The effect of oral metformin on insulin sensitivity in insulin-resistant ponies.

Metformin may be an effective therapeutic option for insulin-resistant (I-R) horses/ponies because, in humans, it reportedly enhances insulin sensitivity (SI) of peripheral tissues without stimulating insulin secretion. To determine the effect of metformin on insulin and glucose dynamics in I-R ponies, six ponies were studied in a cross-over design by Minimal Model analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin was administered at 15 mg/kg bodyweight (BW), orally, twice-daily, for 21 days to the metformin-treated group. The control group received a placebo. A FSIGT was conducted before and after treatment. The Minimal Model of glucose and insulin dynamics rendered indices describing SI, glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). The body condition score (BCS), BW and cresty neck score (CNS) were also assessed. There was no significant change in SI, Sg, AIRg, DI, BW, BCS or CNS in response to metformin, or over time in the control group. There were no measurable benefits of metformin on SI, consistent with recent work showing that the bioavailability of metformin in horses is poor, and chronic dosing may not achieve therapeutic blood concentrations. Alternatively, metformin may only be effective in obese ponies losing weight or with hyperglycaemia.

Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies.

OBJECTIVE: To determine pharmacokinetics and plasma steady-state kinetics of metformin after oral or nasogastric administration in insulin-resistant (IR) ponies. ANIMALS: 8 IR ponies. PROCEDURES: Metformin (30 mg/kg) was administered to 8 ponies via nasogastric tube Blood samples were collected at intervals for 24 hours. Plasma concentrations of metformin were measured via liquid chromatography-electrospray tandem mass spectroscopy Pharmacokinetic variables were determined via noncompartmental analysis. Metformin (15 mg/kg, PO, twice daily [8 am and 5 pm]) was administered to 4 ponies for an additional 20 days, and blood samples were obtained every 2 days. Plasma concentration at steady state (Css) was determined. RESULTS: Mean±SD elimination half-life (t1/2) of metformin was 11.7±5.2 hours, maxima plasma concentration was 748±269 ng/mL at 54±32 minutes, mean area under the curve was 355±92 microg.h/mL, and apparent clearance was 90.6±28.1 mL/min/kg. The Css was 122±22 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Metformin reportedly enhances insulin sensitivity of peripheral tissues without stimulating insulin secretion, but bioavailability in horses is low. The t1/2 of metformin in IR ponies was similar to that in humans. Actual clearance of metformin adjusted for bioavailability in IR ponies was similar to that in humans; however, during chronic oral administration at dosages reported in efficacy studies, the Css of metformin was less than values associated with therapeutic efficacy in humans The apparent lack of long-term efficacy of metformin in horses is likely attributable to low bioavailability, rather than to rapid clearance.

Potential treatments for insulin resistance in the horse: a comparative multi-species review.

Insulin resistance and hyperinsulinaemia increase the risk of laminitis and horse owners and veterinarians should attempt to enhance insulin sensitivity in at-risk groups. In obese animals this may be achieved, in part, by promoting weight loss and increasing exercise, but such intervention may not be appropriate in non-obese insulin-resistant animals, or where exercise is contra-indicated for clinical reasons. An alternative approach to controlling insulin sensitivity in obese and non-obese horses may be the use of certain herbal compounds that have shown promise in humans and laboratory animals, although little is known of the effects of these compounds in horses. The herbs can be grouped according to their primary mechanism of action, including activators of the peroxisome proliferator-activated receptors, anti-obesity compounds, anti-oxidants, compounds that slow carbohydrate absorption, insulin receptor activators and stimulators of glucose uptake, with some herbs active in more than one pathway. Certain herbs have been prioritised for this review according to the quality and quantity of published studies, the reported (or extrapolated) safety profile, as well as potential for efficacy, all of which will hopefully motivate further research in this field.

Habituation of arousal responses after intermittent hypercapnic hypoxia in piglets.

RATIONALE: Clinical studies have demonstrated arousal deficits in infants suffering obstructive sleep apnea, and some infant deaths have been attributed to such an arousal deficit. OBJECTIVES: To evaluate whether arousal deficits can be induced by intermittent asphyxia during normal development. METHODS AND MEASUREMENTS: Young piglets were exposed to intermittent hypercapnic hypoxia for 4 days from age 9.55 +/- 0.5 days. Arousal responses were compared between control animals and animals exposed to intermittent hypercapnic hypoxia. Outcome measures included time to arouse after onset of the respiratory stimulus and frequency of arousals during recovery. MAIN RESULTS: Arousal deficits emerged after successive exposures to hypercapnic hypoxia on Day 1, and were exacerbated on Day 4, although after overnight recovery, the deficit only became evident during the second and subsequent episode of hypercapnic hypoxia. On Day 1, time to arouse increased from 16.9 +/- 7.1 seconds in the first epoch to 41.7 +/- 28.6 seconds in the fourth epoch (p = 0.004 between cycles, one-way analysis of variance). In the recovery periods after hypercapnic hypoxia, there were 64% fewer arousals than baseline on Day 1 and 90% fewer arousals on Day 4. Respiratory effort, measured by VT across 10 breaths before the arousal, increased from 25.7 +/- 7.6 on Day 1 to 29.1 +/- 6.8 ml/kg on Day 4 (p < 0.001, two-way analysis of variance, Day 4 vs. Day 1, respectively). CONCLUSIONS: These studies demonstrate that acute and chronic arousal deficits can be induced by intermittent asphyxia, on a background of otherwise normal postnatal development.

Effect of stimulus cycle time on acute respiratory responses to intermittent hypercapnic hypoxia in unsedated piglets.

To determine whether stimulus frequency affects physiological compensation to an intermittent respiratory stimulus, we studied piglets (n = 43) aged 14.8 +/- 2.4 days. A 24-min total hypercapnic hypoxia (HH) (10% O(2)-6% CO(2)-balance N(2) = HH) was delivered in 24-, 8-, 4-, or 2-min cycles alternating with air. Controls (n = 10) breathed air continuously. Minute ventilation and temperature were not different between the 2-min and 24-min groups, with neither different from controls during recovery. Piglets exposed to 8-min cycles had ventilatory stimulation, whereas those exposed to 4-min cycles had significant depression of ventilation. Despite this, piglets in these intermediate intermittent HH (IHH) groups (8- and 4-min cycles) showed more severe acidosis and attenuated temperature changes (P < 0.001 and P < 0.01 for pH and temperature vs. 24 min, respectively). Cycle time affected the ability of young piglets to tolerate IHH. More severe respiratory acidosis developed when IHH was delivered in intermediate (4 min or 8 min) cycles compared with the same total dose as a single episode or in short (2 min) cycles.