ПРИЛОЗИ. Одд. за мед. науки, XLII 1, 2021 МАНУ CONTRIBUTIONS. Sec. of Med. Sci., XLII 1, 2021 MASA 10.2478/prilozi-2021-0010 ISSN 1857-9345 UDC: 616.379-008.64:612.395.6 EFFECT OF CALORIE RESTRICTION AND EXERCISE ON TYPE 2 DIABETES Hira Shakoor1, Vasso Apostolopoulos2, Jack Feehan2, 3, Habiba Isse Ali1, Leila Cheikh Ismail 4, 5, Ayesha Salem Obaid S. Al Dhaheri1, Lily Stojanovska1, 2 1 Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates, Al Ain, United Arab Emirates 2 Institute for Health and Sport,Victoria University, Melbourne, Australia 3 Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, St. Albans, Australia 4 Department of Clinical Nutrition and Dietetics, College of Health Sciences, University of Sharjah, Sharjah, UAE 5 Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK Corresponding author: Lily Stojanovska, Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates. Email:lily.stojanovaska@ uaeu.ac.ae Phone: +971525308064 ABSTRACT Type-2 diabetes (T2D) is a chronic condition, generally regarded as an irreversible, that is among the top 10 causes of death globally. The hallmark of T2D is hyperglycemia, which results from disturbances in insulin sensitivity, insulin secretion, β-cell dysfunction and insulin resistance. Several clinical and lifestyle factors are involved in the progression of T2D, such as obesity and physical inactivity. A high-calorie diet is the main contributor to the development of obesity, which results in T2D, as obesity or increased intra-abdominal adipose tissue is related to insulin resistance. Technological advances have contributed to individuals having a more sedentary lifestyle, leading to obesity and T2D. T2D can be treated with lifestyle interventions, such as diet and exercise. Herein, we highlight the positive impact of a very low-calorie diet (VLCD) and lifestyle modalities in the treatment and prevention of T2D. An inclusion of VLCD 400-800 kcal/day for 8 weeks and ≥ 150 minutes exercise 5 times a week as lifestyle interventions can decrease glucose levels to normal, reduce HbA1c and improve insulin resistance and sensitivity. Therefore, a potential mechanism in maintaining glucose homeostasis and remission of T2D by VLCD and exercise reduces body weight. Keywords: Hyperglycemia, very low-calorie diet, insulin sensitivity, insulin resistance, type 2 diabetes INTRODUCTION Type-2 Diabetes (T2D) is a complex meta- T2D, which is forecasted to increase to 693 mil- bolic disorder characterized by hyperglycemia due lion by 2045 [3]. This increasing trend in diabetes to an impairment in macronutrient metabolism. incidence is a significant economical burden, and T2D is associated with a high risk of micro- and currently, about US $727 billion are being spent an- macrovascular co-morbid disease [1]. The first nually on those suffering from T2D equating to one known reference to T2D comes in Egyptian manu- in every eight dollars spent on healthcare [3]. T2D scripts from 3000 years ago [2], and in the modern was first considered as one of the central compo- era is amongst the top 10 causes of death world- nents of metabolic syndrome. However, it is now wide. Globally, 425 million people are affected by recognized as a complex endocrine and metabolic 110 Hira Shakoor et al. disorder that results in hyperglycemia secondary to durance Training” OR “Resistance Training” OR advancing insulin resistance [4]. “Combined Training.” Although many articles Calorie restriction and exercise are known are available that discuss the effects of dietary re- to promote healthy aging and decrease hypergly- striction and exercise individually on diabetes, the cemia; hence, it is central to the management of current review primarily focused on the combined T2D [5]. Studies show that very low-calorie diets effect of the two on T2D outcomes. Studies that (VLCD) for short durations are effective in man- focus on human studies were identified and those aging T2D [6,7]. VLCDs cause significant weight articles containing relevant data were thoroughly loss with reductions of 5-10% body weight im- reviewed (Fig. 1). The reviewing process consid- proving blood glucose, lipid profile and blood ered the modification of lifestyle (calorie restric- pressure [8]. However, adhering to chronic and tion and exercise) and how this modality reduces extreme diets like VLCD is challenging for this the burden of T2D. population, and has some negative consequences on health [5]. This review focuses on the thera- PATHOGENESIS OF TYPE 2 DIABETES peutic potential and challenges of VLCD and ex- ercise for the management of T2D. Diabetes is condition characterized by dis- METHODOLOGY ruption in the balance between