Module 3: Glucose Homeostasis - Regulation, measurementm and development of T2D

homeostasis

• Maintenance of a relatively consistent internal environment

• disturbances to homeostatic balance can lead to disease

glucose homeostasis

• balance between hepatic glucose production and peripheral glucose uptake and utilization in relative range

excorine function of the pancreas (release fluids onto surface or into body cavities)

digestive enzymes - 90% of what the pancreas does. - lipases, proteases

endocrine function of the pancreas (directly into bloodstream)

hormones - control blood glucose concentration

4 cell types in the Islet of Langerhans

• alpha cells - release glucagon

• beta cells - release insulin

• delta cells - release somatostatin inhibitory peptide hormone, regulates release of various hormones

• F cells - release pancreatic polypeptide

alpha cells

endocrine cells in the pancreatic islets that secrete glucagon to raise blood glucose levels when blood sugar is low

beta cells

specialized endocrine cells in the pancreas that produce, store, and release the hormone insulin to control blood sugar levels when they get too high

insulin

• polypeptide hormone produced by beta cells in pancreas

• primarily anabolic - getting glucose out of bloodstream and into cells - glycogenesis

insulin is stimulated by

glucose, amino acids, and GI hormones (gastrin and cholecystokinin) - ozempic?

insulin facilitates

• glucose uptake and glycogen synthesis

• lipid and protein synthesis

Insulin gets glucose into the cells and tissues

so that they can use it or store it - IN IN IN

When insulin is released into the bloodstream,

C-peptide is equally released with it

c-peptide testing measures

how much natural insulin your pancreas makes by tracking byproduct released when insulin is produced - tests beta-cell function

glucagon

• counters insulin

• polypeptide hormone produce by alpha cells

• primarily catabolic - want to mobilize fuels

• high when fasted

glucagon function

• maintains plasma glucose between meals

• mobilizes glucose from the liver

glucagon is for when the glucose is gone

and you need to mobilize stored energy

normal healthy range for blood glucose concentration even when fasted

4.4-5.6 mmol/L

hypoglycemic =

below 4.4

insulin and glucagon work together to keep blood glucose concentration in

normal range - they counter each other

in a fasted/post-absorptive state (digestion is complete, nothing entering bloodstream) main goal is

increase blood glucose

when body wants to increase blood glucose, it releases

glucagon

muscle cannot

release free glucose into the blood stream

• holds onto it because it lacks the enzyme glucose-6-phosphate phosphatase

• can’t convert G6-P to free glucose, so it is used within the muscle

• it is trapped

the liver can

get glucose(mobilize) into the blood even if you haven’t eaten because glucose is stored as glycogen

glucagon’s effect on the liver in a fasted/post-absorptive state

• increase gluconeogenesis

• increase glycogenolysis (and decrease glycogenesis)

• increase glucose release

you body stores most of glucose in

muscle, only 1/5 is in the liver

over an overnight fast, the liver’s stored glycogen

drops over 50%

gluconegenesis

formation of “new glucose” from metabolic intermediates like lactate, glycerol, or amino acids like alanine and glutamine

the liver does not have unlimited glucose, but it can technically

fuel your body for days

GLUT2

transporter made in the liver that moves glucose out of the liver into the blood, works bidirectionally in the liver

glycogenolysis

breakdown of glycogen into glucose

order of intermediates in glycogenolysis

glycogen → G1-P (glycogen phosphorylase) → G6-P, (phosphoglucomutase) → glucose (G6-P phosphatase)

glycogen phosphorylase

• enzyme

• breaks down glycogen to G1-P

Phosphoglucomutase

• enzyme

• converts G1-P to G6-P

Phosphatase

• enzyme

• converts G6-P to glucose so it can be used

G6-P phosphatase only exists in

the liver, so only the liver can release free glucose into the blood

hexokinase

• enzyme

• adds a phosphate to glucose to make G6-P

• traps it in the cell

• works in muscle and liver

in fasted/post-absorptive state, what does glucagon do to adipose tissue

• increase lipolysis, this is another fuel source and glucagon focuses on mobilizing fuels

