insulin sensitivity of C2C12 cells after subsequent conditioning with 3T3-L1 cells. These results indicate that macrophage USP2A hampers obesity-elicited insulin resistance via an adipocyte-dependent mechanism.     

Gurmarin sensitivity of sweet taste responses is associated with co-expression patterns of T1r2, T1r3, and gustducin

Gurmarin (Gur) is a peptide that selectively suppresses sweet taste responses in rodents. The inhibitory effect of Gur differs among tongue regions and mouse strains. Recent studies demonstrated that co-expression levels of genes controlling sweet receptors (T1r2/T1r3 heterodimer) versus Gα-protein, gustducin, are much lower in Gur-insensitive posterior circumvallate papillae than in Gur-sensitive anterior fungiform papillae. Here, we investigated the potential link of Gur-sensitivity with the co-expression for T1r2/T1r3 receptors and gustducin by comparing those of taste tissues of Gur-sensitive (B6, dpa congenic strains) and Gur-weakly-sensitive (BALB) strains. The results indicated that co-expression ratios among T1r2, T1r3, and gustducin in the fungiform papillae were significantly lower in Gur-weakly-sensitive BALB mice than in Gur-sensitive B6 and dpa congenic mice. This linkage between Gur-sensitivity and co-expression for T1r2/T1r3 receptors versus gustducin suggests that gustducin may be a key molecule involved in the pathway for Gur-sensitive sweet responses.     

Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3

Vitamin D status and the relationship between serum 25(OH) vitamin D concentrations and the components of insulin resistance were examined in 120 patients with chronic kidney disease stage 2 and 3. Insulin sensitivity/resistance was calculated by the quantitative insulin sensitivity check index (QUICKI). In this analysis, the prevalence of insulin resistance was 42 %. Only 17 % of patients had serum 25(OH) vitamin D concentration in the recommended range (>/=30 ng/ml), 42 % suffered from vitamin D insufficiency and 41 % had moderate vitamin D deficiency. Insulin resistance significantly correlated with serum 25(OH)D and 1,25(OH)(2)D concentrations, renal function and protein excretion rate. Our results support the increasing evidence that vitamin D deficiency may be one of the factors participating in the development of insulin resistance already in the early stages of chronic kidney disease.     

Insulin Resistance is Associated with MCP1-Mediated Macrophage Accumulation in Skeletal Muscle in Mice and Humans

Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.     

鞘脂类对胰岛素信号的调控——Ⅱ型糖尿病研究的新兴领域

胰岛素抵抗是Ⅱ型糖尿病的病理基础之一,近年来已成为Ⅱ型糖尿病研究的关键和热点．众多研究发现,机体内鞘脂类物质水平的改变直接影响胰岛素信号的强弱．神经酰胺和神经节苷脂GM3对胰岛素信号具有负向调控作用,介导胰岛素抵抗的形成,该调节效应依赖于细胞膜上微囊蛋白．1-磷酸鞘氨醇则通过氧化还原途径增强胰岛素信号．微囊蛋白功能性活动和1-磷酸鞘氨醇的介导作用均与钙信号相关,因此,可通过实时检测细胞外钙内流和细胞内钙瞬间变化,从离子通道水平进一步探索鞘脂类调节胰岛素信号的相关机制．本文综述了鞘脂类物质调控胰岛素信号的机制,干预鞘脂类水平和改善胰岛素抵抗的策略,将为鞘脂类物质在Ⅱ型糖尿病预防和治疗的研究及应用提供有力的帮助．     

Dysregulation of microRNA-125a contributes to obesity-associated insulin resistance and dysregulates lipid metabolism in mice

Obesity is associated with an increased risk of developing insulin resistance (IR) and type 2 diabetes (T2D). A diverse group of factors including miRNA has been implicated in the pathogenesis of these two metabolic conditions, although underlying molecular mechanisms involved are not well defined. Here, we provide evidence that hepatic miR-125a levels are diminished in both genetic as well as dietary mouse models of obesity. Overexpression of miR-125a enhanced insulin signaling and attenuated cellular lipid accumulation in HepG2 cells and Hepa1–6 cells. Likewise, treatment of mice with ago-miR-125a increased insulin sensitivity, similar to overexpression of miR-125a, whereas treatment of mice with antago-miR-125a blunted the insulin sensitivity. Furthermore, overexpression of miR-125a in mice previously fed a high-fat diet (HFD), significantly improved insulin sensitivity, and attenuated obesity-linked hepatic steatosis and hepatocyte lipid accumulation. In addition, we show that ELOVL fatty acid elongase 6 (Elovl6) is a direct target of miR-125a, and participates in miR-125a mediated regulation of insulin sensitivity and lipid metabolism. These data led us to conclude that dysregulated miR-125a expression augments the development of obesity-induced IR and that miR-125a might serve as a therapeutic target for the development of new drug(s) in the clinical management of metabolic diseases.     

2 型糖尿病合并非酒精性脂肪肝病患者IGF-1 与胰岛素抵抗关系研究

研究胰岛素样生长因子-1(IGF-1)与2型糖尿病(T2DM)胰岛素抵抗关系。有研究证实给予IGF-1后,可改善胰岛素抵抗、肝脏脂质代谢,IGF-1基因缺失的动物会产生胰岛素抵抗和高胰岛素血症,低水平的IGF-1还可能与非酒精性脂肪肝病(NAFLD)肝纤维化有关,而T2DM和NAFLD与胰岛素抵抗共存,T2DM合并NAFLD患者IGF-1水平更低。IGF-1与胰岛素抵抗关系密切,IGF-1水平能反映胰岛素抵抗的严重程度,为IGF-l在今后治疗T2DM和NAFLD的提供了潜在的临床应用前景。