Control In Diabetic Dogs Research Articles

Ex Vivo Immune Function and Modulatory Effects of Calcitriol in Dogs with Naturally Occurring Diabetes Mellitus.

Human patients with type 1 diabetes mellitus (T1DM) are susceptible to several long-term complications that are related to glycemic control and immune dysregulation. Immune function remains relatively unexplored in dogs with naturally occurring diabetes mellitus (NODM). Calcitriol improves various aspects of immune function in a variety of species, but its effect in diabetic dogs remains unexplored. Therefore, the objectives of this study were to (i) evaluate immune function in dogs with NODM and determine if differences exist based on the level of clinical control and (ii) assess the immunomodulatory effects of calcitriol. Twenty diabetic dogs (clinically controlled, n = ten, not controlled, n = ten) and 20 non-diabetic, healthy control dogs were included in this prospective, case-control study. Whole blood was incubated with calcitriol (10-7 M) or negative control, after which the samples were divided for phagocytosis and leukocyte cytokine response experiments. The phagocytosis of opsonized Escherichia coli (E. coli) was evaluated with flow cytometry. The samples for leukocyte cytokine response evaluations were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate buffer solution (PBS; negative control), and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured in supernatant using a canine-specific multiplex bead-based assay. The leukocytes from diabetic dogs produced higher concentrations of IL-10 (p = 0.01), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) than the control dogs while controlling for the intervention and stimulant. Calcitriol decreased the supernatant concentrations of TNF-α (p < 0.001) and IL-8 (p = 0.04) with concomitant increases in IL-6 (p = 0.005). Diabetic dogs had a lower percentage of leukocytes undergoing phagocytosis (p < 0.0001) but a higher number of bacteria phagocytized per cell (p = 0.001) when compared to the control dogs. Calcitriol had no effect on phagocytic capacity. Lastly, the status of clinical control in diabetic dogs did not yield differences in immune function. These results support that dogs with NODM exhibit immune dysregulation and warrant additional investigation.

Treating inflammatory conditions such as periodontal disease can improve glycaemic control in diabetic dogs.

Treating inflammatory conditions such as periodontal disease can improve glycaemic control in diabetic dogs.

Owner preference for insulin delivery device and glycaemic control in diabetic dogs.

To assess treatment satisfaction and owner preference for two delivery devices (VetPen, MSD Animal Health, and U40 insulin syringes) and the effect on glycaemic control in diabetic dogs treated with porcine insulin zinc suspension. Randomised prospective cross-over study with two arms, each of 8 weeks. Twenty client-owned diabetic dogs on insulin treatment by U40 syringe were enrolled. Dogs were randomly assigned to receive insulin by syringe or pen injector for 2 months, followed by 2 months of the other injection method. Treatment satisfaction and owners' insulin delivery device preference were assessed using a questionnaire. Glycaemic control was assessed using a clinical score, serum fructosamine and glycated haemoglobin (HbA1c%) at the time of the enrolment (T0) and the end of each arm of treatment (T2 and T4). Treatment satisfaction differed for the two types of the delivery device when the order that each device was used was taken into consideration. Owners who used the syringe first did not have a significant preference for an injection device. In contrast, owners who used the pen injector first expressed a significant preference for VetPen compared to syringes. No significant differences in the number of dogs of Groups 1 and 2 with good and poor glycaemic control at T2 and T4 were detected. Overall treatment satisfaction and preference for the two delivery methods were similar. However, VetPen was preferred by owners who were randomised to use this device first. Glycaemic control did not appear to be affected by the insulin delivery device used.

Influence of type of starch and feeding management on glycaemic control in diabetic dogs.

The present study evaluated the effects of two diets with different starch sources and two feeding methods on the glycaemic control in dogs with diabetes mellitus. The diets had similar nutrient contents (40% starch and 16% dietary fibre), one formulated with 46% of broken rice and the other with 42% sorghum and 10% lentils (as-fed). Ten client-owned diabetic dogs were fed with each diet for 2months, in a crossover design. Five dogs received NPH human insulin and food every 12h (feeding method 1), and the other five received insulin every 12h but were fed three times a day (feeding method 2). In feeding method 2, morning insulin was higher than the evening dose and dogs received the second meal after 4 to 5h of the morning insulin and meal. Parameters evaluated included insulin dosage, 12- and 8-h glycaemic curves, complete blood count, biochemical profile and urinalysis. Glycaemic curves were analysed by ANOVA with repeated measures. Glycaemic control parameters (fasting, mean, minimum and maximum glycaemia and serum fructosamine) and glucose area under the curve (AUC) were calculated and analysed by paired t test (p<0.05). In feeding method 1, dogs fed the sorghum-based diet presented lower mean (p=0.04) and minimum blood glucose concentrations (p=0.03), and a tendency to lower maximum blood glucose (p=0.06) and glucose AUC (p=0.08) than when fed the rice-based diet. When food was provided twice a day, the ingestion of the rice-based diet resulted in higher post-prandial glucose response than the diet with sorghum and lentil. In feeding method 2, there was no effect of diet on the assessed parameters (p>0.05). No differences in insulin dosage were observed between groups or feeding methods (p>0.05). Providing two meals a day followed by insulin administration associated with the sorghum- and lentil-based diet improved glycaemic control in diabetic dogs.

