JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
E-M03

Signalment (JPC #1475184):  Domestic shorthair cat.

HISTORY:  This cat was kept in a laboratory animal colony and had clinical signs of diabetes mellitus.

SLIDE A: HISTOPATHOLOGIC DESCRIPTION:  Pancreas:  Diffusely, all the islets of Langerhans are 90% effaced and expanded by pale, eosinophilic, amorphous, hyaline to waxy, weakly birefringent material (amyloid).  The few remaining islet cells are either necrotic with hypereosinophilic cytoplasm and pyknotic nuclei or degenerate with marked cytoplasmic vacuolation.  The exocrine pancreas is multifocally expanded by multiple, up to 1mm diameter, unencapsulated, well circumscribed, pale nodules composed of hyperplastic pancreatic acinar cells which have abundant eosinophilic cytoplasm and few zymogen granules.  Peripheral to and within these hyperplastic foci are few lymphocytes and plasma cells and rare nondegenerate neutrophils.  Focally, there is a large (1mm diameter) Pacinian corpuscle composed of a delicate capsule surrounding many concentric “onion skinned” lamellae of flattened cells around a central nerve fiber (normal structure).

SLIDE B: HISTOPATHOLOGIC DESCRIPTION:  Pancreas (Congo red):  The material effacing the islets of Langerhans stains diffusely red-orange (congophilic) and exhibits apple green birefringence when viewed with polarized light (amyloid).

MORPHOLOGIC DIAGNOSIS:  1.  Pancreas, islets of Langerhans:  Amyloidosis, diffuse, severe, with islet cell loss, domestic shorthair, feline.

2. Pancreas, exocrine: Hyperplasia, nodular, multifocal, mild.

GENERAL DISCUSSION:

• Pancreatic Islets consist of several cell types that secrete different products

• Alpha cells:  Glucagon (stimulates glycogenolysis, gluconeogenesis, lipolysis)
• Beta cells:  Insulin and islet-amyloid polypeptide (IAPP - amylin); present in all islets and comprise the majority of cells (amylin suppresses glucagon production and inhibits gastric digestive function; insulin stimulates glucose uptake and glycogenesis in response to hyperglycemia)

• Delta cells: Somatostatin (inhibits release of glucagon, insulin and pancreatic polypeptide)

• PP cells:  Pancreatic polypeptide (antagonizes cholecystokinin – inhibits exocrine pancreas secretion and gall bladder contraction and delays gastric emptying)
• Epsilon cells: Ghrelin (appetite stimulant and suppresses insulin secretion)

• Insulin is an anabolic hormone released by beta cells in response to glucose and other nutrients (e.g. amino acids, fatty acids) and hormones
  • Target organs are liver, skeletal muscle, and fat
  • Required for transmembrane transport of glucose and amino acids, glycogen formation in the liver and skeletal muscle, conversion of glucose to triglycerides, and nucleic acid and protein synthesis
• Islet Amyloid Polypeptide (IAPP) is normally secreted with insulin, has several normal physiologic functions:
  • Involved in the suppression of satiety and fat storage, glucose homeostasis, suppression of glucagon release, vasodilation, gastric emptying, and excretion of calcium, potassium, and sodium
• Diabetes Mellitus (DM) is an endocrine disorder common in cats and dogs and rare in cattle, small ruminants, pigs, and horses
  • Polygenic Diabetes
  • Type 1: Absolute insulin deficiency due to autoimmune destruction of beta cells
  • Type 2: Peripheral insulin resistance and beta cell dysfunction
  • Type S: occurs when insulin action is antagonized by hormones and drugs or pancreatic inflammation that cause β-cell destruction
  • Specific Type: Disorders of the exocrine pancreas, endocrinopathies, insulin antagonistic drugs, genetic syndromes
  • Monogenic Diabetes
    • No useful animal model currently exists
    • Maturity-onset diabetes of the young (MODY): Defective glucose sensing due to mutations in DNA coding transcription factors
    • Mitochondrial diabetes: Beta cell dysfunction and impaired glucose metabolism due to mutations in mitochondrial DNA

PATHOGENESIS:

Amyloidosis:

