Gestational Diabetes Mellitus with Diabetic Ketoacidosis in a Yorkshire Terrier Bitch

Introduction

Both in humans and dogs, pregnancy is associated with insulin resistance that causes suppression of glucose intracellular transport mechanisms and increase of blood glucose concentrations.¹ Gestational diabetes mellitus (GDM) is a clinical condition demonstrating a variable degree of glucose intolerance that can start during pregnancy or after parturition.² This condition is characterized by low insulin secretion and increased peripheral insulin resistance. In humans, it has been suggested that GDM and insulin-resistant DM could be the same disease. This theory was further substantiated by the observation that both conditions have the same risk factors, such as race, obesity, age, hypertension, and dyslipidemia.^3,4 In humans, the incidence of the condition is reported to be between 1 and 14%.^5,6 Canine GDM is thought to be a rare condition, having been diagnosed in only 15 cases, including Swedish elkhounds (nine cases), Alaskan malamute, border collie, Labrador retriever, Norwegian elkhound, Siberian husky, and Swedish dachsbracke pregnant bitches.^7,8 To the authors' knowledge, the development of GDM with diabetic ketoacidosis (DKA) in a small breed dog has not been previously published. This report describes the clinical presentation, diagnosis, and treatment of GDM with DKA in a Yorkshire terrier bitch during pregnancy.

Table 1 Complete Blood Count, Serum Biochemistry, and Blood Gas Analysis in a 6 Yr Old Yorkshire Terrier Bitch with DKA Diagnosed at Day 62 of Pregnancy

BASO, basophils; BUN, blood urea nitrogen; Cl chloride; DKA, diabetes ketoacidosis; EOS, eosinophils; GLU, glucose; HGB, hemoglobin; HCO₃, bicarbonate; HCT, hematocrit; K, potassium; LYM, lymphocytes; MONO, monocytes; Na, sodium; NEU, neutrophils; PaCO₂, partial pressure of carbon dioxide; PLT, platelets; RBC, red blood count; RDW, red blood cell distribution width; WBC, white blood count.

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Case Report

A 6 yr old pregnant Yorkshire terrier (62 days after mating; weighing 6.5 kg) presented with a history of acute onset of vomiting, inappetence, and cough. Polyuria and polydipsia were also reported by the owners. The bitch was housed indoors, fed dry dog food, and was adequately vaccinated and dewormed. The owner reported that the bitch had two previous pregnancies that had resulted in normal whelping without any complications.

On physical examination, the dog was alert and responsive, and had tachypnea. Mucous membranes were pink, capillary refill time was 2 sec, and heart rate was 120 beats/min. Rectal temperature was 37.8°C and systolic blood pressure^a was 100 mm Hg. The dog was assessed as 7% dehydrated. Abdominal distention with no other abnormalities was noted on palpation. A complete blood count and serum biochemistry^b showed mild regenerative normocytic and normochromic anemia, mild lymphocytosis with left shift, hyperglycemia, and ketonemia. The level of anemia was similar to that found in pregnant bitches in previous reports.⁹ Plasma ketones were observed using a urine stick^c corresponding to a value of 80 mg/dL.¹⁰ Venous blood gas analysis^b showed metabolic acidosis (Table 1). Urinalysis revealed low urine specific gravity, ketonuria, and glucosuria (Table 2).

TABLE 2 Urinalysis of a 6 Yr Old Yorkshire Terrier Bitch with DKA Diagnosed at Day 62 of Pregnancy

USG, Urine specific gravity.

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Thoracic radiographs showed a mild, diffuse interstitial pattern and abdominal radiographs revealed six fetal skeletons. A presumptive diagnosis of bacterial pneumonia was made based on radiographs and the clinical status. The bitch was hospitalized, and oxygen supplementation was provided via oxygen cage for the entire period. Fluid therapy using rehydratant electrolytes 3rd solution^d (an Italian crystalloid solution similar to Plasma-Lyte) at a dosage of 55 mL/h for the first 12 hours was initiated. Two hours after the initial treatment, 2 IU/kg of regular insulin^e was administered intravenously at a constant rate infusion of 0.8 IU/kg/h. Empiric antibiotic therapy with intravenous cephazolin^f 30 mg/kg was also initiated. Ranitidine^g 1 mg/kg and metoclopramide^h 0.2 mg/kg were also included into the therapeutic plan. Beclomethasone dipropyonateⁱ (0.4 mg/d) together with acetylcysteine^j (100 mg/d) were nebulized respectively, to promote anti-inflammatory and bronchodilation actions and to facilitate removal of secretions from the respiratory tree.¹¹ Blood glucose level was rechecked every 2 hr until normalized.

