title: Pancreatic beta-cell failure in obese mice with human-like CMP-Neu5Ac hydroxylase deficiency.
abstract: Type 2 diabetes is highly prevalent in human populations, particularly in obese individuals, and is characterized by progressive pancreatic β-cell dysfunction and insulin resistance. Most mammals, including Old World primates, express two major kinds of sialic acids, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), typically found at the distal ends of glycoconjugate chains at the cell surface. Humans are uniquely unable to produce endogenous Neu5Gc due to an inactivating mutation in the CMP-Neu5Ac hydroxylase (CMAH) gene. The CMAH enzyme catalyzes the generation of CMP-Neu5Gc by the transfer of a single oxygen atom to the acyl group of CMP-Neu5Ac. Here, we show that mice bearing a human-like deletion of the Cmah gene exhibit fasting hyperglycemia and glucose intolerance following a high-fat diet. This phenotype is caused not by worsened insulin resistance but by compromised pancreatic β-cell function associated with a 65% decrease in islet size and area and 50% decrease in islet number. Obese Cmah-null mice also show an ∼40% reduction in response to insulin secretagogues in vivo. These findings show that human evolution-like changes in sialic acid composition impair pancreatic β-cell function and exacerbate glucose intolerance in mice. This may lend insight into the pathogenesis of type 2 diabetes in obese humans.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kavaler
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.forename: Alice
authors.initials: A
authors.lastname: Jih
authors.forename: WuQiang
authors.initials: W
authors.lastname: Fan
authors.forename: Maria
authors.initials: M
authors.lastname: Hedlund
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D001120:Arginine; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D005947:Glucose