Effect of acarbose on postprandial blood glucose concentrations in healthy cats fed low and high carbohydrate diets

Abstract

Objectives

Feeding a low carbohydrate diet is recommended for diabetic cats; however, some cats may require diets containing moderate-to-high carbohydrate and may benefit from the use of therapeutic agents to improve glycemic control. The aim of the study was to determine the effect of the α-glucosidase inhibitor acarbose on postprandial plasma glucose concentration when combined with commercially available feline diets high and low in carbohydrate.

Methods

Twelve healthy, adult, non-obese, neutered cats were enrolled. Plasma glucose concentrations were assessed over 24 h after feeding high and low carbohydrate diets, with and without acarbose, during single and multiple meal tests, in a crossover study. Commercially available feline diets were used, which were high and low in carbohydrate (providing 51% and 7% of metabolizable energy, respectively).

Results

In cats fed the high carbohydrate diet as a single meal, mean 24 h glucose concentrations were lower when acarbose was administered. Mean glucose concentrations were lower in the first 12 h when acarbose was given once daily, whereas no significant difference was observed in mean results from 12–24 h. Acarbose had little effect in cats eating multiple meals. Compared with consumption of the high carbohydrate diet with acarbose, lower mean 24 h and peak glucose concentrations were achieved by feeding the low carbohydrate diet alone.

Conclusions and relevance

In healthy cats meal-fed diets of similar composition to the diets used in this study, acarbose has minimal effect when a low carbohydrate diet is fed but reduces postprandial glucose concentrations over 24 h when a high carbohydrate diet is fed. However, mean glucose concentrations over 24 h are still higher when a high carbohydrate diet with acarbose is fed relative to the low carbohydrate diet without acarbose. Future studies in diabetic cats are warranted to confirm these findings.

Introduction

Type 2 diabetes is a common endocrinopathy in cats.^1–3 Cats and humans with glucose concentrations above normal but below those considered diabetic during fasting or a glucose tolerance test are considered prediabetic,^4,5 and prediabetic humans are at greatly increased risk of developing type 2 diabetes.⁴ Minimizing the increase in glucose concentration following a meal is a primary goal for the management of prediabetic and diabetic humans.⁶ In these patients, it is considered more important to normalize postprandial hyperglycemia than fasting glucose concentrations, and low carbohydrate diets, oral hypoglycemic agents and insulin therapy are recommended, when necessary, to achieve glycemic control.⁶

Current treatment of diabetic cats consists of insulin therapy and nutritional management.¹ Insulin therapy is the most effective treatment in achieving glycemic control, and its effectiveness may be increased when combined with a low carbohydrate diet or by using oral hypoglycemic agents.^7,8 Typically, low carbohydrate diets are recommended for the management of diabetes, but diabetic cats with other complicating conditions such as chronic renal failure and persistent obesity, may require moderate-to-high carbohydrate diets to reduce protein and fat intake, respectively.⁹ The postprandial increase in glucose after moderate-to-high carbohydrate meals in cats is of greater magnitude and considerably longer duration (12–24 h)^10–12 than in dogs (3–6 h)¹³ and humans (2–3 h),^6,14 and is exacerbated in overweight or obese cats.^12,15

A goal of dietary therapy in prediabetic and diabetic humans is to lower postmeal plasma glucose by using diets with reduced glycemic load and glycemic index, and, when necessary, by the use of therapeutic agents, such as the α-glucosidase inhibitor acarbose, to improve glycemic control.^6,16,17 Acarbose is a complex oligosaccharide of microbial origin that competitively inhibits α-glucosidase and α-amylase, enzymes involved in the digestion of complex carbohydrates into monosaccharides in the brush border of the small intestinal mucosa.¹⁸ It delays absorption of glucose from the intestinal tract, and in humans reduces postprandial blood glucose and insulin concentrations after a carbohydrate meal, and in dogs improves glycemic control.^19,20 Major side effects of acarbose are gastrointestinal disturbances such as loose stools, diarrhea, flatulence and abdominal pain;^18,21 however, these effects tend to decrease with time because of adaptation of the carbohydrate digestive enzyme capacity.^18,22,23

Glycemic control was not better in diabetic cats receiving acarbose and fed a low carbohydrate diet compared with those receiving a low carbohydrate food alone.²⁴ Nevertheless, some diabetic cats with renal failure or obesity consuming moderate-to-high carbohydrate diets might benefit from acarbose. Currently, there are no published data demonstrating a benefit of administering acarbose to cats fed a high carbohydrate diet, or how the magnitude of the effect on postprandial glucose concentrations compares with feeding a low carbohydrate diet alone. The aim of this study was to determine in healthy cats the impact of acarbose on postprandial plasma glucose concentrations when combined with commercially available feline diets high and low in carbohydrate.