• There are over 15 biochemically distinct forms of amyloid associated with many clinical syndromes.
• Amorphous, hyaline to waxy substance consisting of abnormally folded protein deposited extracellularly, forming characteristic β -pleated sheets and exhibiting congophilia
• Composed of about 95% fibril proteins; 5% P component and other glycoproteins
  • P Component: Found in all forms of amyloid; nonproteinaceous substance; derived from the connective tissue in which amyloid is deposited
• Classes of Amyloidosis:
  • Systemic (Generalized)
  • Primary (Immunocyte dyscrasias with amyloidosis)
    • AL (amyloid light chain): Composed of immunoglobulin λ light chains; associated with monoclonal B cell proliferation (multiple myeloma, extramedullary plasmacytoma)
  • Secondary (Reactive systemic amyloidosis)
    • AA (amyloid-associated): Derived from serum amyloid associated (SAA) protein – an apolipoprotein produced in the liver in response to IL-1, IL-6 and TNF-a; SAA easily detectable in plasma during the acute phase of inflammation
  • Familial
    • AF (amyloid-familial): Hereditary autosomal recessive condition in Abyssinian and Siamese cats and Chinese shar pei, beagle, gray collies, English foxhound dogs; likely associated with SAA; can be localized to just kidney
  • Localized
  • IAPP (amyloid of endocrine organs): Derived from islet amyloid polypeptide (IAPP, aka amylin) – normally secreted by beta cells of pancreas.
  • Aβ (senile/old age amyloidosis): Neurodegenerative disease, senile plaques, cerebral amyloid angiopathy (rare in animals)
  • Apolipoprotein AI (Apo AI): Deposition of amyloid in pulmonary vasculature of aged dogs
• Nonendocrine tumors: Amyloid-producing odontogenic tumor of cat and dog; ameloblastomas
  • PrPsc: Prion diseases (chronic wasting disease) forming amyloid plaques in brain in addition to intraneuronal vacuolation (N-M08, N-M09)
  • Gastrointestinal: Age-related; unknown precursor protein (NOT AA)
• In humans and cats, Apolipoprotein E is co-deposited with amyloid fibrils in systemic amyloidosis, islet amyloidosis, and amyloid-producing odontogenic tumors, suggesting that ApoE may affect the mechanism of amyloidosis in various animal species (Miyazaki, J Comp Pathol. 2020)

Diabetes:

