Subscribe to RSS
DOI: 10.1055/a-1510-8896
Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome
Abstract
Insulin resistance is the hallmark of Type 2 Diabetes and is still an unmet medical need. Insulin resistance lies at the crossroads of non-alcoholic fatty liver disease, obesity, weight loss and exercise resistance, heart disease, stroke, depression, and brain health. Insulin resistance is purely nutrition related, with a typical molecular disease food intake pattern. The insulin resistant state is accessible by TyG as the appropriate surrogate marker, which is found to lead the personalized molecular hepatic nutrition system for highly efficient insulin resistance remission. Treating insulin resistance with a molecular nutrition-centered approach shifts the treatment paradigm of Type 2 Diabetes from management to cure. This allows remission within five months, with a high efficiency rate of 85%. With molecular intermittent fasting a very efficient treatment for prediabetes and metabolic syndrome is possible, improving the non-alcoholic fatty liver disease (NAFL) state and enabling the body to lose weight in a sustainable manner.
Key words
insulin resistance - diabetes remission - non-alcoholic fatty liver - weight loss resistance - epigeneticsPublication History
Received: 09 February 2021
Accepted after revision: 12 May 2021
Article published online:
30 June 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Madsen KS, Chi Y, Metzendorf MI. et al. Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database System Rev 2019; 1-122
- 2 Ferrannini E, Gall W, Nannipieri M. et al. Identification of novel insulin resistance metabolites in a non-diabetic population by global biochemical profiling. Canad J Diabetes 2009; 33: 208
- 3 Nannini RD, Joyce BT, Zheng Y. et al. Epigenetic age acceleration and metabolic syndrome in the coronary artery risk development in young adults study. Clin Epigenet 2019; 160-169
- 4 De Rosa V, Galgani M, Santopaolo M. et al. Nutritional control of immunity: Balancing the metabolic requirements with an appropriate immune function. Semin Immunol 2015; 27: 300-309
- 5 Chavez-Reyes J, Escarcega-Gonzalez CE, Chavira-Suarez E. et al. Susceptibility for Some Infectious Diseases in Patients with Diabetes: The Key Role of Glycemia. Front Public Health 2021; 9: 559-595
- 6 Vestergaard Jensen A, Faurholt-Jepsen D, Banbaek Egelund G. et al. Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study. Clin Infect Dis 2017; 29: 2091-2098
- 7 Gardner JP, Li S, Srinavasan SR. et al. Rise in Insulin Resistance Is Associated with Escalated Telomere Attrition. Circulation 2005; 111: 2171-2177
- 8 Chen S, Chen Y, Liu X. et al. Association of Insulin Resistance with Chronic Kidney Disease in Non-Diabetic Subjects with Normal Weight. PLoS One 2013; 1-9
- 9 Won Lee, Ha Park S. Association between depression and nonalcoholic fatty liver disease: Contributions of insulin resistance and inflammation. J Affect Disord 2021; 278: 259-263
- 10 Geraets AFJ, Köhler S, Muzambi R. et al. The association of hyperglycemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study. Diabetologia 2020; 63: 2315-2328
- 11 Rundek T, Gardener H, Xu Q. et al. Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the northern Manhattan study. Arch Neurol 2010; 67: 1195-1200
- 12 Ford AH, Flicker L, Graeme GJ. et al. Insulin resistance and depressive symptoms in older men: the health in men study. Am J Geriatr Psychiatry 2015; 23: 872-880
- 13 Nägga K, Gustavsson AM, Stomrud E. et al. Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology 2018; 90: e73-e81
- 14 Sung H, Siegel RL, Rosenberg PS. et al. Emerging cancer trends among young adults in the USA: Analysis of a population-based cancer registry. Lancet 2019; 4: E137-E147
- 15 Li X, Li G, Cheng T. et al. Association between triglyceride-glucose index and risk of incident diabetes: A secondary analysis based on a Chinese cohort study: TyG index and incident diabetes. Lipids Health Dis 2020; 8: 236
- 16 Ren H, Yang Y, Wang F. et al. Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19. Cardiovasc Diabetol 2020; 19: 58
