**6. Future directions and recommendations**

The most studied adipokines in type 2 DM subjects with VLCD are adiponectin and leptin. Adiponectin is a 244-amino acid hormone synthesized by mature white adipose tissue in subcutaneous, visceral and perivascular adiposity [42]. Adiponectin increases as fat mass decreases, and some of its functions are adipogenesis, adipocyte lipid storage (a "healthy" expansion of adipose tissue) and adipocyte insulin sensitivity via increased GLUT4-mediated glucose uptake [43]. The beneficial metabolic effects of adiponectin are in part related to its capacity to modulate the energy sensor 5′ adenosine monophosphate-activated protein kinase (AMPK) [44]. The regulation of adiponectin is a very complex system; however, low plasma adiponectin levels are associated with overweight, obesity and type 2 DM [43, 45]. The exact mechanisms involved in downregulation of adiponectin are not fully understood. Dietary restriction regimens in all its varieties (e.g., VLCD, calorie restriction, intermittent fasting, etc.) have been documented to exert beneficial metabolic effects in patients with type 2 DM derived from weight loss and concomitant modulation of adipokine levels. VLCD appears to have the most profound and rapid positive effect on weight loss, insulin resistance, β-cell function, inflammation and OS than other calorie-restricted regimens [3, 46–49]. However, the majority of studies performed, thus far, have failed to demonstrate significant changes in adiponectin serum levels after VLCD regimens in obese and type 2 DM individuals, despite

Conversely, leptin is a 167-amino acid hormone secreted mainly by white adipose tissue and is positively correlated with body fat content [51]. Leptin regulates energy homeostasis by inhibiting appetite (anorexigenic effects), thereby inducing the weight loss. In obese subjects, circulating levels of leptin are increased [52]. Interestingly, after a three-week regimen with VLCD in obese women, Anderlová et al. demonstrated a significant reduction on leptin serum levels and an increase of soluble leptin receptor levels, with no significant effects on adiponectin [6]. In addition, Lips et al. directly compared the effects between VLCD and bariatric surgery (Roux-en Y gastric bypass) on systemic inflammation markers in obese women. Three months after both interventions such as leptin and adiponectin serum levels were reduced and increased, respectively, by both regimens, although a more favorable inflammatory profile was observed in the VLCD cohort [53]. Noteworthy, VLCD has also been shown to positively affect inflammatory markers in obese type 2 DM subjects. Mraz et al. evidenced that a two-week VLCD regimen (~600 cal/day) decreased body weight and fasting glycemia accompanied by decreased C-reactive protein and IL-6 plasma levels in obese type 2 DM women. Moreover, these subjects experienced a reduction in inflammatory markers at the mRNA level, including chemokine receptors (e.g., CCR-1, CCR-2, CCR-5, IL-6 receptor) in peripheral

monocytes and chemokines (CCL-8 and CXCL-10) in subcutaneous adipose tissue [8].

OS is a condition of imbalance between oxidative species and antioxidant defense [54]. Several lines of evidence suggest a close relationship between inflammation and OS [55–57]. Indeed, various OS markers are up regulated in subjects with type 2 DM [58–60], where a chronic lowgrade inflammation state is present. Regimens with calorie-restricted diets have been reported

improvements on metabolism [6, 8, 50].

46 Diabetes and Its Complications

**5. VLCD and OS**

There is no doubt about the beneficial metabolic effects linked to VLCD regimens in type 2 DM. Such beneficial effects by VLCD go beyond glycemic and lipid control, since VLCD has shown to reduce OS and inflammation. Perhaps, in addition to its associated safety profile, VLCD regimens are now taking a privileged position in the treatment of type 2 DM, because of their capacity (in part) to exert rapid and substantial weight loss without the common risks associated with bariatric surgery. However, particular points that need to be addressed in VLCD trials are whether these types of diets are viable treatments for long-term diabetes remission and these regimens are applicable in primary care settings. Specifically, there is a need for more evidence related to the VLCD-associated benefits and safety, in longer and larger studies, which fortunately may be available soon because of current ongoing clinical trials evaluating this scenario.

Indeed, the Diabetes Remission Clinical Trial (DiRECT) is an ongoing trial intended to determine whether a weight management program (i.e., consisting in a VLCD regimen, food reintroduction and long-term weigh loss maintenance steps) delivered in a routine primary care setting and is a practical and successful treatment to achieve type 2 DM remission after 2 years [32]. This study started in 2016 and the obtained results are promising.

