{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:09:44Z","timestamp":1777414184900,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006485","name":"National Institute of Genetic Engineering and Biotechnology","doi-asserted-by":"publisher","award":["1 U54 GM104940"],"award-info":[{"award-number":["1 U54 GM104940"]}],"id":[{"id":"10.13039\/501100006485","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.<\/jats:p>","DOI":"10.3390\/ijms23031884","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T23:37:48Z","timestamp":1644363468000},"page":"1884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology"],"prefix":"10.3390","volume":"23","author":[{"given":"Frank","family":"Greenway","sequence":"first","affiliation":[{"name":"Clinical Trials Unit, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Loveridge","sequence":"additional","affiliation":[{"name":"Diabetes Relief, Layton, UT 84041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Grimes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tori R.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Development and Cell Biology, University of California Irvine, Irvine, CA 92617, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Irvine, Orange, CA 92868, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott A.","family":"Hepford","sequence":"additional","affiliation":[{"name":"Well Cell Global LLC, Houston, TX 77079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Fontenot","sequence":"additional","affiliation":[{"name":"Lafayette Arthritis and Endocrine Clinic, Lafayette, LA 70506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Candi","family":"Nobles-James","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Wilson","sequence":"additional","affiliation":[{"name":"Well Cell Support LLC, Houston, TX 77079, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam M.","family":"Starr","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Asheville Orthopedic Associates P.A, Asheville, NC 28801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Abdelsaid","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Mercer University School of Medicine, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley T.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Eselle Health, Inc., La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan R. T.","family":"Lakey","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Irvine, Orange, CA 92868, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"ref_1","unstructured":"Center for Disease Control and Prevention (2021, December 21). Long-Term Trends in Diabetes, Available online: https:\/\/www.cdc.gov\/diabetes\/statistics\/slides\/long_term_trends.pdf."},{"key":"ref_2","unstructured":"Center for Disease Control and Prevention (2020). 2020 National Diabetes Statistics Report."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1016\/S0140-6736(12)60283-9","article-title":"Prediabetes: A high-risk state for diabetes development","volume":"379","author":"Tabak","year":"2012","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2018). Economic costs of diabetes in the U.S. 2017. Diabetes Care, 41, 917\u2013928.","DOI":"10.2337\/dci18-0007"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2021). 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021. Diabetes care, 44, S111\u2013S124.","DOI":"10.2337\/dc21-S009"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.2337\/dc21-0013","article-title":"Application of 2021 american diabetes association glycemic treatment clinical practice recommendations in primary care","volume":"44","author":"Colling","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2021). Introduction: Standards of medical care in diabetes-2021. Diabetes Care, 44, S1\u2013S2.","DOI":"10.2337\/dc21-Sint"},{"key":"ref_8","unstructured":"Food and Drug Administration (2010, January 19). Fda Revises Labels of Sglt2 Inhibitors for Diabetes to Include Warnings about Too Much Acid in the Blood and Serious Urinary Tract Infections, Available online: https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious."},{"key":"ref_9","unstructured":"Adhikari, R., and Blaha, M. (2021, January 19). New Insights into Prescribing of Sglt2 Inhibitors and Glp-1 Receptor Agonists by Cardiologists in 2020: Major Barriers Limiting Role. Available online: https:\/\/www.acc.org\/latest-in-cardiology\/articles\/2021\/01\/19\/14\/27\/new-insights-into-prescribing-of-sglt2-inhibitors-and-glp-1-receptor-agonists-in-2020."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5824","DOI":"10.1210\/jcem.86.12.8105","article-title":"Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus","volume":"86","author":"Kahn","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/dmrr.198","article-title":"The importance of first-phase insulin secretion: Implications for the therapy of type 2 diabetes mellitus","volume":"17","author":"Tiengo","year":"2001","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_12","unstructured":"Abbvie (2021, August 31). Lupron Depot-Ped: Dosing and Administration. Available online: https:\/\/www.lupronpedpro.com\/dosing-and-administration.html."