HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ionut, V. Articles by Bergman, R. N. PubMed PubMed Citation Articles by Ionut, V. Articles by Bergman, R. N.

RESEARCH ARTICLE

NOVEL CANINE MODELS OF OBESE PRE-DIABETES AND OF MILD TYPE 2 DIABETES

¹Keck School of Medicine of USC

Submitted 24 July 2009 ; revised 28 September 2009 ; accepted in final form 16 October 2009

Human type 2 diabetes (T2DM) is often characterized by obesity-associated insulin resistance (IR) and beta-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in beta-cell function leading to mild diabetes or impaired glucose tolerance. Lean dogs (n=12) received a high-fat diet that increased visceral (52%, p<0.001) and subcutaneous (130%, p<0.001) fat and resulted in a 31% reduction in insulin sensitivity (SI) (5.8±0.710-4 to 4.1±0.510^-4 uU/ml^-1 min^-1, p<0.05). Animals then received a single low dose of streptozotocin (STZ) (range 30-15 mg/kg). The decrease in beta-cell function was dose dependent and resulted in three diabetes models: a) frank hyperglycemia (high STZ dose); b) mild T2DM with normal or impaired fasting glucose (FG), 2h glucose >200 mg/dl during OGTT and 77-93% AIRg reduction (intermediate dose); and c) pre-diabetes with normal FG, normal 2h glucose during OGTT and 17-74% AIRg reduction (low dose). 12 weeks after STZ animals without frank diabetes had 58% more body fat, decreased β-cell function (17-93%) and 40% lower SI. We conclude that high fat feeding and variable dose STZ in dog results in stable models of obesity, insulin resistance and a) overt diabetes or b) mild T2DM or c) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.

type 2 diabetes; obesity; animal model; streptozotocin