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Free access

Zhenping Liu, Per Bendix Jeppesen, Søren Gregersen, Lotte Bach Larsen, and Kjeld Hermansen

Chronic hyperglycemia and hyperlipidemia cause deleterious effects on β-cell function. Interestingly, increased circulating amino acid (AA) levels are also a characteristic of the prediabetic and diabetic state. The chronic effects of AAs on β-cell function remain to be determined. Isolated mouse islets and INS-1E cells were incubated with or without excess leucine. After 72 h, leucine increased basal insulin secretion and impaired glucose-stimulated insulin secretion in both mouse islets and INS-1E cells, corroborating the existence of aminoacidotoxicity-induced β-cell dysfunction. This took place concomitantly with alterations in proteins and genes involved in insulin granule transport, trafficking (e.g. collapsin response mediator protein 2 and GTP-binding nuclear protein Ran), insulin signal transduction (proteasome subunit α type 6), and the oxidative phosphorylation pathway (cytochrome c oxidase). Leucine downregulated insulin 1 gene expression but upregulated pancreas duodenum homeobox 1 and insulin 2 mRNA expressions. Importantly, cholesterol (CH) accumulated in INS-1E cells concomitantly with upregulation of enzymes involved in CH biosynthesis (e.g. 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonate (diphospho) decarboxylase, and squalene epoxidase) and LDL receptor, whereas triglyceride content was decreased. Our findings indicate that chronic exposure to elevated levels of leucine may have detrimental effects on both β-cell function and insulin sensitivity. Aminoacidotoxicity may play a pathogenic role in the development of type 2 diabetes.

Free access

Berit Svendsen, Ramona Pais, Maja S Engelstoft, Nikolay B Milev, Paul Richards, Charlotte B Christiansen, Kristoffer L Egerod, Signe M Jensen, Abdella M Habib, Fiona M Gribble, Thue W Schwartz, Frank Reimann, and Jens J Holst

The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing ‘L-cell’ and the GIP-producing ‘K-cell’.

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Monisha Rajasekaran, Ok-Joo Sul, Eun-Kyung Choi, Ji-Eun Kim, Jae-Hee Suh, and Hye-Seon Choi

Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1–M2 macrophage polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargc1a, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.

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Jae Woo Jung, Chihoon Ahn, Sun Young Shim, Peter C Gray, Witek Kwiatkowski, and Senyon Choe

Activins and bone morphogenetic proteins (BMPs) share activin type 2 signaling receptors but utilize different type 1 receptors and Smads. We designed AB215, a potent BMP2-like Activin A/BMP2 chimera incorporating the high-affinity type 2 receptor-binding epitope of Activin A. In this study, we compare the signaling properties of AB215 and BMP2 in HEK293T cells and gonadotroph LβT2 cells in which Activin A and BMP2 synergistically induce FSHβ. In HEK293T cells, AB215 is more potent than BMP2 and competitively blocks Activin A signaling, while BMP2 has a partial blocking activity. Activin A signaling is insensitive to BMP pathway antagonism in HEK293T cells but is strongly inhibited by constitutively active (CA) BMP type 1 receptors. By contrast, the potencies of AB215 and BMP2 are indistinguishable in LβT2 cells and although AB215 blocks Activin A signaling, BMP2 has no inhibitory effect. Unlike HEK293T, Activin A signaling is strongly inhibited by BMP pathway antagonism in LβT2 cells but is largely unaffected by CA BMP type 1 receptors. BMP2 increases phospho-Smad3 levels in LβT2 cells, in both the absence and the presence of Activin A treatment, and augments Activin A-induced FSHβ. AB215 has the opposite effect and sharply decreases basal phospho-Smad3 levels and blocks Smad2 phosphorylation and FSHβ induction resulting from Activin A treatment. These findings together demonstrate that while AB215 activates the BMP pathway, it has opposing effects to those of BMP2 on FSHβ induction in LβT2 cells apparently due to its ability to block Activin A signaling.

