Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Obesity and type 2 diabetes are concomitant with low-grade inflammation affecting insulin sensitivity and insulin secretion. Recently, the thioredoxin interacting protein (TXNIP) has been implicated in the activation process of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we aim to determine whether the expression of TXNIP is altered in the circulating immune cells of individuals with type 2 vs type 1 diabetes and whether this can be related to specific causes and consequences of inflammation. METHODS: The expression of TXNIP, inflammatory markers, markers of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress and enzymes involved in sphingolipid metabolism was quantified by quantitative reverse transcription real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) of 13 non-diabetic individuals, 23 individuals with type 1 diabetes and 81 with type 2 diabetes. A lipidomic analysis on the plasma of 13 non-diabetic individuals, 35 individuals with type 1 diabetes and 94 with type 2 diabetes was performed. The effects of ER stress or of specific lipids on TXNIP and inflammatory marker expression were analysed in human monocyte-derived macrophages (HMDMs) and THP-1 cells. RESULTS: The expression of TXNIP and inflammatory and UPR markers was increased in the PBMCs of individuals with type 2 diabetes when compared with non-diabetic individuals or individuals with type 1 diabetes. TXNIP expression was significantly correlated with plasma fasting glucose, plasma triacylglycerol concentrations and specific UPR markers. Induction of ER stress in THP-1 cells or cultured HMDMs led to increased expression of UPR markers, TXNIP, NLRP3 and IL-1ß. Conversely, a chemical chaperone reduced the expression of UPR markers and TXNIP in PBMCs of individuals with type 2 diabetes. The lipidomic plasma analysis revealed an increased concentration of saturated dihydroceramide and sphingomyelin in individuals with type 2 diabetes when compared with non-diabetic individuals and individuals with type 1 diabetes. In addition, the expression of specific enzymes of sphingolipid metabolism, dihydroceramide desaturase 1 and sphingomyelin synthase 1, was increased in the PBMCs of individuals with type 2 diabetes. Palmitate or C2 ceramide induced ER stress in macrophages as well as increased expression of TXNIP, NLRP3 and IL-1ß. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, circulating immune cells display an inflammatory phenotype that can be linked to ER stress and TXNIP expression. Immune cell ER stress can in turn be linked to the specific exogenous and endogenous lipid environment found in type 2 diabetes.

Anti-diabetic activity of fused PPARγ-SIRT1 ligands with limited body-weight gain by mimicking calorie restriction and decreasing SGK1 expression.

A series of benzothiazol-2-one containing α-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds were designed as fused full PPARγ agonist ligands and SIRT1-activating compounds for the treatment of type 2 diabetes (T2D) and its complications. Compound 14d displayed the best in vitro pharmacological profile with full PPARγ agonist activity (Emax = 98%, EC50 = 200 nM), SIRT1 enzymatic activation (+128%) and SGK1 expression inhibition (- 57%) which is known to limit side effects as fluid retention and body-weight gain. Compound 14d showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain by mimicking calorie restriction (CR) and inhibiting SGK1 expression.

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion.

OBJECTIVE: In type 2 diabetes (T2D), pancreatic ß cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress. METHODS: Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis. RESULTS: A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human ß cell lines. CONCLUSION: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of ß cell failure under metabolic stress.

Plasma Dihydroceramides Are Diabetes Susceptibility Biomarker Candidates in Mice and Humans.

Plasma metabolite concentrations reflect the activity of tissue metabolic pathways and their quantitative determination may be informative about pathogenic conditions. We searched for plasma lipid species whose concentrations correlate with various parameters of glucose homeostasis and susceptibility to type 2 diabetes (T2D). Shotgun lipidomic analysis of the plasma of mice from different genetic backgrounds, which develop a pre-diabetic state at different rates when metabolically stressed, led to the identification of a group of sphingolipids correlated with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in the plasma of individuals from two population-based prospective cohorts revealed that specific long-chain fatty-acid-containing dihydroceramides were significantly elevated in the plasma of individuals who will progress to diabetes up to 9 years before disease onset. These lipids may serve as early biomarkers of, and help identify, metabolic deregulation in the pathogenesis of T2D.

Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.

7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds.

[Interaction between environment and genetic background in type 2 diabetes: lessons from animal models]. / Interaction entre facteurs d'environnement et fonds génétique dans le diabète de type 2 - L'apport des modèles animaux.

