Insulinoma in a Dog With Pre-existing Insulin-Dependent Diabetes Mellitus

Introduction

Insulinomas are functional beta cell tumors of the endocrine portion of the pancreas that cause clinical signs by secreting insulin.^1–4 In addition to producing insulin, insulinomas may also secrete other peptide hormones such as pancreatic polypeptide, somatostatin, glucagon, serotonin, and gastrin; but clinical signs are usually from hyperinsulinism.^1–2 Insulin secretion by the tumor cells is independent of typical suppression from hypoglycemia, and excessive secretion of insulin may occur autonomously or in response to glucose stimulation.^1–3 The resulting hyperinsulinemia leads to intermittent and potentially life-threatening hypoglycemia.^1–3 Clinical signs result from the effect of hypoglycemia on the central nervous system and from activation of counterregulatory responses to hypoglycemia.^1–4

Insulinomas are considered malignant tumors in dogs because of the high incidence of metastasis at the time of initial diagnosis, but they are considered benign in humans.^1–5 Middle-aged to older dogs are most commonly affected.^1–4,6 Common sites of metastasis in dogs include regional lymph nodes, liver, and peripancreatic omentum.^1–3 Pulmonary metastasis is rare.^1–2 Definitive diagnosis relies on documentation of a normal or elevated endogenous serum insulin concentration with concurrent hypoglycemia.^1–3 Surgical resection, with or without adjunctive medical therapy, is considered the treatment of choice when medical imaging shows no evidence of widespread metastasis.^1–3 Development of diabetes mellitus is a potential postoperative complication following surgical removal of the tumor, but the development of an insulinoma in a dog with pre-existing diabetes mellitus has not previously been reported.^1–3,7

The following case report describes the development of an insulinoma in a dog with pre-existing type I or insulin-dependent diabetes mellitus.

Case Report

A 10-year-old, 47.3-kg, castrated male golden retriever was referred to the Small Animal Clinic of the Western College of Veterinary Medicine because of hypoglycemia-induced seizures. Three years previously, the dog was diagnosed with insulin-dependent diabetes mellitus and was being treated with twice-daily subcutaneous (SC) insulin injections.^a Over the previous 8 months, the twice-daily dose of insulin had been gradually tapered because of hypoglycemia with secondary seizures. Three days prior to presentation, insulin therapy was discontinued completely, and intravenous (IV) fluid therapy with 5% dextrose was initiated by the referring veterinarian to treat persistent hypoglycemia. Serum fructosamine concentration was found by the referring veterinarian to be normal (176 μmol/L; reference range 160 to 408 μmol/L).

On physical examination, the dog was lethargic and obese. On arrival, hypoglycemia was documented using a hand-held glucometer^b (2.8 mmol/L; reference range 3.1 to 6.3 mmol/L). A complete blood cell count (CBC) revealed moderate leukocytosis (white blood cells 32.1 × 10⁹/L; reference range 4.80 to 13.9 × 10⁹/L), characterized by neutrophilia (segmented neutrophils 28.25 × 10⁹; reference range 3.0 to 10.0 × 10⁹/L) with a left shift (band neutrophils 0.96 × 10⁹/L; reference range 0.0 to 0.1 × 10⁹/L), and mild monocytosis (monocytes 1.28 × 10⁹/L; reference range 0.08 to 1.0 × 10⁹/L). Hypokalemia (3.3 mmol/L; reference range 3.8 to 5.6 mmol/L), hyperchloremia (122 mmol/L; reference range 103 to 118 mmol/L), low blood urea nitrogen ([BUN] 3.4 mmol/L; reference range 3.5 to 11.4 mmol/L), mild hypercholesterolemia (6.6 mmol/L; reference range 2.70 to 5.94 mmol/L), and elevated sorbitol dehydrogenase (8.0 U/L; reference range 0.0 to 4.0 U/L) were noted. The hypokalemia and low BUN were attributed to losses from fluid diuresis and decreased food intake from partial anorexia. The IV fluid therapy was changed to lactated Ringer’s solution with potassium chloride^c (20 mEq/L) and 5% dextrose at a rate of 118 mL per hour. Hypoglycemia persisted (1.7 mmol/L; reference range 3.1 to 6.3 mmol/L), and a serum sample was submitted for an insulin determination.^d Inappropriate hyperinsulinemia (65.1 μIU/mL; reference range 9.0 to 25.0 μIU/mL) with concurrent hypoglycemia was detected and was suggestive of an insulin-secreting neoplasm. A urinalysis revealed isosthenuria (specific gravity 1.012) and alkalinuria (pH 9.0). The isosthenuria was attributed to fluid diuresis.

Thoracic and abdominal radiographs and abdominal ultrasonography revealed no significant abnormalities. Preprandial serum bile acid concentration (1 μmol/L; reference range 0 to 10 μmol/L) was within the normal reference range. Surgery was delayed for 1 week while waiting for the results of the insulin radioimmunoassay results. Over this week, the dog’s appetite declined, and his blood glucose concentrations ranged from 2.0 to 3.5 mmol/L. Intravenous dextrose supplementation was decreased from 5% to 2.5%. Repeated electrolyte assays indicated that the hypokalemia had been corrected.

