Type 2 diabetes

Question 1

Insulin resistance ?

Answer 1

Insulin is not absent in Type 2 diabetes and may be higher than normal

Question 2

Why does hyperglycaemia arise?

Answer 2

Mainly lack of glucose uptake, not production

Question 3

Skeletal muscle makes the highest contribution to insensitivity to insulin. What does insensitivity mean in this case ?

Answer 3

Insensitivity means that less glucose can be taken up by the skeletal muscle cells causing higher glucose levels in the blood

Question 4

Links to obesity and diet?

Answer 4

• Prevalence of obesity and type 2 diabetes in USA
  shows strong correlation
• Pima Indians who live in the US and have a “Western” diet & lifestyle (high sugar, processed food, low exercise) have 10x rates of type 2 diabetes than those living in Mexico (agricultural work, unprocessed food, low sugar)

Question 5

What is Metabolic syndrome ?

Answer 5

• The medical term for a combination of diabetes, high blood pressure (hypertension) and obesity
• Believed to affect 27% of adult U.S. population

Question 6

Additional symptoms of metabolic syndrome ?

Answer 6

• abdominal obesity
• high triglycerides (TAGs)
• low HDL
• high blood pressure
• elevated blood glucose (but may not be full-blown diabetic)
• often includes other signs of inflammation

Question 7

Excess fat in peripheral tissues can cause insulin resistance ?

Answer 7

• During obesity, fat cell numbers increase and insulin can no longer suppress fatty acid release from adipose tissue
• Diacylglycerols and ceramide
  activate stress-induced pathways that interfere with insulin signalling

Question 8

Inhibition of insulin signalling by free fatty acids ?

Answer 8

• Free fatty acids (FFA) stimulate PKC-theta, which serine phosphorylates and inactivates IRS1/2
• IRS1 cannot now be phosphorylated on the tyr residue by the activated receptor
• Downstream PI3K/PKB signalling is inhibited, interfering with GLUT4 transport to the cell surface (muscle) and increased gluconeogenesis and decreased glycolysis in the liver
• Free fatty acids also competitively inhibit transport of glucose by both the GLUT4 and GLUT2 transporters

Question 9

Adipose tissue as an endocrine organ ?

Answer 9

White adipose tissue (WAT) includes subcutaneous fat and visceral fat (around the organs):
visceral fat produces a variety of bioactive peptides - adipokines - which can alter the bodies response to insulin

Question 10

What is Adiponectin ?

Answer 10

Secreted by adipose tissue: makes other tissues more insulin-sensitive

Question 11

What is Leptin ?

Answer 11

Appetite suppressant secreted by adipose tissue that affects the brain

Question 12

What is TNF-a, IL-6 ?

Answer 12

• Inflammatory cytokines produced by WAT in the
  absence of inflammation
• Over-expressed in obesity and decreased by weight loss. Anti-TNF antibodies ameliorate insulin-resistance in obese rodents

Question 13

Insulin resistance in type 2 diabetes may be due to ?

Answer 13

• Abnormal lipid storage in muscle and liver when adipocytes cannot store additional TAGs
• Triggers inflammation in adipose tissue, particularly via TNFα

Question 14

Adipokines help maintain systemic lipid and glucose homeostasis ?

Answer 14

• When fat mass increases, leptin secretion increases and adiponectin secretion decreases. Both hormones act to prevent lipid accumulation in liver and stimulate fatty acid oxidation
• A consequence of lipid accumulation is an increase in the concentration of ceramide, which promotes insulin resistance
• However, adiponectin counteracts this; when adiponectin binds to its
  receptor, the receptor’s ceramidase activity is activated, and the resulting decrease in ceramide helps
  to restore insulin sensitivity

Question 15

What promotes and what inhibits adiponectin secretion?

Answer 15

Weight loss and caloric restriction promote adiponectin secretion, whereas IL-6 and TNF-alpha inhibit it

Question 16

What is Leptin ?

Answer 16

An appetite suppressant

Question 17

What factor does Leptin play?

Answer 17

Crucial factor in the long-term regulation of food intake and body weight

Question 18

When is Leptin secreted ?

Answer 18

Secreted when fat stores are high and inhibited when

depleted

Question 19

When is there a fall in Leptin?

Answer 19

• Fall in leptin when adipose energy stores are depleted
  enhances appetite and decreases energy utilisation,
  whereas in the fed state high leptin levels decrease the
  drive to eat and enable substrates to be metabolised
• Acts via JAK/STAT signalling on various neurons to affect neuropeptide signalling

Question 20

When was Leptin first identified ?

