L3 pancreas Flashcards
Endocrine Physiology:The Endocrine Pancreas
Cells Type –> ALpha A, Beta B, Delta D, F or PP
Anatomy of endocrine pancreas
Insulin
Consists of 2 chains, A and B, connected by disulfide bridges
Small differences in aa sequence between species
Feline similar to bovine, canine similar to human and identical to porcine in aa sequence
Synthetic human insulin produced through recombinant technology
Also available for injection are beef and pork insulin and a mixed beef/pork combo
Insulin metabolism
Biphasic:
Acute initial response is secretion of preformed insulin
Chronic phase response is synthesis and subsequent secretion of insulin
Enzymes in kidneys and liver metabolise insulin by breaking disulfide bonds, splitting A and B chains
Insulin half-life ~10 minutes
Insulin formulations
Pig ‘natural’ insulin
Synthetic insulin
Injectable insulin formulated to slow release;
different formulations to give choice of how long the insulin lasts:
rapid-acting
short-acting
intermediate-acting
long-acting
ultra long-acting
mixed insulins which may have immediate and more long term effects
Ranges
Starts to work: 15min to 4hrs
Peaks: 30min to 8hrs
Lasts: 3hrs to 42hrs
Metabolic functions of insulin
The main metabolic functions of insulin are anabolic:
promotes the utilization of glucose for energy
conversion of glucose to glycogen
Conversion of fatty acids to triglycerides
Conversion of amino acids to proteins
Acts on a number of sites within metabolic pathways of CHOs, fats and proteins
Liver important
Increases blood flow to muscle and adipose tissue (mediated by action on endothelium to produce NO and cause vasodilation)
Counteracted by increased FA’s as part of the glucose/fatty acid regulatory cycle
Lowers blood glucose
Site of action of insulin
Glucose transport across cell membranes
Insulin is probably best known for its involvement in glucose transport (across cell membranes)
Glucose does not readily penetrate cell membranes
Requires glucose transporters (GLUT) in cell membranes (>12 different types)
There are 4 main GLUT transporters (Glut 1 – 4) and only one of these requires insulin to cause them to facilitate diffusion of glucose
Glut 1
Widely distributed in foetal tissues
Highly expressed in erythrocytes
no mitochondria
need lots of glucose for ATP production from ‘anaerobic respiration’ (glycolysis)
Responsible for low level of basal glucose uptake to sustain cellular respiration in all cells
Upregulation with reduced glucose levels and downregulation with increased glucose levels
Upregulated in many tumours
Glut 2
Bidirectional transporter
Expressed by renal tubular cells (transport reabsorbed glucose out of prox tubule cells), liver cells and pancreatic β cells, as well as enterocytes in the small intestine
Bidirectionality required in liver cells to uptake glucose for glycogenesis, and release of glucose during gluconeogenesis.
In pancreatic β cells, free flowing glucose is required so that the intracellular environment of these cells can accurately gauge the serum glucose levels.
GLUT 1 vs GLUT2 vs passive diffusion graph
GLUT 3
Expressed mostly in neurons and in the placenta
High affinity for glucose so able to transport glucose even when glucose levels are low (hypoglycaemia)
Neurons cannot store glucose (make glycogen) and need a constant supply of glucose to function
Brain energy supply
Brain cells mainly utilise Glut1 and Glut3 transporters
Whilst neurons do not store energy in the form of glucose, astrocytes (neuron support cells) do.
During periods of high demand or hypoglycaemia, astrocytes metabolise intracellular glycogen stores to produce lactate as a source of energy for surrounding neurons
Glut4 transporters have been reported in neurons in cerebral motor areas
supports its suggested role in providing the energy needed for the control of the motor activity
Glut 4
GLUT 4 found in striated muscle cells and adipose cells
Is the insulin-regulated glucose transporter
Responsible for insulin-regulated glucose storage in adipocytes and skeletal muscle fibres
When insulin levels are low, most GLUT 4 is sequestered inside the cell in intracellular vesicles
When insulin binds to the receptors on the cell surface, 2nd messengers cause the fusion of the vesicles to the plasma membrane and glucose can be transported down its concentration gradient
https://www.youtube.com/watch?v=FkkK5lTmBYQ (+1min45sec)
Adipose or skeletal muscle cell
In muscle and adipose tissue, cells are not usually permeable to glucose
When insulin is present and binds to its receptor, it triggers a signal transduction cascade which moves GLUT 4 to the cell surface where GLUT 4 transports glucose into the cell.