Eight days after presentation, the dog underwent an exploratory laparotomy. The dog was premedicated with hydromorphone^e (0.1 mg/kg intramuscularly [IM]) and acepromazine^f (0.03 mg/kg IM) and was induced and maintained on inhaled isoflurane^g in oxygen. Intravenous dextrose was increased to 5%, and blood glucose concentrations were monitored every 15 to 20 minutes throughout surgery. A 2 × 3 × 3-cm, raised, red mass in the right limb of the pancreas was identified and resected. An enlarged mesenteric lymph node just proximal to the pylorus and a 2-mm, white, raised nodule on the right lateral liver lobe were also removed. Tissues submitted for histopathological evaluation confirmed the presence of a pancreatic beta cell carcinoma [Figures 1, 2] with metastases to the regional lymph node and liver. Immunohistochemical staining with guinea pig anti-insulin antibody, using the avidin-biotin-complex peroxidase method, revealed the presence of insulin within the neoplastic cells of the pancreatic mass [Figure 3].

Postoperative recovery of the dog was uneventful, and his blood glucose rose from 3.0 to 10 mmol/L within 4 hours after surgery. Dextrose supplementation was reduced to 2.5% and was discontinued 27 hours after surgery. Because of the risk of pancreatitis, the dog was maintained on IV fluids, with nothing per os for 72 hours. The dog was then slowly introduced to a bland diet and small amounts of water. Ranitidine^h was initiated (2 mg/kg IV q 12 hours) as a prophylactic treatment for possible pancreatitis immediately after surgery. Twice the dog vomited small amounts of fluid following reinstitution of food, but he maintained a good appetite.

Blood glucose concentrations were measured three to five times daily while the dog was hospitalized. By 7 days postoperatively, glucose levels were consistently in the range of 15 to 20.0 mmol/L. Insulin therapy was reinitiated with human recombinant lente insulin^a (0.2 IU/kg SC q 12 hours). The dog’s diet was switched to a low-fat dry foodⁱ for 7 days, and then the owner restarted the dog’s regular maintenance diet.^j Urine dipstick^k assays consistently revealed 4+ glucosuria until the dog was discharged 9 days after surgery.

A blood glucose curve was performed 1 week later by the referring veterinarian. The dog did well at home, and the dose of insulin was increased over the following 2 months to 0.46 IU/kg SC q 12 hours. Three months after surgery, the dog experienced another seizure and was euthanized. A postmortem examination was not allowed.

Discussion

Differential diagnoses for the documented hypoglycemia in this dog included an insulinoma, a non-beta cell tumor, hepatic insufficiency, hypoadrenocorticism, and acquired hypopituitarism with deficiency of growth hormone and/or adrenocorticotropic hormone.^1–3 Sepsis was ruled out because of the chronic history and lack of other supportive findings. An insulinoma was strongly suspected based on the mostly normal laboratory and imaging findings.^1–3 Although an abdominal ultrasound can be useful in identifying a pancreatic mass or sites of metastasis, the sensitivity is considered low.¹ Tumors in the body or right limb of the pancreas, as in the dog reported here, were less commonly visualized than tumors in the left limb of the pancreas in one retrospective analysis.¹ This may account for the inability to visualize the relatively large-sized pancreatic mass using ultrasound in the dog of this report.

The most reliable diagnostic test for an insulinoma is documentation of a normal or elevated serum insulin concentration with concurrent hypoglycemia, as seen in this case.^1,2 A low serum fructosamine concentration, which assesses glycemic regulation over the previous 10 to 14 days, has also been used to support the diagnosis of insulinoma when random blood glucose determinations are normal.⁸ In the case reported here, serum fructosamine was low normal and nondiagnostic. Although not done in this case, somatostatin receptor scintigraphy has also been utilized in the diagnosis of insulinomas in dogs and humans.^9,10 When performed, positive results may also correlate with a favorable response to treatment with the somatostatin analogue octreotide.^1,2,9

Surgical resection is considered the treatment of choice for insulinomas and is also used to help stage the extent of the disease.^1–3,11 In one study, the median survival time was significantly longer in dogs that underwent surgery followed by medical therapy (362 days) than in dogs treated with medical therapy alone (74 days).¹¹ Poor prognostic indicators that have been identified in different studies include evidence of visible metastasis and hypoglycemia in the immediate postoperative period, both of which were documented in this case.⁴ Persistence of hypoglycemia may indicate undetected tumor burden.^1,2 Other major postoperative concerns include development of acute pancreatitis and transient diabetes mellitus from atrophy of the remaining normal beta cells.^1–3,6 In rare cases, postoperative diabetes mellitus may be permanent or prolonged.^1,6

