Pathophysiology Of Type 2 Diabetes Research Articles

Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes.

Over the last decades, the incidence of type 2 diabetes (T2D) is increasing substantially. Emerging evidences from epidemiological studies have shown the association between higher intake of soy isoflavones and reduced risk of T2D and its associated health risks. Daidzein, a soy isoflavone, has been found to have a promising therapeutic potential in managing T2D pathophysiology. Fermented soybean is the major source of daidzein; however, it can also be formed via the consumption of its glycosylated moiety, daidzin with subsequent hydrolysis by intestinal bacterial enzyme. Many studies reported the prophylactic effect of daidzein on the improvement of hyperglycemia, insulin resistance, dislipidemia, obesity, inflammation, and other complications associated with T2D. The molecular mechanisms underlying the action of daidzein include diverged pathways where daidzein has been shown to interact with several signaling molecules and receptors to achieve desirable effect. Although the specific molecular mechanism is still elusive, further studies are thus needed to understand it in detail. In this review, we discuss the antidiabetic potential of daidzein with respect to the evidences from various clinical, preclinical, and cell culture studies and the underlying molecular mechanism in a precise way to have a comprehensive account on this isoflavone with promising therapeutic potential. © 2018 BioFactors, 44(5):407-417, 2018.

Can We RISE to the Challenge of Youth-Onset Type 2 Diabetes?

Over the past three decades, type 2 diabetes (T2D) in adolescents has become steadily more prevalent (1), raising the specter of increasing rates of premature micro- and macrovascular disease as affected youth move into adulthood. While T2D in adolescents is clearly linked to obesity, there is otherwise no explanation for the sudden appearance of what had previously been an adult condition in young people. Despite a steadily growing body of evidence descriptive of T2D in youth (2,3), there is a paucity of information comparing diabetic phenotypes in adults and teenagers. This issue of Diabetes Care contains three papers from the Restoring Insulin Secretion (RISE) Consortium (4–6) that provide the most direct examination of this question yet, with the potential for new understanding of T2D. Present understanding of the pathophysiology of T2D holds that insulin resistance, generally a consequence related to increased adiposity, requires hyperfunction of pancreatic β-cells to maintain glucose tolerance. People whose β-cells cannot make this compensation progress to steadily worsening states of dysglycemia over time (7). Moreover, although insulin resistance does not necessarily cause β-cell failure, hyperglycemia and its associated metabolic disturbances do, such that insufficiently treated diabetes begets more severe diabetes (8). There is evidence in adults with prediabetes that interventions to alleviate insulin resistance (9) or minimize hyperglycemia (10) reduce progression to worse glucose tolerance. Similarly, intensive glucose lowering in adults with T2D can improve hyperglycemia and mitigate the typical course of disease (11). These findings provide the rationale for the RISE Consortium’s efforts (12). The RISE design paper, published in 2014, provides details of this project (12). Three intervention protocols were established, two in adults and one in children, all testing whether β-cell function and metabolic control could be effectively altered by specific interventions. All three studies recruited and randomized …

Pleiotropic Effects of Totum-63—Simultaneous Targeting of Multiple Diabetes Mediators

In 2015, 30.3 million Americans had diabetes, and 84.1 million Americans had prediabetes. Up to 70% of individuals with prediabetes will eventually develop type 2 diabetes (T2D). Additional intervention strategies are needed to manage prediabetes. The pathophysiology of T2D is complex and characterized by alterations in many tissues. We have previously shown that Totum-63 is effective to prevent glucose homeostasis impairments in rodent models of T2D. In an open phase I/II clinical study, Totum-63 also improved glucose and insulin responses to a standardized breakfast in healthy subjects. In order to better understand the mechanisms involved in the beneficial effects of Totum-63, we have conducted early interventions with oral administration of Totum-63 in high fat-fed mice and in db/db mice. Body weight gain and fat mass accumulation, known as early mediators of insulin-sensitivity defectiveness, were markedly lowered. Liver and skeletal muscle insulin signaling pathways were activated in a similar fashion despite lower circulating insulin levels, suggesting an improvement in insulin sensitivity. Hepatic triglyceride content, known as a powerful inductor of liver insulin resistance, was reduced. Totum-63 administration increased liver gene expression of FGF-21, which has been involved in the regulation of many metabolic pathways. In db/db mice, Totum-63 administration delayed the defect of insulin secretion, suggesting a protective role on pancreatic beta-cells. Finally, Totum-63 also showed preventive effects on high fat diet-induced gut microbiota dysbiosis, that has been postulated as a key driver of many metabolic disturbances. In conclusion, Totum-63 displays pleiotropic beneficial effects on tissues known as major contributors to T2D development. Totum-63 is a promising intervention strategy to prevent T2D development, and is currently under investigation in phase II clinical trial. Disclosure V. Chavanelle: Employee; Self; Valbiotis. Y.F. Otero: Employee; Self; Valbiotis. P. Sirvent: Employee; Self; Valbiotis. P.D. Cani: Research Support; Self; Tate&Lyle. Consultant; Self; Biocodex. Stock/Shareholder; Self; A-Mansia Biotech SA. Research Support; Self; Pilèje, Valbiotis. S. Peltier: Board Member; Self; Valbiotis.