When blood glucose decreased to 190 mg/dL, regular insulin was replaced with lente insulin^k subcutaneously, at 0.5 IU/kg q 12 hr. Two hours after beginning lente insulin, the bitch began whelping and six healthy puppies were born in 5 hr. Soon after delivery, blood glucose^b level was 78 mg/dL (reference range 77–125 mg/dL). One milliliter per kilogram of dextrose 33% solution was administered intravenously. All puppies were normal and healthy and started to suckle soon after delivery. On day 2, the bitch ate a small portion of a canned high calorie food,^l and venous blood gas was rechecked, showing a normal acid-base status. Lente insulin was repeated when blood glucose level was high (225 mg/dL; reference range 77–125 mg/dL). Tachypnea resolved by day 3, at which time blood glucose was within normal limits. All puppies were suckling vigorously and were in good condition. On day 4, the bitch and the puppies were discharged with lente insulin treatment continued at home. Thoracic radiographs taken a month later were normal.

Two weeks after the onset of therapy, the bitch was re-examined and the serum fructosamine level was 440 μmol/L (normal range 320–850 μmol/L). Lente insulin therapy was continued and blood glucose level at 1 and 6 mo later was within normal limits.

Discussion

In humans, GDM is a complication occurring in approximately 1–14% of pregnancies, whereas in the bitch it is a rare condition with only 15 reported cases.^5–8 In women with GDM, insulin secretion cannot compensate for the insulin resistance commonly observed in pregnancy. These patients have postprandial hyperglycemia, which represents initial alteration of glucose homeostasis, caused by impairment of first-phase insulin secretion, because of glucose clearance alterations, increased glucose production, free fatty acids plasmatic concentration and ketogenesis, and impaired function of pancreatic β-cells.^12–15 Several hormones released during pregnancy, such as progesterone and cortisol, diminish insulin action and contribute to the diabetogenic condition. Moreover, the human placenta synthesizes large amounts of insulin antagonist hormones during pregnancy.¹⁶ In normal pregnancies, insulin pancreatic production increases to counteract this effect. As pregnancy progresses, the exogenous need for insulin increases. This is why DKA is more common in human pregnancy, mainly during the second and third trimester.¹⁷

Insulin resistance has been observed in adipose and muscular tissues because of the same physiopathologic mechanisms responsible for type 2 DM, such as modifications of insulin receptor and glucose transport and utilization into cells.¹⁸ There is also a lowered activity of insulin receptor substrate-I, and it has been demonstrated that insulin-induced tirosinic phosphorilation of insulin receptor substrate-I is lower in women with GDM than in healthy pregnant women.¹⁹ In GDM, the impaired insulin action causes an increase of nutrients in fetal circulation, such as carbohydrates, lipids, and amino acids, because of placental transfer, and this can cause hyperinsulinism and, consequently, organomegaly and macrosomy.²

GDM can have a negative impact on the fetus, and can compromise pregnancy and birth.^14,20 In addition, respiratory alkalosis is relatively common during pregnancy because of hyperventilation, and is generally compensated by increased renal excretion of bicarbonate.²⁰ This loss of bicarbonate causes a metabolic acidosis that can predispose to DKA.¹⁴