Evaluation of fructosamine concentration as an index marker for glycaemic control in diabetic dogs.

Although fructosamine is a commonly used surrogate marker to assess glycaemic control in diabetic dogs, its diagnostic accuracy has been questioned. The main objective of this study was to evaluate the reliability of fructosamine measurements to diagnose well and poorly controlled diabetes mellitus (DM), using continuous glucose monitoring as a gold standard. Twenty-four dogs with treated DM and continuous glucose monitoring for mean (±SD) 13.1 (±1.7) days were retrospectively analysed. Two assessment strategies were applied to categorize glycaemic control, and fructosamine concentrations were determined shortly after sensor cessation using a colorimetric assay. Correlations of individual fructosamine concentrations with mean glucose as well as percentage of measurements>15mmol/L were not significant (p=0.372, p=0.129). Fructosamine did not differ between dogs with and without hypoglycaemic episodes (p=0.64). Receiver operating characteristic analysis for fructosamine to diagnose either good or poor glycaemic control revealed AUC values of 0.71 (p=0.025) indicating moderate accuracy, and 0.7 (p=0.135) indicating AUC is non-discriminatory, respectively. The respective positive likelihood ratios for the optimal cutoffs to identify good (<396μmol/L) and poor control (>449μmol/L) were three. Fructosamine measurement is an imperfect surrogate marker for classifying glycaemic control in diabetic dogs and can only complement serial glucose measurements.

Flash glucose monitoring in diabetic dogs: a feasible method for evaluating glycemic control.

To alleviate clinical signs and avoid life-threatening complications in dogs with diabetes mellitus, individualized treatment plans and frequent reassessments are necessary. Performing blood glucose profiles every 7-14 days following insulin adjustments and monthly thereafter, is recommended. In 2016, a factory calibrated continuous blood glucose monitoring system was presented as a possible alternative to glucometer readings. The objectives of this study were to summarize the experiences with this new technology and to show, that in combination with simple rules, already the first measurement period can improve glycemic control. The electronic database of the endocrine unit of the clinic was retrospectively searched for diabetic dogs with flash glucose monitoring. In case of repeated sensor implantations, only the first sensor was considered. The recordings of day A (starting at midnight after sensor placement) were compared to the measurements of day B (day before sensor failure) and all owners were contacted to fill in a standardized questionnaire. The final study population consisted of 24 dogs weighing 3.4 to 36 kg. Although the clicking noise during sensor placement irritated most dogs, the application was considered easy and painless. Waiting for disinfectant evaporation and fixation of the sensor disc with forceps helped to avoid sensor detachment when removing the application device. Although transient mild to moderate skin irritations were observed in 80 % of the dogs, 95 % of the owners were highly satisfied with this new monitoring technology. Mean and maximum glucose (p = 0.043, p = 0.003) as well as glucose readings ≥ 11.1 mmol/l (p = 0.032) decreased from day A to B, whereas markers of glycemic variability did not change. Flash glucose monitoring is a feasible, safe method with high user satisfaction and offers a possibility to improve glycemic control in diabetic dogs.

Comparison of serum fructosamine and glycated hemoglobin values for assessment of glycemic control in dogs with diabetes mellitus.

To evaluate the performance of 2 assays for measurement of serum fructosamine (SF) and glycated hemoglobin (HbA1c) values in dogs and to compare the usefulness of the 2 glycated proteins for assessment of glycemic control in dogs with diabetes mellitus (DM). Blood samples from 40 healthy dogs, 13 diabetic dogs, and 23 anemic normoglycemic nondiabetic dogs and results of 200 assessments of glycemic control in 46 diabetic dogs. Colorimetric and immunoturbidimetric methods were used for measurement of SF and HbA1c values, respectively. Linearity and precision were determined. The usefulness of SF and HbA1c values for assessment of glycemic control was evaluated with a clinical scoring method used as the reference standard. Cutoff values obtained from receiver operating characteristic curves were used to identify the percentage of dogs correctly categorized by means of SF and HbA1c values. Mean intra-assay and interassay coefficients of variation were 3.8% and 2.5%, respectively, for the SF assay, and 1.2% and 1.8%, respectively, for the HbA1c assay. Excellent linearity (R2 > 0.99) was obtained for both assays. Values for SF and HbA1c were inversely correlated (r = -0.40 and -0.33, respectively) with clinical score and correctly indicated glycemic control in 99 of 200 (50%) and 88 of 200 (44%) assessments, respectively. The SF and HbA1c assays were precise, had good linearity, and appeared to be suitable for routine use in veterinary medicine. However, they performed poorly for classifying glycemic control in diabetic dogs.