Dietary Flavonoids in the Prevention of T2D: An Overview.

Type 2 diabetes (T2D) is a progressive metabolic disease that is increasing in prevalence globally. It is well established that insulin resistance (IR) and a progressive decline in functional β-cell mass are hallmarks of developing T2D. Obesity is a leading pathogenic factor for developing IR. Constant IR will progress to T2D when β-cells are unable to secret adequate amounts of insulin to compensate for decreased insulin sensitivity. Recently, a considerable amount of research has been devoted to identifying naturally occurring anti-diabetic compounds that are abundant in certain types of foods. Flavonoids are a group of polyphenols that have drawn great interest for their various health benefits. Results from many clinical and animal studies demonstrate that dietary intake of flavonoids might be helpful in preventing T2D, although cellular and molecular mechanisms underlying these effects are still not completely understood. This review discusses our current understanding of the pathophysiology of T2D and highlights the potential anti-diabetic effects of flavonoids and mechanisms of their actions.

RNA-Seq Analysis of Islets to Characterise the Dedifferentiation in Type 2 Diabetes Model Mice db/db.

Type 2 diabetes (T2D) is a global health issue and dedifferentiation plays underlying causes in the pathophysiology of T2D; however, there is a lack of understanding in the mechanism. Dedifferentiation results from the loss of function of pancreatic β-cells alongside a reduction in essential transcription factors under various physiological stressors. Our study aimed to establish db/db as an animal model for dedifferentiation by using RNA sequencing to compare the gene expression profile in islets isolated from wild-type, db/+ and db/db mice, and qPCR was performed to validate those significant genes. A reduction in both insulin secretion and the expression of Ins1, Ins2, Glut2, Pdx1 and MafA was indicative of dedifferentiation in db/db islets. A comparison of the db/+ and the wild-type islets indicated a reduction in insulin secretion perhaps related to the decreased Mt1. A significant reduction in both Rn45s and Mir6236 was identified in db/+ compared to wild-type islets, which may be indicative of pre-diabetic state. A further significant reduction in RasGRF1, Igf1R and Htt was also identified in dedifferentiated db/db islets. Molecular characterisation of the db/db islets was performed via Ingenuity analysis which identified highly significant genes that may represent new molecular markers of dedifferentiation.

The effect of non-TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis.

Inflammatory arthritides are chronic diseases characterised by an increase in cardiovascular risk, largely attributable to the synergy between high-grade systemic inflammation and an elevated prevalence of traditional cardiovascular risk factors. Amongst the latter, insulin resistance and type 2 diabetes (T2D) play a key position. Previous studies demonstrated a potential insulin-sensitizing effect of anti-TNF biologic medications. For converse, less is known about the role of newer biologics or small molecules. For this reason, we performed a systematic review of the literature in order to identify the available data on the effect on insulin resistance of non-TNF targeting biologics and small molecules approved for the treatment of inflammatory arthritides. The search strategy initially retrieved 486 records of which only 10 articles were selected for inclusion in the final review. According to the available evidence, some of the newest molecules, in particular tocilizumab and abatacept, may have a role in improving insulin sensitivity; for converse, anakinra-mediated effect on glucose metabolism may exploit different facets of T2D pathophysiology, such as the preservation of beta-cell function. However, the data available on this issue are largely inconsistent and future, adequately designed studies are still needed to clarify the differential impact of novel therapeutics on individual pathophysiological features of T2D and other emerging cardiovascular risk factors.

