NPB 101: Key Terms on Insulin & Glucagon Explained

two major pathways of H sec regulation

1) physiological changes are sense and relayed to the brain (hypo) where info is integrated; changes in H sec via pituitary occur acting directly on target cells/ glands, regulating sec of Hs

hypothalamus --> pituitary --> gland : H sec

2) H secreting cell directly senses a change in the controlled variable (ex: blood glc lvls) and responds by increasing/ decreasing H secretion in a (-) FB mechanism

pancreas --> alpha/beta cells --> glucagon/ insulin sec

homeostatic regulation of blood glucose

An example of a negative feedback loop.

When high blood sugar (stimulus) is detected by the pancreas (detector and control center), it releases insulin (response) which acts on the body cells and liver (effectors) to take up glucose. This results in a reduction of blood sugar and return to homeostasis.

involves the shuttling of energy stores between ingested nutrients and their stored forms to maintain a relatively constant supply of glucose for all the cells of the body and especially for the brain

carbohydrates

- circulate as glc

- stored as glycogen (liver and muscle)

- 1% of body's energy content

- less than a day's energy source

ROLE: first energy source; needed for brain

fats

- circulates as free FAs in blood

- stored as TG in adipose tissue

- 77% of energy content

- ~2 months worth of energy

ROLE: primary energy reservoir; energy source during a fast

proteins

- circulates as AAs in blood

- stored in muscle as protein

- 22% of energy in body

- death results BEFORE full capacity is used (as muscle is broken down for AA usage for energy) due to structural and functional impairment

ROLE: source of glc for brain during a fast (KBs); last resort for other energy needs

Brain and Glucose

Brain uses glucose for fuel, but cannot store glucose reserves

ketone bodies

made in liver in long periods between meals when glc is depleted

- via transamination: AAs ---> alpha-ketoacids

Post-absorptive state

Catabolic Reactions > Anabolic Reactions

1) Glycogenolysis: Glycogen to glucose

2) Gluconeogenesis: Amino acids to glucose

3) Protein degradation: Protein to amino acids

4) Fat Breakdown: Triglycerides to FA

Absorptive State

Anabolic Reactions > Catabolic Reactions

1) Glycogenesis: Glucose is converted into Glycogen

2) Protein Synthesis: Amino acids converted to Proteins

3) Fat Synthesis: Fatty acids and glycerol converted to Triglycerides

consequences of hypoglycemia

neurological problems, coma, death

- 4 hormones increase glc levels

- 1 hormone decreases glc levels

consequences of hyperglycemia

'Glucotoxicity', most notably in vascular endothelial cells of the retina, kidneys, and capillaries associated with peripheral nerves.

• Retinopathies

• Peripheral nerve damage

• Poor kidney function

• Atherosclerosis

- osmotic diuresis and dehydration

glucose tolerance test

A test of the body's ability to metabolize glucose that involves the administration of a measured dose of glucose to the fasting stomach and the determination of blood glucose levels in the blood or urine at intervals thereafter and that is used especially to detect diabetes.

how a patient reacts when given glucose

islets of Langerhans of the pancreas

endocrine tissue within the pancreas; secretes insulin and glucagon

insulin secretion

regulated by negative feedback when high blood sugar levels trigger its release from beta cells to reduce blood levels of glucose

insulin secretion and stimulation

Insulin release stimulation:

- primary stimulation for insulin secretion is a rise in blood glucose

- increased blood amino acids,

- presence of glucose-dependent insulinotropic pepide (GIP - produced by GI tract) when glc levels are high

- parasympathetic stimulation

Inhibition:

- sympathetic nervous system and Epi secretion

Glucose-dependent insulinotropic polypeptide (GIP)

a hormone that is released from the intestinal mucosa in the presence of glucose, fat, and/or protein and increases insulin release by pancreatic islet cells

stimulates insulin synthesis and release; stimulates beta-cell proliferation

insulin mediated glc uptake

GLUT 4 = insulin dependent

- muscle and adipose tissue

- stored in muscle as glycogen

- glc stored in fat as TGs

GLUT 4 transporter

- facilitated glucose transport, INSULIN dependent

- located in skeletal/heart muscle, adipocytes

GLUT 4 glc uptake mechanism

1) insulin binds to insulin receptor on target cell membrane (peptide H & hydrophilic)

