Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.
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Hongbin Liu, Anthony E Dear, Lotte B Knudsen, and Richard W Simpson
Xiaofeng Wang and Catherine B Chan
n-3 polyunsaturated fatty acids (PUFAs) are a subgroup of fatty acids with broad health benefits, such as lowering blood triglycerides and decreasing the risk of some types of cancer. A beneficial effect of n-3 PUFAs in diabetes is indicated by results from some studies. Defective insulin secretion is a fundamental pathophysiological change in both types 1 and 2 diabetes. Emerging studies have provided evidence of a connection between n-3 PUFAs and improved insulin secretion from pancreatic β-cells. This review summarizes the recent findings in this regard and discusses the potential mechanisms by which n-3 PUFAs influence insulin secretion from pancreatic β-cells.
Guillaume Mabilleau, Marie Pereira, and Chantal Chenu
Type 2 diabetes mellitus (T2DM) leads to bone fragility and predisposes to increased risk of fracture, poor bone healing and other skeletal complications. In addition, some anti-diabetic therapies for T2DM can have notable detrimental skeletal effects. Thus, an appropriate therapeutic strategy for T2DM should not only be effective in re-establishing good glycaemic control but also in minimising skeletal complications. There is increasing evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk.
Hongbin Liu, Yunshan Hu, Richard W Simpson, and Anthony E Dear
Glucagon-like peptide-1 (GLP-1) has been proposed as a target for treatment of type 2 diabetes. GLP-1 has also been demonstrated to improve endothelial cell dysfunction in diabetic patients. Elevated plasmogen activator inhibitor-1 (PAI-1) levels have been implicated in endothelial cell dysfunction. The effect of GLP-1 on PAI-1 expression in vascular endothelial cells has not been explored. In a spontaneously transformed human umbilical vein endothelial cell (HUVEC) line, C11-spontaneously transformed HUVEC (STH) and primary HUVEC cells, GLP-1 treatment, in the presence of a dipeptidyl peptidase IV inhibitor, attenuated induction of PAI-1 protein and mRNA expression by tumour necrosis factor-α (TNF-α). GLP-1 also inhibited the effect of TNF-α on a reporter gene construct harbouring the proximal PAI-1 promoter. In addition, GLP-1 attenuated TNF-α-mediated induction of Nur77 mRNA and TNF-α-mediated binding of nuclear proteins (NPs) to the PAI-1, Nur77, cis-acting response element nerve growth factor induced clone B response element (NBRE). GLP-1 treatment also inhibited TNF-α-mediated induction of Akt phosphorylation. Taken together, these observations suggest that GLP-1 inhibits TNF-α-mediated PAI-1 induction in vascular endothelial cells, and this effect may involve Akt-mediated signalling events and the modulation of Nur77 expression and NP binding to the PAI-1 NBRE.
L Monetini, F Barone, L Stefanini, A Petrone, T Walk, G Jung, R Thorpe, P Pozzilli, and MG Cavallo
Enhanced cellular immune response to bovine beta-casein has been reported in patients with type 1 diabetes. In this study we aimed to establish beta-casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between beta-casein and putative beta-cell autoantigens, reactivity to the latter was also investigated. T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine beta-casein, to 18 overlapping peptides encompassing the whole sequence of beta-casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to beta-casein could not be isolated from HLA-matched and -unmatched control subjects. beta-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 beta-casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM. We conclude that T cell lines specific to bovine beta-casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of beta-casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.
Isabel Göhring and Hindrik Mulder
In this issue of Journal of Endocrinology, Dr Han and colleagues report a protective effect of the glutamate dehydrogenase activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) under diabetes-like conditions that impair β-cell function in both a pancreatic β-cell line and db/db mice. Based on these observations, the authors suggest that BCH could serve as a novel treatment modality in type 2 diabetes. The present commentary discusses the importance of the findings. Some additional questions are raised, which may be addressed in future investigations, as there is some concern regarding the BCH treatment of β-cell failure.
Tingting Yang, Min He, Hailiang Zhang, Paula Q Barrett, and Changlong Hu
Aldosterone, which plays a key role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal cortex. Exaggerated overproduction of aldosterone from ZG cells causes primary hyperaldosteronism. In ZG cells, calcium entry through voltage-gated calcium channels plays a central role in the regulation of aldosterone secretion. Previous studies in animal adrenals and human adrenal adrenocortical cell lines suggest that the T-type but not the L-type calcium channel activity drives aldosterone production. However, recent clinical studies show that somatic mutations in L-type calcium channels are the second most prevalent cause of aldosterone-producing adenoma. Our objective was to define the roles of T and L-type calcium channels in regulating aldosterone secretion from human adrenals. We find that human adrenal ZG cells mainly express T-type CaV3.2/3.3 and L-type CaV1.2/1.3 calcium channels. TTA-P2, a specific inhibitor of T-type calcium channel subtypes, reduced basal aldosterone secretion from acutely prepared slices of human adrenals. Surprisingly, nifedipine, the prototypic inhibitor of L-type calcium channels, also decreased basal aldosterone secretion, suggesting that L-type calcium channels are active under basal conditions. In addition, TTA-P2 or nifedipine also inhibited aldosterone secretion stimulated by angiotensin II- or elevations in extracellular K+. Remarkably, blockade of either L- or T-type calcium channels inhibits basal and stimulated aldosterone production to a similar extent. Low concentrations of TTA-P2 and nifedipine showed additive inhibitory effect on aldosterone secretion. We conclude that T- and L-type calcium channels play equally important roles in controlling aldosterone production from human adrenals.
Haijiang Wu, Xinna Deng, Yonghong Shi, Ye Su, Jinying Wei, and Huijun Duan
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.
J Han and Y Q Liu
Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in β-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced β-cell adaptation, and type 2 diabetic db/db mice as a model to show severe β-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.
M Nasu, T Sugimoto, H Kaji, and K Chihara
Although there is clinical evidence showing that combined therapy with parathyroid hormone (PTH) and estrogen is additively effective in increasing the bone mass of patients with osteoporosis, the mechanism of the interaction between these hormones remains unclear. The present study was performed to determine whether estrogen would affect osteoblast proliferation and function modulated by PTH in human osteoblastic SaOS-2 cells. Human PTH-(1-34) significantly inhibited [(3)H]thymidine (TdR) incorporation, which was attenuated by 24 h pretreatment with 10(-10) to 10(-7) M 17 beta-estradiol (17 beta-E(2)) in a concentration-dependent manner. PTH significantly stimulated alkaline phosphatase (ALP) activity, collagen synthesis and type-1 procollagen mRNA expression after pretreatment with 17 beta-E(2 )in these cells. Tamoxifen, an anti-estrogen, antagonized these 17 beta-E(2)-induced effects. Pretreatment with insulin-like growth factor-I (IGF-I) mimicked estrogen action, and coincubation of 3 microg/ml anti-IGF-I antibody antagonized the effects of 17 beta-E(2 )as well as those of IGF-I. In the presence of 17 beta-E(2 )pretreatment, PTH strongly stimulated IGF-binding protein (IGFBP)-5 mRNA expression in these cells, and recombinant IGFBP-5 increased type-1 procollagen mRNA expression and ALP activity. In conclusion, estrogen attenuates PTH-induced inhibition of osteoblast proliferation and PTH stimulates osteoblast function in the presence of estrogen pretreatment. IGF-I and/or IGFBP-5 seemed to be involved in the estrogen-induced modulation of PTH action on osteoblast proliferation and function.