Starch sources influence lipidaemia of diabetic dogs

BackgroundHyperlipidaemia is considered a cause of other diseases that are clinically important and potentially life threatening. Combination of pea and barley as exclusive starch sources is known to interfere with glycemic control in diabetic dogs, but their effect on lipid profile of hiperlipidaemic dogs is yet to be evaluated. Twelve adult diabetic dogs were fed three dry extruded diets with different starch sources and different fat levels: peas and barley (PB), maize (Mi), and peas, barley and rice (Ba) with 15.7, 15.6 and 9.0% of their dry matter as fat, respectively. Plasmatic cholesterol and triglycerides concentration curves over 10 h were obtained after 60 days on each diet and with the same NPH insulin dose. ANOVA test or Friedman test were used to compare the dietary effects on triglycerides and cholesterol variables among the diets.ResultsDogs presented lower mean (p = 0.05), fasting (p = 0.03), and time 8-h postprandial (p = 0.05) triglyceridemia after PB diet period than Ba diet period and time 4-h postprandial (p = 0.02) lower after PB than Mi diet. Cholesterolemia mean, minimum, maximum, area under the cholesterol curve and times points: 2, 4, 6, 8 and 10-h postprandial, had lower values after PB ingestion in comparison to Mi, without difference to Ba diet.ConclusionInclusion of pea and barley, as exclusive starch sources, in therapeutic diets for diabetic dogs can minimize plasmatic triglycerides and cholesterol concentration at fasting and at different postprandial time, compared to the maize diet or diet with lesser fat content.

Serum glycated albumin: Potential use as an index of glycemic control in diabetic dogs

Measurements of serum fructosamine, glycated hemoglobin, and glycated albumin (GA) complement serum glucose concentration for better management of diabetes mellitus (DM). Especially, the serum fructosamine test has long been used for diagnosing and monitoring the effect of treatment of DM in dogs. However, fructosamine tests are currently not performed in veterinary medicine in Japan. GA and fructoasmine levels have been shown to strongly correlate. However, the clinical implications of using GA remain to be elucidated. Therefore, the purpose of the current study was threefold: 1) Determine whether GA% is altered by acute hyperglycemia in normal dogs, simulating stress induced hyperglycemia; 2) Demonstrate that GA% does not dynamically change with diurnal variation of blood glucose concentration in diabetic dogs; and 3) Investigate whether GA% is capable of providing an index of glycemic control for 1-3 weeks in diabetic dogs as is the case with diabetic human patients. Our study demonstrated that serum GA% remains very stable and unaltered under acute hyperglycemic conditions (intravenous glucose injection) and in spite of diurnal variation of blood glucose concentration. Furthermore, serum GA% can reflect long-term changes (almost 1-3 weeks) in blood glucose concentration and the effect of injected insulin in diabetic dogs.

Diagnostic Significance of Serum Glycated Albumin in Diabetic Dogs

Measurements of serum fructosamine, glycated hemoglobin, and glycated albumin (GA) are increasingly used to complement serum glucose concentration for better management of diabetes mellitus. Fructosamine tests are currently not performed in veterinary medicine in Japan. As such, the measurement of GA may serve as a replacement test. Therefore, in the current study, serum GA and fructosamine were evaluated for a positive correlation in dogs, and, depending on the correlation, a reference range of GA percentage would also be determined from healthy control dogs. The degree of glycemic control in diabetic dogs was determined by fructosamine concentration. A positive correlation between GA and fructosamine was observed with both normal and diabetic animals. In addition, the reference interval of serum GA percentage in control dogs was determined to be 11.4-11.9% (95% confidence interval). Interestingly, no significant difference in serum GA percentages was observed between samples from diabetic dogs with excellent glycemic control and control dogs. However, good, fair, and poor glycemic control diabetic dogs resulted in a significant increase in serum GA percentages in comparison with control dogs. These results suggest that serum GA may be a useful diagnostic indicator, substituting for fructosamine, to monitor glycemic control in diabetic dogs.

