title: A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes.
abstract: Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing β-cell mass. We add to that model regulation of 2 aspects of β-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into "Starling's Law of the Pancreas," whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals.
authors.affiliation: Laboratory of Biological Modeling (J.H., A.S.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Pharmacology and Brehm Diabetes Research Center (L.S.S.), University of Michigan, Ann Arbor, Michigan 48105.
authors.forename: Joon
authors.initials: J
authors.lastname: Ha
authors.affiliation: Laboratory of Biological Modeling (J.H., A.S.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Pharmacology and Brehm Diabetes Research Center (L.S.S.), University of Michigan, Ann Arbor, Michigan 48105.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: Laboratory of Biological Modeling (J.H., A.S.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Pharmacology and Brehm Diabetes Research Center (L.S.S.), University of Michigan, Ann Arbor, Michigan 48105.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Sherman
mesh_terms: D000818:Animals; D050110:Bariatric Surgery; D031204:Caloric Restriction; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000517:prevention & control / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000517:prevention & control / Q000628:therapy; D059305:Diet, High-Fat; D005260:Female; D007333:Insulin Resistance; D008962:Models, Theoretical; D009765:Obesity / Q000150:complications / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D012074:Remission Induction