- 17 Corona G, Pittocaro A, Vena W. et al. Diabetes is the most important cause for mortality in COVID-19 hospitalized patients: Systematic review and meta-analysis. Rev Endocr Metab Disord 2021; 1-22
- 18 McGovern AP, Thomas NJ, Vollmer SJ. et al. The disproportionate excess mortality of COVID-19 in younger people with diabetes warrants vaccination prioritization. Diabetologia 2021; 64: 1184-1186
- 19 Kaiser A, Vollenweider P, Waeber G. et al. Prevalence, awareness and treatment of type 2 diabetes mellitus in Switzerland: the CoLaus study. Diabet Med 2012; 29: 190-197
- 20 Araujo J, Cai J, Stevens J. Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009–2016. Metab Syndr Relat Disord 2019; 17: 46-52
- 21 Kerr D, Miles P. Very low-calorie diets in diabetes: The Bournemouth experience. J Diabetes Nursing 2000; 4: 108-111
- 22 Willi SM, Martin K, Datko FM. et al. Treatment of Type 2 Diabetes in Childhood Using a Very-Low-Calorie Diet. Diabetes Care 2004; 27: 348-353
- 23 Xin Y, Davies A, Briggs A. et al. Type 2 diabetes remission: 2-year within-trial and lifetime-horizon cost-effectiveness of the Diabetes Remission Clinical Trial (DiRECT)/Counterweight-Plus weight management program. Diabetologia 2020; 63: 2112-2122
- 24 Baskota A, Li S, Dhakal N. et al. Bariatric Surgery for Type 2 Diabetes Mellitus in Patients with BMI<30 kg/m2: A Systematic Review and Meta-Analysis. PLoS One 2015; 10: e0132335
- 25 Vistisen D, Witte DR, Tabak AG. et al. Patterns of Obesity Development before the Diagnosis of Type 2 Diabetes: The Whitehall II Cohort Study. PLoS Med 2014; 11: e1001602
- 26 Wu S, Fischer-Hoch SP, Reninger B. et al. Metabolic Health Has Greater Impact on Diabetes than Simple Overweight/Obesity in Mexican Americans. J Diabetes Res. 2016 Article ID 4094876
- 27 Eckel N, Li Y, Kuxhaus O. et al. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30-year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol 2018; 6: 714-724
- 28 Pietiläinen KH, Sysi-Aho M, Rissanen A. et al. Acquired obesity is associated with changes in the serum lipidomic profile independent pf genetic effects – a monozygotic twin study. PLoS One 2007; 2: e218
- 29 Owei I, Umekwe N, Provo C. et al. Insulin-sensitive and insulin-resistant obese and non-obese phenotypes: Role in the prediction of incident pre-diabetes in a longitudinal biracial cohort. BMJ Open Diabetes Res Care 2017; 5: e000415
- 30 Mongraw-Chaffin M, Foster MC, Anderson CAM. et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol 2018; 71: 1857-1865
- 31 Bagnatti M, Ogunkolade W, Marshall C. et al. Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation. Cell Death Disease 2016; 7: 2329
- 32 Telles S, Pal S, Sharma SK. et al. The association between the lipid profile and fasting blood glucose with weight-related outcomes in healthy obese adults. BMC Res Notes 2018; 11: 383
- 33 Lee J, Kim B, Kim W. et al. Lipid indices as simple and clinically useful surrogate markers for insulin resistance in the U.S. population. Sci Rep 2021; 11: 2366
- 34 Lim TK, Lee HS, Lee YJ. Triglyceride to HDL-cholesterol ratio and the incidence risk of type 2 diabetes in community-dwelling adults: A longitudinal 12-year analysis of the Korean Genome and Epidemiology Study. Diabetes Res Clin Pract 2020; 163: 108150
- 35 Rojas-Humpire R, Olarte-Durand M, Medina-Ramirez S. et al. Insulin Resistance Indexes as Biomarkers of Lifetime Cardiovascular Risk among Adults from Peru. J Nutr Metab 2021; 6633700: 1-8
- 36 Si Y, Fan W, Shan W. et al. Association between triglyceride glucose index and coronary artery disease with type 2 diabetes mellitus in middle-aged and elderly people. Medicine (Baltimore) 2021; 100: e25025
- 37 Arpon A, Milagro FI, Santos JL. et al. Interaction among sex, aging, and epigenetic process concerning visceral fat, insulin resistance, and dyslipidemia. Front Endocrinol 2019; 10: 496
- 38 Çin Aslan NN, Yardimci HH, Koç N. et al. Triglycerides/high-density lipoprotein cholesterol is a predictor similar to the triglyceride–glucose index for the diagnosis of metabolic syndrome using International Diabetes Federation criteria of insulin resistance in obese adolescents: a cross-sectional study. J Pediatr Endocrinol Metab 2020; 33: 777-784
