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      A low-carbohydrate diet in place of SGLT2i therapy in a patient with diabetic cardiomyopathy

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          Abstract

          Summary

          In patients with diabetes mellitus, the toxic milieu caused by abnormal glucose and free fatty acid handling can lead to heart failure (HF). Referred to as diabetic cardiomyopathy (DMCM), this syndrome often exists in the absence of conventional risk factors for HF such as history of myocardial infarction or hypertension. Low-carbohydrate diets (LCDs) have recently been endorsed as an efficacious therapeutic dietary approach to prevent and reverse cardiometabolic disease including type 2 diabetes mellitus (T2DM). LCDs improve systemic insulin resistance (IR), reverses cardiac remodelling in a rodent model and downregulates the expression of sodium–glucose co-transporter 2 (SGLT2) receptors in the kidney. It is therefore conceivable that a lifestyle approach such as adopting an LCD can be offered to patients with DMCM. The reported case is that of a 45-year-old man with a 15-year history of non-ischaemic cardiomyopathy, T2DM and obesity. The patient volunteered to engage in a 16-week low-carbohydrate dietary intervention trial and then self-selected to remain on this diet for 1 year. The whole-food LCD was based on simple ‘traffic light’ style food lists and not designed to restrict calories, protein, fat or salt. After 1 year, the patient had lost 39 kg and his cardiometabolic markers had significantly improved. LCDs present a potentially beneficial approach for patients with DMCM and could be considered as a lifestyle intervention before SGLT2i therapy is commenced.

          Learning points
          • Diabetic cardiomyopathy (DMCM) is a syndrome precipitated mainly by the detrimental effects of glucose metabolism disorders such as insulin resistance and diabetes.

          • Low-carbohydrate diets (LCD) mimic many effects of sodium–glucose co-transporter 2 inhibitors (SGLT2i).

          • LCDs are a dietary pattern which can have significant and beneficial effects on metabolic and anthropometric markers in patients with DMCM.

          • LCDs and SGLT2i therapy could be combined and may achieve better clinical outcomes for patients with DMCM.

          • Combination therapy may be carried out under close supervision as the real risk for diabetic ketoacidosis remains.

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          Most cited references16

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          Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

          SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.
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            Diabetic Cardiomyopathy

            A strict bidirectional relationship exists between diabetes mellitus and heart failure. Diabetic cardiomyopathy is a specific cardiac manifestation of patients with diabetes characterized by left ventricular hypertrophy and diastolic dysfunction in the early phase up to overt heart failure with reduced systolic function in the advanced stages. The pathogenesis of this condition is multifactorial and recognizes as main promoting factors the presence of insulin resistance and hyperglycemia. Diabetic cardiomyopathy exerts a negative prognostic impact in affected patients and no target treatments are currently available. More efforts are needed to better define the diagnostic and therapeutic approach in this specific setting.
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              Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus

              There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                13 December 2023
                01 October 2023
                : 2023
                : 4
                : 23-0086
                Affiliations
                [1 ]Deakin University School of Nursing and Midwifery , Geelong, Victoria, Australia
                [2 ]Human Potential Centre , Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand
                [3 ]School of Nursing and Midwifery , Centre for Quality and Patient Safety, Institute for Health Transformation, Deakin University, Geelong, Victoria, Australia
                [4 ]The Centre for Quality and Patient Safety , Institute of Health Transformation -Western Health Partnership, Western Health, St Albans, Victoria, Australia
                [5 ]Faculty of Health and Medical Sciences , University of Copenhagen, Copenhagen, Denmark
                [6 ]Faculty of Health Sciences , University of Southern Denmark and Steno Diabetes Centre, Odense M, Denmark
                [7 ]School of Public Health and Preventive Medicine , Monash University, Melbourne, Victoria, Australia
                [8 ]Department of Cardiology , Austin Health, Heidelberg, Victoria, Australia
                Author notes
                Correspondence should be addressed to S Kleissl-Muir; Email: skleisslmuir@ 123456deakin.edu.au
                Author information
                http://orcid.org/0000-0001-7506-1332
                Article
                EDM230086
                10.1530/EDM-23-0086
                10762572
                38103377
                9d8e8a61-3b4d-49f6-94ea-196c87f4c0ca
                © the author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                History
                : 12 July 2023
                : 15 November 2023
                Funding
                Funded by: Diabetes Victoria, doi http://dx.doi.org/10.13039/501100020647;
                Categories
                Adult
                Male
                White
                Australia
                Heart
                Diabetes
                Novel Treatment
                Novel Treatment

                adult,male,white,australia,heart,diabetes,novel treatment,december,2023
                adult, male, white, australia, heart, diabetes, novel treatment, december, 2023

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