Cardiovascular Disease and Diabetes: Two Sides of the Same Coin!

Cardiovascular disease (CVD) and type 2 diabetes (T2DM) are rapidly rising around the globe. Empirical researches demonstrated rapid increase in mortality and morbidity related to CVD and T2DM. Much of the diabetes-associated morbidity and mortality predominantly reflects its deleterious effect on macrovascular and microvascular diseases. The microvascular complications of T2DM include retinopathy, neuropathy and nephropathy and the macrovascular complications include ischemic heart disease, cerebrovascular disease and peripheral vascular diseases. Research indicates that coronary heart disease (CHD) is the major cause of mortality in people with T2DM. Herein, this chapter reviews relationship between CVD and T2DM, associated complications and effectiveness of relevant treatment modalities to treat/prevent diabetic macrovasculopthy. Macrovascular disease occur due to underlying obstructive atherosclerotic changes of major arteries which cause functional and structural abnormalities of blood vessels. The long-term complications can be controlled and prevented by controlling glycemia, maintaining normal lipid profiles, adopting a healthy lifestyle and using pharmacological interventions. Clinical trials have shown that lifestyle interventions help in prevention and reduction of CVD risk, but evidence for long-term CVD outcomes is lacking. A multidisciplinary approach involving patients, health professionals and researchers and governments should be undertaken to reduce the incidence and prevalence of diabetes-related cardiovascular complications

Molecular Mechanisms Involved in Insulin- and Leptin-mediated Regulation of Hypothalamic Proglucagon Gene Expression and Action of Glucagon-like Peptides on Hypothalamic Neuropeptides

The hypothalamus is a central regulator of energy homeostasis. Recently, proglucagon-derived peptides have emerged as potential appetite regulators. The proglucagon gene is expressed in the periphery and also in selective hypothalamic neurons. The regulation of hypothalamic proglucagon by two key regulators of energy balance, insulin and leptin, remains unstudied. Central glucagon-like peptide (GLP)-1 receptor (GLP-1R) activation by exendin-4, a long-acting GLP-1R agonist, induces anorexia; however, the specific hypothalamic neuronal populations activated by exendin-4 remain largely unknown. The role of GLP-2 as a central appetite regulator is poorly understood. In this thesis, using murine hypothalamic cell lines and mice as experimental models, mechanisms involved in the direct regulation of proglucagon gene by insulin and leptin were studied, and the actions of exendin-4 and GLP-2 on hypothalamic neuropeptides were determined. It was found that insulin and leptin regulate hypothalamic proglucagon mRNA by activating Akt and signal transducer and activator of transcription 3, respectively. Insulin and leptin did not regulate human proglucagon promoter regions, but affected proglucagon mRNA stability. In mice, intracerebroventricular exendin-4 and GLP-2 induced anorexia, activated proopiomelanocortin- and neuropeptide Y-expressing neurons in the arcuate nucleus and neurotensin- and ghrelin-expressing neurons in major hypothalamic appetite-regulating regions. In the hypothalamic neuronal models, exendin-4 and GLP-2 activated cAMP-response element-binding protein/activating transcription factor-1, and regulated neurotensin and ghrelin mRNA levels via a protein kinase A-dependent mechanism. Overall, the in vivo and in vitro findings suggest that these neuropeptides may serve as potential downstream mediators of exendin-4 and GLP-2 action. This research demonstrates direct regulation of hypothalamic proglucagon by insulin and leptin in vitro, and reports a previously unrecognized link between central GLP-1R and GLP-2R activation and regulation of hypothalamic neuropeptides. A better understanding of the regulation of hypothalamic proglucagon and central GLP-1R and GLP-2R activation is important to further expand our knowledge of feeding circuits.Ph

The Cytokine Ciliary Neurotrophic Factor (CNTF) Activates Hypothalamic Urocortin-Expressing Neurons Both In Vitro and In Vivo

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The Cytokine Ciliary Neurotrophic Factor (CNTF) Activates Hypothalamic Urocortin-Expressing Neurons Both <i>In Vitro</i> and <i>In Vivo</i>

<div><p>Ciliary neurotrophic factor (CNTF) induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examined its effects on urocortin-1 neurons post-exposure. Through double-label immunohistochemistry using specific antibodies against c-Fos and urocortin-1, we showed that central CNTF administration significantly activated urocortin-1 neurons in specific areas of the hypothalamus. Taken together, our studies point to a potential role for CNTF in regulating hypothalamic urocortin-1-expressing neurons to mediate its recognized effects on energy homeostasis, neuronal proliferaton/survival, and/or neurogenesis.</p></div

Acute CNTF treatment activates hypothalamic neurons.

<p>Immunohistochemistry was performed to assess neuronal activation by c-Fos-immunoreactivity (ir) in wild-type mice treated with intracerebroventricular (i.c.v.) saline or CNTF (0.5 µg/ml). A–F: Representative photomicrographs showing expression of c-Fos-ir in the hypothalamic ARC, VMH, LH, dDMH, vDMH, PeV, and PVN regions in coronal sections of mouse hypothalami (as indicated on the images). Scale bar: 1 mm. Inset in each image represents a higher magnification of the boxed area. Scale bar: 100 µm. A and D represent negative control images for the anti-c-Fos antibody. DAB staining: nuclear brown (c-Fos). 3V, third ventricle. G: Bar graph showing the number of c-Fos-ir neurons in the hypothalamic regions at 2 h post-treatment. Data in the bar graph are expressed as mean ± SEM (n = 4 animals/group; *<i>P</i><0.05; **<i>P</i><0.01).</p

Effect of CNTF on phosphorylation of signaling proteins in the mHypoE-20/2 neuronal cells.

<p>(A–E) mHypoE-20/2 neurons were serum starved for 12–16 h before treatment with 10 ng/ml (0.45 nM) CNTF (+) or vehicle alone (−) over a 60 min time course. Western blot analysis of cell lysates was performed using phospho-specific antibodies directed against (A) STAT3, (B) JAK2, (C) ERK1/2, (D) Akt, and (E) ACC. All results shown are normalized to G-protein β subunit relative to corresponding control protein levels at each time point and are expressed as mean ± SEM (n = 4 independent experiments, *<i>P</i><0.05). Representative Western blots are shown.</p

Expression profile of CNTF receptor and appetite-regulating neuropeptides in the mHypoE-20/2 neuronal cell line.

<p>(A) mHypoE-20/2 neurons were imaged using a phase contrast microscope at 100× magnification. (B) RNA harvested from mHypoE-20/2 neurons and hypothalamus control was used as a template for semi-quantitative RT-PCR. Listed in the table is the presence (+) or absence (−) of specific genes, including NPY, neuropeptide Y; AgRP, agouti-related peptide; POMC, proopiomelanocortin; urocortin-1; urocortin-2; neurotensin; BDNF, brain-derived neurotrophic factor; Gad 67, glutamate decarboxylase 67; CNTFRa, ciliary neurotrophic factor receptor alpha.</p

An originally scaled test unit of a modular gas cooled receiver of 56 MW thermal power

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