Type 2 diabetes: a sacrifice program handling energy surplus

Abstract

Type 2 diabetes mellitus (T2DM) is closely associated with obesity, while interactions between the two diseases remain to be fully elucidated. To this point, we offer this perspective to introduce a set of new insights into the interpretation of T2DM spanning the etiology, pathogenesis, and treatment approaches. These include a definition of T2DM as an energy surplus-induced diabetes characterized by the gradual decline of β cell insulin secretion function, which ultimately aims to prevent the onset of severe obesity through mechanisms of weight loss. The body employs three adaptive strategies in response to energy surplus: the first one is adipose tissue expansion to store the energy for weight gain under normal weight conditions; the second one is insulin resistance to slow down adipose tissue expansion and weight gain under overweight conditions; and the third one is the onset of T2DM following β cell failure to reverse the weight gain in obese conditions. The primary signaling molecules driving the compensatory responses are adenosine derivatives, such as adenosine triphosphate (ATP), acetyl coenzyme A (acetyl-CoA), and reduced nicotinamide adenine dinucleotide (NADH). These molecules exert their effects through allosteric, post-translational, and transcriptional regulation of metabolic pathways. The insights suggest that insulin resistance and T2DM are protective mechanisms in the defense against excessive adiposity to avert severe obesity. The perspective provides a unified framework explaining the interactions between the two diseases and opens new avenues in the study of T2DM.

Keywords

T2DM / insulin resistance / energy metabolism / ATP / mitochondrial overheating

References

[1] Muller TD, Bluher M, Tschop MH et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21: 201- 23.

[2] Tobias DK, Merino J, Ahmad A et al. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine. Nat Med 2023; 29: 2438- 57.

[3] Canfora EE, Meex RCR, Venema K et al. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol 2019; 15: 261- 73.

[4] Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature 2019; 576: 51- 60.

[5] Ye J. Mechanisms of insulin resistance in obesity. Front Med 2013; 7: 14- 24.

[6] American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes-2024. Diabetes Care 2024; 47: S145- 57.

[7] Muller TD, Finan B, Bloom SR et al. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019; 30: 72- 130.

[8] Klein S, Gastaldelli A, Yki-Jarvinen H et al. Why does obesity cause diabetes? Cell Metab 2022; 34: 11- 20.

[9] Calejman CM, Doxsey WG, Fazakerley DJ et al. Integrating adipocyte insulin signaling and metabolism in the multi-omics era. Trends Biochem Sci 2022; 47: 531- 46.

[10] Weng L, Tang WS, Wang X et al. Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy. Nat Commun 2024; 15: 133.

[11] Chen J, Zhou Y, Liu Z et al. Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG. Science 2024; 383: eadi3332.

[12] Hagberg CE, Spalding KL. White adipocyte dysfunction and obesity-associated pathologies in humans. Nat Rev Mol Cell Biol 2023; 25: 270- 89.

[13] Nelson ME, Madsen S, Cooke KC et al. Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance. Cell Metab 2022; 34: 227- 39.e6.

[14] Weyer C, Foley JE, Bogardus C et al. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type Ⅱ diabetes independent of insulin resistance. Diabetologia 2000; 43: 1498- 506.

[15] Santoro A, Kahn BB. Adipocyte regulation of insulin sensitivity and the risk of type 2 diabetes. N Engl J Med 2023; 388: 2071- 85.

[16] Régnier M, Carbinatti T, Parlati L et al. The role of ChREBP in carbohydrate sensing and NAFLD development. Nat Rev Endocrinol 2023; 19: 336- 49.

[17] Singh C, Jin B, Shrestha N et al. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits. Cell Metab 2024; 36: 144- 58.e7.

[18] James DE, Stockli J, Birnbaum MJ. The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol 2021; 22: 751- 71.

[19] Liu K, Jin X, Zhang X et al. The mechanisms of nucleotide actions in insulin resistance. J Genet Genomics 2022; 49: 299- 307.

[20] Ye J. Mechanism of insulin resistance in obesity: a role of ATP. Front Med 2021; 15: 372- 82.

[21] Lee JH, Zhang Y, Zhao Z et al. Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. Int J Obes (Lond) 2017; 41: 645- 51.

[22] Berg JM, Tymoczko JL, Gatto GJ et al. Lipid biosynthesis. In: Berg JM, Tymoczko JL, Gatto GJ, Stryer L (eds.), Biochemistry. Chapter 21. 8th ed. New York: W. H. Freeman and Company, 2015.

[23] Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome — an allostatic perspective. Biochim Biophys Acta 2010; 1801: 338- 49.

[24] Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 2013; 93: 1- 21.

