Physiology 3120 Lecture Notes - Lecture 5: Irs2, Ketosis, Glycosuria
9 May 2018
School
Department
Course
Professor
Physiology 3120
Dr. Hardy
Diabetes
Diabetes Mellitus
- Diabetes—Greek--large volume of urine
- mellitus—Latin--a sweet taste.
- The ancient Indians tested for diabetes by observing whether ants were attracted to a person's
urine, and called the ailment "sweet urine disease" (Madhumeha). The Korean, Chinese, and
Japanese words for diabetes also mean "sweet urine disease"
- Characterized by:
o Hyperglycemia (high circulating blood glucose)
o Polyphagia (eating with weight loss)
o Polyuria (high urine volume)
o glycosuria (glucose in urine)
o water and electrolyte loss
- In severe cases:
o Ketosis (high ketone bodies in circulation poisonous)
o acidosis
o coma and death (long term, if untreated)
- Long-term complications:
o Retinopathy
o nephropathy (impaired kidney function)
o angiopathy (blood clots could lead to amputations)
o increased susceptibility to infection.
- Type I
o insulin-dependent (total lack of insulin being produced)
o autoimmune disease destruction of pancreatic cells
o early onset juvenile diabetes
o ~10% of diabetics
- Type II
o insulin resistant/impaired insulin secretion (still making insulin but not responding to it
o lifestyle-overweight, sedentary
o onset in mid-life
o 90% of diabetics
Type 1 Diabetes
- A failure to secrete sufficient insulin to regulate glucose utilization
- Autoimmune disease T cells from the thymus gland attack the beta cells
- ~ 10% of all diabetes; early onset
- Insulin-dependent
- Early symptoms: high glucose, dehydration, low energy.
- In the left image, you can see the brown is +ive insulin staining cells
- In the middle image, you can see an
infiltration of the T cells (purple cells)
- Overtime, you are left with the
remaining portion of the islets of
langerhans (alpha and delta cells etc)
and when you try to stain for insulin,
there is no stain (complete loss of beta
cells and so a complete loss of insulin)
find more resources at oneclass.com
find more resources at oneclass.com
What happens without Insulin?
- Inability to transport glucose into cells (such as adipose or muscle cells)
- So an alternate energy source needed – breakdown of protein and fat to create more ATP
Other sources of energy-protein
- Gluconeogenesis
- muscle broken down to AA
- AA converted to glucose in muscle/liver (used by liver, brain)
o So its as if the muscle is taking a hit to help the liver to generate
energy
- results in:
o muscle wasting
o weight loss
- this image shows that an image that does not have insulin has overall muscle
wasting – muscle is degraded and is broken down into amino acids
- this is hwy some diabetic patients lose weight (its muscle weight)
- Lipolysis
- mobilization of triglycerides and free fatty acids from stores
- by-products include ketones
- high ketones are a marker of diabetes.
- ketoacidosis can lead to death (poison)
- we lose a bit of fat in the adipose cell and it is broken down into free fatty acids
- these fatty acids are used in the TCA cycle to generate ATP this is called free fatty acid
oxidation (the alternate source to generate ATP)
- problem with this long term: this process leads to ketone by products (high levels of ketones
generated from free fatty acid oxidation) and long term high ketones lead to ketoacidosis
Fate of high serum Glucose
1. Increased glucose filtration--water excretion dehydration
o When we have lots of glucose in circulation, that puts a stress on the kidneys which
increases glucose filtration
2. Conversion of glucose to sorbitol the polyol pathway damaging to lens, nerves and
capillaries
o Sorbitol has major toxic effects to the eye (this is why diabetics can lose their vision)
3. Increased glycosylation ie. addition of cellulose, a glycan of proteins the glyoxal pathway .
Glycation end-products protein damage and misfolding.
o If increase the glycosylation of any protein, this will impair the protein function and
protein folding (so this has a wide effect on many processes in the body)
4. De novo synthesis of diacylglycerol (DAG) leasing to increased protein kinase C (PKC) activation
nephropathy
o High levels of DAG in the kidney activated PKC (an intracellular kinase)
o This leads to kidney failure
find more resources at oneclass.com
find more resources at oneclass.com
Type II Diabetes: Insulin Resistance
- Glucose meal stimulates insulin release
- Insulin stimulates:
o glucose uptake by cells
o glycogenesis
o lipogenesis
o protein synthesis
o leptin secretions
- i.e. promotes energy utilization and storage
Insulin Resistance
- What is it?
o decreased cellular responses to insulin
▪ there is lots of insulin around but the receptor is not responding to it as well
o hyperglycemia
▪ bc we have a lack of GLUT4 being translocated to the PM
o impaired insulin secretion
▪ beta cells are not working to its full functional
capacity
- Complex interplay of factors contribute to IR
o Diet, lifestyle and genetic makeup
o There are no direct genetic links to type 2 diabetes but there
could be certain mutations in genes that could predispose
you to have more obesity or high levels of lipids (so genes
are a more indirect effect in type 2 diabetes)
o Obesity is what leads to insulin resistance in organs like the adipose cell or the muscle
cell
Mechanisms of Insulin Resistance
- What specifically causes a patient to develop type II diabetes? we dont really know!
- So…What do we know?
1. changes in InsR phosphorylation (acquired/genes?)
2. changes in InsR signaling (acquired/genes?)
3. inactivity and obesity (diet and lifestyle)
4. role of TNF- and FFAs
5. Impairment of PPARγ (acquired/genes?)
o Thats a very important transcription factor
6. contribution of genetics (genes) (
Phase 2: Autocrine action of insulin
- IRS- Insulin Receptor Substrate
- insulin receptor is a tyrosine kinase receptor – its a heterodimer that is bound to insulin and
leads to downstream signaling effects like phosphorylation of the insulin receptor,
phosphorylation of IRS1 and downstream signaling
events like activation of PI3 kinase and ultimately
translocation of GLUT4 to the cell surface of the muscle
of adipose cell
- if any aspect of this pathway is impaired, it can lead to
insulin resistance
- this is so that insulin resistance = impairing insulin
receptor activation
find more resources at oneclass.com
find more resources at oneclass.com