• Regardless of etiopathogenesis, all forms of DM result in a generalized catabolic state once the insulin-secreting capacity of beta cells is reduced to ≤20% of normal
• Impaired glucose tolerance is an early development typical of all forms of DM
• Polygenic Diabetes
  • Type 1 DM (humans and cattle; not a significant mechanism in dogs or cats):
  • Absolute hypoinsulinemia resulting from beta cell depletion by selective autoimmune destruction
  • Beta cell apoptosis is mediated by perforin released by cytotoxic CD8+ T lymphocytes
  • Beta cells are particularly susceptible to injury by free radicals, IL-1, IFN-gamma, and TNF-alpha; the latter two in concert can 1) nearly abolish glucose-stimulated insulin secretion and 2) induce de novo expression of class II MHC molecules on beta cells, and can independently upregulate class I MHC expression on beta cells
    • Increased MHC expression -> promotes homing of autoreactive lymphocytes to the pancreas (also promoted by IL-2)
  • Differentiation of helper T lymphocytes is towards the Th1 pathway, but IL-10 (Th2 pathway) may also play a role in beta cell destruction
• Type 2 DM (humans and cats):
  • Risk factors include increased age, male gender, neutered, physical inactivity, glucocorticoid and progestin administration, and obesity
    • Downregulation of GLUT4 glucose transporter in muscle and fat
    • Reduced receptor affinity for insulin
    • Decreased adiponectin (anti-inflammatory properties and positive correlation with insulin sensitivity)
    • Post receptor defects in oxidative and non-oxidative metabolism
    • Is due to both inadequate insulin secretion and increased resistance to insulinic effects in peripheral tissues.
  • Insulin Resistance
    • Skeletal muscle is the most important site of insulin resistance
      • Defective postreceptor insulin processing causing decreased glycogen synthesis in myocytes
    • Islet Amyloid Polypeptide (IAPP)
      • Antagonizes insulin-stimulated glucose uptake into myocytes
      • Inhibits glycogen synthetase
      • promotes breakdown of muscle glycogen
      • Beta Cell Dysfunction
    • Beta cell function and numbers decrease, alpha cell numbers decrease, and delta cell fraction remains normal (cats and humans)
    • Decreased synthesis of the glucose transporter in the beta cell membrane due to desensitization of GLP-1 (defective glucorecognition)
    • Islet Amyloidosis (localized amyloid)
      • Increased IAPP production due to insulin resistance causes an increased IAPP:insulin ratio resulting in IAPP-induced membrane disruption followed by extracellular fibril formation in close association with beta cell membranes (fibrillogenesis), inducing apoptosis or necrosis of the beta cells
    • Glucose Toxicity
      • Prolonged hyperglycemia > downregulation of glucose transporters on beta cell membranes > downregulation of expression of insulin and PDX1 genes (PDX1 gene is normally phosphorylated in response to glucose, stimulating transcription of the insulin gene; this process is impaired in DM) > impaired insulin secretion by beta cells and induction of peripheral insulin resistance > glycogen accumulation in islet cells > cell death
    • Lipotoxicity
      • Persistently high serum fatty acids suppress insulin secretion by beta cells
    • Glucolipotoxicity is associated with increased intracellular concentrations of long-chain acyl-coenzyme A molecules
  • Specific types of polygenic DM:
    • Type S: occurs when insulin action is antagonized by hormones and drugs or pancreatic inflammation cause β-cell destruction
      • Nonspecific islet destruction in acute pancreatic necrosis of adult dogs
    • Secondary to insulin antagonism by diabetogenic drugs or hormones (e.g. glucocorticoids, glucagon, epinephrine, progesterone (pregnancy), thyroxine, or growth hormone) > sustained hyperglycemia
  • Alpha and delta cells also exhibit impaired responsiveness to glucose > increased serum glucagon concentration > increased hepatic glycogenolysis > exacerbation of hyperglycemia and ketoacidosis (the latter by stimulating hepatic fatty acid oxidation)
  • Monogenic Diabetes
  • Lack islet amyloidosis and hypertriglyceridemia and have normal islet insulin staining
    • Maturity-Onset Diabetes of the Young (MODY) (humans)
    • Comprise about 5% of total clinical cases of diabetes in humans
    • Heritable mutations that are passed on as autosomal dominant traits to offspring in humans
    • Body weight distribution includes both normal weight and obese individuals
    • Transcription Factor Mutations: Mutation in an autosomal gene (HNF4A, HNF1A, IPF1, HNF1B, or NEUROD1) coding for transcription factors regulating insulin expression and transport of insulin within the beta cell à impaired insulin secretion with normal insulin production and islet morphology
    • Glucokinase Mutations: Mutation in the GCK gene coding for glucokinase à inhibiting normal glycogen synthesis à chronic mild hyperglycemia
    • Mitochondrial Diabetes (“maternally inherited diabetes and deafness”) (humans)
      • Manifests as a pronounced age-dependent deterioration of pancreatic function and insulin production
      • An A3243 mutation in a mitochondrial DNA gene coding for mitochondrial tRNA (Leu, URR) à beta cell dysfunction and impaired glucose metabolism
    • Diabetes Insipidus (DI)
    • Endocrine disorder characterized by the lack of antidiuretic hormone (ADH) or the insensitivity of the distal renal tubules and collecting ducts to ADH
    • ADH is synthesized in the hypothalamus and secreted by the pars nervosa of the pituitary and is responsible for water conservation
    • Findings of DI include dilute urine despite a high serum osmolality, absence of renal disease, and increased urine osmolality in response to ADH administration
    • Clinical signs include PU, PD, and a near continuous demand for water
    • Clinical pathology findings include a decreased urine specific gravity <1.010, decreased urine osmolality <290 mosmol/kg, and possibly a hypernatremia due to dehydration
    • Central Diabetes Insipidus
      • Most often the sequela of a primary pituitary neoplasm, but can also result from metastatic, inflammatory, or parasitic disease, or post hypophysectomy for pituitary-dependent hyperadrenocorticism (may resolve in days to months after surgery)
      • Complete: The body is devoid of releasable ADH
      • Partial: The hypothalamus releases an inadequate amount of ADH with increasing serum osmolality, suggesting a limited secretory capacity and decreased sensitivity of the osmoreceptors.
    • Nephrogenic Diabetes Insipidus
      • The target cells in the renal tubules are refractory to normal or increased concentrations of circulating ADH
      • Can be seen secondary to pyometra
      • Documented as a familial disorder in huskies where a mutation affects the V₂ receptor affinity for ADH