Materials and methods

Overview of experimental design

Four diet–treatment combinations – high carbohydrate, low protein diet or low carbohydrate, high protein diet (Table 1), with or without acarbose (Glucobay; Bayer Australia Limited) – were assessed in each of 12 healthy cats in a factorial crossover design. Prior to feeding the test diets, all cats were fed a standard feline maintenance ‘washout’ diet (Purina One; Nestle Purina PetCare), moderate in carbohydrate and protein, providing 32%, 34% and 34% metabolizable energy (ME) from carbohydrate, protein and fat, respectively,²⁵ for 2 weeks. Following 24 h testing utilizing single and multiple meals (11 small meals) in the third week, three cats were randomly allocated to each of four groups. Each group was randomly allocated to one of four sequences of the diet–treatment combinations (high carbohydrate, high carbohydrate with acarbose, low carbohydrate, low carbohydrate with acarbose), defined by a Latin square. All four combinations were fed within each time period; that is, each group commenced with a different combination, and then combinations were fed in the same order for all cats. Each diet–treatment combination was fed for 2 weeks. In the third week of feeding, plasma glucose concentrations were measured during two feeding regimens, single meal and multiple meal feeding tests. Acarbose was given at 25 mg per cat orally once daily at the time of feeding for the preceding 2 weeks of the test week and during the single meal feeding test, and at 12.5 mg per cat orally 12 hourly on the day before and during the multiple meal feeding test. Cat signalment, testing protocol and glucose results for the single meal feeding test using the high carbohydrate diet have also been reported previously as part of a study to assess the associations between meal size, gastric emptying and postprandial plasma glucose, insulin and lactate concentrations in meal-fed cats.²⁶

Table 1

Energy densities of the test diets, and caloric distributions expressed as percentages of metabolizable energy (ME), fed to healthy cats with and without acarbose in a crossover study. Each cat was randomly assigned to one of the four diet–treatment combination sequences defined by a balanced Latin square design. Each diet–treatment combination was fed to each cat (n = 12) for 3 weeks

Approximate energy density (ME)	Diet
	High carbohydrate*	Low carbohydrate^†
Energy density kcal/100 g^‡	370	116
Energy density kcal/100 g^§	353	112
Carbohydrate (%)^§	51	7
Protein (%)^§	21	46
Fat (%)^§	28	47

Kitekat Krunch (Mars Petcare)

†

Purina DM Diabetes Management Formula (Ralston Purina)

‡

ME calculated using the equation proposed by the National Research Council in 2006

ME calculated using the modified Atwater factors²⁵

Animals

Twelve adult, non-obese, healthy, neutered domestic cats (six males, six females) were used in the study. Mean initial body weight was 3.6 ± 0.6 kg (median 3.8 kg), and body condition ranged from 4–6 on a nine-point system.²⁷ Body weight was maintained within 95–105% of initial weight throughout the study period. Cats were considered clinically healthy based on physical examination and routine hematologic analyses, and tested negative for feline immunodeficiency virus (Agen Biomedical Ltd). Healthy, rather than diabetic, cats were used in the study because postprandial hyperglycemia in diabetic cats is also affected by insulin dose and degree of glycemic control, which would confound identifying effects of acarbose on postprandial blood glucose concentrations. In addition, feeding a high carbohydrate diet to diabetic cats would decrease the probability of remission, and would be considered unethical. The project was approved by the University of Queensland’s animal ethics committee (approval number SVS/230/03). All cats were rehomed at the conclusion of the study.

Blood sampling

Blood collection was performed via vascular access ports (Le Petite CompanionPort; Norfolk Vet Products) implanted prior to the start of the study, as previously described.²⁸ Packed cell volume was monitored during the study, and there were no differences before or after each test, or between tests (data not shown).

Testing protocol

On day 1 of each test week, a meal of 50 kcal/kg was fed and uneaten food removed 30 mins later. Cats were then fasted for 23.5 h; on day 2, a 24 h single meal feeding test was performed. On day 3, the total amount of 50 kcal/kg of the test diet was subdivided into multiple small meals and offered over 24 h to mimic the ad libitum feeding pattern, followed by the 24 h multiple meal feeding test on day 4. In non-test weeks, cats were fed their respective test diets once daily to maintain body weight within 95–105% of their initial body weight. Food bowls were weighed daily prior to each feeding to calculate the amount of food consumed in 24 h. Food intake was recorded daily, cats were weighed weekly, and the amount fed adjusted accordingly. Cats were allowed free access to water at all times.