- 39 Kron V, Verner M, Smetana P. et al. The Changes of Cholesterol Profile at the Different Insulin Resistance Range in the Czech Republic. Medicina (Kaunas) 2021; 57: 249
- 40 Lyu K, Zhang Y, Zhang D. et al. A Membrane-Bound Diacylglycerol Species Induces PKCε-Mediated Hepatic Insulin Resistance. Cell Metab 2020; 32: 654-664
- 41 Lee Y, Lai HTM, de Oliveira Otto MC. et al. Serial biomarkers of de novo lipogenesis fatty acids and incident heart failure in older adults: The Cardiovascular Health Study. J Am Heart Assoc 2020; 9: e014119
- 42 Rasmussen BB, Holmbäck UF, Volpi E. et al. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J Clin Invest 2002; 110: 1687-1693
- 43 Imamura F, Fretts AM, Marklund M. et al. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. PLoS Med 2020; 17: e1003102
- 44 Kitae A, Hashimoto Y, Hamaguchi M. et al. The triglyceride and glucose index is a predictor of incident nonalcoholic fatty liver disease: A Population-Based Cohort Study. Can J Gastroenterol Hepatol 2019; 121574: 1-7
- 45 Jimenez-Rivera C, Hadjiyannakis S, Davila J. et al. Prevalence and a risk factor for non-alcoholic fatty liver in children and youth with obesity. BMC Pediatrics 2017; 17: 113
- 46 Kolb H, Kempf K, Röhling M. et al. Insulin: too much of a good thing is bad. BMC Med 2020; 18: 224
- 47 Wadolowska L, Hamulka J, Kowalkowska J. et al. Skipping Breakfast and a Meal at School: Its Correlates in Adiposity Context. Report from the ABC of Healthy Eating Study of Polish Teenagers. Nutrients 2019; 11: 1563
- 48 Joo HJ, Kim GR, Park EC. et al. Association between Frequency of Breakfast Consumption and Insulin Resistance Using Triglyceride-Glucose Index: A Cross-Sectional Study of the Korea National Health and Nutrition Examination Survey (2016–2018). Int J Environ Res Public Health 2020; 17: 3322
- 49 Jakubowicz D, Landau S, Tsameret S. et al. Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients with Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial. Diabetes Care 2019; 42: 2171-2180
- 50 Breen C, Ryan M, McNulty B. et al. High saturated-fat and low-fiber intake: A comparative analysis of nutrient intake in individuals with and without type 2 diabetes. Nutr Diabetes 2014; 4: e104
- 51 Tiedemann LJ, Schmid SM, Hettel J. et al. Central insulin modulates food valuation via mesolimbic pathways. Nat Commun 2017; 8: 16052
- 52 Pugnaloni S, Alia S. Mancini et al. A Study on the Relationship between Type 2 Diabetes and Taste Function in Patients with Good Glycemic control. Nutrients 2020; 12: 1112-1122
- 53 Luukkonen PK, Sädevirta S, Zhou Y. et al. Saturated Fat Is More Metabolically Harmful to the Human Liver Than Unsaturated Fat or Simple Sugars. Diabetes Care 2018; 41: 1732-1739
- 54 Fryk E, Olausson J, Mossberg K. et al. Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study. Lancet 2021; 65: 103264
- 55 Grubelnik V, Zmazek J. Markovič et al. Mitochondrial Dysfunction in Pancreatic Alpha and Beta-cells Associated with Type 2 Diabetes Mellitus. Life 2020; 10: 348
- 56 Hannon BA, Thompson SV, Edwards CG. et al. Dietary Fiber Is Independently Related to Blood Triglycerides Among Adults with Overweight and Obesity. Curr Dev Nutr 2018; 28: 094
- 57 Dong Y, Chen L, Gutin B. et al. Total, Insoluble, and Soluble Dietary Fiber Intake and Insulin Resistance and Blood Pressure in Adolescents. Eur J Clin Nutr 2019; 73: 1172-1178
- 58 Gao X, Wang Y, Sun G. High dietary choline and betaine intake is associated with low insulin resistance in the Newfoundland population-. Nutrition 2017; 33: 28-34
- 59 Azemati B, Rajaram S, Jaceldo-Siegl K. et al. Animal-Protein Intake Is Associated with Insulin Resistance in Adventist Health Study 2 (AHS-2) Calibration Substudy Participants: A Cross-Sectional Analysis. Curr Dev Nutr 2017; 1: e000299
- 60 Meir AY, Rinott E, Tsaban G. et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomized controlled trial. Gut. 2021: 1-11
- 61 Castro-Barquero S, A Tresserra-Rimbau A, Vitelli-Storelli F. et al. Dietary Polyphenol Intake is Associated with HDL-Cholesterol and A Better Profile of Other Components of the Metabolic Syndrome: A PREDIMED-Plus Sub-Study. Nutrients 2020; 12: 689-696