• adipose tissue has some receptors

Hypothetical: G6P phosphatase deficiency

• this would put you at risk in fasted states of hypoglycemia because you would not be able to mobilize glucose

• you would have to constantly consume glucose

glucose homeostasis is largely controlled by the balance between

hepatic glucose output and peripheral glucose uptake

in fasted state, glucagon promotes hepatic glucose production to maintain

glycemia - liver releases glucose while you fast in your sleep

regulation of postprandial (fed) glucose homeostasis timeline

• eat food

• glucose uptake rises

• stimulates the pancreas to release insulin and decrease glucagon

• insulin works to get the fuels to the adipose and muscle tissues by increasing peripheral glucose uptake

• insulin signal the liver to stop producing glucose because there are sufficient fuels

• as the tissues take up the glucose, blood glucose goes back down

insulin’s effect on skeletal muscle in fed state

• goal is to increase glucose use and storage

  • glucose uptake into skeletal muscle

  • trapping glucose inside the cell

  • increase glycogenesis and glycolysis

    • restock muscle glycogen

    • clear glucose from bloodstream

glucose uptake in muscles in a fasted state

requires a transporter (GLUT) to get from blood/extracellular fluid into muscle fiber

in muscles GLUT1 functions

at rest

in muscles, GLUT4 is

most important and is highly regulated

• stored in vesicles in cytosol → translocates to sarcolemma in response to approproate signal

• insulin signaling cascade causes this

in postprandial/absorptive state, overall goal is

decrease blood glucose

trapping glucose in the muscle

• glucose and ATP → hexokinase → G6-P and ADP

  • hexokinase phosphorylates glucose entering muscle cell and glucose becomes trapped because a phosphate is added

phosphofructokinase

major rate-limiting enzyme that catalyzes conversion of G6-P into 2 pyruvate to → acetyl-CoA → ATP

• stimulate if energy is needed - ex. energy demand in muscle, pyruvate is formed (glycolysis)

glycolysis

• glucose from blood enters muscle through GLUT4

• hexokinase adds a phosphate and traps it, turning it into G6-P

• phosphofructokinase converts it into pyruvate

glycogenesis

• glucose enters muscle through GLUT4

• hexokinase adds phosphate and converts is to G6-P

• phosphoglucomutase converts G6P into G1P

• glycogen synthase converts G1-P to Glycogen to store it

phosphoglucomutase

• converts G1P to G6P to make glucose

• converts G6P to G1P to make glycogen

in postprandial state, insulin - muscle

• increases glucose uptake

• glucose phosphorylated by hexokinase

• increase glycogenesis and glycolysis

insulin affect on adipose tissue in postprandial state

• Main goal = decrease FFA mobilization (major) and increase glucose uptake (minor)

• major decrease in lipolysis

• minor increase in glucose uptake

• increase in TG synthesis (lipogenesis)

why does lipolysis decrease majorly with insulin

• the body wants to use what you just consumed (carbs!)

• too much lipolysis is bad because too much FFA in blood can be toxic

hormone sensitive lipase (HSL)

intracellular enzyme that breaks down stored fats to release fatty acids and glycerol into the body; insulin puts a brake on it

during lipolysis,

beta-adrenergic receptor stimulation activates cAMP signaling cascade to phosphorylate HSL, increase its activity, and activate lipolysis

insulin signaling degrades cAMP to

reduce signal and inhibit lipolysis

lipolysis breaks down TGs into

3 FAs and glycerol

de novo lipogenesis

metabolic process that converts excess dietary carbs into new FAs inside the body

esterification

joins FA and glycerol backbone and turns them into TGs

CD36

fatty acid transporter on that adipocyte membrane that brings FAs into the adipocyte

insulin stimulates

glucose uptake and promotes fat storage

sequence from glucose to new fatty acids

glucose → pyruvate (glycolysis) → TCA →acetyl-coA → de novo lipogenesis→ FA

beta-oxidation

burns fatty acids for energy inside the mitochondria

high carb intake can drive

de novo lipogenesis - this is considered not good, can drive metabolic disease if overdone

insulin’s effect on the liver

• major goal: decrease glucose output

• decrease glucose release

• increase glucose uptake, glycogenesis and glycolysis

counter-regulatory hormones of insulin

generally oppose and act to raise blood glucose levels

• glucagon

• glucocorticoids (cortisol)

