TYPE 2 DIABETES: DIAGNOSIS, TREATMENT and MEASUREMENT Flashcards
What is the diagnosis of diabetes?
Random blood glucose >11.1 (3 or 2 and symptomatic)
OGTT and 2 hours. >7.8 is IGT or >11.1 DM
Fasting >5.6 IGT or >7 DM
For HBA1c high risk is 42-47 mmmol/mol, DM>48
What proportion of DM is T1?
About 10%. T2Dm prevalence rising and often under diagnosed in many areas of the world. Levels are rising at a faster rate than predicted, 25% of americans and responsible for 10% of cardiovascular deaths. T1DM is also increasing, perhaps better at diagnosing
What happens in you leave T1DM/T2 untreated?
DKA and death
T2. left untreated, microvascular, macrovascular, renal, retinal and neural pathology develops gradually
What are insulin’s actions?
Promote energy storage. suppresses gluconeogenesis
stimulates glucose uptake in muscle and fat
•stimulates glycogen synthesis in muscle and liver •suppresses adipose tissue lipolysis and stimulates lipogenesis in liver and adipose tissue • •suppresses protein breakdown •stimulates cell proliferation
What organs are affected in T2DM?
- PANCREAS increased glucagon and decreased insulin
- INTESTINE reduced incretin effect
- FAT Increased lipolysis decreased glucose uptake
- BRAIN neurotransmitter dysfunction
- KIDNEY increased glucose reabsorbtion
- MUSCLE decreased glucose uptake
What is a constant?
Beta cell output x insulin resistance = constant
What are consequences of insulin resistance?
Consequences of dm - protein glycation, oxidative stress, sub clinical inflammation, hypertension, low HDL, high triglycerides and impaired fibrinolysis. All associated with increased vascular disease. Metabolic syndrome, micro and macro vascular complications.
What are general causes of insulin deficiency?
Causes of insulin deficiency: Autoimmune b cell destruction (infection?) Glucotoxicity/lipotoxicity (obesity) damages the pancreas Genetic variation (fam history of diabetes) Inc cortisol/adrenalin (stress) – opposes insulins effects by inc glucose levels Impaired incretin response Inc glucagon
What is insulin resistance defined as?
- Conventionally = rate at which plasma glucose levels decrease per unit increase in plasma insulin
- Involves both stimulation of glucose uptake by peripheral tissues and suppression of glucose production by the liver (though suppression more sensitive than glucose uptake)
- Dose dependent characteristics to maximize the efficiency of nutrient utilization after a meal and the provision of glucose during fasting.
- Insulin resistance leads to a rightwards shift in the curve
What is the main cause of morbidity in T2DM?
Macrovascular disease is responsible for 65% of deaths in T2DM, CVD events more fatal than those without DM. Having diabetes but no previous MI gives you the same risk of having an MI as someme without diabetes that has had a previous MI
What are the main types of treatment in T2DM?
1) Insulin sensitisation: weight loss, exercise, metformin, thiazolidinediones, PPAR gamma agonists – glitazones (pioglitazone, rosiglitazone)
2) Insulin augmentation: sulphonylureas (glipizide, glimepiride), incretin autmentation – GLP 1augmentation (exenatide, liraglutide) DPP4 antagonists (sitagliptin, cidagliptin), insulin anaglogues (human insulin, glargine, lispro, islet cell transplantation)
3) Absorption inhibition: alpha glucosidase inhibitors (acrabose), bariatric surgery
4) Inflammation suppression (anakinra IL receptor antagonist), salsalate (asprin analogue – in high doses stops b cell inflammation and its dysfunction)
5) Renal reabsorbtion inhibitors renal re-absorption inhibition sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin, canagliflozin)
Eg screening before the onset of T2DM
Prevention with diet, exercise and metformin in those with IGT
At what levels does resistance occur?
- PLASMA: reduced blood flow
- Endothelium: Endothelial transporter defects
- Insulin receptor
• Obesity→ inflammation→ TNF alpha and serine phosphorylation of the IRS
What is more sensitive - peripheral uptake of glucose or inhibition of gluconeogenisis?
suppression of hepatic glucose production is much more sensitive to insulin than is glucose utilisation by peripheral tissues
half-maximal suppression of gluconeogenesis achieved at ~15 mU/L insulin
half-maximal stimulation of glucose utilisation achieved at ~60 mU/L insulin
How do obesity and stress lead to insulin resistance?
