Term
| In what cells is insulin not needed for glucose uptake? |
|
Definition
neurons, WBC/RBC/PLT, hepatocytes*
* although insulin does influence levels of hepatic enzymes that promote glycolysis or glycogen synthesis, or reduce glucongeogensis |
|
|
Term
| What glucose carriers require insulin? |
|
Definition
| GLUT-4 (myocytes and adipocytes) |
|
|
Term
| What is the effect of glucagon on blood glucose? |
|
Definition
| increases BG by stimulating gluconeogensis and glycogenolysis |
|
|
Term
| What is the primary effect of catecholamines on pancreatic beta cell release of insulin? |
|
Definition
Decrease insulin release from pancreatic beta cells*
*beta-adernergic stimulus does increase insulin secretion, however, pancreatic beta cells primarily have alpha-adernergic receptors so the overall effect is decreased insulin secretion |
|
|
Term
| What is the effect of alpha-adrenergic stimulation on blood [glucose]? |
|
Definition
Increased [BG]
decreased secretion of insulin by pancreatic beta-cells
increases secretion of growth hormone by pituitary |
|
|
Term
| What is the effect of beta-adrenergic stimulation on blood [glucose]? |
|
Definition
Increased [BG]
increased hepatic glycogenolysis
does increase insulin secretion, but there aren't many beta-AR receptors on pancreatic beta cells so this doesn't impact BG |
|
|
Term
| How does cortisol affect BG and through what mechanisms? |
|
Definition
increased [BG]
stimulated gluconeogenesis and creates a state of insulin resistance |
|
|
Term
| What is the substrate for hepatic gluconeogensis in fasting cattle and to a lesser extent horses? |
|
Definition
Proprionate
*from rumen fermentation (cattle), and colonic fermentation (horses) |
|
|
Term
| What is the substrate for hepatic gluconeogensis in fasting monograstrics? |
|
Definition
| products of protein and lipid catabolism are used to maintain gluconeogenesis |
|
|
Term
| What type of collection tube can be used to block continued in vitro glycolysis by RBC/WBC/PLT during sample transport/storage? |
|
Definition
NaF tubes (gray stopper)
Flouride complexes with Mg preventing Mg's participation as a cofactor for phosphopyruvate hydratase (aka enolase) in the glycolytic pathway
**but this isn't perfect, it take some time for the effect to occur (up to an hour), NAF can induce hemolysis which can also affect assays, F- also inhibits glucose oxidase which is sometimes used in glucose assays |
|
|
Term
| What is the stimulus for insulin secretion by pancreatic beta cells? |
|
Definition
| increased blood concentrations of glucose, growth hormone, glucagon, and/or amino acids |
|
|
Term
| What is the stimulus for glucagon secretion by pancreatic alpha cells? |
|
Definition
increased blood concentrations of amino acids and cortisol
decreased blood concentrations of glucose |
|
|
Term
| What is the stimulus for hepatic glycogenolysis? |
|
Definition
| increased epinephrine and glucagon |
|
|
Term
| What hormones promote increased hepatic gluconeogenesis? |
|
Definition
|
|
Term
| What hormone promotes hepatic glycolysis? |
|
Definition
insulin
**also inhibits hepatic gluconeogenesis and glycogenolysis |
|
|
Term
| How does insulin promote hepatic uptake of glucose, despite the fact that the hepatic glucose receptor (Glut-2) is not insulin dependent? |
|
Definition
| insulin promotes glucokinase activity |
|
|
Term
| What is the effect of sample type on blood [glucose] and why? |
|
Definition
[BG] is higher in serum/plasma compared to whole blood.