• growth hormone

• catecholamines (epinephrine and norepinephrine)

how does glucagon raise blood glucose

stimulates liver glycogenolysis and gluconeogenesis

key effect of cortisol (glucocorticoid) on glucose

• promotes gluconeogenesis and reduces tissue glucose uptake

counter-regulatory hormones are most active during

fasting, exercise, stress

catecholamines impact on glucose homeostasis

goal - increase blood glucose and increase fuel use

• stimulates glucagon release

catecholamine impact on liver

• increase glucose release

• increase gluconeogenesis

• increase glycogenolysis

catecholamine impact on adipose tissue

• decreases lipogenesis

• increased lipolysis

catecholamine impact on muscle tissue

• increase glycogenolysis

• increased glycolysis

insulin is a _______ of glycogenolysis

negative regulator

insulin is a _______ of glycogenesis

positive regulator

insulin is a ______ of lipolysis

negative regulator

insulin is a _______ of protein synthesis

positive regulator - anabolic

insulin is a ______ of muscle glycolysis

positive regulator - burning as fuel source

insulin is a _________ of gluconeogenesis

negative regulator - you do not need more

insulin is a __________ of liver glycolysis

positive regulator - encourage using new fuels

ketogenesis

the metabolic process where the liver breaks down fatty acids and ketogenic amino acids to produce ketone bodies for alternative cellular energy. often needed on a low carb diet, brain needs carbs

insulin is a __________ of ketogenesis

negative regulator

insulin is a ________ of muscle glucose uptake

positive regulator

insulin is elevated after a meal and signals to

decrease hepatic glucose production and increase peripheral glucose uptake (ex. skeletal muscle, adipose tissue)

insulin decreases

lipolysis from adipose tissue

Type 1 diabetes

• typically diagnosed in childhood or adolescence

• pancreas does not produce insulin (beta cells don’t release it)

• daily insulin required for management

• insufficient evidence to suggest lifestyle strategies can prevent or delay diagnosis

type 2 diabetes

• 90% of all diabetes cases in Canada

• classic onset is in adulthood - it is getting younger

• often associated with obesity

• defects in insulin action

• strong evidence to suggest lifestyle strategies can prevent diagnosis

Both T1 and T characterized by

hyperglycemia if not treated

~3 million canadians have

diabetes

t2d risk factors

• high-risk population

• over 40

• higher blood glucose and insulin

• overweight/obesity

• hypertension

• hyperlipidemia

• first-degree relative with T2

young adults of _________ descent face higher risk of prediabetes and diabetes

South Asian - higher fat composition, greater insulin resistance

Insulin sensitivity (IS)

degree to which the body’s cells respond to insulin

insulin resistance (IR)

an impaired response of peripheral tissues to respond to insulin

impaired glucose tolerance (IGT)

a state of hyperglycemia that is associated with insulin resistance following ingestion of carbs; aka glucose intolerance

impaired fasting glucose (IFG)

high post-absorptive blood glucose concentration; issue with glycemic control

glycemic control

ability to keep blood glucose concentration within a normal range

insulin resistance blocks affects of insulin on

adipose, liver, and muscle

hyperinsulinemia

condition where you have a higher level of insulin in your blood than what is considered normal

with impaired glucose tolerance, at first

the pancreas compensates by increasing insulin production to maintain euglycemia(normal) which leads to hyperinsulinemia