Cardiovascular sexual dimorphism in a diet-induced type 2 diabetes rodent model, the Nile rat (Arvicanthis niloticus)

Abstract

Background: The Nile rat (Arvicanthis niloticus) is an emerging laboratory model of type 2 diabetes. When fed standard rodent chow, the majority of males progress from hyperinsulinemia by 2 months to hyperglycemia by 6 months, while most females remain at the hyperinsulinemia-only stage (prediabetic) from 2 months onward. Since diabetic cardiomyopathy is the major cause of type-2 diabetes mellitus (T2DM)-related mortality, we examined whether sexual dimorphism might entail cardiac functional changes. Our ultimate goal was to isolate the effect of diet as a modifiable lifestyle factor.

Materials and methods: Nile rats were fed either standard rodent chow (Chow group) or a high-fiber diet previously established to prevent type 2 diabetes (Fiber group). Cardiac function was determined with echocardiography at 12 months of age. To isolate the effect of diet alone, only the small subset of animals resistant to both hyperinsulinemia and hyperglycemia were included in this study.

Results: In males, Chow (compared to Fiber) was associated with elevated heart rate and mitral E/A velocity ratio, and with lower e'-wave velocity, isovolumetric relaxation time, and ejection time. Of note, these clinically atypical types of diastolic dysfunction occurred independently of body weight. In contrast, females did not exhibit changes in cardiovascular function between diets.

Conclusions: The higher prevalence of T2DM in males correlates with their susceptibility to develop subtle diastolic cardiac dysfunction when fed a Western style diet (throughout most of their lifespan) despite no systemic evidence of metabolic syndrome, let alone T2DM.

Fig 1. Metabolic phenotype in the males and females from the Fiber (black boxes) and Chow (grey boxes) groups.

Body weight (A), fasting blood insulin (B) and glucose (FBG, C) were measured. Boxes indicate the minimum, 25^th percentile, median, 75^th percentile, and maximum. Significant differences between dietary groups or sexes are indicated with ** for p<0.01. In males, N equals 4 and 5 for body weight and 3 and 4 for insulin and FBG in the Fiber and Chow group, respectively. In females, N equals 3 and 6 for body weight, insulin and FBG in the Fiber and Chow group, respectively. Kruskal-Wallis results are indicated on each panel; data are from the same animals for which echocardiography was performed, with the exception of Fiber females for the insulin data only, and Chow females which represent a distinct group of age-matched animals.

Fig 2. Morphology in males and females from the Fiber (black boxes) and Chow (grey boxes) groups.

The following parameters were measured: left ventricular (LV) mass (A), left ventricular internal diameter (LVID, B and C), left ventricular posterior wall thickness (LVPW, D and E), interventricular septum wall thickness (IVS, F and G) at end-diastole (d, left panels B, D, F) and end-systole (s, right panels C, E, G). Boxes indicate the minimum, 25^th percentile, median, 75^th percentile, and maximum. BPM indicates beat per minute. In males, N equals 4 and 5 for Fiber and Chow groups, respectively. In females N equals 3 and 8 in Fiber and Chow groups, respectively. Significant differences between dietary groups or sexes are indicated with * for p<0.05. Kruskal-Wallis results are indicated on each panel.

Fig 3. Systolic function in males and females from the Fiber (black boxes) and Chow (grey boxes) groups.

The following indicators were measured: heart rate (A), stroke volume (B), cardiac output (C), ejection fraction (D), fractional shortening (E). Boxes indicate the minimum, 25^th percentile, median, 75^th percentile, and maximum. In males, N equals 4 and 5 in the Fiber and Chow group, respectively. In females N equals 3 and 8 in the Fiber and Chow group, respectively. Significant differences between dietary groups or sexes are indicated with ** for p<0.01 and * for p<0.05. Kruskal-Wallis results are indicated on each panel.

Fig 4. Diastolic function in males and females from the Fiber (black boxes) and Chow (grey boxes) groups.

The figure includes mitral E velocity (A), mitral A velocity (B), E/A ratio (C), isovolumetric relaxation time (IVRT, D), isovolumetric contraction time (IVCT; E), ejection time (F), tissue Doppler e’-wave velocity (G), a’-wave velocity (H), ratio e’/a’ (I), ratio E/e’ (J), and myocardial performance index (TEI index, K). Boxes indicate the minimum, 25^th percentile, median, 75^th percentile, and maximum. In males, N equals 4 and 5 in the Fiber and Chow group, respectively. In females N equals 3 and 7–8 in the Fiber and Chow group, respectively. Significant differences between dietary groups or sexes are indicated with *** for p<0.001, ** for p<0.01 and* for p<0.05. Kruskal-Wallis results are indicated on each panel.