Single meal feeding test

The single meal feeding test was used to mimic the feeding pattern observed in cats fed restricted energy to maintain ideal body weight or achieve weight loss. Typically, the majority of the food is eaten shortly after feeding. During this test, each cat was required to eat at least 90% of one meal of 50 kcal/kg within 30 mins of being fed at time 0, and uneaten food was withdrawn. One cat failed to do this when fed the high carbohydrate diet without acarbose and so was excluded from all analyses of data for the single meal feeding test. Blood samples (1 ml) were collected 30 and 5 mins before and at 1, 2, 3, 4, 6, 8, 10, 12, 15, 18 and 24 h after feeding the meal at time 0. Cats were fed immediately upon conclusion of the test. Blood samples were collected more frequently in the first 12 h because that is when most changes in glucose concentration were expected. We have previously reported that in healthy, lean cats fed a single meal of the same high carbohydrate diet used in the present study, there is a sharp increase in plasma glucose concentration in the first 6 h after the meal, and the median peak occurs at 10 h.¹²

Multiple meal feeding test

During this test, the total energy intake (50 kcal/kg) was divided into 11 equal meals of 4.55 kcal/kg/meal and fed over a 24 h period to mimic the feeding pattern observed in cats when food is freely available, but to restrict energy intake to the amount fed in the single-meal-feeding test. Food was provided at the start of the test (time 0) and at the same times as the blood samplings (1, 2, 3, 4, 6, 8, 10, 12, 15, 18 and 24 h), resulting in more frequent feeding earlier in the 24 h period, to reflect the relatively greater amount eaten when food is freshly provided to cats.²⁹ Blood samples (1 ml) were collected at the same time points as for the single meal feeding test, and food was given immediately after each sample was taken.

Sample handling and analysis

Blood samples for glucose analysis were placed into lithium heparin tubes. After collection, samples were kept on ice for 8 mins and then centrifuged at 1500 g for 10 mins, and plasma aliquots were stored at −70 °C in microvials until analysis. Plasma glucose concentrations were measured by a commercial laboratory (QML Pathology, Brisbane, QLD, Australia) on a chemistry analyzer (Roche Integra 800 chemistry analyzer; Roche Diagnostics).

Statistical analyses

The effects of acarbose and dietary carbohydrate were analyzed separately for single and multiple meal feeding tests. For all analyses, the unit of analysis was the cat diet acarbose combination where diet indicates low or high carbohydrate, and acarbose was either not included or included. ‘Baseline’ concentrations were calculated as the means of concentrations 30 and 5 mins before feeding. Mean plasma glucose concentrations were calculated for the first 12 and 24 h postfeeding by calculating the areas under the plasma glucose concentration curve for 12 or 24 h after feeding using the trapezoidal method,³⁰ then dividing by 12 or 24, respectively.

Times to peak for glucose concentration were calculated as the time from (first) feeding (time 0) to time of the highest measured glucose concentration. Times for glucose concentration to exceed baseline were calculated based on 90% ranges of differences, calculated using the pooled variance of the two fasting samples within cats.³¹ Times for glucose concentration to return to baseline were calculated using only cat diet acarbose combinations where glucose exceeded baseline; these were calculated as the first time after glucose exceeded baseline when it was less than the sum of the cat’s baseline and the 90% range of difference. Linear interpolation between time points was used when times for glucose concentration to exceed and return to baseline were calculated.

The effects of acarbose and dietary carbohydrate on peak and mean plasma glucose concentration over 12 and 24 h were analyzed using linear regression with cat and time period fitted as fixed effects. Times to peak glucose concentration and times for glucose concentration to exceed and return to baseline were compared using Cox proportional hazards models, with stratification by cat. For cat–treatment combinations where glucose concentration did not exceed baseline, or where glucose concentration did not return to baseline, times were right-censored at 24 h. For both linear regression and Cox models, the main effects of acarbose and dietary carbohydrate were fitted and interaction between these assessed. This incorporated the factorial design of the study. The interaction term was removed if the P value for interaction was not low. Mean plasma glucose concentrations were also compared after fitting diet– acarbose combination as a four-level variable. Statistical analyses were performed using Stata version 8.2 and 12.1 (StataCorp). All variables were summarized as means ± SEM except where indicated.

Results

For all variables tested in the third week of feeding the washout diet, mean values from the meal feeding tests were similar among cats (data not shown).

Single meal feeding test

Mean 24 h plasma glucose concentrations

The effects of acarbose depended on diet (P for interaction = 0.017; Figure 1a,b; Table 2). There was no significant effect of acarbose in cats fed the low carbohydrate diet (P = 0.743). However, when administered the high carbohydrate diet, mean 24 h glucose concentration was lower when acarbose was fed (P = 0.003; Figure 1a,b; Table 2).