[25] Li Q, Hagberg CE, Silva Cascales H et al. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. Nat Med 2021; 27: 1941- 53.

[26] Ye J. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocr Metab Immune Disord Drug Targets 2007; 7: 65- 74.

[27] Zhang J, Gao Z, Yin J et al. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem 2008; 283: 35375- 82.

[28] Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond) 2009; 33: 54- 66.

[29] Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab 2019; 1: 754- 64.

[30] Pico C, Palou M, Pomar CA et al. Leptin as a key regulator of the adipose organ. Rev Endocr Metab Disord 2022; 23: 13- 30.

[31] Liu Y, Qian SW, Tang Y et al. The secretory function of adipose tissues in metabolic regulation. Life Metab. 2024; 3: loae003.

[32] Wang H, Ye J. Regulation of energy balance by inflammation: common theme in physiology and pathology. Rev Endocr Metab Disord 2015; 16: 47- 54.

[33] Ye J, Gao Z, Yin J et al. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293: E1118- 28.

[34] Yu L, Zhang X, Ye S et al. Obesity and COVID-19: mechanistic insights from adipose tissue. J Clin Endocrinol Metab 2022; 107: 1799- 811.

[35] Seo JB, Riopel M, Cabrales P et al. Knockdown of Ant2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat Metab 2019; 1: 86- 97.

[36] Page MM, Johnson JD. Mild suppression of hyperinsulinemia to treat obesity and insulin resistance. Trends Endocrinol Metab 2018; 29: 389- 99.

[37] Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 2012; 61: 4- 13.

[38] Wei X, Ke B, Zhao Z et al. Regulation of insulin degrading enzyme activity by obesity-associated factors and pioglitazone in liver of diet-induced obese mice. PLoS One 2014; 9: e95399.

[39] Fu Z, Wu Q, Guo W et al. Impaired insulin clearance as the initial regulator of obesity-associated hyperinsulinemia: novel insight into the underlying mechanism based on serum bile acid profiles. Diabetes Care 2022; 45: 425- 35.

[40] Varney MJ, Benovic JL. The role of G protein-coupled receptors and receptor kinases in pancreatic β-cell function and diabetes. Pharmacol Rev 2024; 76: 267- 99.

[41] Kolic J, Sun WG, Cen HH et al. Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease. Cell Metab 2024; 36: 1619- 33.e5.

[42] Myers MG Jr, Grammer TC, Wang LM et al. Insulin receptor substrate-1 mediates phosphatidylinositol 3’-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. J Biol Chem 1994; 269: 28783- 9.

[43] Lee YH, Wang MY, Yu XX et al. Glucagon is the key factor in the development of diabetes. Diabetologia 2016; 59: 1372- 5.

[44] Finan B, Capozzi ME, Campbell JE. Repositioning glucagon action in the physiology and pharmacology of diabetes. Diabetes 2020; 69: 532- 41.

[45] Capozzi ME, D’Alessio DA, Campbell JE. The past, present, and future physiology and pharmacology of glucagon. Cell Metab 2022; 34: 1654- 74.

[46] Wewer Albrechtsen NJ, Pedersen J, Galsgaard KD et al. The liver-α-cell axis and type 2 diabetes. Endocr Rev 2019; 40: 1353- 66.

[47] Ye J, Hu Y, Wang C et al. Cellular mechanism of diabetes remission by bariatric surgery. Trends Endocrinol Metab 2023; 34: 590- 600.

[48] Mann JP, Savage DB. What lipodystrophies teach us about the metabolic syndrome. J Clin Invest 2019; 129: 4009- 21.

[49] Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 2019; 129: 3990- 4000.

[50] Xourafa G, Korbmacher M, Roden M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat Rev Endocrinol 2024; 20: 27- 49.

[51] Kitada M, Koya D. Autophagy in metabolic disease and ageing. Nat Rev Endocrinol 2021; 17: 647- 61.

[52] Elmaleh-Sachs A, Schwartz JL, Bramante CT et al. Obesity management in adults: a review. JAMA 2023; 330: 2000- 15.

[53] Kanda H, Hayakawa T, Tsuboi S et al. Higher Body Mass Index is a predictor of death among professional sumo wrestlers. J Sports Sci Med 2009; 8: 711- 2.

[54] Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577- 89.

[55] Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168: 960- 76.

[56] Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 2018; 19: 579- 93.

[57] Zhu Q, An YA, Scherer PE. Mitochondrial regulation and white adipose tissue homeostasis. Trends Cell Biol 2022; 32: 351- 64.

