Short-Term Estrogen Replacement Effects on Insulin Sensitivity and Glucose Tolerance in At-Risk Cats for Feline Diabetes Mellitus.

Male domestic cats that are neutered and overweight are at an increased risk for developing a type-2-like diabetes mellitus. Beneficial effects of 17β-estradiol (E2) on glucose homeostasis may be lost with neutering and thereby account for increased diabetes risk. To evaluate this, adult male neutered overweight cats (n=6) were given daily E2 (1.0 μg/kg) or vehicle (Vh; ethanol, 1.0 μL/kg) in a single crossover trial of 14-day periods with a 7-day washout. The E2 and Vh were voluntarily ingested on food. The E2 dosage was determined in a pre-trial to significantly and transiently reduce food intake with no measurable change in plasma E2 concentration. During treatments, physical activity was assessed with collar-mounted accelerometers on days 9-11, and tests of intravenous insulin tolerance and intravenous glucose tolerance were conducted on days 13 and 14, respectively. Over the 14 days, E2 compared to Vh treatment reduced (p=0.03) food intake (- 22%) but not enough to significantly reduce body weight; activity counts were not significantly changed. With E2 compared to Vh treatment, the late-phase plasma insulin response of the glucose tolerance test was less (p=0.03) by 31%, while glucose tolerance and insulin sensitivity indexes were not significantly changed. The results indicate that oral E2 at a dosage that moderately affects food intake may reduce insulin requirement for achieving glucose homeostasis in neutered male cats. Further investigation is needed to identify the mechanism underlying the E2 effect

Effect of oral estradiol treatment (E2) (1.0 μg/kg) on body weight, food intake and energy intake.

<p>^aSignificantly (p = 0.03) different from the corresponding vehicle value.</p><p>^bBody weights between days 12–14 were not recorded due to necessary food withholding.</p><p>^cAverage determined over 11 days. Food intake for days 12–14 were not recorded due to necessary food withholding for catheterization and tolerance testing.</p><p>Effect of oral estradiol treatment (E2) (1.0 μg/kg) on body weight, food intake and energy intake.</p

Box-whisker plots demonstrating results of food intake over successive 3-day intervals prior to and during 14-day treatment periods when vehicle, 0.5, 1.0, or 2.0 μg/kg of E2 were ingested daily for 5 days.

<p>Boxes represent the 25 to 75^th percentile, central lines represent medians, and whiskers show the minimum and maximum observations on 8 cats. Where letters above plots are different, food intake observations are different (p≤0.05).</p

Effects of oral estradiol (E2) (1.0 μg/kg) and control vehicle (Vh) (1.0μL/kg) on study outcomes in overweight adult male cats (median [range], n = 6).

<p>^aDifferent from the mean of the corresponding variable.</p><p>Effects of oral estradiol (E2) (1.0 μg/kg) and control vehicle (Vh) (1.0μL/kg) on study outcomes in overweight adult male cats (median [range], n = 6).</p

Proximate analysis and ingredient list of the diet^a.

<p>Ingredients^b: Corn gluten meal, chicken, wheat flour, brewers rice, ground yellow corn, animal fat preserved with mixed-tocopherols, egg product, sodium caseinate, phosphoric acid, calcium carbonate, potassium chloride, animal digest, salt, L-Lysine monohydrochloride, dried whey, choline chloride, dicalcium phosphate, taurine, zinc sulfate, ferrous sulfate, manganese sulfate, Vitamin E supplement, niacin, citric acid, Vitamin A supplement, calcium pantothenate, thiamine mononitrate, copper sulfate, riboflavin supplement, Vitamin B-12 supplement, pyridoxine hydrochloride, folic acid, Vitamin D-3 supplement, calcium iodate, biotin, menadione sodium bisulfite complex, sodium selenite.</p><p>^aAs determined by the University of Missouri Agricultural Experiment Station Chemical Laboratories.</p><p>^bAs reported on the product label.</p><p>Proximate analysis and ingredient list of the diet<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130696#t001fn002" target="_blank">^a</a>.</p

Box-whisker plots of plasma insulin concentrations (μU/mL) of the IVGTTs of adult, overweight (>25% body fat), male, neutered cats (n = 6) when given vehicle (open boxes) and 1.0 μg/kg E2 (shaded boxes).

<p>Boxes represent the 25 to 75^th percentile, central lines represent medians, and whiskers show minimum and maximum observations. Asterisk indicates difference (p = 0.03) between E2 and Vh treatment observations at 90 min.</p

Box-whisker plots of daily food intake of 8 cats during 3-day periods preceding (days -3 to -1), during (days 0 to 5), and after (days 6 to 14) oral ingestion of vehicle (open boxes) and E2 at dosages of 0.5 (stippled boxes), 1.0 (diagonal line boxes), and 2.0 (shaded boxes) μg/kg body weight.

<p>Boxes represent the 25 to 75^th percentile, central lines represent medians, and whiskers show the minimum and maximum observations on 6 cats. Food intake observations within 3-day periods are different (p≤0.05) where letters above plots are different.</p

Effect of estradiol (1.0 μg/kg) on reputed insulin sensitivity indicators determined from intravenous glucose tolerance test (IVGTT) results (n = 6) and correlation of the indicators with the insulin sensitivity index (k_ivitt) of the intravenous insulin tolerance test (IVITT).

<p>^aSignificance (p =) of Wilcoxon signed-rank test of differences between vehicle and estradiol treatment observations on the indicator. ns = not significant, p > 0.05.</p><p>^bSpearman coefficient (ρ) and significance (p =) of correlation between observations during vehicle treatment. ns = not significant, p > 0.05.</p><p>^cAUC = area-under-the-curve. HOMA = (baseline insulin × baseline glucose)/22.5. QUICKI = 1/[log(baseline insulin) + log(baseline glucose)]. k_ivitt = (baseline plasma glucose - 15 min plasma glucose)/baseline plasma glucose.</p><p>Effect of estradiol (1.0 μg/kg) on reputed insulin sensitivity indicators determined from intravenous glucose tolerance test (IVGTT) results (n = 6) and correlation of the indicators with the insulin sensitivity index (k_ivitt) of the intravenous insulin tolerance test (IVITT).</p