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1056\/NEJM197911083011903","article-title":"Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings","volume":"301","author":"Lang","year":"1979","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1053\/meta.2003.50078","article-title":"Pancreatic beta-cell function and insulin sensitivity in japanese subjects with impaired glucose tolerance and newly diagnosed type 2 diabetes mellitus","volume":"52","author":"Kanauchi","year":"2003","journal-title":"Metabolism"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s001250051322","article-title":"Autonomic regulation of islet hormone secretion--implications for health and disease","volume":"43","author":"Ahren","year":"2000","journal-title":"Diabetologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5334","DOI":"10.1210\/en.2009-0600","article-title":"Glucose generates coincident insulin and somatostatin pulses and antisynchronous glucagon pulses from human pancreatic islets","volume":"150","author":"Hellman","year":"2009","journal-title":"Endocrinology"},{"key":"ref_17","first-page":"4491","article-title":"Direct measurement of pulsatile insulin secretion from the portal vein in human subjects","volume":"85","author":"Song","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Laurenti, M.C., Matveyenko, A., and Vella, A. (2021). Measurement of pulsatile insulin secretion: Rationale and methodology. Metabolites, 11.","DOI":"10.3390\/metabo11070409"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2337\/diabetes.52.1.102","article-title":"Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1210\/jc.2004-1133","article-title":"Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: A new analysis","volume":"90","author":"Ferrannini","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0026-0495(90)90064-J","article-title":"Intraportal hyperinsulinemia decreases insulin-stimulated glucose uptake in the dog","volume":"39","author":"McGuinness","year":"1990","journal-title":"Metabolism"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"922","DOI":"10.2337\/diab.35.8.922","article-title":"Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type i diabetic humans","volume":"35","author":"Komjati","year":"1986","journal-title":"Diabetes"},{"key":"ref_23","first-page":"559","article-title":"Glucose uptake and pulsatile insulin infusion: Euglycaemic clamp and [33H] glucose studies in healthy subjects","volume":"113","author":"Schmitz","year":"1986","journal-title":"Acta Endocrinol. (Copenh.)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1210\/er.2018-00226","article-title":"Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia","volume":"40","author":"Stanley","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.2337\/db15-0629","article-title":"The brain-to-pancreatic islet neuronal map reveals differential glucose regulation from distinct hypothalamic regions","volume":"65","author":"Rosario","year":"2016","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.mam.2015.01.003","article-title":"Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes","volume":"42","author":"Satin","year":"2015","journal-title":"Mol. Asp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1007\/s00125-009-1520-7","article-title":"Beta cell (dys)function in non-diabetic offspring of diabetic patients","volume":"52","author":"Stadler","year":"2009","journal-title":"Diabetologia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1056\/NEJM198805123181902","article-title":"Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes","volume":"318","author":"Turner","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"538","DOI":"10.2337\/diacare.27.2.538","article-title":"Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the framingham offspring cohort","volume":"27","author":"McKeown","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00125-004-1603-4","article-title":"Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women","volume":"48","author":"McAuley","year":"2005","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"505","DOI":"10.3945\/ajcn.112.042457","article-title":"Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes","volume":"97","author":"Ajala","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.2337\/dc08-0426","article-title":"Weight change in diabetes and glycemic and blood pressure control","volume":"31","author":"Feldstein","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1210\/jcem.85.10.6919","article-title":"Effect of weight loss on the pulsatile insulin secretion","volume":"85","author":"Zarkovic","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E560","DOI":"10.1152\/ajpendo.00561.2002","article-title":"Rosiglitazone prevents the impairment of human islet function induced by fatty acids: Evidence for a role of ppargamma2 in the modulation of insulin secretion","volume":"286","author":"Lupi","year":"2004","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2337\/diabetes.49.5.735","article-title":"Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: A direct metformin effect on pancreatic beta-cells","volume":"49","author":"Patane","year":"2000","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"776","DOI":"10.2337\/diabetes.50.4.776","article-title":"Glucagon-like peptide 1 increases secretory burst mass of pulsatile insulin secretion in patients with type 2 diabetes and impaired glucose tolerance","volume":"50","author":"Ritzel","year":"2001","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2337\/diacare.27.6.1487","article-title":"Use and abuse of homa modeling","volume":"27","author":"Wallace","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.2174\/1381612826666200909142126","article-title":"Effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on