Insulin and Diabetes Flashcards
What is the relationship between visceral adipose tissue and insulin action?
As visceral adiposity increases the glucose disposal capacity of insulin is reduced
Visceral adipose tissue and insulin action
As visceral adiposity increases the glucose depositing capacity of insulin reduces
Insulin resistance syndrome
Physiological response is inadequate for amount of insulin secreted
Biochemical abnormalities of insulin resistance syndrome?
Cardohydrate:
Insulin resistance
Hyperinsulinemia
Lipid:
High TG
Low HDL-C
Small, dense LDL
Fribrinolysis:
Increased PAI-1
Clinical manifestations of insulin resistance syndrome?
Central obesity Glucose intolerance Atherosclerosis Hypertension Polycystic ovary syndrome
How does obesity cause cardiovascular disease?
What epithelial dysfunction occurs in insulin resistance syndrome?
Insulin resistance syndrome is associated with endothelial dysfunction. When you have insulin resistance, you produce superoxide, you quench nitric oxide, leading to vasoconstriction, clotting, and laying down of atheroma.
What happens to PAI-1 in insulin resistance syndrome?
INCREASED PAI-1:
high PI-1 opposing the action of TPA, there is slowing of the breakdown of clot, but it’s also very important in the vessel wall. Because if PI-1 is elevated in the vessel wall, there is a decreased formation of plasmin. And that plasmin is necessary to remove the collagen tissue from the atheromatous plaque, so that smooth muscle cells can move in and stabilize the plaque. So a high PI-1 in the vessel wall, is as very common in the diabetic patient, is associated with an increase in plaque rupture and cardiac events.
Insulin resistance syndrome and left ventricular hypertrophy
Also associated with left ventricular hypertrophy, which may partially explain the high incidence of congestive heart failure we see in the diabetic patient
What is metabolic syndrome a good marker for?
Cardiovascular mortality - better than statins
Major complication of hyperinsulinemia?
Hyperinsulinemia leads to activation of SNS = increase in Na reabsorption and arterial tone
= hypertension
Major complication of hyperglycaemia?
Overstimulation of pancreatic -cell function
→ Reduction of insulin secretion
= type 2 diabetes
Adipose tissue is an active endocrine organ
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Mechanisms by which adipose tissue may influence cancer risk:
Production of sex steroid hormones (e.g., estrogen, androgen)
- Effects on insulin sensitivity and production of insulin-like growth factors
- Actions on other hormones in adipose tissue (e.g., leptin, adiponectin)
- Increases in oxidative stress and chronic low-grade inflammation that affect the body’s immune response
Risk factors for sleep apnoea
Family history Obesity: 80 % of sleep apnea patients Increasing age Male gender Large tonsils / adenoids Small mandible, large neck Smoking, alcohol, sedatives
Consequences of sleep apnoea
Social / Psychological: work, family
Personal: fatigue, tired, depression, irritability, impotence, memory
More accidents: work home motor vehicle
Higher death rates with severe apnea
Hypertension, Congestive Heart Failure
Associated: Heart Attacks, Strokes, A Fib
Promotes obesity and diabetes
Drug treatments for obesity
Sibutramine
Orlistat
Rimonabant
Incretins
Orlistat
Gastrointestinal Lipase Inhibitor
Acts against pancreatic lipase causing fat malabsorption
Not systematically absorbed
GI adverse effects
Fat soluble vitamin deficiencies
Orlistat is a useful adjunctive treatment for producing:
weight loss
Improving glycemic control
Serum lipid levels
Blood pressure
In obese patients with type 2 diabetes who are being treated with metformin.
Incretins
Incretins are GI hormones that are released after meals and stimulate insulin secretion
GLP1 and GIP are incretins
GIP is not effective in stimulating insulin
GLP 1 is effective- hence GLP1 signalling system – successful drug target
Incretin effect
The “Incretin Effect” describes the phenomenon whereby a glucose load delivered orally produces a much greater insulin secretion than the same glucose load administered intravenously
The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes- why?
The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone.
GLP-1 effect in humans
GLP-1 is an incretin secreted fromL-cells of the jejunum and ileum
Stimulates glucose- dependent insulin secretion
Suppresses glucagonsecretion
Slows gastric emptying
Leads to reduced food intake
Improves insulin sensitivity
(in animal models increases B cell mass and improved function)
Incretins role in glucose homeostasis
Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated. The subsequent increase in glucose uptake in muscles and reduced glucose output from the liver help maintain glucose homeostasis.
Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner. GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.
Dapagliflozin
A novel insulin-independent approach to remove excess glucose and help weight loss
Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule
Bariatric surgery
Weight loss surgery, also called bariatric or metabolic surgery, is sometimes used as a treatment for people who are very obese. It can lead to significant weight loss and help improve many obesity-related conditions, such as type 2 diabetes or high blood pressure.
Band can stretch if people eat too much and need it fixed, gastric bypass is permanent
Gastric bypass
The goal of is to achieve and maintain a healthier body weight.
Mean weight loss 2 years after gastric bypass is > 65% of excess weight loss (EWL)
Most of the weight loss occurs in the first 6 months after surgery
With a continuation of gradual loss throughout the first 18–24 months.