The respective roles of predisposing genetic factors and environmental factors in the development of type 2 diabetes (T2D) in obese subjects is poorly documented. Rodent models have been set up in an attempt to better understand of the differential effect of a prolonged metabolic stress induced by a high fat diet on glycaemic control according to the genetic background. In utero growth retardation resulting from a hypocaloric diet in pregnant rats induces a dramatic alteration of the development of islet cells leading to diabetes and insulin secretory defects in adult age. Experimentally induced diabetes in rodents results in hyperglycaemia and hyperinsulinemia in the fetus related to accelerated endocrine pancreas maturation responsible for the onset of diabetes in the adult. Deranged metabolic environment during fetal life may therefore further contribute to the onset of diabetes in the adult. Normal mouse strains with different genetic backgrounds show a wide range of responses to a high fat diet, with strains resistant to the diet and other more or less sensitive to the diet, the most sensitive exhibiting obesity diabetes and, insulin deficiency. The inability of the ß cell to respond to the increased insulin demand related to insulin resistance seems to be pivotal in the pathophysiologic process and a new notion is emerging: "nutritional genetics" which studies the influence of nutrients on gene expression.

Analysis of sterol-regulatory element-binding protein 1c target genes in mouse liver during aging and high-fat diet.

BACKGROUND: The sterol regulatory element-binding protein (SREBP) 1c contributes to the transcriptional coordination of cholesterol, fatty acid, and carbohydrate metabolisms. Alterations in these processes accelerate the progression of hepatic steatosis and insulin resistance during aging and obesity. METHODS: Using an ex vivo chromatin immunoprecipitation coupled to microarray (ChIP-on-chip) technique combined with genome-wide gene expression analysis, we analyzed the transcriptomic adaptations mediated by Srebp-1c binding to gene promoters in the liver of mice fed with a low-fat diet or a high-fat diet (HFD) for either 1 or 12 months. RESULTS: Aging had a higher transcriptional impact than HFD and modified the expression of genes involved in fatty acid oxidation and oxidative stress. HFD was associated with a marked induction of genes involved in lipid and cholesterol metabolism. The prolonged high-fat feeding together with the aging effects stimulates inflammatory pathways. ChIP-on-chip applied to aging and HFD analyses revealed that the binding of SREBP-1c to a series of promoters accompanied a paralleled modification of gene expression. Therefore, SREBP-1c could play a role in aging and high-fat feeding through the regulation of genes involved in lipid metabolism and inflammatory response. CONCLUSIONS: This study represents an original ex vivo experiment to elucidate the molecular events involved in metabolic disorders.

S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice.

BACKGROUND AND PURPOSE: Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile. EXPERIMENTAL APPROACH: Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events. KEY RESULTS: S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time. CONCLUSIONS AND IMPLICATIONS: In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.

Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans.

BACKGROUND AND PURPOSE: Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. EXPERIMENTAL APPROACH: Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. KEY RESULTS: GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect. CONCLUSION AND IMPLICATIONS: Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. LINKED ARTICLE: This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x.

Peripheral injections of melanin-concentrating hormone receptor 1 antagonist S38151 decrease food intake and body weight in rodent obesity models.

The compound S38151 is a nanomolar antagonist that acts at the melanin-concentrating hormone receptor 1 (MCH(1)). S38151 is more stable than its purely peptide counterpart, essentially because of the blockade of its N-terminus. Therefore, its action on various models of obesity was studied. Acute intra-cerebroventricular (i.c.v.) administration of S38151 in wild-type rats counteracted the effect of the stable precursor of melanin-concentrating hormone (MCH), NEI-MCH, in a dose-dependent manner (from 0.5 to 50 nmol/kg). In genetically obese Zucker fa/fa rats, daily i.c.v. administration of S38151 induced dose-dependent (5, 10, and 20 nmol/kg) inhibition of food intake, water intake, and body weight gain, as well as increased motility (maximal effect observed at 20 nmol/kg). In Zucker fa/fa rats, intraperitoneal injection of S38151 (30 mg/kg) induced complete inhibition of food consumption within 1 h. Daily intraperitoneal injection of S38151 (10 and 30 mg/kg) into genetically obese ob/ob mice or diet-induced obese mice is able to limit body weight gain. Furthermore, S38151 administration (10 and 30 mg/kg) does not affect food intake, water intake, or body weight gain in MCHR1-deleted mice, demonstrating that its effects are linked to its interaction with MCH(1). These results validate MCH(1) as a target of interest in obesity. S38151 cannot progress to the clinical phase because it is still too poorly stable in vivo.