plasma glucose levels and glucose uptake by the tissues, with re- sultant hyperglycemia. High plasma glucose con- A literature search was conducted using a centrations stimulate insulin secretion from the Science Direct, PubMed, Web of Science, SCO- β-cells of the pancreas, which in turn stimulates PUS, Springer and Google Scholar databases. glucose uptake by the peripheral tissues, most no- Search terms included “Diabetes” OR “Type 2 tably the liver, muscle and fat tissue. Insulin also Diabetes” OR “Hyperglycemia” OR “Hyperinsu- acts to suppress muscle glycogenolysis, adipose linemia” OR “Insulin Resistance” AND “Patho- lipolysis and hepatic gluconeogenesis to main- genesis” OR “Inflammation” OR “Cytokines” OR tain glucose homeostasis [9]. In diabetic patients, “β-cells dysfunction” AND “Dietary Interven- chronic hyperglycemia, with resultant hyperin- tion” OR “Calorie Restriction” OR “Low-Calorie sulinemia leads to progressive insulin resistance, Diet” OR “Very Low-Calorie Diet” OR “Fasting” impairing glucose uptake. A positive cycle of in- AND “Lifestyle Intervention” OR “Physical Ac- sulin resistance and hyperglycemia leads to per- tivity” OR “Exercise” OR “Aerobic” OR “En- sistent hyperinsulinemia. Over time, the pancreatic Fig. 1. Search Methodology EFFECT OF CALORIE RESTRICTION AND EXERCISE ON TYPE 2 DIABETES 111 β-cells cannot maintain insulin production, leading decrease in the uptake and utilization of glucose to dysfunction [10]. Additionally, insulin is a pow- results in hyperglycemia 21. Additionally, obesity erful inhibitor of lipolysis; even mild elevations of and intra-abdominal adipose tissue are also related insulin in the plasma cause a remarkable reduction to insulin resistance, with evidence suggesting that in free fatty acid levels [11]. in T2D it increases in parallel with adiposity [19]. When glucose homeostasis is disrupted, the Adipose tissue is sequestered in different locations risk of T2D increases. The pathophysiology of throughout the body, with varied physiological im- T2D centres on two main factors: progressive pe- pacts, with the primary two forms being subcuta- ripheral resistance to insulin and pancreatic β-cell neous fat under the skin, and visceral fat surround- dysfunction with their eventual failure. ing the abdominal organs. Subcutaneous fat is considered to be less active, with lower adipokine secretion and less macrophage infiltration [20]. Insulin resistance Visceral adipose tissue is a highly active secretory Chronic hyperglycemia due to factors such organ, releasing adipokines (such as adiponectin, as poor diet and obesity leads to ongoing insulin leptin, interleukin [IL-6] and tumor necrosis fac- release, and eventually the tissues lose responsivity tor-α) directly into the portal circulation affecting to the hormone. Resistance to insulin action leads to hepatic glucose and lipid metabolism. High levels the impairment of insulin-mediated glucose uptake of adipokines induce a pro-inflammatory and oxi- in peripheral tissues (particularly the muscle and dative state, further reducing insulin sensitivity and fat); impairment of triglyceride uptake by the adi- exacerbating insulin resistance [21]. Together, in- pose tissue and incomplete suppression of hepatic sulin resistance and β-cell dysfunction eventually glucose output. To maintain glucose homeostasis lead to T2D (Fig. 2). in these conditions, β-cells secrete more insulin, leading to hyperinsulinemia [16]. Chronic hyper- insulinemia causes a reduction in the sensitivity of Pancreatic β-cells insulin, known as resistance. The main outcome of In T2D, the early stages of β-cell dysfunc- insulin resistance is to reduce glucose uptake and tion are characterized by impairment of the secre- utilization by most body cells, with the exception of tion of insulin and ultimately leads to the onset of neuronal and endothelial cells. Consequently, this glucose intolerance [13]. In the first phase of the Fig. 2. Pathophysiology of type-2 diabetes 112 Hira Shakoor et al. progression of diabetes, insulin secretion is elevat- to microvascular complications in older people. ed to maintain glucose homeostasis in the face of Generally, complications of T2D are divided into insulin resistance and the resulting hyperglycemia two categories: [14]. However, in the second phase, when the dis- 1. Acute metabolic complications, which ease progresses, there is an impairment of newly are generally short term, such as ketoacidosis, synthesized insulin. This condition is reversible hypoglycemia and hyperglycemia. in some patients by ongoing glycemic control. 2. Late systemic complications, which are On the other hand, if hyperglycemia persists,