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662075, associated with a twofold increased risk for T2D in males. rs146662075 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

Disentangling the Role of Melatonin and its Receptor MTNR1B in Type 2 Diabetes: Still a Long Way to Go?

Type 2 diabetes (T2D) is a complex genetic metabolic disorder. T2D heritability has been estimated around 40-70%. In the last decade, exponential progress has been made in identifying T2D genetic determinants, through genome-wide association studies (GWAS). Among single-nucleotide polymorphisms mostly associated with T2D risk, rs10830963 is located in the MTNR1B gene, encoding one of the two receptors of melatonin, a neurohormone involved in circadian rhythms. Subsequent studies aiming to disentangle the role of MTNR1B in T2D pathophysiology led to controversies. In this review, we will tackle them and will try to give some directions to get a better view of MTNR1B contribution to T2D pathophysiology. Recent studies either based on genetic/genomic analyses, clinical/epidemiology data, functional analyses at rs10830963 locus, insulin secretion assays in response to melatonin (involving or not MTNR1B) or animal model analyses have led to strong controversies at each level of interpretation. We discuss possible caveats in these studies and present ways to go beyond these issues, towards a better understanding of T2D molecular mechanisms, keeping in mind that melatonin is a versatile hormone and regulates many functions via its primary role in the body clock.

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Cutting the brakes to prevent Type 2 Diabetes onset: augmenting insulin secretion and conserving pancreatic beta‐cell mass by deleting Gαz

The hyperglycemia of Type 2 Diabetes (T2D) results from a combination of factors, including insulin resistance, impaired and inefficient insulin secretion, and destruction of pancreatic beta‐cells. The second messenger molecule, cyclic AMP (cAMP), amplifies glucose‐stimulated insulin secretion and has been suggested to preserve beta‐cell mass. Pathways that inhibit beta‐cell cAMP production are pathologically upregulated in T2D. One such pathway is mediated by Prostaglandin E2 (PGE2) receptor 3 (EP3), a G protein‐coupled receptor whose expression, as well as that of its natural ligand, PGE2, are both up‐regulated in islets collected from T2D mice and humans. While EP3 is ubiquitously expressed, in the beta‐cell it couples to a unique and non‐ubiquitously expressed G protein, Gz. We hypothesized the genetic elimination of the catalytic a‐subunit of Gz (Gαz) would augment beta‐cell function and mass, preventing or delaying the onset of hyperglycemia in the BTBR ob/ob mouse model of T2D. As expected, Gαz‐null ob/ob mice were as obese and as insulin resistant as wild‐type ob/ob mice, consistent with little to no liver, adipose, or muscle Gaz expression, but displayed near‐normal fasting blood glucose levels. Fasting euglycemia in Gaz‐null ob/ob mice correlated directly with elevated plasma insulin levels, suggesting that Gαz‐null ob/ob beta‐cells were able to better compensate for the increased insulin demand of obesity and insulin resistance. To test this directly, we isolated islets from Gaz‐null and wild‐type ob/ob mice, and found higher insulin content and insulin secretion from Gaz‐null ob/ob islets. To further elucidate the molecular mechanisms augmenting beta cell function in Gaz‐null ob/ob islets, we considered the influence of Gaz on glucagon‐like peptide‐1 (GLP‐1), which is a cAMP‐stimulatory gut/islet hormone. We postulated that, in the beta‐cell, Gaz signaling competes with GLP‐1 receptor signling to block the full effects of GLP‐1 on beta‐cell function and/or mass. To test this hypothesis, we subjected wild‐type and Gaz‐null ob/ob mice to intraperitoneal and oral glucose challenge, and found the Gaz‐null mutation partially restored glucose tolerance after an oral glucose challenge but not an intraperitoneal glucose challenge. Plasma levels of the GLP‐1 were not different between the genotypes, but intra‐islet GLP‐1 produced and secreted by alpha cells was altered in Gaz‐null ob/ob islets. Increased GLP‐1 responsiveness of Gaz‐null ob/ob islets was tested directly ex‐vivo by treatment with the stable GLP‐1 analog, exendin‐4. In sum, we identified a key role for Gαz in the islet pathophysiology of T2D and confirmed that deleting Gaz allowed for a more efficient response of the beta‐cell to a physiologic potentiator of insulin secretion and beta‐cell mass, GLP‐1.Support or Funding InformationMolecular and Applied Nutrition Training Program T32