Glucose freely diffuses between RBC and plasma, however, there is less water in RBC than in plasma therefore the blood glucose concentration in RBC (aka whole blood) is lower than the glucose concentration in plasma/serum*
*the magnitude of difference between samples is proportional to HCT |
|
|
Term
| What is the most current methodology of measuring serum [glucose] |
|
Definition
photometric assay- most use glucose oxidase, glucose dehydrogenase, or hexokinase for the initial reaction
-in other assays glucose reacts with (o-toluidine) or reduces (copper, ferricyanide) reagents to produce color changes
all detected via spectrophotometry or reflectance photometry |
|
|
Term
| Describe the methodology of non-photometric glucose assays |
|
Definition
o2 is consumed and hydrogen peroxide is produced in the glucose oxidase reaction and the rate of production or usage can be measured with specific electrodes
**less chemical and photometric interferences compared with the photometric assays
F- and bromide negatively interfer by inhibiting glucose oxidase |
|
|
Term
| How does epinephrine induce hyperglycemia? |
|
Definition
Stimulate hepatic glycogenolysis
Decrease insulin secretion
increase growth hormone secretion --> impaired uptake of glucose by adipocytes and myocytes
and may also stimulate ACTH secretion --> cortisol (decrease number and efficiency of insulin dependent glucose transporters (GLUT-4) and increase glucagon (increased gluconeogenesis and glycogenolysis) |
|
|
Term
| How do glucocorticoids induce hyperglycemia? |
|
Definition
stimulate hepatic gluconeogenesis
create a state of insulin resistance (decreased number and efficiency of glucose transporters (GLUT-4) --> increased glucagon (stimulates gluconeogenesis and glycogenolysis) |
|
|
Term
| Describe the mechanism of hyperglycemia associated with diestrus |
|
Definition
| progesterone release from the corpus luteum promotes release of growth hormone (from pituitary or in the dog ductal epithelial cells of the mammary gland) --> inhibits uptake of glucose by myocytes and adipocytes |
|
|
Term
| What are the two major criteria for type 2 diabetes? |
|
Definition
Defect in insulin secretion
Post-insulin receptor defects in target cells |
|
|
Term
| What molecule is often associated with diabetes in cats? |
|
Definition
| over production of Amylin (amyloid polypeptide) by beta-pancreatic cells --> accumulation and destruction of beta cells and may also be involved in insulin resistance in target cells |
|
|
Term
| Describe the pathogenesis of glucose toxicosis |
|
Definition
persistent hyperglycemia --> down regulation of glucose transporters on beta pancreatic cells --> decreased sensitivity to hyperglycemia and impaired insulin secretion
*may play a role in both types of DM |
|
|
Term
| Describe the pathogenesis of obesity as a predisposing factor for DM in cats (and people) |
|
Definition
decreased GLUT-4 expression develops in obese cats prior to DM --> decreased sensitivity to hyperglycemia and reduced insulin secretion
alterations in non-esterified fatty acids, leptin and glucagon concentrations in obese cats may also contribute |
|
|
Term
| Describe the pathogenesis of endocrine diabetes mellitus associated with acromegaly in dogs and cats |
|
Definition
| excess growth hormone secretion from pituitary --> growth hormone creates insulin resistance through affecting insulin receptors and postreceptor pathways (decreased insulin uptake by myocytes and adipocytes; GLUT-4) |
|
|
Term
| Describe the pathogenesis of endocrine diabetes mellitus associated with glucagonoma? |
|
Definition
| (functional neoplasm of pancreatic alpha-cells) Excess glucagon --> antagonizes insulin activity by stimulating gluconeogenesis and inhibiting glucose utilization and storage |
|
|
Term
| Describe the pathogenesis of endocrine diabetes mellitus associated with hyperadrenocorticism |
|
Definition
| Cortisol inhibits glucose uptake by myocytes and promotes hepatic release of glucose by stimulating gluconeogenesis (also contributed to hepatocellular vacuolation through promoting glycogen production) |
|
|
Term
| Describe the pathogenesis of endocrine diabetes mellitus associated with hyperpituitarism (of which acromegaly is one form- just increased GH) |
|
Definition
(reported in cats and horses) Usually associated with functional pituitary adenoma that can secrete:
GH --> inhibits glucose uptake by muscle and adipose, promotes glycogenolysis in muscle
Or ACTH--> increased cortisol production in adrenals --> increased glucagon secretion by pancreas --> promotes glycogenolysis in muscle and liver, and also promotes hepatic gluconeogenesis)
other hormones may also be produced that do not necessarily affect glucose metabolism |
|
|
Term
| T/F hyperthyroidism in cat may be associated with insulin resistant diabetes mellitus |
|
Definition
|
|
Term
| How could pheochromocytomas contribute to high BG in affected animals? |
|
Definition
Increased secretion of epinephrine stimulates growth hormone production by the pituitary (inhibition of glucose uptake by muscle and adipose), epinephrine also promotes glycogenolysis in muscle and liver
**the patient's glycogen stores may limit magnitude of hyperglycemia |
|
|
Term
| Describe the pathogenesis of hyperglycemia in bovine milk fever |
|
Definition
Calcium is necessary (enzyme cofactor) for processing proinsulin --> insulin so hypocalcemic cows might actually have insulin deficiency
**concurrent epinephrine and cortisol mediated stress my contribute to insulin resistance and hepatic glycogenolysis (epinephrine) and gluconeogenesis (cortisol) |
|
|
Term
| Describe the features of canine hepatocutaneous syndrome and pathogenesis of associated hyperglycemia in these patients |
|
Definition
Dogs have liver failure and concurrent superficial necrolytic dermatitis. Diabetic state appears to develop after the onset of liver disease but causal effect has not been proven.