Figure 1

(a) Mean (± SEM) plasma glucose concentrations during the single meal feeding test before and after consumption of four diet–treatment combinations in a crossover study in healthy cats (n = 11). This figure has also been published in Rand JS, ed. Clinical endocrinology of companion animals. Chichester: Wiley-Blackwell, 2013, p 176, reprinted with permission. (b) Mean 24 h plasma glucose concentrations during the single meal feeding test following consumption of four diet–treatment combinations in a crossover study in healthy cats (n = 11). The P value for the interaction between acarbose and diet was 0.004, so interaction was assumed. The P values for differences between means (acarbose vs no acarbose) within the high and low carbohydrate diets were, respectively, 0.003 and 0.743

Table 2

Distribution of variables for 11 healthy cats after being fed a single meal high or low in carbohydrate, with and without acarbose in a crossover study

Variable	High carbohydrate	High carbohydrate + acarbose				Low carbohydrate	Low carbohydrate + acarbose
			Effect of acarbose					Effect of acarbose
			Change*	95% CI	P value			Change*	95% CI	P value
Baseline glucose mg/dl (mmol/l)^† ‡	86.2 (4.8)	89.1 (4.9)				90.6 (5.0)	90.7 (5.0)
Glucose 24 h mean mg/dl (mmol/l)^‡ §	103.5 ± 1.3 (5.7 ± 0.1)	97.8 ± 2.0 (5.4 ± 0.1)	−5.9 (–0.3)	−9.6 to −2.2 (−0.5 to −0.1)	0.003	92.5 ± 1.5 (5.1 ± 0.1)	93.1 ± 1.7 (5.2 ± 0.1)	0.6 (0.03)	−3.1 to 4.3 (–0.2 to 0.2)	0.743
Glucose 0–12 h mean mg/dl (mmol/l)^‡ §	105.7 ± 1.4 (5.9 ± 0.1)	91.2 ± 1.3 (5.1 ± 0.1)	−14.7 (–0.8)	−19.4 to −9.9 (–1.1 to −0.6)	<0.001	93.0 ± 1.7 (5.2 ± 0.1)	94.1 ± 2.3 (5.2 ± 0.1)	1.2 (0.1)	−3.6 to 6.1 (–0.2 to 0.3)	0.611
Glucose 12–24 h mean mg/dl (mmol/l)^{‡ ¶ ∞}	119.4 ± 2.3 (6.6 ± 0.1)	120.6 ± 3.5 (6.7 ± 0.2)	1.5 (0.1)	−2.2 to 5.1 (–0.1 to 0.3)	0.416	107.4 ± 1.6 (6.0 ± 0.1)	107.3 ± 1.6 (6.0 ± 0.1)	1.5 (0.1)	−2.2 to 5.1 (–0.1 to 0.3)	0.416
Peak glucose mg/dl (mmol/l) ^{‡ ¶ ∞}	118.6 ± 3.1 (6.6 ± 0.2)	119.2 ± 4.4 (6.6 ± 0.2)	1.8 (0.1)	−5.4 to 9.0 (–0.1 to 0.5)	0.617	100.1 ± 1.5 (5.6 ± 0.1)	103.4 ± 4.6 (5.7 ± 0.3)	1.8 (0.1)	−5.4 to 9.0 (–0.1 to 0.5)	0.617
Time to peak glucose (h)^∞ #	12.0 (3.0–18.0)	18.0 (6.0–18.0)	0.65	0.32–1.30	0.219	3.0 (2.0–24.0)	6.0 (2.0–18.0)	0.65	0.32–1.30	0.219
Time until glucose exceeded baseline (h)^∞**	1.1 (0.5–4.9) 100% (11/11)	10.4 (4.3–16.0) 100% (11/11)	0.36	0.15–0.85	0.020	1.8 (0.6 to >24.0) 73% (8/11)	14.7 (1.0 to >24.0) 55% (6/11)	0.36	0.15–0.85	0.020
Time until glucose returned to baseline (h)^∞**	17.9 (13.5 to >24.0) 82% (9/11)	21.6 (6.5–23.2) 100% (11/11)	2.02	0.74–5.48	0.170	5.8 (2.4 to >24.0) 75% (6/8)	8.0 (3.2–15.2) 100% (6/6)	2.02	0.74–5.48	0.170

Difference between means for acarbose compared with no acarbose or, for times to peak, to exceed baseline and return to baseline; hazard ratios for acarbose compared with no acarbose

†

Baseline value was calculated for each cat as the mean of concentrations 30 and 5 mins before feeding

‡

Means or means ± SEM are reported

The P value for interaction between acarbose and diet was low (⩽0.017) so the effect of acarbose was assumed to differ between these diets

The effect of acarbose did not differ significantly between diets (P for interaction ⩾0.417). As such, the effect of acarbose was assumed to be the same within each of these diets