Inflammatory cytokines, fatty acids lead to TNFalpha and JNK that lead to serine not tyrosine phosphorylation of the IRS
What evidence number one is that there insulin resistance is important in the pathogenesis of T2DM. Think associated conditions
Insulin resistance is known to occur to be a consistent feature of states associated with T2DM. They looked at varying degrees of igt and the insulin response
Number 2 evidence for insulin resistance? Think glucose progression
in progression through increasing glucose levels to diabetes insulin resistance precedes insulin deficiency
Number 3 evidence for insulin resistance? Think direct comparison
An isolated defect in insulin sensitivity has a more prolonged and pronounced effect than does an isolated change in the pattern of insulin secretion
study 7 lean without diabetes,13 obese without diabetes,14 obese with T2DM
determine typical post-prandial insulin profiles in normoglycaemic and T2DM individuals
suppress endogenous insulin secretion and simulate post-prandial insulin profiles by infusion
infuse glucose to mimic rate of glucose entry into the circulation following carbohydrate ingestion
Number 4 IR, think Blood glucose.
When insulin and glucose levels are independently controlled, insulin resistance can be seen to affect the blood glucose more than insulin deficiency. Measure this using a hyperinsulinaemic euglyceamic clamp
Number 5 IR think family
- Normoglycaemic relatives of patients with T2DM are insulin resistant but not insulin deficient
Number 5 IR think prediction
- Insulin resistance predicts T2DM whereas beta cell dysfunction does not
Those who had very low insulin sensitivity to begin with were much more likely to develop DM, they did not have impaired beta cell function at baseline
Number 6 IR think transition
- Insulin resistance is what changes in the transition from normoglycaemia to hyperglycaemia
Number 7 IR think prevention
- T2DM can be prevented by strategies that alleviate insulin resistance such as diet, exercise and metformin
What is the time scale between diabetes and insulin resistance?
Insulin resistance precedes diabetes by many years
How does insulin secretion occur?
It is made from pro-insulin with an alpha chain, beta chain and c peptide chain.
What augments the insulin response to glucose?
GIP and GLP1, which are thought to be responsible for 50-70% of the post prandial rise in insulin
What factors influence insulin secretion?
glucose, fatty acids, amino acids: + arginine: + autonomic nervous system activity: - other pancreatic hormones (glucagon, somatostatin): - incretin gut peptides (GIP, GLP-1): + sex steroids: + sulphonylurea drugs: +
What factors accompany insulin deficiency?
- amyloid deposition in the pancreas
- impaired insulin processing
- defects in glucokinase and nuclear signalling (e.g. HNF-4)
- KATP channel over-activity (e.g. mutations impairing sensitivity to ATP)
Evidence 1 ID? Think families
- Regular pulsatility of insulin secretion is disrupted in those at risk of DM. Beta cell mass increase in insulin resistant states such as obesity and pregnancy, and beta cell responsiveness also increases. Insulin output from the pancreas adapts to prevailing insulin sensitivity.
Evidence 2 ID? Think in physiological IR states
Beta cell mass increases in insulin resistant states (e.g. obesity, pregnancy) Beta cell responsiveness increases in insulin resistant states (e.g. nicotinic acid administration) (how much insulin B cell release in response to a given glucose stimulus). HYPERBOLIC NORMAL RELATIONSHIP
What is the deposition index
Beta cell output x insulin resistance. the disposition index quantifies how well the pancreas is able to respond to decreasing insulin sensitivity
It gets less and less as you become diabetic
Evidence 3 ID. Think compensation
for a given level of insulin resistance, compensatory hyperinsulinaemia is reduced in those at risk of diabetes. Give OGTT to IGT patients
Evidence 4 ID. Think post meal
The initial response to glucose is reduced. Draw graph of what happens post meal
Does high insulin in some of the original experiments mean high insulin activity?
In type 2 diabetes the proinsulin processing into insulin and c peptide can be impaired so you get proinsulin with only 64 and 65 removed for example. They found that these propeptides of insulin corss reacted as insulin in the original assays used and these propeptides have little biological activity. So the high insulin seen may be due to the immunoactivity but this doesn’t mean high
biological activity
Evidence 4 ID think insulin processing
5.processing of insulin for secretion is disrupted in diabetes Phase 1 insulin, proinsulin and incident diabetes: If you follow up patients and see what predicts their development of diabetes. 27 yr follow up, measured glucose, insulin sensitivity etc the only independent predictor of T2DM was the acute insulin response to glucose and proinsulin levels. The more proinsulin the higher your risk of diabetes and the less you AIR is the higher your risk of diabetes. So these two things which are related to impaired insulin secretion caused diabetes.
Evidence 5 ID think predictors
the great majority of genetic predictors of Type 2 diabetes concern insulin beta cell function •
5 reasons why insulin production is difficult to measure?
Very difficult as insulin produced in very inaccessible area of the body, the hepatic portal vein, also because of the closed loop system between insulin and glucose. Between the pancreas and the periphery there is a complex pathway of distribution. 50% is uptaken on first pass metabolism through the liver . Then some goes into extra cellular fluid, some into plasma and then some is renally excreted. Phasic/ pulsatile production.
Is influenced by many factors:
1) INCRETIN hormones increase the sensitivity of insulin release
2) INCREASED SNS/INFLAMMATORY TONE suppresses insulin production