Hyperglycemia is likely multifactorial: may involve alterations in amino acid, fatty acid, and zinc metabolism, as well as glucagon and growth hormone |
|
|
Term
| What three drugs have been associated with persistent hyperglycemia (> 2 days) in dogs and cats? |
|
Definition
Glucocorticoids- promotes hepatic gluconeogenesis and inhibits muscle uptake of blood glucose, increased glucagon secretion (promotes glycogenolysis in muscle and liver, and gluconeogenesis in liver)
Thyroid hormone- mechanism unknown, possibly defective insulin secretion
Megesterol acetate (steroid that decreases circulating androgens and estrogen, used to prevent estrus)- hepatic gluconeogenesis and release of growth hormone (maybe only in cats) --> inhibition of glucose uptake in muscle and adipose |
|
|
Term
| What two conditions are associated with "infectious" diabetes mellitus? |
|
Definition
BVD in cattle (damage to pancreatic beta cells)
Sepsis in all species (an early response to endotoxemia is insulin resistance), hypoglycemia develops later in the course of disease. Also as diabetic animals are more susceptible to infection sepsis could be either the cause or the result of diabetes mellitus in some animals |
|
|
Term
| What is an early effect of endotoxin on insulin function? |
|
Definition
|
|
Term
| Describe the pathogenesis of hyperglycemia associated with increased [NH4] in cattle and horses |
|
Definition
NH4 stimulates release of glucagon (increased glycogenolysis in muscle and liver, increased gluconeogenesis in liver)
**because this mechanism relies upon adequate hepatic function the increased [NH4] would need to be the result of increased [NH4] production (e.g. urea toxicity in cattle, strenuous exercise and/or intestinal disease in horses), or increased [NH4] intake (cattle eating feed with excess anhydrous NH3) |
|
|
Term
| In what breeds of dog has a genetic form of DM been confirmed? |
|
Definition
Keeshond: clinical onset before 6 months of age, associated with beta cell hypoplasia
Samoyed (occurred in adults, pathogenesis not determined)
other dog breeds have a higher incidence of diabetes (malamute, Finnish spitz, mini schnauzer, mini poodle, english springer spaniel) but no genetic basis has yet been established |
|
|
Term
| Describe the pathogenesis of hyperglycemia associated with ketamine? |
|
Definition
| ketamine stimulates release of epinephrine --> increased glycogenolysis in liver and muscle, also inhibits glucose uptake by liver and muscle via stimulation of growth hormone |
|
|
Term
| Describe the pathogenesis of hyperglycemia associated with ethylene glycol intoxication |
|
Definition
| inhibition of glycolysis and the krebs cycle which may result in indirect stimulation of gluconeogenesis |
|
|
Term
| Describe the pathogenesis of hyperglycemia associated with xylazine and detomidine administration |
|
Definition
| These drugs are alpha-2 adrenergic agonists --> they inhibit insulin secretion by pancreatic beta cells reducing glucose uptake by tissues |
|
|
Term
| What is the pathogenesis of hyperglycemia associated with administration of propranolol and other beta blockers? |
|
Definition
| Beta adrenergic blockers inhibit insulin release (B2 stimulation normally promotes insulin release) |
|
|
Term
| Describe the pathogenesis of the Somogyi effect |
|
Definition
| Excess injected insulin results in profound hypoglycemia that stimulates glucagon, epinephrin, cortisol and growth hormone secretion --> all promote hyperglycemia, because the diabetic animal cannot release insulin to normalize BG hyperglycemia develops |
|
|
Term
| Describe the pathogenesis of hyperglycemia associated with morphine administration? |
|
Definition
| Morphine stimulates the release of growth hormone and ACTH (cortisol) |
|
|
Term
| What are the two in vitro causes of sometimes profound hypoglycemia in sample? |
|
Definition
in vitro glycolysis in WBC, RBC, PLT and possibly bacteria
