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      Calcium Signaling in the Ventricular Myocardium of the Goto-Kakizaki Type 2 Diabetic Rat

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          Abstract

          The association between diabetes mellitus (DM) and high mortality linked to cardiovascular disease (CVD) is a major concern worldwide. Clinical and preclinical studies have demonstrated a variety of diastolic and systolic dysfunctions in patients with type 2 diabetes mellitus (T2DM) with the severity of abnormalities depending on the patients' age and duration of diabetes. The cellular basis of hemodynamic dysfunction in a type 2 diabetic heart is still not well understood. The aim of this review is to evaluate our current understanding of contractile dysfunction and disturbances of Ca 2+ transport in the Goto-Kakizaki (GK) diabetic rat heart. The GK rat is a widely used nonobese, nonhypertensive genetic model of T2DM which is characterized by insulin resistance, elevated blood glucose, alterations in blood lipid profile, and cardiac dysfunction.

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          Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity.

          Jonathan Buchanan, Pradip Mazumder, Ping Hu … (2005)
          Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28-37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased beta-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-alpha regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-alpha regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.
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            Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming.

            C Bastianutto, R Rizzuto, Guy Rutter … (1999)
            In recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca(2+) concentration. Here, we analyzed the significance of Ca(2+) signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP](m) and [ATP](c), respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca(2+) signals caused increases in [ATP](m) and [ATP](c) that depended on two parameters: (i) the amplitude of the Ca(2+) rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca(2+) elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP](m) upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca(2+) in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells.
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              Structural-functional relationships in diabetic nephropathy.

              S M Mauer, M Steffes, E Ellis … (1984)
              Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.
              Article 0 comments Cited 131 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                L. Al Kury:
                ORCID: http://orcid.org/0000-0002-8338-7655
                Journal
                Journal ID (nlm-ta): J Diabetes Res
                Journal ID (iso-abbrev): J Diabetes Res
                Journal ID (publisher-id): JDR
                Title: Journal of Diabetes Research
                Publisher: Hindawi
                ISSN (Print): 2314-6745
                ISSN (Electronic): 2314-6753
                Publication date Collection: 2018
                Publication date (Electronic): 10 April 2018
                Volume: 2018
                Electronic Location Identifier: 2974304
                Affiliations
                1College of Natural and Health Sciences, Zayed University, Abu Dhabi, UAE
                2Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
                3Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine
                4Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar
                5School of Forensic & Applied Sciences, University of Central Lancashire, Preston, UK
                Author notes

                Academic Editor: Kim Connelly

                Author information
                http://orcid.org/0000-0002-8338-7655
                http://orcid.org/0000-0001-7198-7920
                http://orcid.org/0000-0002-3200-3949
                http://orcid.org/0000-0002-0224-0556
                Article
                DOI: 10.1155/2018/2974304
                PMC ID: 5914098
                SO-VID: 09d2bf8a-bfd5-45d8-a560-6699dda04a5a
                Copyright © Copyright © 2018 L. Al Kury et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 October 2017
                Date revision received : 16 January 2018
                Date accepted : 8 March 2018
                Funding
                Funded by: Zayed University
                Funded by: Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
                Funded by: United Arab Emirates University
                Funded by: College of Medicine and Health Sciences, United Arab Emirates University
                Categories
                Subject: Review Article

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