cardiorenal and metabolic outcomes in people without diabetes","volume":"27","author":"Papazafiropoulou","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117090","DOI":"10.1016\/j.lfs.2019.117090","article-title":"Molecular mechanisms by which sglt2 inhibitors can induce insulin sensitivity in diabetic milieu: A mechanistic review","volume":"240","author":"Yaribeygi","year":"2020","journal-title":"Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0140-6736(19)31149-3","article-title":"Dulaglutide and cardiovascular outcomes in type 2 diabetes (rewind): A double-blind, randomised placebo-controlled trial","volume":"394","author":"Gerstein","year":"2019","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"569","DOI":"10.7326\/M17-0939","article-title":"Hemoglobin a1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the american college of physicians","volume":"168","author":"Qaseem","year":"2018","journal-title":"Ann. Intern. Med."},{"key":"ref_43","unstructured":"Abernethy, A. (2021, April 28). Insulin Gains New Pathway to Increased Competition, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/insulin-gains-new-pathway-increased-competition."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/152091501750220073","article-title":"Chronic intermittent intravenous insulin therapy: A new frontier in diabetes therapy","volume":"3","author":"Aoki","year":"2001","journal-title":"Diabetes Technol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.curtheres.2019.04.003","article-title":"Effects of periodic intensive insulin therapy: An updated review","volume":"90","author":"Dong","year":"2019","journal-title":"Curr. Ther. Res. Clin. Exp."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.2337\/db11-1462","article-title":"Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling","volume":"61","author":"Matveyenko","year":"2012","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S245","DOI":"10.2337\/diabetes.51.2007.S245","article-title":"Pulsatile insulin secretion: Detection, regulation, and role in diabetes","volume":"51","author":"Porksen","year":"2002","journal-title":"Diabetes"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E206","DOI":"10.1152\/ajpendo.00406.2014","article-title":"Comparison of the physiological relevance of systemic vs. Portal insulin delivery to evaluate whole body glucose flux during an insulin clamp","volume":"308","author":"Farmer","year":"2015","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_49","first-page":"163","article-title":"Case series: Reversal of diabetic neuropathy utilizing physiologic insulin resensitization","volume":"6","author":"Tucker","year":"2021","journal-title":"Int. J. Diab. Metab. Disord."},{"key":"ref_50","first-page":"9","article-title":"Extraordinary rapid would healing time in diabetic patients treated with microburst insulin infusion","volume":"2","author":"Elliott","year":"2018","journal-title":"Int. Res. J. Publ. Health"},{"key":"ref_51","first-page":"116","article-title":"Microburst insulin infusion: Results of observational studies\u2014Carbohydrate metabolism, painful diabetic neuropathy and hospital\/emergency department utilization","volume":"4","author":"Elliott","year":"2017","journal-title":"J. Diab. Metab. Disord. Contr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1053\/meta.2000.17700","article-title":"Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy","volume":"49","author":"Dailey","year":"2000","journal-title":"Metabolism"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Villaverde, Z., Tucker, T., Hepford, S., Lakey, J., and Hinman, R. (2021). Improved kidney function following physiologic insulin resensitization treatment modality. J. Endocrinol. Disord., 5.","DOI":"10.31579\/2640-1045\/080"},{"key":"ref_54","first-page":"49","article-title":"Pulsatile insulin infusion as a treatment option for patients with type 2 diabetes and stage iii kidney failure\u2014Results from a pilot study","volume":"6","author":"Manessis","year":"2021","journal-title":"Diabetes care"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"70","DOI":"10.2337\/db21-112-LB","article-title":"112-lb: Pulsatile insulin treatment as a treatment option for patients with type 2 diabetes and stage 3 kidney failure","volume":"70","author":"Quach","year":"2021","journal-title":"Diabetes"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/0140-6736(93)91645-3","article-title":"Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus","volume":"342","author":"Aoki","year":"1993","journal-title":"Lancet"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1089\/dia.2011.0118","article-title":"Pharmacology of intravenous insulin administration: Implications for future closed-loop glycemic control by the intravenous\/intravenous route","volume":"14","author":"Skjaervold","year":"2012","journal-title":"Diabetes Technol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4158\/EP.5.4.174","article-title":"Effect of intensive insulin therapy on progression of overt nephropathy in patients with type 1 diabetes mellitus","volume":"5","author":"Aoki","year":"1999","journal-title":"Endocr. Pract."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:15:50Z","timestamp":1760134550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,8]]},"references-count":58,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031884"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031884","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,8]]}}}