Citation: Cincione, R.I.; Losavio, F.; Cibelli, G.; Messina, G.; Polito, R.; Casula, E.; Cincione, P.P.; Amatruda, M.; Limone, P. Revised Protein Sparing Diet in Obesity and Type 2 Diabetes Mellitus. Nutrients 2022, 14, 5325. https://doi.org/10.3390/ nu14245325 Academic Editors: Luigi Barrea, Giovanna Muscogiuri and Ludovica Verde Received: 30 October 2022 Accepted: 10 December 2022 Published: 15 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article Revised Protein Sparing Diet in Obesity and Type 2 Diabetes Mellitus Raffaele Ivan Cincione 1, *, Francesca Losavio 1 , Giuseppe Cibelli 1 , Giovanni Messina 1 , Rita Polito 1 , Elias Casula 2 , Pamela Pia Cincione 3 , Marco Amatruda 3 and Pierpaolo Limone 4 1 Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy 2 IRCCS Santa Lucia Foundation, 00128 Rome, Italy 3 Faculty of Medicine, University of Foggia, 71122 Foggia, Italy 4 Department of Humanities, University of Foggia, 71122 Foggia, Italy * Correspondence: ivan.cincione@unifg.it Abstract: Effective nutrition therapy is a pressing issue in obesity and type 2 diabetes mellitus (T2DM) management. As such, this research aimed to determine the performance of a revised dietary strategy built on the protein-sparing diet in obesity and type 2 diabetes mellitus with regard to obtaining a rapid and stable improvement in glucometabolic control, body weight, body composition, and energy metabolism when applying the strategy in just twenty-one days. The revised protein-sparing diet differs from the traditional protein-sparing modified fast (PSMF) because it does not include foods. The daily calorie intake of this diet is exclusively derived from Isolate whey protein in addition to a formulation of Isolate whey protein enriched with essential amino acids in free form, with the addition of lipids such as extra virgin olive oil and coconut oil as a source of medium chain fatty acids, where the latter is taken for only the first four days of the diet, together with the use, for the same duration, of extended-release metformin, as the only antihyperglycemic allowed. Anthropometric measurements, bioimpedance analysis, indirect calorimetry, and blood chemistry assessments were conducted at the beginning of the study, time 0 (T0), and at the end, time 1 (T1), i.e., on the 21st day. The main outcomes of the revised protein-sparing diet after only twenty-one days were a reduction in body weight with the predominant loss of visceral atherogenic abdominal fat and, therefore, a possible contextual reduction in ectopic fat deposits together with a simultaneous reduction in insulin resistance and normalization of insulin levels, maintenance of free fat mass and basal metabolism, restoration of metabolic flexibility, and improvement of the glucometabolic and lipidic parameters. These results demonstrate the promising potential of the revised protein-sparing diet as an “etio- logic tool” in the integrated nutritional treatment of metabolic diseases such as obesity and type 2 diabetes mellitus. Keywords: revised protein sparing diet; type 2 diabetes mellitus; obesity; body composition; indirect calorimetry; free fat mass; fat mass; ectopic fat; metabolic inflexibility; diabetes reversal 1. Introduction Metabolic diseases such as obesity and type 2 diabetes mellitus (T2DM) are considered 21st-century global epidemics that can affect people of all ages, with their incidence and prevalence continuing to dramatically increase. These two conditions determine increased morbidity and mortality derived from their associated chronic comorbidities, such as cardiovascular diseases, which lead to reduced life expectancy and high costs for the health system [1–4]. For this purpose, a healthy lifestyle and body weight are essential steps in the man- agement of both pathologies and related complications. Current therapeutic approaches include lifestyle modification, pharmacologic therapy, and bariatric surgery. Regarding lifestyle interventions, such as the Mediterranean diet that exert positive health effects Nutrients 2022, 14, 5325. https://doi.org/10.3390/nu14245325 https://www.mdpi.com/journal/nutrients