Type 2 diabetes Flashcards
Insulin resistance ?
Insulin is not absent in Type 2 diabetes and may be higher than normal
Why does hyperglycaemia arise?
Mainly lack of glucose uptake, not production
Skeletal muscle makes the highest contribution to insensitivity to insulin. What does insensitivity mean in this case ?
Insensitivity means that less glucose can be taken up by the skeletal muscle cells causing higher glucose levels in the blood
Links to obesity and diet?
- 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)
What is Metabolic syndrome ?
- The medical term for a combination of diabetes, high blood pressure (hypertension) and obesity
- Believed to affect 27% of adult U.S. population
Additional symptoms of metabolic syndrome ?
- 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
Excess fat in peripheral tissues can cause insulin resistance ?
- 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
Inhibition of insulin signalling by free fatty acids ?
- 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
Adipose tissue as an endocrine organ ?
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
What is Adiponectin ?
Secreted by adipose tissue: makes other tissues more insulin-sensitive
What is Leptin ?
Appetite suppressant secreted by adipose tissue that affects the brain
What is TNF-a, IL-6 ?
- 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
Insulin resistance in type 2 diabetes may be due to ?
- Abnormal lipid storage in muscle and liver when adipocytes cannot store additional TAGs
- Triggers inflammation in adipose tissue, particularly via TNFα
Adipokines help maintain systemic lipid and glucose homeostasis ?
- 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
What promotes and what inhibits adiponectin secretion?
Weight loss and caloric restriction promote adiponectin secretion, whereas IL-6 and TNF-alpha inhibit it
What is Leptin ?
An appetite suppressant
What factor does Leptin play?
Crucial factor in the long-term regulation of food intake and body weight
When is Leptin secreted ?
Secreted when fat stores are high and inhibited when
depleted
When is there a fall in Leptin?
- 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
When was Leptin first identified ?
First identified in obese mice as the product of the OB gene
Explain experiment on Homozygous ob/ob mice ?
- 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
Leptin administration to most obese people does not ?
Restore normal body mass (a great disappointment to the pharmaceutical industry)
How are the levels of leptin in obesity ?
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
What does continuous high levels of plasma leptin (hyper-leptinaemia) result in ?
Leptin resistance and associated insulin resistance
Leptin resistance may result from ?
The inappropriate activation of proteins called suppressors
of cytokine signaling (SOCS): these bind to phosphorylated tyrosine residues in IRS1 and disrupt signalling
Insulin resistance can lead to beta cell failure ?
- 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
What does Type 2 diabetes increase the risk of ?
Increases both the risk of many cancers (e.g. pancreatic, bowel, liver and breast) and also the risk of developing dementias
Treatment of Type 2 diabetes?
- 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)
Explain how Sulfonylurea Drugs Inhibit ATP-gated K+channels in beta cells ?
- 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
What is Metformin (Glucophage) and what does it activate ?
- 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
What do Thiazolidinedione drugs activate ?
PPAR pathways
What does PPARs (peroxisome proliferator activated receptor): bind to ?
Fatty acids or derivatives, then bind to retinoid X receptor (RXR) and become powerful transcription factors
What does PPARγ regulate ?
Regulates the differentiation of fibroblasts into adipocytes and lipid synthesis and
storage in adipocytes
What does PPARα regulate ?
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
What does PPARδ regulate ?
Regulates β oxidation and energy dissipation through uncoupling of mitochondria: acts in the liver and muscle
What is GLP-1 and GIP (Glucose-dependent insulinotropic peptide) produced by ?
- 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
How do you target GLP-1?
- 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)