∞

Estimated changes and associated confidence intervals (CIs) are for the main effects of acarbose; that is, for changes from no acarbose to acarbose pooled across high and low carbohydrate diets

Median (range); P value for interaction was 0.908 so the effect of acarbose was assumed to be the same within each of these diets

Median (range) % (numerator/denominator) of cats for which glucose concentration exceeded/returned to baseline by 24 h after feeding; P value for interaction ⩾0.164 so the effect of acarbose was assumed to be the same within each of these diets

When acarbose was not given, mean 24 h glucose concentration was higher after feeding the high carbohydrate diet relative to the low carbohydrate one (estimated increase 10.9 mg/dl [0.6 mmol/l]; 95% confidence interval [CI] 7.3–14.6 mg/dl; P <0.001; Figure 1a,b; Table 2). The increase due to diet was less when acarbose was given (estimated increase due to high vs low carbohydrate diet 4.5 mg/dl [0.2 mmol/l]; 95% CI 0.8–8.1 mg/dl; P = 0.019; Figure 1a,b; Table 2). Mean 24 h glucose concentration was higher when the high carbohydrate diet with acarbose was given relative to the low carbohydrate diet without acarbose (estimated increase 5.1 mg/dl [0.3 mmol/l]; 95% CI 1.4–8.7 mg/dl; P = 0.009; Figure 1a,b; Table 2).

Mean 0–12 h and 12–24 h plasma glucose concentrations

The effect of acarbose on mean 0–12 h glucose concentration differed by diet (P value for interaction <0.001; Figure 1a; Table 2). Acarbose had no significant effect when cats were fed the low carbohydrate diet (P = 0.611); however, when cats were fed the high carbohydrate diet, administration of acarbose decreased mean 0–12 h glucose concentration (P <0.001; Figure 1a; Table 2). When acarbose was not given, mean 0–12 h glucose concentration was higher after feeding the high carbohydrate diet relative to the low carbohydrate one (estimated increase 12.7 mg/dl [0.7 mmol/l]; 95% CI 8.0–17.5 mg/dl; P <0.001; Figure 1a; Table 2). There was no significant change due to diet when acarbose was given (estimated change due to high vs low carbohydrate diet −3.1 mg/dl [–0.2 mmol/l]; 95% CI −7.8 to −1.7 mg/dl; P = 0.194; Figure 1a; Table 2).

The effect of acarbose on mean glucose concentration from 12–24 h did not differ significantly between diets (P value for interaction 0.416; Figure 1a; Table 2). Mean glucose concentration from 12–24 h was 10.6 mg/dl (0.6 mmol/l) higher (95% CI 6.9–14.2 mg/dl; P <0.001) for the high carbohydrate compared with the low carbohydrate one (Figure 1a; Table 2).

Peak plasma glucose concentration

The effect of acarbose did not differ significantly between diets (P value for interaction 0.734; Table 2). Peak glucose concentration was not significantly changed by acarbose (P = 0.617; Table 2) but was 16.9 mg/dl (0.9 mmol/l) higher (95% CI 9.6–24.1 mg/dl; P <0.001; Table 2) for the high carbohydrate compared with the low carbohydrate diet.

Times to peak and times for plasma glucose to exceed and return to baseline

The effects of acarbose on times to peak, to exceed and to return to baseline did not differ significantly between diets (P values for interaction 0.908, 0.164 and 0.243, respectively). Acarbose did not significantly alter time to peak (P = 0.219) but peak occurred later with the high carbohydrate diet (hazard ratio [HR] 0.44; 95% CI 0.21–0.95; P = 0.037) relative to the low carbohydrate diet (Table 2). Acarbose delayed time until glucose exceeded baseline (P = 0.020) and these times were shorter for the high carbohydrate diet (P = 0.051; Table 2). Times until glucose returned to baseline did not alter significantly when acarbose was given (P = 0.170), but times until glucose returned to baseline were longer when the high carbohydrate diet was fed (HR for high carbohydrate diet relative to the low carbohydrate diet 0.12; 95% CI 0.03–0.47; P = 0.002; Table 2).

Multiple meal feeding test

Mean 24 h plasma glucose concentration

The effect of acarbose did not differ significantly between diets (P value for interaction 0.204; Figure 2a,b; Table 3). There was some evidence that acarbose reduced mean 24 h glucose concentration (P = 0.096; Figure 2a,b; Table 3). Mean 24 h glucose concentration was 7.6 mg/dl (0.4 mmol/l) higher for the high carbohydrate (95% CI 3.6–11.5 mg/dl; P = 0.001) compared with the low carbohydrate diet (Figure 2a,b; Table 3). Mean 24 h glucose concentration did not differ significantly between the high carbohydrate diet with acarbose and the low carbohydrate diet without acarbose; however, the estimated difference was imprecise (estimated increase 4.2 mg/dl [0.2 mmol/l]; 95% CI −1.4 to 9.8 mg/dl; P = 0.132; Figure 2a,b; Table 3).