- 62 McKaye J, Ho S, Jane M. et al. Overweight & obese Australian adults and micronutrient deficiency. BMC Nutr 2020; 1: 12
- 63 Hall E, Volkov P, Daveh T. et al. Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. BMC Med 2014; 12: 103
- 64 Maples J, Brault JJ, Wiczak CA. et al. Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity. Am J Physiol Endocrinol Metab 2015; 309: E345-E356
- 65 Bacha F, Klinepeter Bartz S, Puvau M. et al. Metabolic flexibility across the spectrum of glycemic regulation in youth. JCI Insight 2021; 6: e146000
- 66 Irvin MR, Joehanes R, Mendelson M. et al. Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study. Circulation 2014; 130: 565-572
- 67 Mamtani M, Kulkarni H, Dyer TD. et al. Genome- and epigenome-wide association study of the hypertriglyceridemic waist in Mexican American families. Clin Epigenetics 2016; 6: 1-14
- 68 Lai C, Parnell LD, Smith CE. et al. Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A. Am J Clin Nutr 2020; 112: 1200-1211
- 69 Arpón A, Milagro FI, Ramos-Lopez O. et al. Epigenome-wide association study in peripheral white blood cells involving insulin resistance. Sci Rep 2019; 9: 2445-2456
- 70 Rohner M. Method for evaluating foods, and nutritional systems for the prevention and treatment of chronic disease. European Patent EP3166639B1.
- 71 Rohner M. Method for Weight Reduction. European Patent EP1962826B1.
- 72 Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. The product of fasting glucose and triglycerides as a surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord 2008; 6: 299-304
- 73 Masson W, Siniawski D, Lobo M. et al. Association between triglyceride/HDL cholesterol ratio and carotid atherosclerosis in postmenopausal middle-aged women. Endocrinol Nutr 2016; 63: 327-332
- 74 Bedogni G, Bellentani S, Miglioli L. et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006; 6: 33
- 75 Achilike I, Hazuda HP, Fowler SP. et al. Predicting the development of the metabolically healthy obese phenotype. Int J Obes 2015; 39: 228-234
- 76 Banks WA, Farr SA, Salameh TS. et al. Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. Int J Obes 2018; 42: 391-397
- 77 Kelly J, Karlsen M, Steinke G. Type 2 Diabetes Remission and Lifestyle Medicine: A Position Statement from the American College of Lifestyle Medicine.. Am J Lifestyle Med 2020; 14: 406-419
- 78 Ades PA, Savage PD, Marney AM. et al. Remission of recently diagnosed type 2 diabetes mellitus with weight loss and exercise. J Cardiopulm Rehabil Prev 2015; 35: 193-197
- 79 Ma M, Liu H, Yo J. et al. Triglyceride is independently correlated with insulin resistance and islet beta-cell function: a study in a population with different glucose and lipid metabolism states. Lipids Health Disease 2020; 19: 121-133
- 80 Lim EL, Hollingsworth KG, Aribisala MJ. et al. Reversal of type 2 diabetes: normalization of beta-cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-2514
- 81 Ye X, Kong W, Zafar MI. et al. Serum triglycerides as a risk factor for cardiovascular diseases in type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Cardiovasc Diabetol 2019; 18: 48-58
- 82 Halldin AK, Björkelund C. Cholesterol and triglyceride levels in midlife and risk of heart failure in women, a longitudinal study: the prospective population study of women in Gothenburg. BMJ Open 2020; 10: 1-8
- 83 Toth PP, Philip S, Hull M. et al. Association of Elevated Triglycerides with Increased Cardiovascular Risk and Direct Costs in Statin-Treated Patients. Mayo Clin Proc 2019; 94: 1670-1680
- 84 Shimoda M, Miyoshi-Takai M, Irie S. et al. Inadequate Triglyceride Management Worsens the Durability of Dipeptidyl Peptidase-4 Inhibitor in Subjects with Type 2 Diabetes Mellitus. J Diabetes Res 2017; 5856475: 1-8
- 85 Khan RS, Bril F, Cusi K. et al. Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease. Hepatology 2018; 70: 711-724
- 86 Farell A, Green H, Williams J. et al. Adapting medical weight loss strategies to NAFL – is it effective). AASLD 2019; 065
- 87 Hydes TJ, Favi S, Loomba R. et al. Evidence-based clinical advice for nutrition and dietary weight loss strategies for the management of NAFL and NASH. Clin Mol Hepatol 2020; 26: 383-400