Free access

E Zoidis, C Ghirlanda-Keller, M Gosteli-Peter, J Zapf, and C Schmid

In osteoblasts only the type III Na(+)-dependent phosphate (NaPi) transporter isoforms Pit-1 and Pit-2 have been identified. We tested the effects of extracellular Pi, Ca(2+) and IGF-I on Na(d)Pi transport and Pit-1 or Pit-2 mRNA expression in rat osteoblastic (PyMS) cells. The v(max) of Na(d)Pi transport was higher in cells kept in Pi-free, serum-free medium for 24 h than in controls at 1 mM Pi (2.47+/-0.20 vs 1.83+/-0.17 nmol/mg protein x 10 min). The apparent affinity constant (K(M)) for Pi remained unchanged. Pi withdrawal for 24 h did not impair cell viability whereas increasing the extracellular Pi to 5 mM resulted in cell death. Pit-1 (but not Pit-2) mRNA was upregulated following Pi deprivation, Ca(2+) treatment or after treatment with 1 nM IGF-I, known to stimulate Na(d)Pi transport and cell proliferation. IGF-I also stimulated Na(d)Pi transport and Pit-1 mRNA in primary rat calvarial osteoblasts. Expression of Pit-1 mRNA in vivo and the coordinate regulation of Pit-1 mRNA and Pi transport in osteoblastic cells suggest that Pit-1 is a candidate transporter of physiological relevance in bone.

Free access

DR Brigstock

The CCN family comprises cysteine-rich 61 (CYR61/CCN1), connective tIssue growth factor (CTGF/CCN2), nephroblastoma overexpressed (NOV/CCN3), and Wnt-induced secreted proteins-1 (WISP-1/CCN4), -2 (WISP-2/CCN5) and -3 (WISP-3/CCN6). These proteins stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Many of these activities probably occur through the ability of CCN proteins to bind and activate cell surface integrins. Accumulating evidence supports a role for these factors in endocrine pathways and endocrine-related processes. To illustrate the broad role played by the CCN family in basic and clinical endocrinology, this Article highlights the relationship between CCN proteins and hormone action, skeletal growth, placental angiogenesis, IGF-binding proteins and diabetes-induced fibrosis.

Free access

Weixia Han, Chen Wang, Zhifen Yang, Lin Mu, Ming Wu, Nan Chen, Chunyang Du, Huijun Duan, and Yonghong Shi

Renal fibrosis is the major pathological characteristic of diabetic nephropathy (DN). Reportedly, increased SIRT1 expression played a renal protective role in animal models of DN. This study was designed to elucidate the molecular mechanisms underlying the protective effects of SRT1720, an SIRT1 activator, against diabetes-induced renal fibrosis. Type 2 diabetic mice (db/db) were treated with SRT1720 (50 mg/kg/day) by gavage for 10 weeks. Renal proximal tubular epithelial cells (HK-2 cells) were treated with high glucose (HG, 30 mM) in the presence or absence of SRT1720 (2.5 µM) for 48 h. We observed that impaired SIRT1 expression and activity were restored by SRT1720 administration in db/db mice as well as in HG-treated HK-2 cells. Moreover, SRT1720 administration improved the renal function, attenuated glomerular hypertrophy, mesangial expansion, glomerulosclerosis and interstitial fibrosis and inhibited TGFB1 and CTGF expressions and nuclear factor κB (NF-KB) activation in db/db mice. Similarly, HG-induced epithelial-to-mesenchymal transformation (EMT) and collagen IV and fibronectin expressions were inhibited in SRT1720-treated HK-2 cells. Mechanistic studies demonstrated that SRT1720 suppressed HIF1A, GLUT1 and SNAIL expressions both in vivo and in vitro. Furthermore, HIF1A or GLUT1 knockdown effectively abrogated HG-induced EMT and collagen IV and fibronectin expressions in HK-2 cells. These findings suggest that SRT1720 prevented diabetes-induced renal fibrosis via the SIRT1/HIF1A/GLUT1/SNAIL pathway.