DAFNE and DESMOND are education programmes for which type of diabetes?
DAFNE (Type 1 Diabetes)
DESMOND (Type 2 Diabetes)
Dietary aims for type 2 diabetes
Lose weight if overweight or obese
Low Glycaemic Index carbohydrates
An individualised approach to diet taking into consideration the person’s personal and cultural preferences
Eat more of certain foods such as vegetables, fruits, wholegrains, fish, nuts and pulses
Eat less red and processed meat, refined carbohydrates and sugar sweetened beverages.
What is the glycaemic index?
The glycaemic index (GI) is a system of ranking carbohydrate-containing foods according to how quickly they affect blood glucose levels after a meal.
Evidence: In patients with type 2 Diabetes following a low GI or low GI load diet results in a 0.5% reduction in HbA1c.
Twice daily mixed insulin regime
Fixed meal patterns
Regular snacks
Consistent amount of carbohydrate at meals
Lighter lunch?
Less flexibility and control for the patient
Basal bolus insulin regimen
Non fixed meal patterns
Regular snacks not required
Variable amounts of carbohydrate at meals
More flexibility and control for the patient
More injections
What is DAFNE?
Dose Adjustment For Normal Eating
Nationally accredited structured education programme in intensive insulin therapy & self management.
People with Type 1 diabetes are taught to match their insulin dose to their chosen food intake
Basal bolus regime (1-2 injections of background insulin each day and quick acting insulin with meals
Test blood glucose minimum of 4 times per day including before meals and before bed
Type 1 Diabetes: Managed through insulin.
For best control, adjust insulin to take account of:
-Food (Carbohydrates)
-Physical activity
-Alcohol
-Sickness.
DAFNE: Group education course to teach patients insulin management.
DAFNE aims and style
Aims
- Less guesswork. More freedom. Better health.
- ↑ autonomy, competency & confidence.
- Skills-based training for self management.
Style
- Person-centered.
- Collaborative & interactive.
Follows adult learning best practice:
- “Experiential learning” (learning through reflection on doing)
- Peer assisted learning.
- Practical skill-based training.
DAFNE pros?
Reduced HbA1c without increasing the risk of severe hypoglycaemia
Benefits on both blood sugar control and psychological wellbeing after DAFNE remain at 1,2 and 7 years post course
Severe hypoglycaemia is reduced by more than 60% producing cost savings through reduced paramedic call outs, A&E attendances and admissions
Previous treatment for type 1 diabetes before DAFNE
Previously treatment for type 1 diabetes involved two injections of insulin daily of containing a mixture of two types of insulin.
The dose of insulin was fixed, therefore patients had to eat at the same time everyday and eat similar amounts of carbohydrates everyday. They also had to has a snack between meals to prevent hypos.
Less flexible,
How is insulin synthesised?
Original transcript: pre-pro insulin
Signal sequence removed: proinsulin (in rough endoplasmic reticulum)
Transfer to Golgi apparatus
Peptidases break off the C peptide leaving an A and B chain linked by disulphide bonds
One mole of C-peptide is secreted for each mole of insulin
Significance of c-peptide is that it’s inert, and thus a good index of insulin secretion.
How is insulin released into circulation?
Pancreas supplied by branches of the coeliac, superior mesenteric, and splenic arteries.
The venous drainage of the pancreas is into the portal system.
Half of the secreted insulin is metabolized by the liver in it’s first pass; the remainder is diluted in the peripheral circulation
C-peptide is more accurate index of insulin secretion in peripheral circulation (not metabolized by liver)
Hepatic portal vein is only a fraction of the cardiac output, so insulin levels in the peripheral circulation (where you can easily sample) are much diluted. One mole of C-peptide is secreted for each mole of insulin
How do β cells sense rise in glucose?
No glucose receptor
GLUT2 / Glucokinase can be thought of as the sensor
Effector is rise in ATP due to glucose oxidation
MAIN PATH- glucose entry to ATP production via glycolysis and TCA = closure of special K channel, which is ATP-gated (negatively) and consequent membrane depolarization.
→ increased Ca entry, and intracellular Ca → triggers insulin exocytosis.
THUS anything that can depolarize the B cell, or otherwise raise intracellular Ca
→ insulin release.
For example metformins, a common class of insulin-potentiating drugs, act to directly close the K/ATP channel, thus increasing insulin release by-passing the normal mechanisms.
Also, parasympathetic stimulation can increase insulin release. This it due to muscarinic R activation, which via intracellular signalling, leads to Ca release from intracellular stores.
Sympathetic stimulation, via alpha receptors, leads to a reduced sensitivity of the channel, leading to reduced likelihood of closure, and hence decreased inuslin release.
What does insulin binding to its receptor do?
The insulin receptor is a member of the tyrosine kinase superfamily
Insulin binding to its receptor
Activates cascade of protein phosphorylation, which stimulate or inhibit specific metabolic enzymes by modulating enzyme phosphorylation
Modulates activity of metabolic enzymes by regulating gene transcription
Insulin binds to its receptor (1),
→ starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5), and fatty acid synthesis (6) (http://en.wikipedia.org/wiki/Insulin_receptor).