Development of a highly responsive needle-type glucose sensor using polyimide for a wearable artificial endocrine pancreas

To produce a long-life, stable, miniature glucose sensor for a wearable artificial endocrine pancreas (WAEP), we developed a novel microneedle-type glucose sensor using polyimide, designated the PI sensor (outer diameter, 0.3 mm; length, 16 mm), and investigated its characteristics in vitro and in vivo. In the in vitro study, we tested the sensor in 0.9% NaCl solution with varying glucose concentrations and observed an excellent linear relationship between the sensor output and glucose concentration (range: 0-500 mg/100 ml). In in vivo experiments, the PI sensor was inserted into the abdominal subcutaneous tissue of beagle dogs (n = 5), and interstitial fluid glucose concentrations were monitored after sensor calibration. Simultaneously, blood glucose concentrations were also monitored continuously with another PI sensor placed intravenously. The correlation and time delay between subcutaneous tissue glucose (Y) and blood glucose concentrations (X: 30-350 mg/100 ml) were Y = 1.03X + 7.98 (r = 0.969) and 6.6 +/- 1.2 min, respectively. We applied the new WAEP system/PI sensor and an intravenous insulin infusion algorithm developed previously for glycemic control in diabetic dogs. The use of the WAEP system resulted in excellent glycemic control after an oral glucose challenge of 1.5 g/kg (post-challenge blood glucose levels: 176 +/- 18 mg/100 ml at 65 min and 93 +/- 23 mg/100 ml at 240 min), without any hypoglycemia. Thus, we confirmed that our new PI sensor has excellent sensor characteristics in vitro and in vivo. The new WAEP using this sensor is potentially suitable for clinical application.

Strict glycemic control in diabetic dogs with closed-loop intraperitoneal insulin infusion algorithm designed for an artificial endocrine pancreas.

The ultimate goal of the development of an artificial endocrine pancreas is to achieve long-term strict glycemic regulation. To establish the physiological insulin delivery route of the artificial endocrine pancreas, intraperitoneal insulin infusion may be important. For this purpose, we tried to develop a closed-loop intraperitoneal insulin infusion algorithm by analyzing the pharmacokinetics of intraperitoneal regular insulin absorption using a mathematical model. The parameters for this algorithm were calculated to simulate the plasma insulin profile after intraperitoneal insulin injection as closely as possible. To evaluate the appropriateness of this algorithm, we tried glycemic control after an oral glucose load of 2 g/kg or a meal load of 80 kcal/kg in diabetic dogs by applying the algorithm. With the use of the subcutaneous insulin lispro infusion algorithm, which we have previously reported, alloxan-induced diabetic dogs exhibited postprandial hyperglycemia and delayed hyperinsulinemia, followed by hypoglycemia after an oral glucose load of 2 g/kg. However, by using the intraperitoneal insulin infusion algorithm, excellent glycemic control (postprandial blood glucose levels of 9.1 +/- 0.8 mmol/l at 70 min and 3.8 +/- 0.3 mmol/l at 240 min, respectively) could be achieved without any associated delayed hyperinsulinemia or hypoglycemia. Glycemic excursion after a meal load of 80 kcal/kg was also controlled from 3.9 to 10.1 mmol/l. Our results confirm that the intraperitoneal insulin infusion algorithm in vivo is feasible and that this algorithm can be superior to the subcutaneous insulin lispro infusion algorithm in the regulation of blood glucose.

Relation of fructosamine to serum protein, albumin, and glucose concentrations in healthy and diabetic dogs

Summary The relation of the glycated serum protein, fructosamine, to serum protein, albumin, and glucose concentrations was examined in healthy dogs, dogs with hypo- or hyperproteinemia, and diabetic dogs. Fructosamine was determined by use of an adaptation of an automated kit method. The reference range for fructosamine in a composite group of control dogs was found to be 1.7 to 3.38 mmol/L (mean ± sd, 2.54 ± 0.42 mmol/L). Fructosamine was not correlated to serum total protein, but was highly correlated to albumin in dogs with hypoalbuminemia. To normalize the data with respect to albumin, it is suggested that the lower limit of the reference range for albumin concentration (2.5 g/dl) be used for adjustment of fructosamine concentration and only in hypoalbuminemic dogs. In 6 hyperglycemic diabetic dogs, fructosamine concentration was well above the reference range. It is concluded that although fructosamine may be a potentially useful guide to assess the average blood glucose concentration over the preceding few days in dogs, further study is required to establish its value as a guide to glucose control in diabetic dogs.

Pathogenesis of diabetic retinopathy.

