Pancreas anatomy and physiology

Describe the location of the pancreas

• one part along the greater curvature of the stomach, other part cranial to the duodenum

What is the exocrine function of the pancreas?

• digestive enzymes - in response to GI hormones

• bicarbonate to neutralise stomach acid → response to secretin

What are the 3=6 digestive enzymes produced by the pancreas?

1. trypsin and carboxypeptidase → proteins/peptides

2. lipase

3. amylase

4. phospholipase

5. ribonuclease

6. deoxyribonuclease

What are the 3 cells with endocrine function in the pancreas? What are their relative proportions?

1. beta - insulin

2. alpha - glucagon

3. delta - somatostatin

In order of percentage (60-70% beta, 20-25% alpha, 10% delta)

Outline somatostatin:

1. where is it produced

   1. paracrine function

1. hypothalamus (PVN), stomach, intestine, pancreas

2. suppresses insulin and glucagon secretion from beta and alpha cells

Outline insulin:

1. type of hormone

2. secreted by?

3. synthesis chain

1. peptide

2. beta cells

3. preprohormone → prohomone, proinsulin - > insulin

How is proinsulin stored?

• intracytoplasmic - ready to be released quickly when needed

What must be removed from proinsulin to activate insulin?

• C-peptide

Outline insulin structure:

1. chains

2. connection

1. 2 chains: alpha and beta

2. two disulphide bonds

Outline how insulin is degraded - 2 ways

1. liver/kidney via cleavage of 2 disulphide bonds

2. within target cells after receptor binding

Outline C-peptide and secretion:

1. what is it

2. how is it released

3. active?

4. what do we measure it for

1. connecting peptide for insulin

2. equal amounts to insulin

3. biologically inactive → removed at a slower rate

4. pancreatic function: if we have insulin but no C-peptide, tells us it’s injected, not self-produced insulin

Outline insulin kinetics:

1. half life

2. where does it enter into circulation?

3. first organ it acts on?

4. C-peptide in liver?

1. 5-8 mins

2. veins → portal system

3. liver → general circulation

4. not removed

3 methods of insulin secretion

1. glucose and amino acids

2. GI hormones (GIP and GLP-1)

3. ANS: PNS and SNS

Insulin:

1. results in what process (building or breaking?)

2. method of release from beta cells

3. overall purpose

1. anabolic

2. calcium-mediated exocytosis

3. energy → storage

How do GI hormones trigger insulin release?

1. increase in concentration of GIP and GLP-1 when food reaches intestine → insulin release (in advance of absorption)

Outline how the PSNS affects insulin release

1. increased PSNS → insulin secretion

2. via vagus nerve

3. vagus nerve increases GI motility and digestion

4. higher insulin secretion after feeding

Outline how the SNS affects insulin release

1. direct innervation

2. indirect response via adrenaline

3. stress response - hyperglycaemia

4. insulin secretion is inhibited (as well as its action)

What is meant by:

1. first phase insulin release

   1. second phase?

1. insulin released from its vesicles in response to a stimulus

2. active production of insulin by beta cells in pancreas to maintain levels required according to stimulus

How does insulin release from beta cells work?

1. increased blood glucose

2. GLUT-2 transporters allow glucose to enter

3. phosphorylation of glucose

4. ATP production

5. ATP inhibits potassium channel (drug target)

6. increased K+ intracellularly → depolarisation

7. VG Ca2+ channels open

8. influx of Ca2+ triggers insulin exocytosis

Is insulin always needed to promote glucose uptake?

NO

• insulin dependent cells don’t need insulin receptor for glucose uptake

• insulin dependent cells need it

What type of hormone is insulin?

water soluble

What transmission pathway does insulin use?

• tyrosine kinase

what is a determinant of insulin sensitivity in a cell

density of receptors

Outline GLUT-4 receptor:

1. what does insulin stimulate

2. what are GLUT-4 proteins?