Answer 20

First identified in obese mice as the product of the OB gene

Question 21

Explain experiment on Homozygous ob/ob mice ?

Answer 21

• Homozygous ob/ob mice ate continually, had elevated cortisol, shivered, did not reproduce, had severe insulin resistance, and were obese
• When leptin was injected, the mice lost weight, temperature returned to normal, as did circulating glucose and insulin

Question 22

Leptin administration to most obese people does not ?

Answer 22

Restore normal body mass (a great disappointment to the pharmaceutical industry)

Question 23

How are the levels of leptin in obesity ?

Answer 23

Leptin is in fact elevated in many cases of obesity

• This is because in some obese people, the brain does not respond to leptin, so they keep eating despite adequate (or excessive) fat stores, a concept known as ‘leptin resistance’
• This causes the fat cells to produce even more leptin

Question 24

What does continuous high levels of plasma leptin (hyper-leptinaemia) result in ?

Answer 24

Leptin resistance and associated insulin resistance

Question 25

Leptin resistance may result from ?

Answer 25

The inappropriate activation of proteins called suppressors | of cytokine signaling (SOCS): these bind to phosphorylated tyrosine residues in IRS1 and disrupt signalling

Question 26

Insulin resistance can lead to beta cell failure ?

Answer 26

- Glucose absorption and metabolism by the β cells of the pancreas leads to insulin secretion - The β cells respond to insulin resistance by secreting more insulin - The insulin processing machinery becomes overwhelmed, resulting in the accumulation of unfolded or misfolded protein: the unfolded protein response (UPR) - If the UPR continues, apoptosis is triggered, β cells die, and insulin secretion ceases - Type 2 diabetic will now need insulin injections

Question 27

What does Type 2 diabetes increase the risk of ?

Answer 27

Increases both the risk of many cancers (e.g. pancreatic, bowel, liver and breast) and also the risk of developing dementias

Question 28

Treatment of Type 2 diabetes?

Answer 28

- Diet and exercise to reduce obesity, manage blood glucose, increase insulin sensitivity of muscles are the best - Currently used oral hypoglycemic drugs target three processes: insulin secretion, tissue insulin sensitivity, and absorption and digestion of carbohydrates (e.g. acarbose)

Question 29

Explain how Sulfonylurea Drugs Inhibit ATP-gated K+channels in beta cells ?

Answer 29

- Bind to the SUR1 subunits, closing the channels and stimulating insulin release - Overcome insulin resistance by stimulating secretion of insulin, e.g. tolbutamide, glipizide - Note: diazoxide has the opposite effect: it opens the channel to prevent insulin secretion in the case of pancreatic tumours

Question 30

What is Metformin (Glucophage) and what does it activate ?

Answer 30

- Most common medication for type 2 diabetes - Activates AMPK: AMPK phosphorylates and inactivates acetyl-CoA carboxylase, which makes malonyl-CoA during fatty acid synthesis - AMPK pathway also inhibits cholesterol synthesis, stimulates fatty acid breakdown, and other pathways

Question 31

What do Thiazolidinedione drugs activate ?

Answer 31

PPAR pathways

Question 32

What does PPARs (peroxisome proliferator activated receptor): bind to ?

Answer 32

Fatty acids or derivatives, then bind to retinoid X receptor (RXR) and become powerful transcription factors

Question 33

What does PPARγ regulate ?

Answer 33

Regulates the differentiation of fibroblasts into adipocytes and lipid synthesis and storage in adipocytes

Question 34

What does PPARα regulate ?

Answer 34

Regulates the uptake and β oxidation of fatty acids and the formation of ketone bodies during fasting: expressed in liver, kidney, heart, skeletal muscle, and brown adipose tissue

Question 35

What does PPARδ regulate ?

Answer 35

Regulates β oxidation and energy dissipation through uncoupling of mitochondria: acts in the liver and muscle

Question 36

What is GLP-1 and GIP (Glucose-dependent insulinotropic peptide) produced by ?

Answer 36

- The endocrine cells of the intestine following ingestion of food and stimulate insulin secretion, although only GLP-1 effective in diabetes - However, GLP-1 has a very short half-life in vivo and so not practicably useful

Question 37

How do you target GLP-1?

Answer 37

- Exendin-4: a powerful stimulator of the GLP-1 receptor, stimulating insulin and inhibiting glucagon secretion. Found in the saliva of the gila monster - Exenatide (Byetta): a synthetic version of exendin-4 with a longer half-life – in animals it also increases beta cell numbers in the pancreas. Injection. - Vildagliptin (Galvus): inhibits the inactivation of GLP-1 and GIP by inhibiting dipeptidyl peptidase-4 (DPP-4)