TYPICAL CLINICAL FINDINGS:

Diabetes Mellitus:

• Weight loss despite a normal to increased appetite (decreased utilization of glucose, amino acids and fatty acids)
• Polyuria (osmotic diuresis)
• Polydipsia (compensatory to counteract dehydration)
• Polyphagia (decreased glucose uptake by satiety center cells)
• Muscle atrophy (diversion of amino acids from protein synthesis to gluconeogenesis)
• Dehydration (if compensatory polydipsia is inadequate to match polyuria)
• Clinical pathology:

• Persistent fasting hyperglycemia and glucosuria
• DM may be diagnosed based on a single blood glucose sample if glucosuria and ketonuria are present
• Increased glycosylated hemoglobin (gHb): reflects blood glucose concentration over the preceding 2-3 months
• Increased fructosamine: reflects blood glucose concentration over the preceding 2-3 weeks (fructosamine is the gold standard for monitoring glycemic control in diabetic cats)
• Hyperlipidemia (increased lipolysis, decreased uptake of free fatty acids by adipocytes)
• Hypercholesterolemia
• Increased ALT and ALP activity
• Hypokalemia (solute loss in urine)
• Proteinuria (secondary to lower urinary tract infection or glomerular disease)
• Ketonemia, ketonuria, and ketoacidosis occur with diabetic ketoacidosis and may result in titrational metabolic acidosis with elevated anion gap

• Urinary tract infections due to glucosuria ( coli, Proteus sp., Aerobacter aerogenes)
• Hindlimb weakness with plantigrade posture (diabetic neuropathy)

TYPICAL GROSS FINDINGS:

Islet Amyloidosis:

• None

Diabetes Mellitus:

• Liver: Hepatomegaly (due to hepatic lipidosis secondary to hyperlipidemia and reduced ability of hepatocytes to export lipoproteins due to lack of glucose availability and ATP shortage)
• Pancres: Small white foci representing amyloid deposition may be evident in islets
• Eyes: Cataracts: Common in diabetic dogs, rare in cats
• Urinary bladder: Emphysematous cystitis (gas-producing gram-negative bacterial infection)
• Blood vessels: Atherosclerosis: Deposition of cholesterol and lipid in arteries (dogs)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Amyloidosis:

• Pancreas:

• Glycogen-type vacuolar degeneration of beta +/- alpha cells and ductal and ductular epithelium is common
• Islet amyloidosis is characteristic of type 2 DM in >90% of cynomolgus macaques and humans and 22-100% of affected cats (may also be noted in healthy cats incidentally):

• Pink (sometimes more basophilic) amorphous material in and around capillaries and islet cells that eventually replaces normal architecture

• Liver (part of systemic amyloidosis): Diffuse hepatic lipidosis with biliary epithelial vacuolation
  • Amyloid deposition in perisinusoidal spaces between sinusoidal lining and hepatocytes (space of Dissé)
• Adrenal gland: occur in all species within cortex but not medulla
• Thyroid glands: deposition of amyloid in the interstitium as part of degenerative change in dog, cat, cattle
• Spleen: part of generalized amyloidosis as part of primary (AL) or secondary (AA)
  • Involve germinal center and difficult to see without special stains
• Small intestine and stomach (part of systemic amyloidosis): amyloid in lamina propria of villa and submuosa

Diabetes Mellitus:

• Kidney: Glycogen nephrosis/diabetic nephropathy (deposition of glycogen in tubular epithelium of the loop of Henle and distal convoluted tubules); +/- fatty degeneration of the proximal convoluted tubule epithelium; +/- glomerulosclerosis
• Eye:

• Diabetic retinopathy (uncommon):  Increased thickness of capillary basement membrane, loss of pericytes, capillary shunts and microaneurysms
• Diabetic cataract (common in dogs, uncommon in cats): excess glucose in aqueous > excess glucose in lens, shunted to sorbitol pathway of metabolism > excess sorbitol > increased osmotic pressure in lens

• Peripheral nerves (diabetic neuropathy): Axonal degeneration, segmental demyelination and remyelination in distal parts of motor and sensory nerves