Review: Biomarkers and Role in the Prediction and Detection of Type 2 Diabetes and Its Complications

Biomarkers are Novel and Revered Tools and Technologies (NORETs) which have helped previous studies anticipate diverse disease conditions and complications as well as provide similarly close prognosis for them. These NORETs in rare but common studies regarding Type 2 Diabetes (T2D) has helped health care professionals and scientists identify health-worthy indications relating to T2D complications and potential risk factors. Biomarkers in its own way debuting in the diagnosis and prognosis of T2D has provided health care professionals with the basic kits of understanding how these diseases manifest from seemingly mild problems which we often times ignore to complicated problems, also indicating possible causes. In this study, the pathophysiology of T2D was subtly exhausted pointing the focus towards the rapidly modifying metabolic manifestations of T2D as well as its risk complications. This study thus reveals the on-going advancement of biomarkers in fully understanding, identifying, diagnosing and treating T2D

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target.

Recent advances in the development of protein tyrosine phosphatase 1B inhibitors for Type 2 diabetes.

Diabetes mellitus is the most serious and prevalent metabolic disorders worldwide, complications of which can decrease significantly the quality of life and contribute to premature death. Resistance to insulin is a predominant pathophysiological factor of Type 2 diabetes (T2D). Protein tyrosine phosphatase 1B (PTP1B) is an important negative factor of insulin signal and a potent therapeutic target in T2D patients. This review highlights recent advances (2012-2015) in research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of T2D, and novel PTP1B inhibitors with an emphasis on their chemical structures and modes of action.

Endocrine and metabolic diurnal rhythms in young adult men born small vs appropriate for gestational age.

Sleep disturbances and alterations of diurnal endocrine rhythms are associated with increased risk of type 2 diabetes (T2D). We previously showed that young men born small for gestational age (SGA) and with increased risk of T2D have elevated fat and decreased glucose oxidation rates during nighttime. In this study, we investigated whether SGA men have an altered diurnal profile of hormones, substrates and inflammatory markers implicated in T2D pathophysiology compared with matched individuals born appropriate for gestational age (AGA). We collected hourly blood samples for 24 h, to measure levels of glucose, free fatty acids (FFA), triglycerides (TG), insulin, C-peptide, leptin, resistin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), incretins (GLP-1 and GIP), and inflammatory markers (TNF-α and IL-6) in 13 young men born SGA and 11 young men born AGA. Repeated measurements analyses were used to analyze the diurnal variations and differences between groups. The SGA subjects had increased 24-h glucose (P=0.03), glucagon (P=0.03) and resistin (P=0.003) levels with no difference in diurnal rhythms compared with AGA controls. We found significant diurnal variations in levels of blood glucose, plasma TG, FFA, insulin, C-peptide, GLP-1, GIP, leptin, visfatin, TNF-α, IL-6 and PAI-1. The variation in FFA levels differed between the groups during the evening. Plasma ghrelin and glucagon levels did not display diurnal variations. Young men born SGA exhibit elevated 24-h blood glucose, and plasma glucagon and resistin levels with no major differences in diurnal rhythms of these or other key metabolic hormones, substrates or inflammatory markers implicated in the origin of adiposity and T2D.

Considerations for Defining Cytokine Dose, Duration, and Milieu That Are Appropriate for Modeling Chronic Low-Grade Inflammation in Type 2 Diabetes.