Figure 2

(a) Mean (± SEM) plasma glucose concentrations during the multiple meal feeding test of four diet–treatment combinations in a crossover study in healthy cats (n = 12). (b) Mean 24 h plasma glucose concentrations during the multiple meal feeding test of four diet–treatment combinations in a crossover study in healthy cats (n = 12). The P value for the interaction between acarbose and diet was 0.204, so no interaction was assumed; the P value for the main effect of acarbose was 0.096

Table 3

Distribution of variables for 12 healthy cats after being fed multiple meals high or low in carbohydrate, with and without acarbose in a crossover study

Variable	High carbohydrate	High carbohydrate + acarbose				Low carbohydrate	Low carbohydrate + acarbose
			Effect of acarbose					Effect of acarbose
			Change*	95% CI	P value			Change*	95% CI	P value
Baseline glucose mg/dl (mmol/l)^† ‡	92.9 (5.2)	97.4 (5.4)				93.4 (5.2)	92.0 (5.1)
Glucose 24 h mean mg/dl (mmol/l)^{‡ § ¶}	110.2 ± 4.3 (6.1 ± 0.2)	104.3 ± 2.8 (5.8 ± 0.2)	−3.3 (–0.2)	−7.3 to 0.6 (–0.4 to 0.0)	0.096	100.1 ± 2.9 (5.6 ± 0.2)	99.3 ± 2.9 (5.5 ± 0.2)	−3.3 (–0.2)	−7.3 to 0.6 (–0.4 to 0.0)	0.096
Glucose 0–12 h mean mg/dl (mmol/l)^{‡ § ¶}	116.2 ± 4.9 (6.5 ± 0.3)	112.5 ± 3.5 (6.2 ± 0.2)	−3.8 (–0.2)	−9.5 to 1.9 (–0.2 to 0.6)	0.179	104.9 ± 3.9 (5.8 ± 0.2)	101.0 ± 3.6 (5.6 ± 0.2)	−3.8 (–0.2)	−9.5 to 1.9 (–0.2 to 0.6)	0.179
Glucose 12–24 h mean mg/dl (mmol/l)^‡ ∞	122.7 ± 5.8 (6.8 ± 0.3)	114.9 ± 3.5 (6.4 ± 0.2)	−8.0 (–0.4)	−14.4 to −1.5 (–0.8 to −0.1)	0.017	111.9 ± 2.5 (6.2 ± 0.1)	114.3 ± 3.4 (6.3 ± 0.2)	2.3 (0.1)	−4.2 to 8.7 (–0.2 to 0.5)	0.476
Peak glucose mg/dl (mmol/l)^{‡ § ¶}	156.9 ± 11.4 (8.7 ± 0.6)	136.0 ± 5.0 (7.6 ± 0.3)	−15.3 (–0.9)	−31.0 to −0.4 (–1.7 to −0.0)	0.056	124.2 ± 7.7 (6.9 ± 0.4)	114.4 ± 7.0 (6.4 ± 0.4)	−15.3 (–0.9)	−31.0 to −0.4 (–1.7 to −0.0)	0.056
Time to peak glucose (h)^¶ #	4.0 (3.0–24.0)	6.0 (4.0–24.0)	0.54	0.27–1.10	0.090	4.0 (1.0–12.0)	8.0 (2.0–24.0)	0.54	0.27–1.10	0.090
Time until glucose exceeded baseline (h)^¶ **	1.5 (0.6–23.5) 100% (12/12)	2.4 (1.2 to >24.0) 92% (11/12)	0.52	0.25–1.11	0.091	1.6 (0.6 to >24.0) 75% (9/12)	4.3 (1.0 to >24.0) 67% (8/12)	0.52	0.25–1.11	0.091
Time until glucose returned to baseline (h)^¶ **	11.7 (6.0 to >24.0) 75% (9/12)	12.9 (7.6–14.5) 100% (11/11)	0.73	0.30–1.74	0.474	5.7 (2.3–9.7) 100% (9/9)	9.3 (3.3 to >24.0) 63% (5/8)	0.73	0.30–1.74	0.474

Difference between means for acarbose compared with no acarbose or, for times to peak, to exceed baseline and return to baseline; hazard ratios for acarbose compared with no acarbose

†

Baseline value was calculated for each cat as the mean of concentrations 30 and 5 mins before feeding

‡

Means or means ± SEM are reported

The effect of acarbose did not differ significantly between diets (P for interaction ⩾0.204). As such, the effect of acarbose was assumed to be the same within each of these diets