ULTRASTRUCTURAL FINDINGS:

• Fibrils: non-branching, 7.5-10 nm diameter, hollow-cored tubules of indeterminant length (crisscross in and out of the plane of section)
• Characteristic beta-pleated sheet configuration of amyloid fibrils is appreciable only on examination by x-ray diffraction

ADDITIONAL DIAGNOSTIC TESTS:

Amyloid:

• Amyloid is congophilic (high affinity for Congo red stain) and displays apple green birefringence under polarized light when stained with Congo red; pre-treatment with potassium permanganate or dilute sulfuric acid diminishes congophilia of AA amyloid, but not of AL or IAPP-derived islet amyloid

Diabetes Mellitus: 

• Glucose tolerance test may be used to confirm or exclude a diagnosis of DM when blood glucose test results are equivocal, but is rarely used in practice
• Serum glycated albumin may be a useful substitute for fructosamine for monitoring glycemic control in diabetic cats

DIFFERENTIAL DIAGNOSIS:

Islet Amyloidosis:

• None

Diabetes Mellitus

• Hyperglycemia: Hyperadrenocorticism, epinephrine effect (i.e. “stress” especially in cats), diestrus, postprandial, drugs (glucocorticoids, progestens, thiazide diuretics)
• Lipemia: Postprandial, hyperadrenocorticism, hypothyroidism, hepatopathy, pancreatitis, starvation
• PU/PD: Diabetes insipidus, hyper/hypoadrenocorticism, hypercalcemia, hyperthyroidism, liver failure, medullary washout, psychogenic polydipsia, pyometra, renal disease

COMPARATIVE PATHOLOGY:

Islet Amyloidosis:

• Deposition of amyloid in pancreatic islet of cats, macaques, baboons, and humans may be associated with type 2 diabetes mellitus
• Cats: incidence of islet amyloidosis same in diabetic and control cats – amyloidosis as a cause of DM is controversial, but may contribute to progression of disease; may indicate disturbed β cell function and a prediabetic state as islet amyloid is associated with decrease in β cell numbers

Diabetes Mellitus:

• Cats > 10 years old have highest incidence; obese and/or castrated males affected more commonly than females.
• Dogs: Type II peak incidence at 7-9 years of age; females twice as likely as males to be affected; most common cause of DM in dogs is loss of islets due to exocrine pancreas necrosis or pancreatitis; genetic basis for juvenile onset type I DM demonstrated in keeshonds and suspected in golden retrievers (islet hypoplasia); islet amyloidosis not a feature of DM, but may be found in islet cell tumors
  • Familial AA amyloidosis in Chinese Shar-Pei dogs
• Cattle with type 1 DM: pathogenesis similar to type 1 DM in humans; bovine pestivirus (BVD) and aphthovirus (FMD) may provoke autoimmune lymphocytic insulitis as both diseases are associated with DM; may develop mild islet fibrosis, focal mineralization and lymphocytic insulitis
• Horse (rare): production of hyperimmune serum in liver of horses
  • Occasional deposition in the submucosal in nasal cavity
• Islet amyloidosis also occurs in humans, other primates, domestic and wild cats, and transgenic ob/ob mice
• Pancreatic islet amyloidosis is a common post-mortem finding in racoons, both wild and captive.
• Mice: Group B Coxsackie viruses and encephalomyocarditis virus implicated in development of type 1 DM
• Rats and mice: Wild type rodent IAPP (rIAPP) is non-amyloidogenic
• Guinea pig: incidental finding surrounding splenic follicles, hepatic sinusoidal lining, kidney, adrenal cortex
• NHP: High incidence of type 2 DM in colony of sooty mangabeys; 100% of diabetic and 23% of non-diabetic animals demonstrated pancreatic amyloid; fructosamine and triglyceride levels were best indicators of diabetes
• Type 2 DM also commonly seen in Rhesus monkeys, black Celebes monkeys, aging Chimpanzees
  • Histologic lesion limited to endocrine Islets of Langerhans
  • Concurrent IAPP secreted with insulin may form amyloids
  • Amyloidosis is common in NHP, but renal amyloidosis in uncommon
• Bird (Sanderlings): report of severe amyloidosis in the liver
• African tiger snake: report of spleen amyloidosis associated with disseminated mycobacteriosis

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