Although pregnancy may cause resistance to insulin, exacerbating diabetes in bitches with a pre-existing condition or inducing mild insulin resistance in some normal bitches, the complete pathogenesis of pregnancy-induced insulin resistance is still poorly understood. ^21–23 It has been stated that intrahepatic alterations of gluconeogenic and glycolytic pathways can induce insulin resistance and consequently GDM.^1,21 Moreover, the increase in insulin resistance is associated with an increased production of growth hormone (GH), leading to subclinical or clinical hyperglycemia. GH increase in relation to the increase in progesterone in both pregnant and nonpregnant animals appears to be secondary to mammary gland GH de novo synthesis. During the luteal phase of the nonpregnant cycle, mainly in older bitches, progesterone can stimulate GH hypersecretion.^22–25 Furthermore, progesterone, estradiol, GH, placental lactogen, and placental cytokines are believed to be involved in the pathogenesis of the disease.¹ The existence and role of the canine placenta's insulinase has not yet been studied.

Finally, an association between tumor necrosis factor (TNF-α) and insulin resistance has been reported.²⁶ An increase in TNF-α in peripheral blood and placental mononuclear cells related to insulin resistance has been demonstrated in obese pregnant women.^27,28 Pneumonia can contribute to an increase of serum TNF-α, as demonstrated in humans, rats, and dogs.^29–32

In this case report, it is possible that the presumed pneumonia led to an increase in TNF-α, which may have contributed to insulin resistance.

To the authors' knowledge, this report details the first case of GDM in a small breed bitch with the presence of ketone bodies. A retrospective study suggested that GDM affects mainly middle-aged bitches in the second half of pregnancy, with a breed predisposition toward Nordic Spitz breeds because of the number of dogs involved (11 of 13). ⁸ In that study, DM was permanent in 5 of 13 bitches, suggesting that chronic hyperglycemia might have caused irreversible damage to β-cells by means of glucotoxicity.³³ In another study, it was reported that lack of prompt resolution of hyperglycemia might have resulted in secondary DM becoming permanent. ⁷

DKA is a life-threatening complication of DM both in humans and dogs that results from a combination of factors, including insulin resistance, lack of insulin, loss of electrolytes, acidosis, and dehydration.^34,35 Most animals with DKA have concurrent diseases, such as pyelonephritis, pancreatitis, pyometra, hyperadrenocorticism, renal failure, and heart failure.³⁶ The affected dogs typically show polyuria, polydipsia, loss of weight, and polyphagia. Other less common clinical signs include vomiting, weakness, and lethargy.¹ Diagnosis is based on history, clinical signs of systemic illness and DM, ketonemia, and ketonuria.^10,35

Medical management of DKA includes fluid therapy (to reduce glycemia by dilution, restore cardiac output, and improve tissue perfusion and blood pressure), correction of acidosis, restoration of renal function, and delivery of insulin to its tissue receptors.³⁴ Insulin administration is used to block ketogenesis, by increasing ketone bodies utilization, thus decreasing gluconeogenesis, promoting glucose utilization, and decreasing proteolysis.^37,38 A decrease of blood glucose concentration of approximately 50 mg/dL/hr is the goal during insulin therapy.¹ Dogs presenting with a blood glucose level of >600 mg/dL, such as the case reported here, should be intensively managed. Correction of electrolytes, particularly potassium, phosphorus, and magnesium, is also essential. Bicarbonate administration is not routinely used because the unmeasured anions are ketoacids that act as precursors of bicarbonate during treatment with insulin. Insulin enhances utilization of ketones and inhibits further production of ketoacids by decreasing lipolysis.^37,38

Another important aspect of GDM therapy both in humans and dogs is whether DM is permanent or transient. High blood glucose levels during pregnancy in women lead to a high probability of developing future non-insulin–dependent DM, mainly for those with concurrent risk factors, such as increased body mass index, maternal age, history of GDM, and family history of diabetes.³⁹

In this case, long-acting insulin therapy was started immediately after normalization of blood glucose, because delivery had occurred and there were concerns about insulin resistance. The insulin was continued after discharge because DM was still present after delivery. The full recovery of the patient was likely due to the rapid diagnosis and response to fluids, insulin, and antibiotic therapies.

Medical management of pregnant bitches with GDM with appropriate therapy that begins as soon as possible may increase the success rate of this life-threatening disease by decreasing maternal morbidity and improving fetal survivability.