3. what are two main tissues we find this occur in

1. translocation of GLUT4 to membrane

2. insulin-responsive glucose transporters

3. muscle and adipose tissues

Outline these 3 transporter types and where we find them:

1. GLUT-1

2. GLUT-2

3. GLUT-4

1. insulin independent glucose transport - CNS, RBC

2. facilitated insulin independent glucose transport - liver, islet glucose sensor

3. insulin-dependent glucose transport - muscle and fat

What are the 3 macronutrients insulin acts on and what 4 main organs

1. carbs, protein and fat

2. liver, brain, muscle, fat

How does insulin act in muscle

1. promotes glucose uptake

2. increases glycogenesis

Outline insulin influence in the liver:

1. what transporter takes up glucose

2. what does it inhibit

3. what does it promote

1. GLUT-2

2. glycogen phosphorylase (glycogenolysis) and gluconeogenesis

3. glycogen synthase (glycogenesis) and lipogenesis

What glucose transporter do we find in the brain, what is the exception?

1. GLUT-1: based on conc gradient, no insulin involvement

2. EXCEPT in the satiety centre

Why do we see increased hunger in diabetes mellitus?

• insulin doesn’t trigger satiety centre in brain → appetite increase

Insulin and fat metabolism:

1. inhibits

2. stimulates

3. promotes?

1. hormone sensitive lipase (HSL) → decreases lipolysis

2. de novo lipogenesis

3. lipoprotein liipase → increases delivery of fatty acid into tissues

How does excess glucose → fat precursor?

1. glucose → increased TCA cycle intermediates (citrated)

2. activate acetyl CoA carboxylase (ACC)

   1. malonyl CoA (fat precursor) produced

Insulin and protein metabolism:

1. increases

2. inhibits

3. depresses?

1. amino acid uptake by tissue, rate of transcription and translation

2. catabolism of proteins

3. rate of gluconeogenesis within liver - inhibiting enzymes and lowering supply of aas from tissues

Outline glucagon:

1. cells secreted by?

2. structure

3. preprohormone?

4. half-life

5. metabolised where?

1. alpha cells in Islets of Langerhans

2. 29 aas

3. preproglucagon

4. 5-6mins

5. liver and kidneys

Glucagon actions:

1. builds or breaks?

2. primary site of action

3. responds to what?

4. what ratio determines actions?

5. what do alpha cells respond to?

1. catabolic

2. liver

3. glucagon increasing in conc, insulin decreasing in conc

4. insulin: glucagon

5. low blood glucose level

Glucagon and the liver:

• function

• when is it activated?

• stimulates?

1. maintains blood glucose levels in the inter-prandial period

2. during negative energy balance (starvation)

3. glycogenolysis, gluconeogenesis

How is glycogen converted into glucose?

1. Glycogen is phosphorylated (ATP→ AMP), glycogen phosphorylase enzyme
   → glucose 1-phosphate → glucose 6-phosphate → glucose

how is glucose converted into glycogen by insulin?

1. glucose → glucose—6-phosphate → glucose-1-phosphate → UDP, glycogen synthase → glycogen

Outline glucagon secretion

1. inhibited by high glucose levels, decrease → glucagon secretion increases

2. stimulated by high amino acid levels (alanine and arginine are most important) → gluconeogenesis

what does glucagon protect from?

• post-prandial hypoglycaemia

• maintains glucose levels, especially after protein-rich meal (insulin is released), otherwise low blood glucose would occur

Fill in the table

What is meant by hormonal antagonism?

• two hormones that have opposing effects e.g. insulin and glucagon

• importance in recognising, both can be present and have different effects - the ratio affects the outcome

Outline diabetes mellitus:

1. what is it described as?

2. how does it affect tissue use of different micronutrients?

3. what affect does it have on other organs?

4. result in the blood?

1. relative/absolute insulin deficiency

2. decreased tissue utilisation of glucose, increased utilisation of aas and fatty acids.

3. increased hepatic glycogenolysis and gluconeogenesis

4. hyperglycaemia → glucose accumulates in circulation

What are the two types of diabetes mellitus?

1. Type 1 - immune-mediated or idiopathic

2. Type 2 - insulin resistance w. relative deficiency

What causes type 1 diabetes?