It has been manifested that individuals under VLCD regimens may suffer from psychological stress (e.g., increase in cortisol levels), which may be associated with weight regain after the discontinuation of VLCD regimens [62]. Interestingly, the Prevention of WEight Regain in diabetes type 2 (POWER) was designed to evaluate the effectiveness of adding a psychological intervention to a VLCD regimen in overweight type 2 DM individuals [63].

Clear recommendations for individuals with type 2 diabetes who would like to improve or reverse their condition by VLCD regimens await further studies. Nevertheless, all individuals with newly diagnosed type 2 DM should be informed about the possibility of reversing their disease by a diet regimen, not commonly offered as a treatment by general practitioners. This will bring hopes and motivation to individuals who are categorized as possessing an incurable disease. It is important to mention that not all individuals are capable to execute a task that comprises a relative drastic change to their lifestyle that has been maintained for years. Hence, structured programs that involve groups of dieticians, nurses, doctors and psychologists are required in order to treat this disease and lead to disease remission. Health Services around the globe will continue to suffer from the cost burden of type 2 DM as its incidence is projected to increase worldwide [64]. Even if a small proportion of type 2 DM individuals reverse their condition, the savings in health programs, particularly in developing countries, will be substantial.

[5] Leslie WS, Taylor R, Harris L, Lean MEJ. Weight losses with low energy formula diets in obese patients with and without type 2 diabetes: systematic review and metaanalysis.

Very Low-Calorie Diets in Type 2 Diabetes Mellitus: Effects on Inflammation, Clinical and…

http://dx.doi.org/10.5772/intechopen.72167

49

[6] Anderlová K, Křemen J, Doležalová R, Housová J, Haluzíková D, Kunešová M, Haluzík M. The influence of very-low-calorie diet on serum leptin, soluble leptin receptor, adiponectin and resistin levels in obese women Physiological Research [Clinical Trial] 2006;

[7] Tumova ESW, Jones PH, Vrablik M, Ballantyne CM, Hoogeveen RC. The impact of rapid weight loss on oxidative stress markers and the expression of the metabolic syndrome in obese individuals. Journal of Obesity. 2013;**2013**(729515):1-10. DOI: 10.1155/2013/729515

[8] Mraz M, Lacinova Z, Drapalova J, Haluzikova D, Horinek A, Matoulek M, Trachta P, Kavalkova P, Svacina S, Haluzik M. The effect of very-low-calorie diet on mrna expression of inflammation-related genes in subcutaneous adipose tissue and peripheral monocytes of obese patients with type 2 diabetes mellitus. The Journal of Clinical Endocrinology

[9] Vilchez-López FJ Campos Martín C, Amaya-García MJ, Sánchez-Vera P, Pereira-Cunill JL. Las dietas de muy bajo valor calórico (DMBVC) en el manejo clínico de la obesidad mór-

[11] Johansson K, Neovius M, Hemmingsson E. Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: A systematic review and meta-analysis of randomized controlled trials. The American Journal of

[12] Tsai AG, Wadden TA. The evolution of very-low-calorie diets: An update and meta-

[13] Velentgas P, Dreyer NA, Nourjah P, Smith SR, Torchia MM. Developing A Protocol For Observational Comparative Effectiveness Research: A User's Guide. Rockville (MD);

[14] Karter AJ, Nundy S, Parker MM, Moffet HH, Huang ES. Incidence of remission in adults with type 2 diabetes: The diabetes & aging study. Diabetes Care. 2014;**37**(12):3188-3195.

[15] Muller-Stich BP, Senft JD, Warschkow R, Kenngott HG, Billeter AT, Vit G, et al. Surgical versus medical treatment of type 2 diabetes mellitus in nonseverely obese patients: A systematic review and meta-analysis. Annals of Surgery. 2015;**261**(3):421-429. DOI: 10.1097/

[16] Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity and type 2 diabetes: What can be unified and what needs to be individualized? The Journal of Clinical Endocrinology and Metabolism. 2011;**96**(6):1654-1663. DOI: 10.1210/

bida. Nutrición Hospitalaria. 2013;**28**(2):275-285. DOI: 10.3305/nh.2013.28.2.6285

and Metabolism. 2011;**96**(4):E606-E613. DOI: 10.1210/jc.2010-1858

[10] Group M. Very low calorie diets. Drug & Ther Bull. 2012;**50**(5):54-57

Clinical Nutrition. 2014;**99**(1):14-23. DOI: 10.3945/ajcn.113.070052

analysis. Obesity. 2006;**14**(8):1283-1293. DOI: 10.1038/oby.2006.146

2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126190

International Journal of Obesity. 2016;**41**(1):96-101. DOI: 10.1038/ijo.2016.175

**55**:277-283

DOI: 10.2337/dc14-0874

SLA.0000000000001014

jc.2011-0585