Insulin receptor
Insulin receptors
Transmembrane proteins
Belong to a large class of tyrosine kinase receptors (add phosphate groups to other proteins/enzymes)
activated by insulin and also by IGF-I and IGF-II
α and β subunits come together in a heterodimer
does insulin just signal glucose homeostasis
Insulin: summary of actions on carbohydrates (3)
- Stimulates glucose uptake (mediated by GLUT4) by striated muscle and adipose tissue
- Stimulates glycogenesis in liver & skeletal muscle & glycolysis in muscle and adipose tissue
- Inhibits glucose production (gluconeogenesis and glycogenolysis) in liver
Overall insulin decreases blood glucose by promoting uptake by cells (utilisation & storage) whilst blocking 2 mechanisms by which liver increases glucose into blood
Control of insulin secretion
Most important factor is concentration of blood glucose
High blood glucose stimulates insulin secretion (via GLUT2 in pancreatic β cells)
A number of GIT hormones stimulate insulin secretion (incretins):
Gastrin, Cholecystokinin, Secretin
GLP (glucagon-like peptide) – analogues used for treatment of type 2 DM
Other stimulatory factors include presence of aa’s and fa’s in intestines, glucagon, ACh (ANS)
Inhibitory factors include catecholamines (adrenaline and noradrenaline) and somatostatin (GHIH) (from pancreas, not hypothalamus)
Classification of diabetes
Diabetes is classed as one of 4 types, depending on cause:
Type 1
Type 2
Gestational/ dioestrus
Other specific types (e.g. due to pancreatitis or XS glucocorticoids)
Type 1 diabetes
Immune-mediated destruction of β cells
50% DM in dogs
Patients are insulin-dependent
This is an insulitis of an islet of Langerhans in a patient who will eventually develop type I diabetes mellitus. The presence of the lymphocytic infiltrates in this oedematous islet suggests an autoimmune mechanism for this process.
Type 2 diabetes
Insulin resistance -> hyperinsulinaemia Obesity-related Glucose toxicity will cause β-cell failure -> diabetes Most common form in humans and cats Rare in horses, very rare in dogs
Pre-diabetes
Elevated blood glucose without any symptoms (yet!)
Fat cats with elevated BG (above normal but not in diabetic range) – test BG levels for obese cats, especially Burmese
Not likely to have glucose in urine (otherwise would be seeing clinical signs)
BG elevated due to stress often puts cats in the prediabetes range (stress hyperglycaemia)
Consider home monitoring
Gestational/dioestrous associated diabetes
Progesterone is produced during the luteal phase of the bitch’s oestrus cycle and induces the production of growth hormone by the mammary glands.
Growth hormone generally counteracts insulin action.
Other causes of diabetes
Cause β-cell destruction OR insulin resistance
Destruction
Pancreatitis – about 30% dogs
Maybe associated with EPI (exocrine pancreatic insufficiency)
Marked insulin resistance
Hyperadrenocorticism (Cushing’s) – about 5-10% develop DM
Acromegaly (GH xs) – very rare cause in dogs
“About 10% of canine Cushing’s disease cases are complicated by diabetes mellitus.”
Why glycosuria?
Persistant high blood glucose (>12 mmol/L) exceeds renal capacity to reabsorb glucose
Weight loss & hyperlipidaemia
Catabolism (increased lipolysis and protein degradation) as no longer under influence of insulin
Catabolism as an energy source due to loss of glucose in urine
Reliance on fat metabolism
Weight loss & hyperlipidaemia
Catabolism (increased lipolysis and protein degradation) as no longer under influence of insulin
Catabolism as an energy source due to loss of glucose in urine
Reliance on fat metabolism
Hypoglycaemia
Need to maintain glucose within a narrow range 3.3 – 6.5 mmol/L, through the actions of both insulin and glucagon
Hypoglycaemia leads to confusion, seizures, coma
Neurons have no glycogen stores to fall back on
Consequence of excess insulin (insulinoma or, more commonly, insulin-treated diabetic)
Why is glucose homeostasis important?