[58] Nikolic I, Leiva M, Sabio G. The role of stress kinases in metabolic disease. Nat Rev Endocrinol 2020; 16: 697- 716.

[59] Liu Y, Birsoy K. Metabolic sensing and control in mitochondria. Mol Cell 2023; 83: 877- 89.

[60] Bennett CF, Latorre-Muro P, Puigserver P. Mechanisms of mitochondrial respiratory adaptation. Nat Rev Mol Cell Biol 2022; 23: 817- 35.

[61] Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 5th ed. New York: W. H. Freeman and Company, 2008.

[62] Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011; 25: 1895- 908.

[63] Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab 2018; 27: 299- 313.

[64] Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2018; 19: 121- 35.

[65] Xian H, Liu Y, Rundberg Nilsson A et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021; 54: 1463- 77.e11.

[66] Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell 2018; 172: 22- 40.

[67] Wu H, Ballantyne CM. Skeletal muscle inflammation and insulin resistance in obesity. J Clin Invest 2017; 127: 43- 54.

[68] Rohm TV, Meier DT, Olefsky JM et al. Inflammation in obesity, diabetes, and related disorders. Immunity 2022; 55: 31- 55.

[69] Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am J Physiol Endocrinol Metab 2013; 304: E466- 77.

[70] Zhu Q, An YA, Kim M et al. Suppressing adipocyte inflammation promotes insulin resistance in mice. Mol Metab 2020; 39: 101010.

[71] Wernstedt Asterholm I, Tao C, Morley Thomas S et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20: 103- 18.

[72] Tang T, Zhang J, Yin J et al. Uncoupling of inflammation and insulin resistance by NF-κB in transgenic mice through elevated energy expenditure. J Biol Chem 2010; 285: 4637- 44.

[73] Gao Z, Zhang J, Henagan TM et al. p65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice. Am J Physiol Endocrinol Metab 2015; 308: E496- 505.

[74] Meizlish ML, Franklin RA, Zhou X et al. Tissue homeostasis and inflammation. Annu Rev Immunol 2021; 39: 557- 81.

[75] LaMoia TE, Shulman GI. Cellular and molecular mechanisms of metformin action. Endocr Rev 2021; 42: 77- 96.

[76] Ido Y, Kilo C, Williamson JR. Cytosolic NADH/NAD⁺, free radicals, and vascular dysfunction in early diabetes mellitus. Diabetologia 1997; 40: S115- 7.

[77] Cao X, Ye X, Zhang S et al. ADP induces blood glucose through direct and indirect mechanisms in promotion of hepatic gluconeogenesis by elevation of NADH. Front Endocrinol 2021; 12: 663530.

[78] Goodman RP, Markhard AL, Shah H et al. Hepatic NADH reductive stress underlies common variation in metabolic traits. Nature 2020; 583: 122- 6.

[79] Amorim JA, Coppotelli G, Rolo AP et al. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022; 18: 243- 58.

[80] Xiao W, Loscalzo J. Metabolic responses to reductive stress. Antioxid Redox Signal 2020; 32: 1330- 47.

[81] Wang Y, Stancliffe E, Fowle-Grider R et al. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells. Mol Cell 2022; 82: 3270- 83.e9.

[82] Levine DC, Kuo HY, Hong HK et al. NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding. Nat Metab 2021; 3: 1621- 32.

[83] Pan X, Heacock ML, Abdulaziz EN et al. A genetically encoded tool to increase cellular NADH/NAD⁺ ratio in living cells. Nat Chem Biol 2024; 20: 594- 604.

[84] Xiong X, Li X. Type 2 diabetes originated from non-alcoholic fatty liver disease. Life Metab. 2023; 2: load007.

[85] Davies M, Faerch L, Jeppesen OK et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021; 397: 971- 84.

[86] Le J, Chen Y, Yang W et al. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta pharmaceutica Sinica. B 2024; 14: 437- 54.

[87] Day EA, Ford RJ, Smith BK et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab 2019; 1: 1202- 8.

[88] Scott B, Day EA, O’Brien KL et al. Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans. Nat Metab 2024; 6: 651- 8.

[89] Xiao S, Li VL, Lyu X et al. Lac-Phe mediates the effects of metformin on food intake and body weight. Nat Metab 2024; 6: 659- 69.

[90] Drucker DJ. Prevention of cardiorenal complications in people with type 2 diabetes and obesity. Cell Metab 2024; 36: 338- 53.

[91] Nahra R, Wang T, Gadde KM et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 2021; 44: 1433- 42.

[92] Tillner J, Posch MG, Wagner F et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab 2019; 21: 120- 8.

[93] American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2024. Diabetes Care 2024; 47: S158- 78.

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