Bromide interference with glucose oxidase assays |
|
|
Term
| Insulinomas can develop independently or as part of what syndrome? |
|
Definition
| Multiple endocrine neoplasia type 1 (pituitary, parathyroid, pancreas) |
|
|
Term
| What is the mechanism of hypoglycemia associated with xylitol intoxication in dogs? |
|
Definition
increased insulin secretion (more potent stimulus than glucose)
**xylitol also stimulates insulin secretion in goats and cattle but they have minimal exposure to xylitol |
|
|
Term
| Describe the pathogenesis of hypoglycemia associated with hypoadrenocorticism |
|
Definition
| decreased cortisol secretion thus decreased hepatic gluconeogenesis and increased insulin sensitivity in target cells (loss of stimulus for glucagon release) |
|
|
Term
| What conditions are associated with hypoglycemia secondary to decreased insulin antagonists? |
|
Definition
hypoadrenocorticism (cortisol is a major stimulus for glucagon secretion)
Hypopituitarism (decreased secretion of growth hormone (normally inhibits insulin mediated uptake of glucose in adipose and muscle) and decreased secretion of ACTH --> cortisol (loss of stimulus for glucagon production)
**despite these mechanisms hypoglycemia is an uncommon problem in animals with hypopituitarism |
|
|
Term
| What conditions are associate with hypoglycemia as a result of decreased gluconeogenesis? |
|
Definition
hepatic insufficiency
hypoadrenocorticism (loss of cortisol)
neonatal/juvenile in toy breed dogs
starvation (depletion of lipid, protein and other metabolites necessary for gluconeogenesis, these animals will be emaciated) |
|
|
Term
| What conditions are associated with hypoglycemia as a result of increased glucose utilization? |
|
Definition
lactational hypoglycemia (spontaneous bovine ketosis)- mammary demand for glucose exceeds capacity of hepatic gluconeogenesis --> increased fatty acid metabolism and ketosis
Excertional (hunting dogs, endurance horses): Muscle glycolysis consumes glucose faster than it can be replaced by glycogenolysis or gluconeogenesis*
*short strenuous exercise is typically associated with hyperglycemia due to catecholamine release |
|
|
Term
| What non-beta-cell neoplasms have been associated with hypoglycemia? |
|
Definition
leiomyoma(sarcoma), hepatocellular carcinoma, renal carcinoma*
*mechanisms are unclear, may be associated with release of insulin-like substance, excessive glucose utilization by neoplastic cells, or liver disfuction (hepatocellular carcinoma or metastatic neoplasia) |
|
|
Term
| Describe the pathogenesis of hypoglycemia in sepsis* *keeping in mind initial response to endotoxin is insulin resistance so septic patients may be hyperglycemic |
|
Definition
Increased tissue utilization of glucose: -decreased tissue perfusion --> anaerobic glycolysis, which requires more glucose to generate ATP than oxidative phosphorylation
-WBC in the inflammatory response also consume glucose (insulin independent)
-Decreased hepatic glucongeogenesis due to acidosis and decreased delivery of precursor molecules
**if there are numerous bacteria (e.g. pyothroax) glucose utilization by bacteria may contribute (esp. in cavitary effusions) |
|
|
Term
| T/F ketotic hypoglycemia sometimes develops in late term pregnancy in dogs |
|
Definition
| true pathogenesis is unknown |
|
|
Term
| What enzyme deficiency in maltese dogs has been associated with hypoglycemia? |
|
Definition
Malonyl-coenzyme A decarboxylase deficiency
hypoglycemia is likely the result of decreased gluconeogenesis because malonyl-COA affects the function of pyruvate carboxylase (involved in gluconeogenesis) |
|
|
Term
| How do sulfonyluruea compounds (glipizide and glyburide) contribute to hypoglycemia? |
|
Definition
| aka oral hypoglycemic agents: these drugs directly stimulate insulin secretion and improve cellular responses to insulin |
|
|
Term
| How does ethanol contribute to hypoglycemia? |