Estimated changes and associated confidence intervals (CIs) are for the main effects of acarbose; that is, for changes from no acarbose to acarbose pooled across high and low carbohydrate diets

∞

The P value for interaction between acarbose and diet was low (0.028) so the effect of acarbose was assumed to differ between these diets

Median (range); P value for interaction was 0.557 so the effect of acarbose was assumed to be the same within each of these diets

Median (range) % (numerator/denominator) of cats for which glucose concentration exceeded/returned to baseline by 24 h after (first) feeding; P value for interaction ⩾0.112 so the effect of acarbose was assumed to be the same within each of these diets

Mean 0–12 h and 12–24 h plasma glucose concentrations

The effect of acarbose on mean 0–12 h glucose concentration did not differ significantly between diets (P value for interaction 0.967; Figure 2a; Table 3). There was no significant effect of acarbose in cats fed the low carbohydrate diet (P = 0.179) but mean 0–12 h glucose concentration was 11.4 mg/dl (0.6 mmol/l) higher (95% CI 5.7–17.1 mg/dl; P <0.001) for the high carbohydrate compared with the low carbohydrate diet (Figure 2a; Table 3).

Effects of acarbose on mean glucose concentration from 12–24 h depended on diet (P for interaction 0.028). There was no significant effect of acarbose in cats fed the low carbohydrate diet (P = 0.476; Figure 2a; Table 3). However, when administered with the high carbohydrate diet, mean glucose concentration from 12–24 h was lower when acarbose was fed (P = 0.017; Figure 2a; Table 3). When acarbose was not given, mean glucose concentration from 12–24 h was higher after feeding the high carbohydrate diet relative to the low carbohydrate one (estimated increase 8.8 mg/dl [0.5 mmol/l]; 95% CI 2.4–15.3 mg/dl; P = 0.009; Figure 2a; Table 3).

Peak plasma glucose concentration

The effect of acarbose on peak glucose concentration did not differ significantly between diets (P value for interaction 0.480; Table 3). Acarbose did not have a large effect on peak glucose concentration (P = 0.056; Table 3) but peak concentration was 27.1 mg/dl (1.5 mmol/l) higher for the high carbohydrate diet (95% CI 11.5–42.9 mg/dl; P = 0.001; Table 3).

Times to peak, and times for plasma glucose to exceed and return to baseline

P values for the interaction between acarbose and diet were high for times to peak, and times for glucose to exceed and return to baseline (P = 0.557, P = 0.700 and P = 0.112, respectively; Table 3). Time to peak was not significantly altered by acarbose (P = 0.090; Table 3) or by diet (HR for high carbohydrate diet relative to the low carbohydrate diet 0.73; 95% CI 0.37–1.46; P = 0.376; Table 3). Times until glucose concentration exceeded baseline were not significantly altered by acarbose (P = 0.091; Table 3) but were earlier for the high carbohydrate diet (HR for high carbohydrate diet relative to the low carbohydrate diet 2.15; 95% CI 1.01–4.58; P = 0.047; Table 3). Times until glucose concentration returned to baseline were not significantly altered by acarbose (P = 0.474; Table 3) but there was some evidence that these times were longer for the high carbohydrate diet (HR for high carbohydrate diet relative to the low carbohydrate diet 0.43; 95% CI 0.17–1.06; P = 0.068; Table 3).

Discussion

The most important finding of this study was that the low carbohydrate diet (2 g carbohydrate/100 kcal, providing 7% ME) resulted in similar or lower mean 24 h and peak glucose concentrations compared with the high carbohydrate diet (14 g carbohydrate/100 kcal, providing 51% ME) with acarbose. This finding suggests that the low carbohydrate diet might have an advantageous glucose lowering effect in diabetic and prediabetic cats compared with feeding a high carbohydrate diet and administering acarbose. There was no beneficial effect on postprandial glucose concentration of adding acarbose to the low carbohydrate diet, which is in agreement with the results of a previous study, which found that 60% of diabetic cats given acarbose and a low carbohydrate diet had improved glycemic control and discontinued insulin, while insulin was discontinued in 66% of cats fed a low carbohydrate food alone,²⁴ indicating no additional beneficial effect.