Insulin receptor
The insulin receptor is a disulfide-linked tetramer with the β-subunits spanning the membrane and the α-subunits located on the exterior surface.
acetyl-CoA carboxylase (ACC). This is the enzyme that starts off lipogenesis, by converting acetyl CoA to malonly CoA. Note here that it’s under inhibitory control by PKA, which in turn depends on cAMP for its activity. If you follow the pathways backward you will see how insulin binding leads to a decrease in cAMP levels, reducing PKA activity, releasing ACC from inhibition, thereby promoting lipogenesis.
phosphatidylinositol-3-kinase phosphorylates membrane phospholipids, the major product being phosphatidylinositol-3,4,5-trisphosphate.
Glucagon receptor
Activates adenyl cyclase
Activates PKA
Encourages lipogenesis
Incretin effect experiment
Evidence for its impairment in T2DM
Major target for new drug development
Experiment:
It involves continuous monitoring of plasma glucose (not shown) as well as insulin. Two sets of measurements. First, you give an oral glucose load and monitor plasma glucose over the course of 2-3 hrs. We know it will rise a bit and we track the time-course and amount of this rise.
Second, you repeat, but this time no oral glucose, instead you attempt to copy as closely as possible the previously-measured change in plasma glucose by iv infusion of glucose. In both cases we track the insulin response.
The result is a much greater insulin response when glucose enters circulation via the oral route than when the same levels are directly infused into the blood. What do we conclude from this?
Something in the GI tract must potentiate insulin release in response to glucose, since insulin release is lower when you by-pass the gut.
Role of incretins in glucose homeostasis
The incretins: glucagon-like peptide-1 (GLP-1) and GIP
Type 1 diabetes impact on adipose and ketone levels
Complete lack of insulin
So adipose tissue breakdown and high ketone levels (ketoacidosis)
Signs and symptoms of hypoglycaemia
AUTONOMIC Hunger Confusion Sweating Shaking Dizziness Tachycardia
Adrenaline and Glucagon release (fight or flight)
NEUROGLYCOPAENIC
Confusion
Drowsiness
Discoordination
Slurred speech
Atypical behaviour (e.g. aggression, irrational reasoning)
Severe: reduced consciousness, coma, convultions.
impaired cerebral function below 3.5mmol/L
How does insulin pumps work?
Small computerised battery operated pump
Pump reservoir – holds 2-3 days worth of insulin 1.8ml-3ml
Infusion set – thin plastic tube with a soft cannula or steel needle at the end. This is inserted just under the skin. Length 6mm
CSII eliminates a large subcutaneous insulin depot of the BG insulin
Stepwise treatment of type 2 diabetes
Type 2 diabetes is traditionally treated in a stepwise manner. Initial therapy is usually diet and increased exercise. However, lifestyle measures generally fail to control glycaemia and, therefore, pharmacological treatment is instigated. Initial therapy is with a single oral drug although monotherapy often fails over a period of time and a combination of two or more oral therapies is used.
Subsequently, failure of all oral combination therapy may occur when -cell failure has progressed to such a degree that additional, exogenous insulin is required
Sulphonylureas mechanism of action
Stimulate insulin secretion Potent Act on beta-cells Closes ATP dependent K+ channels Results in Ca2+ influx and release of insulin storage granules
Blocking of
K+ATP Channels
(as does Glucose)
The incretin effect- β-cell response to oral vs IV glucose
sharp difference between the insulin response to oral glucose compared with the response to intravenous glucose = incretin effect.
Plasma glucose levels are shown in the left panel. The right-hand panel shows the insulin response as measured by C-peptide (a surrogate marker for insulin).
On the left, the blue line demonstrates plasma glucose levels achieved in response to an oral glucose load. The blue line on the right indicates the corresponding insulin response.
The orange lines demonstrate the plasma glucose and C-peptide responses to intravenous glucose.
The difference is the incretin effect, indicated by the shaded area on the right.
Subjects received glucose doses of 25, 50, or 100 g dissolved in a standard volume of 400 ml in a random order.
What are the GLP-1 effects in humans and the role these effects play in normal physiology.
Upon the ingestion of food, plasma glucose levels increase postprandially.
GLP-1 is secreted from intestinal L cells and provides a stimulus to the β-cells to release insulin in a glucose-dependent manner. When plasma glucose levels return to normal, the action of GLP-1 decreases1.
GLP-1 also suppresses glucagon levels that are inappropriately elevated in patients with type 2 diabetes. Lower glucagon levels leads to decreased hepatic glucose output
In the stomach, GLP-1 slows the rate of gastric emptying, which reduces the rate at which meal-derived glucose appears in the circulation
In the brain, GLP-1 promotes satiety and reduces appetite, which leads to a feeling of fullness and a reduction in food intake
All these actions help maintain overall glucose homeostasis.
2 main incretin hormones
GLP-1 (Glucagon-like peptide-1)
GIP (Gastric inhibitory polypeptide)
Inhibition of DPP-4 to increase active GLP 1
Oral tablets