|
Definition
| ethanol oxidizes --> NADH, when there is excessive ethanol the increased ratio of NADH:NAD inhibits gluconeogenesis |
|
|
Term
| What problems in management of a diabetic patient can be identified using a glucose curve? |
|
Definition
insufficient insulin dose (nadir is not low enough (>145) and BG just before insulin administration is too high (>180))
Too short insulin effect
Overlap of insulin effect between doses
Somogyi (excessive insulin dose causes hypoglycemia --> stimulates glucagon, epinephrine and cortisol release --> hyperglycemia that cannot be antagonized due to decreased concentration or functionality of endogenous insulin) |
|
|
Term
|
Definition
ketoamines that are formed by post translational irreversible non enzymatic linking of glucose to albumin and other plasma proteins (mostly IgG)
Half life is ~2-3 weeks but varies by species and pathologic state |
|
|
Term
| Describe the methodology of the fructoasmine assay |
|
Definition
nitroblue tetrazolium assay: In an alkaline medium fructosamine acts as a reducing agent to generate formazine, which is detected spectrophotometrically**
**other reducing agents in serum can cause positive interference. An enzymatic assay was 3-4x lower when compared with the nitroblue tetrazolium assay |
|
|
Term
| What endocrinopathy other than DM has been associated with increased [fructosamine] in dogs? |
|
Definition
hypothyroidism
These animals were normoglycemic, [fructosamine] decreased after starting thyroid hormone supplementation |
|
|
Term
| What conditions have been associated with decreased [fructosamine] |
|
Definition
insulinoma
hypoproteinemia/hypoalbuminemia
hyperthyroidism in cats (this is counterintuitive because hyperthyroid cats can be hyperglycemic due to insulin resistance and impaired insulin secretion....) |
|
|
Term
| Why is the correlation between [albumin] and [fructosamine] relatively poor? |
|
Definition
at lower [albumin], albumin catabolism is decreased, hence circulating lifespan is increased resulting in greater glycosylation per mole of albumin
**forumlas to correct [fructosamine] for hypoalbuminemia/hypoproteinemia have not proven to increase diagnostic value of [fructosamine] for diabetes in dogs |
|
|
Term
| What are the ultimate products of insulin processing from preproinsulin? |
|
Definition
| preproinsulin is made by beta cells --> quickly cleaved to proinsulin and stored in golgi -> stimulus for insulin secretion (hyperglycemia) results in cleavage of proinsulin involving some Ca regulated enzymes to insulin, C-peptide, and split peptides |
|
|
Term
| Why is immunoreactive insulin the preferred terminology for the serum insulin assay? |
|
Definition
| because it measures both proinsulin and insulin AND because it reports values in immunoreactive units of insulin NOT biologically active units of insulin (e.g. injectable) |
|
|
Term
| What is the major assay methodology for immunoreactive insulin? |
|
Definition
radioimmunoassay kits
**chemiluminescent and ELISAs are also available
They are developed for porcine or human insulin and react with canine insulin but have not been validated for other species |
|
|
Term
| What is the effect of sample type on IRI (immunoreactive insulin) assay |
|
Definition
EDTA plasma can falsely increase values in some assays
serum or heparinized plasma are sample of choice |
|
|
Term
| How do anti-insulin antibodies develop in a patient, and how might their presence impact IRI (immunoreactive insulin) assays? |
|
Definition
| Anti-insulin antibodies can develop either from spontaneous pathologic processes or insulin therapy, their presence can falsely increased OR decrease IRI results in some assays |
|
|
Term
| In what conditions would fasting [immunoreactive insulin] be decreased? |
|
Definition
Diabetes mellitus (type 1 decreased insulin due to destruction of beta cells, type 2- when advanced amyloidosis also damages beta cells with resultant decreased insulin production)