Proinflammatory cytokines have been implicated in the pathophysiology of both type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D is an autoimmune disease involving the adaptive immune system responding to pancreatic beta-cells as antigen-presenting cells. This attracts immune cells that surround pancreatic islets (insulitis) and secrete cytokines, such as IL-1beta, IFN-gamma, and TNF-alpha, in close proximity to pancreatic beta-cells. In contrast, there is little evidence for such a focused autoimmune response in T2D. Instead, the innate immune system, which responds to cellular damage and pathogens, appears to play a key role. There are three major sources of proinflammatory cytokines that may impact islet/beta-cell function in T2D: (1) from islet cells, (2) from increased numbers of intraislet macrophages/immune cells, and (3) from increased circulating levels of proinflammatory cytokines due to obesity, presumably coming from inflamed adipose tissue. These differences between T1D and T2D are reflected by significant differences in the cytokine concentration, duration, and milieu. This review focuses on chronic versus acute cytokine action, cytokine concentrations, and cytokine milieu from the perspective of the pancreatic islet in T2D. We conclude that new cytokine models may be needed to reflect the pathophysiology of T2D more effectively than what are currently employed.

Association of a Pro-Inflammatory Axis Comprised By TSP1-TGF-CTGF/CCN2 with a Decrease in Mir-19a-3p in the Pathophysiology of Diabetic Retinopathy

Diabetic retinopathy (DR) is the leading cause of legal blindness in working age adults in the United States with about 18 thousand new cases of blindness each year. Approximately 75% of patients with type-2 diabetes will develop some sign of retinopathy after 15 years. The healthcare costs associated with diabetes related vision loss has been estimated at $500 million annually and the cost rises significantly with the severity of DR. Therefore, preventing the progression of DR from mild non-progressive diabetic retinopathy (NPDR) to progressive diabetic retinopathy (PDR) could ameliorate the economic burden related to diabetes and vision loss. Our laboratory has focused on a pro-inflammatory axis comprised by thrombospondin-1 (TSP1), transforming growth factor β (TGFb) and connective tissue growth factor (CTGF/CCN2) in the pathophysiology of DR. Furthermore, the regulation of this pro-inflammatory axis during disease states in humans associated with acute and chronic inflammation such as type-2 diabetes has not been elucidated. The current prospective study documents a potential regulatory mechanism, namely a microRNA associated with the up-regulation of the pro-inflammatory axis. Patients were recruited between February 2013 to May 2014. In May of 2015 it was determined by this research team that the data was mature for final analysis and, thus the results are the topic of this abstract. The participants were patients with type-2 diabetes (n=36) with either evidence of non-proliferative diabetic retinopathy (NPDR Group, n=16), or with evidence of proliferative diabetic retinopathy (PDR Group, n=20) as well as non-diabetic human subjects (Control Group, n=21). Each patient's history and duration of diabetes was obtained from the medical electronic records.TSP1 was found significantly increased in the NPDR (502±145.03 ng/ml, p<0.05) and PDR (1033.9±136 ng/ml, p<0.001) groups when compared to control group (167±41.9 ng/ml). TGF-β was found significantly increased in the NPDR (32.0±4.49 pg/ml, p<0.001) and PDR (7.75±1.7 pg/ml, p<0.05) groups when compared to control (0.75±0.05 pg/ml). CTGF/CCN2 was found significantly increased in the NPDR and PDR groups, namely 3.69±1.52 ng/ml (p<0.001) and 1.69±0.4 ng/ml (p<0.05) respectively when compared to the control group (0.25±0.049 ng/ml). Tumor necrosis factor-α was found significantly increased (17.3±2.1 pg/ml, p<0.05) in the NPDR group but not in the PDR group (trend for higher levels) when compared to control group (9.61±0.74 pg/ml). Interleukin-4 was found decreased in both the NPDR (1.54±0.23 pg/ml, p<0.05) and the PDR (2.02±0.26, p<0.05) groups when compared with the control group (5.42±1.63 pg/ml). IL-4 recently has been documented as an important regulator of lipid metabolism.When comparing the three groups using an ANOVA, one microRNA, namely miR-19a-3p was found to be the most strongly differentially expressed using a cutoff p-value ≤ 0.05 after a Benjamini-Hochberg correction for multiple testing, recommended when doing panel or array profiling. Figure 1 panel A shows the expression level centered to assay average for miR-19a-3p detected in most samples. Panel B clearly illustrates a significant decrease in miR-19a-3p in both groups, namely NPDR (p<0.0012) and PDR (p<0.049).Interestingly down-regulation of miR-19a was found independent of progression of disease suggesting that the differential expression seen in our study in the NPDR and PDR groups is inherent to the underlying disease. These last observations including the mechanistic steps involved are currently under investigation in our laboratory, since understanding, how the down-regulation of miR-19a leads to up-regulation of TSP1-TGFb-CTGF/CCN2, might have a two-fold potential value in type-2 diabetes. First, it can be used as a biomarker for early diagnosis, prognosis and therapeutic response. Second, a therapeutic approach would be able to restore the mature miRNA levels in the proper tissue/cells. In summary our results support the role of a pro-inflammatory axis in the pathophysiology of type-2 diabetes as a result of differential expression of miR-19a. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thrombin stimulates insulin secretion via protease-activated receptor-3