Effect of oxime ether incorporation in acyl indole derivatives on PPAR subtype selectivity.

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a. Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a, less potent as a dual PPARα/γ activator than 20 c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.

Interleukin-7 regulates adipose tissue mass and insulin sensitivity in high-fat diet-fed mice through lymphocyte-dependent and independent mechanisms.

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions.

Synthesis and evaluation of new polyenic compounds as potential PPARs modulators.

In order to identify new leads for the treatment of type 2 diabetes, polyenic molecules A and B derived from nipecotic acid and dienol derivatives C have been prepared and their effect on PPARs transcriptional activity evaluated and compared to that of rosiglitazone, WY14,643 and GW501516. Among the synthesized compounds, dienol 39 is the most active, increasing WY14,643 PPARα response and demonstrating partial agonist properties on rosiglitazone PPARγ.

Metabolic imbalance of the insulin-like growth factor-I axis in Zucker diabetic fatty rats.

In healthy conditions, insulin-like growth factor-I (IGF-I) acts in a coordinated fashion with insulin to lower glycemia, mainly by increasing insulin sensitivity in peripheral tissues. The aim of this study was to explore the relationship between glucose homeostasis and the endocrine IGF-I axis in Zucker diabetic fatty (ZDF) rats. The plasma levels of glucose, insulin, growth hormone, free IGF-I, total IGF-I (associated to insulin-like growth factor binding proteins plus free), and corticosterone were measured in 13-week-old ZDF rats and in age-matched controls under fasting and postprandial conditions. The plasma IGF-I binding capacity was measured by radioligand binding. In ZDF rats, fasting total and free IGF-I levels were reduced by 22% and 92%, respectively, compared with controls. Postprandial free IGF-I was reduced by 35%, whereas total IGF-I was unaffected. The plasma IGF-I binding capacity in ZDF rats was reduced by 24% after fasting and by 13% under postprandial conditions. A clear correlation between free IGF-I and insulin was observed in postprandial controls but not in ZDF rats. A principal component analysis clearly separated ZDF and control rats into 2 main components under both fasting and postprandial conditions. The first component was determined equally by total IGF-I, bound IGF-I, the free to total IGF-I ratio, and the IGF-I binding capacity. The second component was determined mostly by glucose and insulin. Our results show a marked alteration of the plasma IGF-I levels and of the capacity of plasma to bind IGF-I, and a disturbed relationship between IGF-I and postprandial insulinemia in a rat model of type 2 diabetes mellitus.

Coordinate Transcriptomic and Metabolomic Effects of the Insulin Sensitizer Rosiglitazone on Fundamental Metabolic Pathways in Liver, Soleus Muscle, and Adipose Tissue in Diabetic db/db Mice.

Rosiglitazone (RSG), developed for the treatment of type 2 diabetes mellitus, is known to have potent effects on carbohydrate and lipid metabolism leading to the improvement of insulin sensitivity in target tissues. To further assess the capacity of RSG to normalize gene expression in insulin-sensitive tissues, we compared groups of 18-day-treated db/db mice with increasing oral doses of RSG (10, 30, and 100 mg/kg/d) with untreated non-diabetic littermates (db/+). For this aim, transcriptional changes were measured in liver, inguinal adipose tissue (IAT) and soleus muscle using microarrays and real-time PCR. In parallel, targeted metabolomic assessment of lipids (triglycerides (TGs) and free fatty acids (FFAs)) in plasma and tissues was performed by UPLC-MS methods. Multivariate analyses revealed a relationship between the differential gene expressions in liver and liver trioleate content and between blood glucose levels and a combination of differentially expressed genes measured in liver, IAT, and muscle. In summary, we have integrated gene expression and targeted metabolomic data to present a comprehensive overview of RSG-induced changes in a diabetes mouse model and improved the molecular understanding of how RSG ameliorates diabetes through its effect on the major insulin-sensitive tissues.

Chromosomal mapping of pancreatic islet morphological features and regulatory hormones in the spontaneously diabetic (Type 2) Goto-Kakizaki rat.

