The biological effects of angiotensin II (AngII) are mediated by two major subtypes of AngII receptors, type 1 (AT1R) and type 2 (AT2R). In this study, we attempted to elucidate the role of AngII subtype receptor-specific regulation in migration and proliferation of mouse cultured mesangial (MSG) cells. We found that 100 nM AngII stimulated weak migration of MSG cells. Cell motility increased more in the presence of AT2R than in the presence of AT1R, and it was suppressed by guanylate cyclase inhibitors. On the other hand, the activation of AT1R resulted in increased cell numbers, while AT2R activation inhibited cell proliferation. Moreover, high concentrations of glucose (25 mM) stimulated the expression of AT2R but not AT1R. These results indicate that there are receptor subtype-specific roles in MSG cells, and it is therefore possible that the activation of AT2R stimulates repair of glomerular tissue defect, by regulation of migration and proliferation of MSG cells. Taken together, these results suggest that the relative concentrations of AT1R and AT2R are important factors in the regulation of AngII function in glomerular tissue, and alterations in the concentrations of these receptors may contribute to progression of or protection from diabetic nephropathy.
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- Abstract: Diabetes x
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- Abstract: Hypoglycemia x
- Abstract: Insulinoma x
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- Abstract: IGF* x
- Abstract: Type 1 x
- Abstract: Type 2 x
Yuichiro Takeuchi, Keishi Yamauchi, Junko Nakamura, Satoshi Shigematsu and Kiyoshi Hashizume
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.
Richard W Nelson and Claudia E Reusch
Diabetes mellitus is a common disease in dogs and cats. The most common form of diabetes in dogs resembles type 1 diabetes in humans. Studies suggest that genetics, an immune-mediated component, and environmental factors are involved in the development of diabetes in dogs. A variant of gestational diabetes also occurs in dogs. The most common form of diabetes in cats resembles type 2 diabetes in humans. A major risk factor in cats is obesity. Obese cats have altered expression of several insulin signaling genes and glucose transporters and are leptin resistant. Cats also form amyloid deposits within the islets of the pancreas and develop glucotoxicity when exposed to prolonged hyperglycemia. This review will briefly summarize our current knowledge about the etiology of diabetes in dogs and cats and illustrate the similarities among dogs, cats, and humans.
Lucy M Hinder, Anuradha Vivekanandan-Giri, Lisa L McLean, Subramaniam Pennathur and Eva L Feldman
Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography–tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb; db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) in db/db tissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.
Bernard Khoo and Tricia Mei-Mei Tan
Obesity represents an important public health challenge for the 21st century: globalised, highly prevalent and increasingly common with time, this condition is likely to reverse some of the hard-won gains in mortality accomplished in previous centuries. In the search for safe and effective therapies for obesity and its companion, type 2 diabetes mellitus (T2D), the gut hormone glucagon-like peptide-1 (GLP-1) has emerged as a forerunner and analogues thereof are now widely used in treatment of obesity and T2D, bringing proven benefits in improving glycaemia and weight loss, and, notably, cardiovascular outcomes. However, GLP-1 alone is subject to limitations in terms of efficacy; as a result, investigators are evaluating other gut hormones such as glucose-dependent insulinotropic peptide (GIP), glucagon and peptide YY (PYY) as possible partner hormones that may complement and enhance GLP-1’s therapeutic effects. Such combination gut hormone therapies are in pharmaceutical development at present and are likely to make it to market within the next few years. This review examines the physiological basis for combination gut hormone therapy and presents the latest clinical results that underpin the excitement around these treatments. We also pose, however, some hard questions for the field which need to be answered before the full benefit of such treatments can be realised.
Xin-gang Yao, Xin Xu, Gai-hong Wang, Min Lei, Ling-ling Quan, Yan-hua Cheng, Ping Wan, Jin-pei Zhou, Jing Chen, Li-hong Hu and Xu Shen
Impaired glucose-stimulated insulin secretion (GSIS) and increasing β-cell death are two typical dysfunctions of pancreatic β-cells in individuals that are destined to develop type 2 diabetes, and improvement of β-cell function through GSIS enhancement and/or inhibition of β-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting β-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca2 + channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on β-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored β-cell functions as indicated by the increased plasma insulin level and decrease in the β-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.
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.
GW Aberdeen, GJ Pepe and ED Albrecht
In the present study, we determined whether expression of the messenger ribonucleic acids (mRNAs) for insulin-like growth factor-II (IGF-II), and its principal IGF type-1 receptor and IGF-binding protein-2 (IGFBP-2), as well as basic fibroblast growth factor (bFGF), was developmentally regulated in the baboon fetal adrenal gland. In the second phase of this study, fetal pituitary ACTH was suppressed by the administration of betamethasone to determine the possible effect on the mRNA levels for those factors, i.e. IGF-II and IGFBP-2, shown to be expressed at high levels in the adrenal late in fetal development. Adrenals were obtained from fetuses delivered via Cesarean section on days 60 (early), 100 (mid), and 165 (late) of gestation (term=184 days) from untreated baboons and on day 165 from baboons in which betamethasone was administered to the fetus, or to fetus and mother, every other day between days 150 and 164 of gestation. Although the mRNA levels of IGF-II in the fetal adrenal were similar at early, mid and late gestation, IGF type-1 receptor mRNA levels were approximately 2- to 3-fold greater (P<0.01) at mid than at early or late gestation. In contrast, there was an increase (P<0.001) in fetal adrenal IGFBP-2 and bFGF mRNA levels in late gestation. Although fetal adrenal weights and width of the zone of definitive/transitional cells exhibiting immunocytochemical staining for Delta(5)-3beta-hydroxysteroid dehydrogenase (3beta-HSD) were markedly suppressed (P<0.01) by the administration of betamethasone, IGF-II and IGFBP-2 mRNA expression was not decreased. In summary, very different patterns of mRNA levels for IGF-II, IGF type-1 receptor, IGFBP-2 and bFGF were exhibited in the developing baboon fetal adrenal gland, which may reflect functionally important differences in their respective cellular localization within the cortex, as well as a divergence in the functional development of the fetal, transitional and definitive zones of the baboon fetal adrenal cortex.
James E Bowe, Zara J Franklin, Astrid C Hauge-Evans, Aileen J King, Shanta J Persaud and Peter M Jones
The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.
Haiyong Chen, Hui-Yao Lan, Dimitrios H Roukos and William C Cho
MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic β-cells, while T2D is caused by islet β-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in β-cells, and β-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.