2) protein kinase phosphorylates intracellular protein (chain of biochemical events)

3) intracellular pools of GLUT 4 fuse with cell membrane

4) channel present now for glc uptake into muscle and adipose cells

when insulin signal ends, GLUT 4 brought back into cell

GLUT 2 transporter - liver

liver GLUT 2 = insulin INDEPENDENT

PACKING glc as GLYCOGEN in liver does however NEED INSULIN (glycogenesis)

GLUT 2 transporter - brain

brain GLUT 2 insulin INDEPENDENT

- glc-transporters on blood-brain barrier are always on --> no need for insulin at all

insulin action in resting and contracting skeletal muscle

GLUT 4 --> mechanism of glc transport only in RESTING skeletal muscle

CONTRACTING sk. m. is NOT insulin dependent

- GLUT 4 inserted into membrane when muscles are actively contracting, enabling glc uptake

insulin effects on carb metabolism

insulin is secreted when [Glc] is HIGH:

↑ glu uptake via GLUT 4 in muscle and adipose tissue

↑ glc uptake via GLUT 2 in liver and brain

↓ glycogenolysis (breaking glycogen)

↓ GNG (making glucose in liver)

↑ glycogenesis (making glycogen)

insulin effects on fat metabolism

insulin is secreted when [FA] is HIGH:

↑ glucose uptake into adipose tissue for TG syn via GLUT 4

↑ lipogenesis/ TG syn

↓ lipolysis/ TG breakdown

insulin effects on protein metabolism

insulin is secreted when [AA] is HIGH:

↑ glucose uptake via GLUT 4 in muscle for protein syn

↑ protein synthesis

↓ protein breakdown (proteolysis)

glucagon secretion

•Secretion increases during postabsorptive state

•Sympathetic nervous system

•Epinephrine

•Secretion decreases during absorptive state

•Increases glucose in plasma

secreted by alpha cells of islets of langerhans of pancreas

glucagon actions in liver and adipocytes

liver:

↑ GNG

↑ glycogenolysis (glycogen breakdown)

↓ glycogenesis (glycogen synthesis)

adipocytes:

↓ TG syn (lipogenesis)

↑ lipolysis

glucagon actions in brain and skeletal muscles

brain:

- no direct impact on brain

- however, peripheral tissues save glc for brain and use other sources of fuel for energy

skeletal muscle:

- no direct effects

- absence of insulin allows for increased glycogen breakdown and decreased glc uptake and decreased proteolysis

glucagon effects on carb metabolism

glucagon is secreted when [Glc] is LOW:

↓ glu uptake via GLUT 4 in muscle and adipose tissue

↓ glc uptake via GLUT 2 in liver and brain

↑ glycogenolysis (breaking glycogen)

↑ GNG (making glucose in liver)

↓ glycogenesis (making glycogen)

glucagon effects on fat metabolism

glucagon is secreted when [FA] is LOW:

↓ glucose uptake into adipose tissue for TG syn via GLUT 4

↓ lipogenesis/ TG syn

↑ lipolysis/ TG breakdown

glucagon effects on protein metabolism

minimal/ no effect

- increased AA catabolism in liver

- not breaking down protein

What is the impact of LOW circulating FAs and HIGH AAs on glucagon secretion?

stimulation of glucagon secretion with low FAs and high AAs

GLUT 1

specific to alpha cells and glucagon

- brain and erythrocytes

high blood glucose levels: impact on insulin and glucagon via ATP

Beta cell:

high glc ---> high ATP ---> increased insulin secretion into blood via GLUT 2 (brain and liver)

alpha cell:

high glc ---> high ATP --> decreased glucagon secretion into blood (GLUT 1)

low blood glucose levels: impact on insulin and glucagon via ATP

Beta cell:

low glc ---> low ATP ---> decreased insulin secretion into blood via GLUT 2 (brain and liver)

alpha cell:

low glc ---> low ATP --> increased glucagon secretion into blood (GLUT 1)

diabetes mellitus and hyperglycemia

Caused by underproduction, insufficient secretion or insensitivity to insulin. Excess glucose in blood.