• beta-cell destruction → usually absolute insulin deficiency

What are other potential causes of diabetes mellitus (not type 1/2)

• diseases of exocrine pancreas

• endocrinopathies: cushing’s, acromegaly, phaeochromocytoma, glucagonoma, hyperthyroidism

• genetic defects, drug/chemical induced or infections

How do these diagrams represent type 1 diabetes?

1. normal levels on insulin, some naturally occurring resistance to insulin (brown) and normal glucose levels

2. damage leading to less insulin. For a time, the body can cope and insulin works overtime

3. Insulin levels are too low, blood glucose increases - no control. The liver also starts producing more glucose → increases levels even further (not inhibited by insulin)

Outline how these diagrams represent type 2 diabetes

1. too much insulin and an increased resistance in the tissues, glucose levels are under control.

2. due to increased resistance to insulin, more is produced → more resistance. This causes glucose levels to increase

3. Insulin is no longer effective and cannot be produced (almost become type 1 diabetic), almost total tissue resistance, no blood glucose control → glucotoxicity

What does glucotoxicity effect?

• Beta cell function

What 7 hormones/states can lead to glucose toxicity (think type 2 diabetes)

1. progesterone/agen

2. growth hormone

3. glucocorticoids

4. glucagon

5. catecholamines

6. thyroid

7. obesity

What are potential sites of dysfunction/causes of dysfunction as a result of glucose toxicity that can lead to diabetes mellitus (5)

1. pancreatectomy

2. pancreatitis

3. auto-immunity

4. islet cell hypoplasia

5. chemical toxicity

What are some causes of insulin resistance?

Physiological:

• pregnancy, stress

Pathological

• obesity

• hereditary

• concurrent disease

• endocrinopathies - hyperadrenocorticism, acromegaly (GH excess)

Outline how insulin resistance can lead to diabetes

1. insulin resistance - compensated by extra insulin

2. IR → uncompensated (insufficient even if extra insulin)

• e.g. obese horses

3. Type 2 diabetes mellitus (NIDDM)

In which species do we tend to find type 2 diabetes mellitus?

• most cats

• rare in horses (may be present in late stage PPID)

Physiologically, how does uncompensated IR lead to diabetes mellitus?

• islet failure/glucotoxicy and hyperglycaemia → glucosuria and PU/PD

For diabetes mellitus in dogs, outline the most common causes

1. genetic suceptibility (consider different species in different countries that are more prone than others)

2. immune mediated destruction beta cells

3. pancreatitis with beta cells destruction

4. obesity-induced insulin resistance

5. insulin-antagonistic disease/conditions → cushing’s, met/dioestrus

6. insulin-antagonistic drugs - glucocorticoids

What is the pathogenesis for these developments of canine diabetes mellitus:

1. immune-mediated destruction of Beta cells

2. pancreatitis with beta cell destruction

1. Autoantibodies against insulin and/or beta cells OR progressive decrease in glucose-stimulated insulin secretion

2. spontaneous inflammation

How may insulin antagonism lead to canine DM?

• specific hormones antagonise insulin action

  • cortisol and GH → induce peripheral insulin resistance

State 5 counter regulatory hormones

1. cortisol (hyperadrenocorticism)

2. GH

3. catecholamines

4. glucagon

5. progesterone

For each of these hormones, state what they can cause which in turn may lead to DM?

1. cortisol (hyperadrenocorticism)

2. GH

3. catecholamines

4. glucagon

5. progesterone

1. hyperadrenocorticism - spontaneous and iatrogenic

2. acromegaly

3. phaeochromocytoma

4. glucagonoma

5. dioestrus/gestation (these lead to a surge in GH production, in turn risking acromegaly formation)

For cats, state 6 common causes of diabetes mellitus

1. obesity/diet-induced insulin resistance

2. islet amyloidosis

3. pancreatitis

4. insulin-antagonistic drugs

5. insulin-antagonisti disease (acromegaly)

6. genetics

Why do we obesity related insulin resistance in cats?

• high carbohydrate diet → glucose toxicity

• cats can cope with a higher level of blood glucose before insulin is released, if this is constantly high, we result in DM

Define insulin resistance

• diminished ability of cells to respond to the action of insulin in transporting glucose from the blood into tissues

Why does obesity lead to insulin resistance?