In the present case, the dog was an insulin-dependent diabetic for 3 years prior to development of an insulinoma; therefore, postoperative recurrence of the diabetes was expected. To the authors’ knowledge, this is the only reported case of an insulinoma developing in a previously diabetic dog. In humans, development of an insulinoma in diabetic patients is also exceedingly rare.^12–22 Only a few cases have been reported in people with pre-existing type II diabetes mellitus, and only one case has been reported in a person with type I diabetes mellitus.^12–22 The dog reported here was presumed to have type I diabetes mellitus because of the long-standing history of diabetes mellitus, the requirement for exogenous insulin therapy, and the fact that type I is the most common form of diabetes mellitus seen in dogs.²³ A causative relationship between diabetes and subsequent development of an insulinoma in the few reported human cases has not been established. One hypothesis, however, is that long-term treatment of diabetics with insulinogenic medications such as sulfonylurea, or chronic insulin resistance (as occurs in some diabetics), may induce hyperplasia and adenomatous transformation of beta cells into an insulinoma.¹³

Discrimination among the causes of insulin-mediated hypoglycemia (sulfonylurea or insulin overdose and an insulinoma) in diabetic humans relies on concurrent measurement of serum beta-cell polypeptides (e.g., insulin, C-peptide, and proinsulin levels) and the detection of sulfonylurea measured by high-performance liquid chromatography in the plasma.^17,22,24 People with insulinoma-and sulfonylurea-induced hypoglycemia have elevated serum levels of insulin, C-peptide, and proinsulin; but only patients with sulfonylurea-induced hypoglycemia have measurable plasma concentrations of sulfonlyurea.^22,24 Patients with hypoglycemia induced by an overdose of exogenous insulin have a high serum insulin level but suppressed levels of serum C-peptide.^22,24 In this dog, insulin was measured using a radioimmunoassay that also measures insulin antibodies and exogenous insulin—both of which can result in a false interpretation of endogenous hyperinsu-linemia.²⁵ To avoid such a false positive, measurement of insulin concentration should only be done after sufficient time has elapsed after administration of the last dose of exogenous insulin. For insulins that have maximum durations ranging from 6 to 20 hours in dogs (e.g., Isophane insulin [NPH] or Lente), sampling should be delayed for at least 36 hours after administration of the last exogenous dose.²³ In the case reported here, serum insulin was measured >72 hours after administration of the last dose of exogenous insulin. Alternatively, concurrent measurement of C-peptide could be done to help rule out an insulin overdose as the cause of a dog’s hypoglycemia.^23,24

The existence of insulin resistance, and the erroneous assumption that hypoglycemia in a diabetic animal may be secondary to an overdose of insulin can lead to a delay in the diagnosis of an insulinoma.¹³ In diabetic humans, the time that elapsed from the onset of clinical signs of hypoglycemia to the diagnosis of a concurrent insulinoma ranged from 12 to 24 months.¹⁹ A recent report of a person with type II diabetes mellitus and nocturnal hypoglycemia described how a continuous glucose monitoring system played a major role in diagnosing a concurrent insulinoma.¹⁹ Use of such a device in small animals has been described as a tool for monitoring diabetes mellitus, but not as an aid in diagnosing an insulinoma.²⁶ Continuous monitors may potentially document intermittent hypoglycemia. As the current case illustrates, if hypoglycemia continues to occur in a diabetic animal, especially after complete withdrawal of insulin, the possibility of a coexisting insulinoma should be considered.

If signs of hypoglycemia recur after surgery, as in this case, or if surgery is not an option, medical therapies designed to prevent hypoglycemia should be initiated. Such measures include dietary management, oral glucocorticoids, other anti-insulinogenic drugs (e.g., diazoxide, octreotide, streptozotocin, alloxan), palliative chemotherapy (e.g., doxorubicin and hepatic arterial chemoembolization), and radiation therapy.^{1–3,27–29} In this case, the only additional medical therapy was administered prior to surgery. After discharge the dog was fed frequent, small meals, and exercise was limited. A diet high in fat, protein, complex carbohydrates, and fiber is recommended. Foods high in simple sugars should be avoided. These measures are considered first-line modifications to limit development of hypoglycemia in such cases, but nonresponsive animals may require more aggressive medical therapy.^1–3

The long-term prognosis for a dog with an insulinoma is guarded to poor.^1,30 In a multi-university study, the median normoglycemic interval following surgery was 14 months for dogs when the tumor was confined to the pancreas (i.e., stage I).³⁰ For dogs with evidence of metastasis to regional lymph nodes (i.e., stage II) or with evidence of distant metastasis (i.e., stage III) at the time of surgery, the median normoglycemic interval following surgery was approximately 1 month.³⁰ Dogs with stage I or stage II disease had a median survival time of 18 months, while dogs with stage III disease had a median survival time of <6 months.³⁰ The dog reported here had stage III disease and survived less than the predicted 6 months following surgery.

Conclusion

A 10-year-old golden retriever with diabetes mellitus was diagnosed with an insulinoma. At the time of surgical resection, the tumor had metastasized to the liver and mesenteric lymph node, and the dog only survived 3 months following surgery. The possibility of a coexisting insulinoma should be considered for hypoglycemia in a dog with diabetes mellitus, particularly if insulin overdosage has been ruled out or if hypoglycemia persists after complete withdrawal of insulin.