Diagnoses of Diabetes

normal blood glc = 70-120 mg/dL

DM diagnosis established via:

1) random blood glc concentration of 200 mg/dL or higher

2) fasting glc concentration f 126 mg/dL or higher on more than 1 occassion

3) abnormal oral glc tolerance test (higher than 200 mg/dL)

4) long term memory of blood glc levels is present on RBCs: HbA1c (glycated Hb); greater than 5.7 = prediabetic

Type 1 vs Type 2 DM

Type 1:

- almost no insulin secretion

- typically in childhood

- 10-20% of pts with DM

- defect: autoimmune destruction of beta cells

- Treatment: insulin injections, diet management, exercise

Type 2:

- normal insulin secretion (or excessive)

- typically in adulthood

- 80-90% of pts with DM

- defect: insensitivity of insulin receptors to insulin (Rs not working properly even tho adequate amounts of insulin are present)

- Treatment: dietary control and weight reduction, oral hypoglycemic drugs

- eventually Beta cells are compromised

how are beta cells eventually compromised in Type 2 DM?

beta cells constantly are secreting insulin because of the lack of a (-) FB mechanism

- insulin receptors are not working, so it seems like there is no insulin present

- eventually beta cells become destroyed by the high level of glc that can not be managed with the amount of insulin consistently being secreted

Obesity or excessive fat accumulation within the pancreas are some of the major mechanisms that promote oxidative stress, insulin resistance, and β-cell dysfunction in T2DM

impact of DM on GLUT 4

GLUT 4 needed for glc uptake in skeletal muscle and fat

- receptor signalling is compromised, especially in T2DM

- insulin is not binding, so GLUT 4 does not move to the membrane, and glc is freely moving in blood without uptake

absorptive state complications: DM

just-fed state

- insulin secretion

- GLUT 2 functions in terms of taking up glc into the liver, but glycogenesis is NOT occurring bc of insulin insensitivity at Rs

- GLUT 4 is insulin dependent, so it is not working (again due to R not responding to insulin), so no uptake of glc in muscle or fat

- BRAIN: no problem as NOT insulin dep

DM effect on carb metabolism - insulin (T2DM)

receptors are not responding to insulin so...

glc concentration in blood is increasing since...

GNG is not inhibited

glycogenolysis is not inhibited

glycogenesis is not occurring

glc uptake of GLUT 4 in skeletal muscle and fat is not occurring

NO INSULIN = INCREASED [GLC]

post absorptive state complications: DM

alpha cells lose ability to sense glucose

- compromised in both type 1 and type 2 DM

- inappropriate glucagon secretion, as insulin is not adequately opposing effects

DM effect on carb metabolism - glucagon (T2DM)

insulin is not working properly in body due to receptor insensitivity, which also impacts glucagon levels

with DM glucagon...

- inhibits liver glycogenesis

- increases liver glycogenolysis

- increased liver GNG

the actions of glucagon are not impaired by DM, they are just not opposed by insulin (as that is impacted in DM)

GLUCAGON INCREASES = EVEN MORE [GLC] IN BLOOD

insulin deficiency causes

hyperglycemia and DM

leading to.....

- excessive hunger and thirst

- excessive urination

- glc levels in filtrate exceed kidney's ability to reabsorb it (sweet-tasting urine)

impact on DM on fat metabolism

insulin is not working properly meaning...

- no TG syn

- no glc uptake in adipose tissue via insulin-dep GLUT 4

glucagon's effects are stimulated: increased lipolysis = increased [FA]

lipolysis impacts on body with DM

- weight loss

- ketone formation (FA met byproduct in liver used as alt. source of fuel for brain besides glc)

- sweet-smelling breath

DM and protein metabolism

prevents normal protein metabolism of insulin:

- protein syn is inhibited

- increased proteolysis occurs

- less AA uptake into muscle for protein building

insulin deficiency impacts muscle through muscle wasting - weight loss, etc

- without insulin, it seems as tho there is not much AA in the blood