1. inadequate number of insulin receptors

2. defective insulin receptor structure

3. cell signalling pathway

4. defective GLUT-4 transport proteins

5. problems with translocation of GLUT-4 to membrane

6. interference with function of GLUT-4

What is amylin

• co-secreted with insulin by feline beta cells

• it’s deposited in islets by amyloid

What is the issue with amyloid fibrils?

• cytotoxic → apoptosis of islet cells → defective insulin secretion

• if it’s progressive deposition → diabetes mellitus

when does chronic increased amylin secretioin occur in felines?

• obestiy

• insulin resistant states

• consequence of chronic hyperglycaemia/glucose toxicity

Can we reverse glucotoxicity?

• yes, initially

• may not be after prolonged periods of time

Outline the pathway from obesity → islet destruction in cats

1. obesity, insulin resistance

2. increased insulin secretion

3. increased amylin co-secretion

4. progressive amyloid deposition in islets

5. islet destruction

With felines and type 2 DM

1. is it always the case with cats

2. is it always reversible?

1. no

2. no - often when they present, they’ve been hyperglycaemic for so long, they’re closer to being type 1 diabetic (due to beta cell destruction, think about amylin production)

Insulin-dependent diabetes mellitus: IDDM

• how common in dogs and cats?

• treatment?

• almost 100% dogs, 50-70% cats

• permament insulin deficiency, therefore needs exogenous insulin

Non-insulin dependent diabetes mellitus (NIDDM)

• in cats?

• in dogs?

1. obesity/diet induced insulin resistance

2. insulin - antagonism, drugs - glucocorticoids, progestogens, conditions e.g. dioestrus

Outline equine metabolic syndrome:

1. strong link to…?

2. primary disorder is?

3. most common clinical sign?

4. what do we see high levels of?

1. obesity/regional adiposity

2. insulin resistance

3. laminitis

4. insulin and glucose

What are the 4 stages of diabetes presentation?

1. polyuria

2. polydipsia

3. polyphagia (remember, satiety centre won’t be suppressed)

4. weight loss

For diabetes mellitus and hyperglycaemia:

1. canine blood glucose

2. feline blood glucose

3. general guidline?

1. >10-12.2mmol/L

2. >11 to 15.5mmol/L

3. >10mmol/L

What is the physiological description of the cause of polyuria associated with DM

• osmotic diuresis

Why do we see weight loss with diabetes mellitus

• insulin:glucagon ratio falls → starvation process promoted

• continuous inter-prandial period (mobilised stores, catabolic)

• amino acids used for gluconeogenesis

• increased protein breakdown → muscle wasting

Why can we see cataract formation with DM?

• glucose uptake into lens

  • normally - metabolised into lactate, which diffuses out

• glucose → fructose → sorbitol (doesn’t diffuse)

• trapped → water drawn in

Outline ketoacidosis

• unbalanced insulin:glucagon

• shift to fat metabolism for energy

• more fatty acids used produces ketones (ketoacids)

• ketones build up → metabolic acidosis

What clinical signs will we see with keoacidosis?

• vomiting

• diarrhoea

• anorexia → contribute to dehydration

What may a blood glucose between 5.5 and >10mmol/L

• pre-diabetic

What is feline stress-induced hyperglycaemia

• stress induced cortisol and catecholamines and hyperglycaemia

• usually NO glycosuria unless prolonged stress

  • need to recheck urine in a non-stressed environment

How can we diagnose using fructosamine?

• glycosylated serum proteins (albumin)

• non-enzymatic reaction: proportional to blood glucose concentration

• reflects previous 2-3 weeks of blood glucose

• above 400umon/L = orolonged period of high glucose

What level of fructosamine confirms DM?

• >400umol/L

What lab abnormalities may be associated with DM?

• hypercholesterolemia

• hypertriglyceridemia

• visible lipid in serum/plasma (due to mobilisation of fatty acid from adipose tissue)

• hepatic lipidosis (increased liver enzymes)

what will we excpect in urinalysis of DM?

• USG often >1.025

• glucose

• +_ ketones

• UTI: wbc, rbc, bacteria and proteins