Diabetic retinopathy involves anatomic changes in retinal vessels and neuroglia. The pathogenetic mechanism responsible for retinopathy is imperfectly understood, but much of the mechanism is apparently reproduced by experimental diabetes in animals and by chronic elevation of blood galactose in nondiabetic animals. The evidence that retinopathy is a consequence of excessive blood sugars and their sequelae is consistent with a demonstrated inhibition of retinopathy by strict glycemic control in diabetic dogs. However, retinopathy in the dog model has shown a tendency to resist intervention by strict control. Biochemical and pathophysiological sequelae of hyperglycemia possibly critical to the development of retinopathy in humans and animal models are being studied in many laboratories. Retinopathy occurs in experimental galactosemia in the absence of the renal hypertrophy, mesangial expansion, and glomerular obliteration typical of diabetes in humans and dogs, implying that retinopathy and nephropathy differ appreciably in pathogenesis.

6 Hypoglycaemic Agents Which Do Not Release Insulin

This chapter discusses hypoglycemic agents that do not release insulin. Diabetes mellitus afflicts a significant portion of the population in many countries. For example, an estimated 5.5 million individuals in the United States have some form of diabetes mellitus. Of these, 500,000 are insulin-dependent diabetics (IDDM's) and require exogenous insulin therapy. The remainder of the diabetic population is categorized as noninsulin dependent diabetics (NIDDM's), most often characterized by obesity and insulin resistance. These individuals may be treated by diet, exercise, and/or oral hypoglycemic agents. The most commonly employed agents are sulphonylureas, which act primarily through the stimulation of insulin release. Somatostatin, a tetradecapeptide capable of inhibiting growth hormone release, is originally isolated from bovine hypothalamic tissue. Inhibition of pancreatic hormone release (both insulin and glucagon) is subsequently observed in experimental animals and humans. Several somatostatin analogs improve glycemic control in diabetic dogs and humans. They are of sufficient duration to suggest clinical efficacy. The high cost of production of these peptides and the development of alternative methods of achieving excellent glycemic control, such as insulin pump and intensive subcutaneous insulin therapies, may limit the utility of these peptides.

Metabolic Control in Diabetic Dogs Treated with Pancreatic Autotransplants and Insulin Pumps

Fasting metabolite and hormonal levels were studied prospectively in pancreatectomized dogs who had received grafts of their own pancreas. The results were compared with similarly diabetic animals who received exogenous insulin pumped intravenously either peripherally or portally. All animals were studied for 48-91 wk after pancreatectomy. In the autotransplanted animals, the fasting levels of glucose, lactate, pyruvate, alanine, pancreatic glucagon, insulin, gastric inhibitory peptide, and pancreatic polypeptide were all abnormal. In the peripherally infused animals, the fasting levels of glucose, pyruvate, alanine, free fatty acids, and insulin were also abnormal. In the portally infused animals, pyruvate, alanine, gastric inhibitory peptide, gastrin, and pancreatic polypeptide were abnormal. These results suggest that the portal route of insulin delivery may be necessary if fasting metabolite and hormonal levels are to approximate normal most closely whether exogenous intravenous insulin is replaced by implanted pumps or endogenous insulin is replaced by pancreatic transplants.

Metabolic control in diabetic dogs treated with pancreatic autotransplants and insulin pumps

Metabolic control in diabetic dogs treated with pancreatic autotransplants and insulin pumps

Epithelial and mesothelial basement membranes in diabetic patients and dogs.

The influence of diabetes on the thickness of basement membrane of the ciliary epithelium, lens epithelium, and corneal mesothelium (endothelium) was investigated post mortem in eyes from 27 human subjects and 30 dogs. Ten of the human subjects were diabetic, 10 were non-diabetic matched for age and sex, and seven were non-diabetic subjects who had been diagnosed as hypertensive 2-8 years before death. The dogs comprised three prospectively identified groups: 10 were alloxan diabetic for 5 years and kept in poor glucose control, 10 were alloxan diabetic for 5 years and kept in good glucose control, and 10 were non-diabetic animals. Basement membranes at the three sites measured appeared to be normal in the seven non-diabetic hypertensive subjects. Basement membrane of the ciliary epithelium was found to be significantly thicker than normal both in diabetic human subjects and in poorly controlled diabetic dogs. The thickness of the anterior lens capsule was significantly greater in poorly controlled diabetic dogs than in non-diabetic dogs, and showed a significant positive correlation with duration of diabetes in human subjects. Better glucose control in diabetic dogs resulted in significant inhibition of the epithelial basement membrane thickening. The basement membrane of the corneal mesothelium failed to thicken with diabetes both in human subjects and in animals.