Effect of Calorie Restriction and Exercise on Type 2 
          Diabetes
          This is the Published version of the following publication
              Shakoor, Hira, Apostolopoulos, Vasso, Feehan, Jack, Ali, Habiba I, Ismail, 
              Leila Cheikh, Al Dhaheri, Ayesha S and Stojanovska, Lily (2021) Effect of 
              Calorie Restriction and Exercise on Type 2 Diabetes. PMakedonska 
              Akademija na Naukite i Umetnostite. Oddelenie za Medicinski Nauki. Prilozi, 
              42 (1). pp. 109-126. ISSN 1857-9345  
          The publisher’s official version can be found at 
          https://sciendo.com/article/10.2478/prilozi-2021-0010
          Note that access to this version may require subscription.
          Downloaded from VU Research Repository  https://vuir.vu.edu.au/44596/ 
               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
                             1                      2              2, 3              1
               Hira Shakoor , Vasso Apostolopoulos , Jack Feehan , Habiba Isse Ali , 
                                    4, 5                                  1                 1, 2
               Leila Cheikh Ismail    , Ayesha Salem Obaid S. Al Dhaheri , Lily Stojanovska
               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.
                  METHODOLOGY                                            Diabetes is condition characterized by dis-
                                                                   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 
                      Insulin resistance                                secretion  and  less  macrophage  infiltration  [20]. 
                      Chronic hyperglycemia due to factors such         Visceral adipose tissue is a highly active secretory 
               as poor diet and obesity leads to ongoing insulin        organ, releasing adipokines (such as adiponectin, 
               release, and eventually the tissues lose responsivity    leptin, interleukin [IL-6] and tumor necrosis fac-
               to the hormone. Resistance to insulin action leads to    tor-α) directly into the portal circulation affecting 
               the impairment of insulin-mediated glucose uptake        hepatic glucose and lipid metabolism. High levels 
               in peripheral tissues (particularly the muscle and       of adipokines induce a pro-inflammatory and oxi-
               fat); impairment of triglyceride uptake by the adi-      dative state, further reducing insulin sensitivity and 
               pose tissue and incomplete suppression of hepatic        exacerbating insulin resistance [21]. Together, in-
               glucose output. To maintain glucose homeostasis          sulin resistance and β-cell dysfunction eventually 
               in  these conditions, β-cells secrete more insulin,      lead to T2D (Fig. 2).
               leading to hyperinsulinemia [16]. Chronic hyper-               Pancreatic β-cells
               insulinemia causes a reduction in the sensitivity of           In T2D, the early stages of β-cell dysfunc-
               insulin, known as resistance. The main outcome of        tion are characterized by impairment of the secre-
               insulin resistance is to reduce glucose uptake and       tion of insulin and ultimately leads to the onset of 
               utilization by most body cells, with the exception of    glucose intolerance [13]. In the first phase of the 
               neuronal and endothelial cells. Consequently, this 
                              Fig. 2. Pathophysiology of type-2 diabetes