Free access

Andreas Börjesson and Carina Carlsson

In order to elucidate a possible relationship between β-cell function and conversion of proinsulin to insulin, isolated rat pancreatic islets were maintained in tissue culture for 1 week at various glucose concentrations (5.6–56 mM). Studies were also conducted on islets cultured for 48 h with interleukin-1β (IL-1β). By pulse-chase labelling and immunoprecipitation, the relative contents of newly synthesized proinsulin and insulin were determined. ELISA was used to analyse insulin and proinsulin content in medium and within islets. Using real-time PCR, the mRNA levels of proinsulin converting enzymes (PC1 and PC2) were studied. Islets cultured at 56 mM glucose had an increased proportion of newly synthesized proinsulin when compared with islets cultured at 5.6 mM glucose after a 90-min chase periods, however, no difference was observed after culture at 11 and 28 mM glucose. ELISA measurements revealed that culture at increased glucose concentrations as well as islet exposure to IL-1β increased proinsulin accumulation in the culture media. The mRNA expression of PC1 was increased after culture at 11 and 28 mM glucose. Treatment for 48 h with IL-1β increased the proportion of proinsulin both at 45 and 90 min when compared with control islets. These islets also displayed a decreased mRNA level of PC1 as well as PC2. Calculations of the half-time for proinsulin demonstrated a significant prolongation after treatment with IL-1β. We conclude that a sustained functional stimulation by glucose of islets is coupled to a decreased conversion of proinsulin which is also true for islets treated with IL-1β. This may contribute to the elevated levels of proinsulin found both at the onset of type 1 diabetes as well as in type 2 diabetes.

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M. Tepel, S. Bauer, S. Husseini, A. Raffelsiefer, and W. Zidek


Cytosolic free sodium concentrations ([Na+]i) in intact platelets from 32 type 2 (non-insulin-dependent) diabetic patients and from 27 age- and sex-matched non-diabetic control subjects were measured with the novel sodium-sensitive fluorescent dye sodium-binding-benzofuran-isophthalate. [Na+]i was significantly higher in platelets from type 2 diabetic patients compared with control subjects (40·6 ± 2·4 vs 32·0 ± 2·0 mmol/l, means ± s.e.m., P<0·03). Both systolic and diastolic blood pressure were significantly elevated in diabetic patients compared with control subjects. Analysis of diabetic patients showed a significant association between [Na+]i and diastolic blood pressure (P =0·026). Stimulation of Na/H exchange by thrombin increased [Na+]i in both groups. After inhibition of Na/K/ATPase by ouabain (1 mmol/l), [Na+]i was significantly increased both in diabetic patients and non-diabetic subjects in a similar way (by 40·2 ± 7·3 and 31·7 ± 5·3 mmol/l respectively). It is concluded that increased [Na+]i in cells from type 2 diabetic patients may be related to hypertension.

Journal of Endocrinology (1993) 138, 565–572

Free access

RH McCusker and J Novakofski

Zinc (Zn(2+)), a multifunctional micronutrient, was recently shown to lower the affinity of cell-associated insulin-like growth factor (IGF) binding protein (IGFBP)-3 and IGFBP-5 for both IGF-I and IGF-II, but to increase the affinity of the cell surface type 1 IGF receptor (IGF-1R) for the same two ligands. However, there is a need for data concerning the effects of Zn(2+) on soluble IGFBPs and the type 2 IGF receptor (IGF-2R). In the current work, we demonstrate that Zn(2+) affects the affinity of IGFBP-5 secreted by myoblasts but not IGFBP-4. Zn(2+), at physiological levels, depressed binding of both IGF-I and IGF-II to IGFBP-5, affecting (125)I-IGF-I more than (125)I-IGF-II. Both (125)I-IGF-I and (125)I-IGF-II bound to high and low affinity sites on IGFBP-5. Zn(2+) converted the high affinity binding sites of IGFBP-5 into low affinity binding sites. An IGF-I analog, (125)I-R(3)-IGF-I, did not bind to the soluble murine IGFBP-5. Zn(2+) also decreased the affinity of the IGF-2R on L6 myoblasts. In contrast, Zn(2+) increased IGF-I, IGF-II and R(3)-IGF-I binding to the IGF-1R by increasing ligand binding affinity on both P(2)A(2a)-LISN and L6 myoblasts. Soluble IGFBP-5 and IGFBP-4 depressed the binding of (125)I-IGF-I and (125)I-IGF-II to the IGF-1R, but did not affect binding of (125)I-R(3)-IGF-I. By depressing the association of the IGFs with soluble IGFBP-5, Zn(2+) partitioned (125)I-IGF-I and (125)I-IGF-II from soluble IGFBP-5 onto cell surface IGF-1Rs. This effect is not seen when soluble L6-derived IGFBP-4 is present in extracellular fluids. We introduce a novel mechanism by which the trace micronutrient Zn(2+) may alter IGF distribution, i.e. Zn(2+) acts to increase IGF-1R binding at the expense of IGF binding to soluble IGFBP-5 and the IGF-2R.