The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes (‘module’) including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a ‘tethered ligand’ to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca2+ release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D.

Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.

Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.

Global Gene Expression Profiling in Omental Adipose Tissue of Morbidly Obese Diabetic African Americans.

Adipose tissues play important role in the pathophysiology of obesity-related diseases including type 2 diabetes (T2D). To describe gene expression patterns and functional pathways in obesity-related T2D, we performed global transcript profiling of omental adipose tissue (OAT) in morbidly obese individuals with or without T2D. Twenty morbidly obese (mean BMI: about 54 kg/m2) subjects were studied, including 14 morbidly obese individuals with T2D (cases) and 6 morbidly obese individuals without T2D (reference group). Gene expression profiling was performed using the Affymetrix U133 Plus 2.0 human genome expression array. Analysis of covariance was performed to identify differentially expressed genes (DEGs). Bioinformatics tools including PANTHER and Ingenuity Pathway Analysis (IPA) were applied to the DEGs to determine biological functions, networks and canonical pathways that were overrepresented in these individuals. At an absolute fold-change threshold of 2 and false discovery rate (FDR) < 0.05, 68 DEGs were identified in cases compared to the reference group. Myosin X (MYO10) and transforming growth factor beta regulator 1 (TBRG1) were upregulated. MYO10 encodes for an actin-based motor protein that has been associated with T2D. Telomere extension by telomerase (HNRNPA1, TNKS2), D-myo-inositol (1, 4, 5)-trisphosphate biosynthesis (PIP5K1A, PIP4K2A), and regulation of actin-based motility by Rho (ARPC3) were the most significant canonical pathways and overlay with T2D signaling pathway. Upstream regulator analysis predicted 5 miRNAs (miR-320b, miR-381-3p, miR-3679-3p, miR-494-3p, and miR-141-3p,) as regulators of the expression changes identified. This study identified a number of transcripts and miRNAs in OAT as candidate novel players in the pathophysiology of T2D in African Americans.

Genetics of Type 2 Diabetes: Advances and Future Prospect

Type 2 diabetes (T2D) is a complex metabolic disorder with an increasing incidence worldwide. The disease is characterized by a combination of impairment in insulin secretion from pancreatic beta cells and insulin resistance of peripheral tissues, especially muscle and liver, resulting from interaction between multiple environmental and genetic factors. Life-style changes and obesity are the major causes for the current epidemic of T2D. The rapidly increasing prevalence of Type 2 diabetes makes it a major healthcare problem worldwide. In the developing nations this poses a serious health care burden. In recent years there has been a swing in the onset to younger age group. To date, Genome-Wide Association Scan (GWAS) studies have identified more than 65 common genetic variants associated with T2D or glucose/insulin levels. The recently discovered genes by GWAS suggest a shift from genes involved in insulin action to those involved in insulin secretion, indicating pivotal role of beta- cell dysfunction in the pathogenesis of T2D. However, in most cases the causal variants are not known. Also, the molecular mechanism of the patho-physiology of the disease is still obscure. Functional studies will be required to identify the mechanisms by which the associated signals impair islet function and increase risk of T2D. Understanding the pathophysiology of T2D will provide new and useful information(s) for prevention of the disease and development of new drugs for the treatment of T2D. Pharmacogenetics is another promising clinical application of the genetic findings for T2D. Also, efforts are being made to understand the genetic basis of differences in disease susceptibility by studying the genetic variations among different populations, an area that is important for the future of medicine.