Hypoglycemia not associated with increased insulin secretion (e.g. decreased gluconeogensis [hepatic failure]/glycogenolysis [glycogen storage diseases], increased glucose utilization [lactational, excertional] etc.) |
|
|
Term
| What is the equation for the IRI:glucose and how should it be interpreted? |
|
Definition
IRI:G= [IRI] x 100/ [glucose]
**reference intervals must be established anew for each assay and at each laboratory due to lack of analytical agreement between assays and laboratories |
|
|
Term
| How should you interpret and increased IRI:glucose in a hypoglycemic animal? |
|
Definition
| hypoglycemia is due to increased insulin secretion e.g. insulinoma |
|
|
Term
| How should you interpret and increased IRI:glucose in a normoglycemic or hyperglycemic animal? |
|
Definition
This may indicate insulin resistance
**has been shown to be a reliable method of assessing insulin resistance in cats |
|
|
Term
| How would you interpret a normal/WRI IRI:glucose in a hypoglycemic patient? |
|
Definition
| Hypoglycemia is not associated with increased insulin secretion |
|
|
Term
| How would you interpret a decreased IRI:glucose in a patient with hyperglycemia? |
|
Definition
| this confirms insulin deficiency which could be due to beta cell damage or glucose toxicosis (i.e. insulin secretion is reduced due to prolonged hyperglycemia, which could be secondary to insulin resistance, drugs like glucocorticoids and exogenous progestogens) |
|
|
Term
| What in vivo factors may further complicate interpretation of [IRI], other than assay variation? |
|
Definition
substances other than glucose can affect insulin release from beta cells (e.g. growth hormone, glucagon, amino acids)
much of insulin that is release by the pancreas is removed from portal blood by hepatocytes but peripheral blood is sampled for the assay |
|
|
Term
| T/F the amended IRI:G ratio (subtract 30 mg/DL from [glucose]) should NOT be used |
|
Definition
True
**this was based on a theory in people, that at [glucose < 30 serum [insulin] would be zero. This has not been confirmed in people, has never been evaluated in animals. DO NOT USE |
|
|
Term
| What is the major physiologic role of glucagon? |
|
Definition
| maintain plasma [glucose] during fasting |
|
|
Term
|
Definition
GLP-1 is a peptide hormone related to glucagon, it's release from L cells (large granule cells) in the intestine after feeding stimulating insulin release and minimizing postprandial hyperglycemia
**GLP-1 cross reacts with some immuno assays for glucagon |
|
|
Term
| What is proglucagon and where is it produced? |
|
Definition
The precursor molecule for glucagon and GLP-1, it is produced by pancreatic alpha cells, intestinal L cells, and the parasympathetic nucleus of the vagus nerve
**a variety of other factors determine cleavage into glucagon (pancreas), GLP-1 (intestine) and other GLPs |
|
|
Term
| Is IRG specific to pancreatic glucagon? |
|
Definition
| In some assays there can be cross reactivity with intestinal GLP-1, so the assay should be called glucagon-like immunoreactivity |
|
|
Term
| What analytical factors must be considered when using IRG (glucagon-like immunoreactivity)? |
|
Definition
Stability varies in different species but is generally thought to be quite unstable in blood. The sample (EDTA blood) should be cooled in an ice bath and a protease inhibitor added, plasma is then separated, frozen at -20, and protected from light
**arginine can falsely increase [IRG] which is a problem because arginine was use to stimulated glucagon secretion in IRG validation assays |
|
|
Term
| What underlying diseases have been associated with superficial necrolytic dermatitis in animals? |
|
Definition
Hepatic disease
rarely, glucagonoma (this is a more common cause in people) |
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