The overall capacity for glucose uptake and metabolism at high carbohydrate loads is less in cats than in dogs, given their higher and more prolonged increase in glucose concentration after intravenous or oral glucose challenge, or after a high carbohydrate meal.^32–35 Our results are consistent with previous findings comparing the effects of feeding high and low carbohydrate diets on postprandial glucose concentrations in healthy and diabetic cats.^8,24,36 Collectively, based on these studies and the results of the present study, a low carbohydrate diet is recommended for management of diabetic cats.¹ However, the addition of acarbose to reduce postprandial glycemia could be a useful adjunct therapy in cats with concurrent disease, when a low carbohydrate diet (hence higher in fat and protein) might be contraindicated. Low carbohydrate diets would also be expected to be useful in cats predisposed to diabetes, such as cats with impaired glucose tolerance, which occurs in 20% of obese cats and 80% of cats in diabetic remission.³⁷ These cats have an increased magnitude and duration of the postprandial glucose and insulin response after eating.^12,38

In humans, dogs and cats, carbohydrate is the prin-cipal nutrient determining the magnitude of the postprandial changes in plasma glucose and insulin concentrations.^11,12,39,40 Based on the results of our study, the effect of acarbose depends on the level of carbohydrate in the diet of cats and on the feeding pattern, although effects of other compositional differences between the diets cannot be excluded. When given once daily in cats single meal-fed the high carbohydrate diet, the glucose lowering effect of acarbose persisted for approximately 10–12 h after administration (Figure 1a). Therefore, our results suggest that acarbose is likely to be more efficacious when dosed twice daily to cats fed once or twice daily a high carbohdyrate diet that is consumed soon after it is provided; that is, cats being energy restricted to maintain ideal body weight or achieve weight loss. Although prediabetic or diabetic cats fed a moderate-to-high carbohydrate diet would benefit from acarbose administration, this would probably only occur if most of the food was consumed soon after acarbose was given. Therefore, cats with inappetence associated with concurrent disease, such as more advanced stages of renal failure and consuming multiple smaller meals, would probably have little benefit from acarbose at 12.5 mg every 12 h. It is unknown whether these cats would benefit from a higher dose. For cats consuming a high carbohydrate diet fed in a single meal once or twice daily, acarbose could be given at 25 mg per cat every 12 h, but the side effects are likely to be higher. In cats with no dietary restrictions relating to fat and protein, similar or lower mean glucose concentration can likely be achieved by switching to a low carbohydrate diet, providing 7% ME from carbohydrate, instead of feeding a high-carbohydrate diet and acarbose. This avoids the cost and inconvenience of pilling the cat, and the gastrointestinal side effects such as flatulence and loose stools.

Limitations of this study include that the diets were commercially available feline products with different micro- and macronutrient sources, and different formulations. This would likely influence postprandial glycemic response, particularly because gastric emptying is faster with canned food.⁴¹ However, the aim of this study was to assess what a client-owned, prediabetic or diabetic cat might be fed if it was changed to a prescription low carbohydrate diet designed for diabetic cats, and to compare that with administration of acarbose if the cat continued to be fed a high carbohydrate diet, typical of some grocery-line maintenance diets available for cats. Typical renal and obesity diets are lower in carbohydrate than the high carbohydrate diet used in our study; therefore, the magnitude of the glucose lowering effect of acarbose would be expected to be less. However, because improved remission rates are reported in diabetic cats fed 12% ME compared with 26% ME from carbohydrate,⁸ it would be expected that acarbose would provide some benefit in these cats consuming moderate carbohydrate diets, provided they are eating the food soon after acarbose administration.

Conclusions

Healthy cats fed once or twice a day a high carbohydrate diet of similar composition to that used in our study would likely benefit from the glucose lowering effect of acarbose, provided the food was consumed soon after drug administration (ie, 30 mins), and acarbose was administered twice daily, even in cats fed once daily. This would be most applicable to prediabetic or diabetic obese cats being energy restricted for weight loss and consuming a moderate-to-high carbohydrate diet soon after it was provided. Prompt consumption of food is unlikely to occur in cats with inappetence associated with concurrent disease such as advanced chronic kidney disease and consuming a restricted protein, moderate carbohydrate diet. Although studies in prediabetic and diabetic cats are warranted to confirm the findings of our study, because of ethical considerations associated with the reduced probability of remission in diabetic cats fed moderate-to-high carbohydrate diets,⁸ the study should only be performed in cats that for medical reasons require a higher carbohydrate diet than is recommended for diabetic cats, such as diabetic cats with chronic kidney disease. Based on our findings, prediabetic or diabetic cats without medical reasons for requiring a moderate-to-high carbohydrate diet would likely have as good or better glucose lowering effect after eating if changed to a low carbohydrate diet with approximately 7% of energy from carbohydrate (2 g/100 kcal).

Footnotes

Acknowledgements

Many thanks to Maree Maher, Jo Chapel, Rebekah Scotney and Libby Jolly for the technical support.

Conflict of interest

The authors do not have any potential conflicts of interest to declare.

Funding

Funding was obtained from the Centre for Companion Animal Health, The University of Queensland, Brisbane, QLD, Australia.

The abstract was presented in 2006 at the American College of Veterinary Internal Medicine meeting and at the Nutrition Society of Australia meeting.

Accepted: 29 September 2014

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