Novel canine models of obese prediabetes and mild type 2 diabetes

Abstract

(T2DM) is often characterized by obesity-associated insulin resistance (IR) and ␤-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 ␤-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n ϭ 12) received a high-fat diet that increased visceral (52%, P Ͻ 0.001) and subcutaneous (130%, P Ͻ 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S I) (5.8 Ϯ 0.7 ϫ 10 Ϫ4 to 4.1 Ϯ 0.5 ϫ 10 Ϫ4 U ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30 -15 mg/kg). The decrease in ␤-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose Ͼ200 mg/dl during OGTT and 77-93% AIR g reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR g reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased ␤-cell function (17-93%), and 40% lower S I. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) 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.obesity; animal models; streptozotocin; insulin secretion TYPE 2 DIABETES MELLITUS (T2DM) is a highly prevalent disease with an enormous public and individual health impact. According to the Centers for Disease Control National Diabetes Fact Sheet, in 2007 23.6 million people in the US (7.8% of population) had diabetes, and an estimated 57 million people had prediabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both] (10). The disease's increasing prevalence requires adequate and strong intervention for prevention of new cases and new or improved therapeutic tools for the existing cases (11). T2DM is characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response and is usually associated with obesity (15). Increased body fat and especially visceral fat accumulation have been shown to be risk factors for the development of IGT or diabetes (14). The mechanisms of the initial alterations in the development of T2DM, related to fat deposition and the associated changes in liver, muscle, and adipocyte, are not fully elucidated. Studying the relationship between insulin resistance and hyperinsulinemic compensation (or failure thereof) and the change from normal glucose tolerance to IGT ...

Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

“…In the present study, however, insulin secretion following an oral glucose challenge was impaired in both the HFFD-Sh and -Px groups, resulting in augmented glycemia. There are some key differences between the studies conducted by Ionut et al (14) and those presented in this paper. First, we utilized a surgical (partial pancreatectomy) rather than chemical (STZ) approach to create a pure model of compromised pancreatic mass so that any toxic, off-target effects of STZ could be avoided (e.g., generation of highly reactive ions and DNA strand break within the ␤-cells) (29,40).…”

“…Recently, Ionut et al (14) characterized the development of IGT in a canine model of high-fat diet-induced obesity before and after streptozotocin (STZ)-induced ␤-cell destruction. In the absence of STZ, glucose tolerance was retained during high-fat feeding due to a compensatory increase in insulin secretion, whereas high-fat feeding coupled with an intermediate dose of STZ (18.5 mg/kg) resulted in impaired glucose tolerance due to a 77-93% reduction in ␤-cell function secondary to ␤-cell destruction (14).…”

“…In the absence of STZ, glucose tolerance was retained during high-fat feeding due to a compensatory increase in insulin secretion, whereas high-fat feeding coupled with an intermediate dose of STZ (18.5 mg/kg) resulted in impaired glucose tolerance due to a 77-93% reduction in ␤-cell function secondary to ␤-cell destruction (14). In the present study, however, insulin secretion following an oral glucose challenge was impaired in both the HFFD-Sh and -Px groups, resulting in augmented glycemia.…”

Triglyceride-Based Screening Tests Fail to Recognize Cardiometabolic Disease in African Immigrant and African-American Men

“…VAT adversely affects glucose tolerance status and is associated with rapid weight gain. 39 Therefore, the rapid weight gain that Africans experience after immigration may account, at least in part, for their worse glucose tolerance status. In addition, while the degree of insulin resistance was similar in Africans and African Americans, AIRg, a marker of b-cell function was lower in Africans.…”

Adipose tissue macrophages in non-rodent mammals: a comparative study

“…In these animals, obesity as a result of overnutrition can develop raising health issues and complications in the care of feline and canine patients (de Godoy and Swanson 2013). Moreover, canine obesity is a possible model of human obesity associated metabolic diseases (Ionut et al 2010) but we lack information on the SVF contribution to metabolism in dogs. We also analyze the SVF cells of red fox (Vulpes vulpes), wild boar (Sus scrofa) and horse (Equus ferus caballus).…”