The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents

McBey et al. Lipids in Health and Disease (2021) 20:64 https://doi.org/10.1186/s12944-021-01494-w RESEARCH Open Access The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents David P. McBey1, Michelle Dotzert1 and C. W. J. Melling1,2* Abstract Background: Intensive-insulin treatment (IIT) strategy for patients with type 1 diabetes mellitus (T1DM) has been associated with sedentary behaviour and the development of insulin resistance. Exercising patients with T1DM often utilize a conventional insulin treatment (CIT) strategy leading to increased insulin sensitivity through improved intramyocellular lipid (IMCL) content. It is unclear how these exercise-related metabolic adaptations in response to exercise training relate to individual fibre-type transitions, and whether these alterations are evident between different insulin strategies (CIT vs. IIT). Purpose: This study examined glycogen and fat content in skeletal muscle fibres of diabetic rats following exercise-training. Methods: Male Sprague-Dawley rats were divided into four groups: Control-Sedentary, CIT- and IIT-treated diabetic sedentary, and CIT-exercised trained (aerobic/resistance; DARE). After 12 weeks, muscle-fibre lipids and glycogen were compared through immunohistochemical analysis. Results: The primary findings were that both IIT and DARE led to significant increases in type I fibres when compared to CIT, while DARE led to significantly increased lipid content in type I fibres compared to IIT. Conclusions: These findings indicate that alterations in lipid content with insulin treatment and DARE are primarily evident in type I fibres, suggesting that muscle lipotoxicity in type 1 diabetes is muscle fibre-type dependant. Keywords: Type 1 diabetes mellitus, Exercise, Skeletal muscle fibre, Intramyocellular lipids, Muscle glycogen, Insulin treatment Background Type I diabetes mellitus (T1DM) is an autoimmunerelated disorder characterized by the destruction of insulin-producing beta cells in the pancreatic islets of Langerhans. This results in chronically low levels of circulating insulin and the subsequent loss of glycemic * Correspondence: 1 School of Kinesiology, Western University, Medical Sciences Building 227, London, ON N6A 3K7, Canada 2 Department of Physiology and Pharmacology, Schulich School of Medicine, Western University, London, ON, Canada control. The inability to maintain blood glycemic equilibrium can result in elevated blood glucose (BG) levels, cumulating in a condition known as hyperglycemia. Chronic hyperglycemia can result in the development of cardiovascular disease (CVD), retinopathy, neuropathy, nephropathy, and myopathy, which represent the greatest contributors to morbidity and mortality for patients with T1DM [1–3]. Despite the many advances made in T1DM research, global prevalence of the disease has continued to increase particularly in youth populations [2, 4]. By 2018, T1DM was one of the most frequently © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. McBey et al. Lipids in Health and Disease (2021) 20:64 diagnosed chronic diseases in children and youth, and global prevalence is expected to continue to rise [5]. Traditionally, T1DM was managed using conventional insulin therapy (CIT). This strategy consists of a bolus of insulin taken once or twice daily, coupled with daily urine or BG testing. The modern treatment strategy, known as intensive insulin therapy (IIT), requires BG monitoring throughout the day, adjusting diet and insulin dosage with the goal of maintaining BG as close to the normal range as possible. With the publication of the Diabetes Control and Complications Trial in 1993, the evidence supports a significant long-term benefit of IIT over CIT [3]. Specifically, IIT leads to significant reductions in the long-term development of CVD (42%), retinopathy (76%), neuropathy (69%), and nephropathy (34%), in T1DM cases [6–12]. However, in approximately 20% of these cases, long-term reliance on IIT has been associated with the development of insulin resistance (IR), a phenomenon often associated with type 2 diabetes mellitus (T2DM) [13]. Termed “double diabetes”, these patients are at an increased risk for CVD and other associated morbidities when compared to patients with either T1DM or T2DM alone [14, 15]. As muscle tissue is the final destination for approximately 80–90% of circulating BG in healthy and T2DM patients, muscle IR can be highly disruptive of glucose homeostasis [16–19]. While it has been suggested that the development of IR in these populations has been due to impaired intramuscular glycogen synthesis [17], it has recently been recognized that the presence of IR in T1DM is pathologically different from other conditions like T2DM, though the IR pathogenesis in this already high-risk population remains unknown [15, 20]. One promising theory underlying the development of “double diabetes” in T1DM is the muscle-lipotoxicity theory of IR [7, 13, 21, 22]. This theory posits that the improper storage of intramyocellular lipid (IMCL) metabolites in skeletal muscle leads to disruption of the insulin receptor signalling pathway. The result of this impaired insulin response is the consequent development of chronic hyperglycemia [7]. It is believed that the onset of double diabetes begins with inadequate levels of circulating insulin, which results in an increase in muscle lipid flux that the mitochondria are unable to metabolize. This “metabolic overload” ultimately results in the conversion of free fatty acids into diacylglycerol (DAG) or metabolization into ceramides [23]. The resulting accumulation of these IMCLs initiates the development of IR, as both DAG and ceramides have been shown to interfere with the insulin signalling pathway [24–26] and have been positively correlated with IR severity [13]. Most research regarding muscular adaptations to T1DM h (...truncated)