Insulin resistance and altered endocrine pancreas function are central pathophysiological features of type 2 diabetes mellitus (T2DM). The Goto-Kakizaki (GK) rat is a model of spontaneous T2DM characterised by reduced beta cell mass and genetically determined glucose intolerance and altered insulin secretion. To identify genetic determinants of endocrine pancreas histopathology, we carried out quantitative trait locus (QTL) mapping of histological phenotypes (beta cell mass -BCM and insulin-positive cell area -IPCA) and plasma concentration of hormones and growth factors in a F2 cohort derived from GK and normoglycemic Brown Norway rats. Although IPCA and BCM in the duodenal region of the pancreas were highly positively correlated (P < 10(-6)), and similarly in the splenic region, both measures were poorly correlated when comparing duodenal and splenic phenotypes. Strongest evidence of linkage to pancreas morphological traits was obtained between BCM and chromosome 10 (LOD 3.2). Evidence of significant linkage (LOD 4.2) to plasma corticosterone was detected in a region of chromosome 1 distal to other QTLs previously identified in the GK. Male-specific genetic effects were detected, including linkages (LOD > 4) to growth hormome (GH) on chromosome 6 and prolactin on chromosome 17. These data suggest independent genetic control of the structure and function of ontologically different regions of the endocrine pancreas. Novel QTLs for corticosterone, prolactin and GH may contribute to diabetes in the GK. The QTLs that we have identified in this, and previous genetic studies collectively underline the complex and multiple mechanisms involved in diabetes in the GK strain.

Synthesis of new 8(S)-HETE analogs and their biological evaluation as activators of the PPAR nuclear receptors.

Structural modifications around 8-HETE (8-hydroxyeicosatetraenoic acid), a natural agonist of the PPAR (peroxisome proliferator-activated receptor) nuclear receptors have led previously to the identification of a promising analog, the quinoline S 70655. Series of novel quinoline or benzoquinoline derivatives were designed through the modification of this lead. Variations of the nature of the aromatic core and of the side chains were carried out. The SAR studies indicated the high sensitivity of the upper acid chain to modifications as well as the strong effect of the length and size of the lipophilic side chain. They afforded several new promising PPARalpha/gamma dual agonists with a high PPARalpha activity in vitro.

Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans.

Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARgamma signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARgamma in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARgamma heterodimerization partner retinoid X receptor alpha (RXRalpha), but not RXRbeta, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRalpha proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARgamma-RXRbeta heterodimers, but not PPARgamma-RXRalpha complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRalpha/RXRbeta ratio resulted in increased PPARgamma responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRalpha initiated by UCH-L1 upregulation modulates the relative affinity of PPARgamma heterodimers for SMRT and their responsiveness to PPARgamma agonists, ultimately activating the PPARgamma-controlled gene network in visceral WAT of obese animals and humans.

Exploring functional beta-cell heterogeneity in vivo using PSA-NCAM as a specific marker.

BACKGROUND: The mass of pancreatic beta-cells varies according to increases in insulin demand. It is hypothesized that functionally heterogeneous beta-cell subpopulations take part in this process. Here we characterized two functionally distinct groups of beta-cells and investigated their physiological relevance in increased insulin demand conditions in rats. METHODS: Two rat beta-cell populations were sorted by FACS according to their PSA-NCAM surface expression, i.e. beta(high) and beta(low)-cells. Insulin release, Ca(2+) movements, ATP and cAMP contents in response to various secretagogues were analyzed. Gene expression profiles and exocytosis machinery were also investigated. In a second part, beta(high) and beta(low)-cell distribution and functionality were investigated in animal models with decreased or increased beta-cell function: the Zucker Diabetic Fatty rat and the 48 h glucose-infused rat. RESULTS: We show that beta-cells are heterogeneous for PSA-NCAM in rat pancreas. Unlike beta(low)-cells, beta(high)-cells express functional beta-cell markers and are highly responsive to various insulin secretagogues. Whereas beta(low)-cells represent the main population in diabetic pancreas, an increase in beta(high)-cells is associated with gain of function that follows sustained glucose overload. CONCLUSION: Our data show that a functional heterogeneity of beta-cells, assessed by PSA-NCAM surface expression, exists in vivo. These findings pinpoint new target populations involved in endocrine pancreas plasticity and in beta-cell defects in type 2 diabetes.

4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARalpha/gamma agonists. Part. II: Synthesis and pharmacological evaluation of oxime and acidic head group structural variations.

Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a deficiency in pancreatic beta-cells. Since their discovery, three subtypes of peroxisome proliferator activated receptors have been identified, namely PPARalpha, PPARgamma and PPARbeta/(delta). In this study, we were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group structural variations.