the endocrine pancreas & carbohydrate metabolism

8/2/2019 The Endocrine Pancreas & Carbohydrate Metabolism

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The Endocrine Pancreas:

Although the pancreas is 98% exocrine it also does have 2% endocrine function.

The islets of langerhans are responsible for this endocrine function. The islets are composed of

alpha and beta cells.

- Core of B cells

- Alpha cells on periphery

- Juxtaposition of endocrine cells facilitates cell cell communication. This communication

is paracrine i.e. hormonal or via gap junction coupling i.e. electrochemical.

- The structure of the islet allows tight coupling between insulin and glucagon secretion in

relation to plasma glucose

Cell types

Α cells (20%) secrete glucagon

Β cells (70%) secrete insulin

Delta cells (8%) secrete somatostatin in response to decreased GH in the hypothalamus

Pp cell (1%) secrete pancreatic polypeptide

Epsilon cells (1%) secrete ghrelin in response to increased GH

Islet vasculature



- The vasculature of the islets flows from core to mantle involving fenestrated capillaries.

- This radial blood flow to the periphery facilitates paracrine regulation of glucagon

secretion by insulin (from B cells)

Innervations

- Innervated by both branches of ANS

- Sympathetic = splanchnic…have a variable effect on a and B cell hormone secretion.

A2 adrenergic activation results in decreased insulin and increased glucagon secretion.

B adrenergic activation results in increased insulin secretion.

- Parasymp = vagus…stimulate insulin and glucagon secretion via muscarinic receptors

- Many peptidergic neurons – somatostatin, vasoactive intestinal peptide, calcitonin gene

related peptide

Insulin:

Synthesis:

Preproinsulin

Processed to mature insulin (and C peptide) in golgi apparatus and secretory granules

Enzymes: prohormone convertase 1, 2, 3, carboxypeptidase E cleaves basic aa from C terminus

Proinsulin (<10% bioactivity of insulin)

B cell glucose sensing and insulin secretion

- glucose binds to heteroligomeric insulin receptors stimulating autophosphorylation of

the receptor

- Leads to phosphorylation of the docking proteins IRS1/2

- These proteins are coupled to mitogen activated protein (MAP) kinase and

phosphoinositol 3 (PI3) kinase signaling cascades

- Leads to translocation of the vesicles containing GLUT4 glucose transporter to the

plasma membrane, facilitating glucose uptake by target tissues

- Taken into the B cell through the membrane bound GLUT2 transporter

- Phosphorylated to glucose-6 phosphate by glucokinase to induce glycolysis

- Metabolized to produce ATP



- ATP binds to and inactivates K+ channel

- Membrane depolarization and opening of voltage dependent Ca++ channels

- Increase in intracellular Ca++ triggers exocytosis of the insulin from secretory granules

- Sulphonylurea drugs act at this ATP sensitive potassium channel

-

Insulin is stored in vesicles and released by exocytosis

Regulation of insulin secretion

Direct

Nutrients – glucose, amino acids and fatty acids increase secretion

Neural – sympathetic activity decreases secretion, parasymp increases secretion

Hormonal – gastric inhibitory peptide, glucagon like peptide increase secretion, somatostatin

decreases secretion

Indirect – any agent which influences blood glucose levels

Insulin secretion is biphasic. 98% secretion is stimulated while 2% is basal secretion.

1st

phase – corresponds to the exocytosis of docked granules

2nd

phase – requires mobilization from a reserve pool



Metabolic action

Glucagon

- Synthesized as precursor or processed in extrapancreatic tissue to generate glucagon

like peptide (GLP) and other glucoregulatory peptide hormones

- Stimulus to secretion is decreased blood glucose levels i.e. less than 5mM

- Its actions oppose that of insulin

Regulation of secretion

Direct..

Nutrients – low glucose and amino acids (arginine) stimulate secretion. High glucose inhibits

glucagon secretion in presence of insulin. Fatty acids inhibit secretion

Hormones – gastrointestinal hormones: GIP or cholecystokinin are stimulatory, GLP-1 or

somatostatin are inhibitory. Islet hormones insulin and somatostatin are inhibitory.

ANS – activation of sympathetic and parasymp stimulate secretion

Metabolic actions

- It is a counter regulatory hormone that opposes the aactions of insulin.

- It mainly acts on the liver

- carbohydrate metabolism: increases gluconeogenesis and glycogenolysis and decreases

glycogenesis.



