title: A model of type 2 diabetes in the guinea pig using sequential diet-induced glucose intolerance and streptozotocin treatment.
abstract: Type 2 diabetes is a leading cause of morbidity and mortality among noncommunicable diseases, and additional animal models that more closely replicate the pathogenesis of human type 2 diabetes are needed. The goal of this study was to develop a model of type 2 diabetes in guinea pigs, in which diet-induced glucose intolerance precedes β-cell cytotoxicity, two processes that are crucial to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after 8 weeks of feeding on a high-fat, high-carbohydrate diet, as determined by oral glucose challenge. Diet-induced glucose intolerance was accompanied by β-cell hyperplasia, compensatory hyperinsulinemia, and dyslipidemia with hepatocellular steatosis. Streptozotocin (STZ) treatment alone was ineffective at inducing diabetic hyperglycemia in guinea pigs, which failed to develop sustained glucose intolerance or fasting hyperglycemia and returned to euglycemia within 21 days after treatment. However, when high-fat, high-carbohydrate diet-fed guinea pigs were treated with STZ, glucose intolerance and fasting hyperglycemia persisted beyond 21 days post-STZ treatment. Guinea pigs with diet-induced glucose intolerance subsequently treated with STZ demonstrated an insulin-secretory capacity consistent with insulin-independent diabetes. This insulin-independent state was confirmed by response to oral antihyperglycemic drugs, metformin and glipizide, which resolved glucose intolerance and extended survival compared with guinea pigs with uncontrolled diabetes. In this study, we have developed a model of sequential glucose intolerance and β-cell loss, through high-fat, high-carbohydrate diet and extensive optimization of STZ treatment in the guinea pig, which closely resembles human type 2 diabetes. This model will prove useful in the study of insulin-independent diabetes pathogenesis with or without comorbidities, where the guinea pig serves as a relevant model species.
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA brendan.podell@colostate.edu.
authors.forename: Brendan K
authors.identifier: 0000-0003-2548-8826
authors.initials: BK
authors.lastname: Podell
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Ackart
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Richardson
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: DiLisio
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pulford
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
mesh_terms: D000284:Administration, Oral; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D004032:Diet; D004040:Dietary Carbohydrates; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005247:Feeding Behavior; D005260:Female; D018149:Glucose Intolerance / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D006168:Guinea Pigs; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D006946:Hyperinsulinism / Q000150:complications / Q000188:drug therapy; D006965:Hyperplasia; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin; D016019:Survival Analysis; D015430:Weight Gain / Q000187:drug effects
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D007328:Insulin; D013311:Streptozocin
keywords: Animal model; Glucose intolerance; Guinea pig; Insulin-independent diabetes; Streptozotocin; Type 2 diabetes