- Lipid metabolism: increases ketogenesis i.e. increased fatty acid break down

- Protein metabolism: decreases hepatic protein synthesis and increases breakdown

Pancreatic polypeptide

- 36 amino acid peptide

- Secretion stimulated by

Mixed meal – protein content of meal + protein stimulation

FastingExercising

Acute hypoglycaemia

- Function is not really known but thought to be a satiety factor

Somatostatin

- 14 amino acid peptide

- Synthesized as a prehormone in the pancreas, gut and brain

- Signals via Gia protein coupled receptor & effects are inhibitory



HORMONAL REGULATION OF CARBOHYDRATE METABOLISM:

Glucose:

Storage

- Glycogen is storage form

- Polymeric, highly branched structure

- 10% liver mass, 1-2% muscle mass

- Short to medium term energy reserve – can be rapidly mobilized, NB role in maintaining

blood glucose between meals

- Metabolism is hormonally regulated

as a metabolic fuel

- Yields a significant amount of energy when oxidized

- Efficiently stored

- Can be used by virtually all cells

- Obligatory fuel substrate for the brain…uses 25% of oxidized glucose, neurons cannot

store glucose so need a constant supply

- Sources – diet & glycogen reserves

- After a prolonged period of fasting or intense exercise when these sources are depleted

the body has to have a mechanism to mobilize its reserves and to make its own glucose

de novo



blood glucose levels

hyperglycaemia – supply exceeds demand

normoeuglycaemia – supply and demand matched

hypoglycaemia – demand exceeds supply

euglycaemia is a balancing act between opposing hormonal and biochemical actions

Metabolic fates of glucose



Glycogenesis – making glycogen from glucose for storage

o Stimulated by insulin

o Insulin signals energy abundance

o Activates protein phosphatase 1 which in turn increases glycogen synthase and

decreases glycogen phosphorylase and phosphorylase kinase

o Increased glycogen synthesis and decreased glycogenolysis

Glycogenolysis – breaking down glycogen for energy

- Stimulated by glucagon (from pancreas) and epinephrine (from adrenal medulla)

- Glucagon acts via the Gsα coupled receptor in the liver to increase cAMP and thusincrease PKA

- Epinephrine acts on the B2 adrenergic receptor (Gsα) in muscle to increase cAMP and

Ca++ thus increasing PKA. In liver and adipose tissue it acts on a1 receptor to increase

PIP and Ca++

- Activate GP by activating GPK

- Inhibit GS mediated by PKA



- PKA activates/inhibits key enzymes in glucose/glycogen metabolism

- Opposite effect to insulin

Gluconeogenesis – new glucose from non-carbohydrate sources

- Most active in fasting state, during prolonged exercise and conditions of carbohydrate

starvation

- Livers and a little bit in kidneys

- Pyruvate

- NB so that brain and muscle (unable to make own glucose) can get sufficient glucose to

maintain their metabolic needs

- Brain and muscle supply the metabolic intermediates (raw ingredients) - 7 steps of glycolysis + 3 are replaced



- Hormonal regulation of gluconeogenesis and glycolysis

Glycolysis – breaking down glucose for energy

- Occurs in all cells

- No requirement for O2

- In cytosol

- 10 reactions in 2 phases

Hormonal regulation of fatty acid synthesis:

Acetly CoA carboxylase is rate limiting enzyme

It is a precursor of malonyl CoA. This is a precursor for FA synthesis which works by

inhibiting carnitine acyl transferase I and thus reduces FA entry into mitochondria

ACC is regulated by hormones that control activity of protein kinases and phosphatases

Glucagon (and epinephrine) activates protein kinases which inhibit ACC (& thus

decreases malonyl A levels) – switches lipid metabolism from FA synthesis to oxidation

no more glucose to switch to FAs as an energy source

activate hormone sensitive lipase which hydrolyses triacylglycerols to FAs and glycerol



Insulin activates protein phosphatases with activate/dephosphorylate ACC (so increased

malonyl CoA) – switches lipid metabolism from oxidation to FA synthesis

DIABETES:

A disorder caused by the presence of too much glucose in the blood.

Chronic disorder of carbohydrate, fat and protein metabolism

Characterized by hyperglycaemia, altered metabolism of lipids, ketonuria, carbohydrates and

proteins, increased risk of complications from vascular disease

It is a rising global burden and the number of people with diabetes will double in the next 25

years to reach a total of 366 million.

The link between insulin secreted from the pancreas and diabetes was discovered by Frederick

Banting and Charles Best in 1921.



2 main forms:

Type I and II diabetes have very similar symptoms but have very different causes.

Type 1 = absolute insulin deficiency, unable to produce the insulin signal

Type 2 = relative insulin deficiency with peripheral tissue resistance, do produce insulin but

have lost the ability to respond to the insulin.

However the end result of both is that blood sugar levels become dangerously high.

Other forms include MODY and gestational diabetes

Diagnosis of diabetes

- Random plasma glucose of >11.1 mmol

- Fasting plasma glucose (measures blood glucose in a person who has not eaten anything

for 8 hours) >7.5mmol and/or impaired glucose tolerance



- Symptomatic – frequent urination, blurred vision etc

- Family history

Type 1:

o Accounts for 5-10%

Cause

o Autoimmune destruction of B cells with loss of insulin production

o Thus there is insulin deficiency

o Reduced entry of glucose into peripheral tissues

o Increased hepatic glucose production and release into circulation

o There is an extracellular glucose excess and an intracellular glucose deficiency in many

cells – starvation in the midst of plenty

o Disturbances of carbohydrate, protein and lipid metabolism also contribute to theinsulin deficiency

Genetic and environmental risk factors

- There is linkage to the HLA locus. The DR3 locus increases susceptibility x3, the DR4

locus x4.

- The DR2 locus reduces the risk by >80%

- Environmental triggers include childhood viral infections such as mumps or rubella.



Pathophysiology of Type 1:

Complex metabolic derangements

Hyperglycaemia

Protein breakdown

Ketoacidosis

- Complete insulin deficiency causes unrestrained lipolysis in adipose tissue thus

increasing FA levels

- Increased B oxidation of FAs generates an excess of ACC some of which is diverted from

TCA cycle into ketone body formation

- There can be some spillover into the urine (ketonuria)

- Organic keto acids cause metabolic acidosis at levels of 13mM or more

- Symptoms

Nausea & vomiting, confusion, excessive thirst, headache, acetone on breath, ketonuria,

metabolic acidosis (can lead to coma)

Treatment = insulin replacement therapy

Acts to normalize blood glucose and also to delay the onset of complications

Originally isolated from pigs/cows but now made as a recombinant human protein in bacteria



Oral administration is not successful as insulin is degraded in the GIT

Thus it is usually administered subcutaneously, intravenously or intramuscular.

Main aim is to avoid large fluctuations in the levels of insulin/glucose.

Insulin preparations:

- Best = a mixture of short and medium lasting insulin injected before meals

Type 2:

Etiology

- Genetic susceptibility – polygenic

- Lifestyle risk factors…physical inactivity, obesity (WHO claim that a BMI of <25 would

prevent 64% of type 2 diabetes in US men and 74% in women)

Cause of type 2:

Hepatic Lipotoxicity

- Excess lipid deposition in non adipose tissue causing cell/tissue dysfunction…liver,

skeletal muscle and B cells

- Increases FA beta oxidation



- Decreases insulin sensitivity therefore causing increased gluconeogenesis

- Increased inflammation

- Increased oxidative stress

Characteristic features of type 2:

Classical symptoms – polydypsia (increased fluid intake due to excessive thirst) ,

polyphagia (increased appetite), polyuria

Hyperglycaemia, hyperinsuliaemia

Impaired glucose tolerance

Dyslipidemia (high cholesterol levels)…increased LDL and decreased HDL

Treatment for Type II

Lowering BP, controlling diet and increased exercise

Oral hypoglycaemic agents

Biguanides – metformin

- Lowers blood glucose by increasing uptake into skeletal muscle and inhibiting

gluconeogenesis in the liver

- Mediated by AMP dependent protein kinase

- Liver: decreases A CoA (inhibition of FA synthesis), decreases SREBP-1 (down regulates

expression of lipogenic genes), increases FA oxidation and decreases hepatic lipotoxicity

Sulfonylureas – glibenclamide

- Stimulate first phase insulin release from the B cells so is only useful if islets are still

functional.

- Bind to the KATP receptor on B cells and mimic ATP by blocking the channel, triggering

membrane depolarization, Ca++ entry and insulin release



TZDs (PPARγ agonists) – pioglutazone

- Enhance insulin sensitivity by increasing GLUT4 and decreasing TNF-a, IL-6 and resistin in

liver and muscle

-

Enhances glucose metabolism by net transfer of FAs into adipose tissue

alpha-glucosidase inhibitors

- control postprandial hyperglycaemia by inhibiting digestion of complex CHOs in the

brush border of the villi. Thus slowing the rate of CHO absoption

insulin

- up to 1/3 of patients

- the efforts of the pancreas to overcome insulin resistance cause exhaustion of the beta

cells so they can’t make insulin anymore - if the oral hypoglycaemics don’t work well or if there are serious side effects, insulin is

prescribed

- similar regime to type 1

Long term diabetes complications (Type 1 & 2)

1. Microvascular complications

- Retinopathy, neuropathy, nephropathy

- Related to detrimental effects of chronic hyperglycaemia on endothelial cells in retinal,

renal and microvasculature supporting peripheral nerves

Retinopathy

- Poor glycaemic control is a major risk factor

- Changes in retinal microvasculature

- Increased vascular permeability/macular oedema (non proliferative retinopathy)

- Retinal hypoxia and ischaemia stimulate angiogenesis (proliferative)

Nephropathy

- Progressive disease caused by damage to renal microvasculature

- More common in Type 1

- Leading cause of end stage renal disease

- Pathological changes – glomerular basement membrane thickening, mesangial cell

expansion, ECM accumulation/fibrosis



- Progressive decline in glomerular filtration rate

Neuropathy

- Development is related to degree of glycaemic control

- Endothelial hyperplasia and basement membrane thickening- Increased vasoconstriction and oxidative stress

- Hypoxia and ischaemia

2. Macrovascular complications

- Arteriosclerosis

- Leading cause of death in Type 1 and 2

- Ischaemic heart disease

- Stroke

3. Metabolic complications (Type II)

HHS = hyperosmolar hyperglycaemic syndrome

HONK = hyperosmolar non ketosis

Caused by stress, infection and/or insufficient insulin

DKA = diabetic ketoacidosis

the endocrine pancreas & carbohydrate metabolism

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