TYPE 2 DIABETES: DIAGNOSIS, TREATMENT and MEASUREMENT Flashcards
1
Q
What is the diagnosis of diabetes?
A
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
2
Q
What proportion of DM is T1?
A
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
3
Q
What happens in you leave T1DM/T2 untreated?
A
DKA and death
T2. left untreated, microvascular, macrovascular, renal, retinal and neural pathology develops gradually
4
Q
What are insulin’s actions?
A
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
5
Q
What organs are affected in T2DM?
A
- 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
6
Q
What is a constant?
A
Beta cell output x insulin resistance = constant
7
Q
What are consequences of insulin resistance?
A
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.
8
Q
What are general causes of insulin deficiency?
A
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
9
Q
What is insulin resistance defined as?
A
- 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
10
Q
What is the main cause of morbidity in T2DM?
A
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
11
Q
What are the main types of treatment in T2DM?
A
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
12
Q
At what levels does resistance occur?
A
- PLASMA: reduced blood flow
- Endothelium: Endothelial transporter defects
- Insulin receptor
• Obesity→ inflammation→ TNF alpha and serine phosphorylation of the IRS
13
Q
What is more sensitive - peripheral uptake of glucose or inhibition of gluconeogenisis?
A
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
14
Q
How do obesity and stress lead to insulin resistance?
A
Inflammatory cytokines, fatty acids lead to TNFalpha and JNK that lead to serine not tyrosine phosphorylation of the IRS
15
Q
What evidence number one is that there insulin resistance is important in the pathogenesis of T2DM. Think associated conditions
A
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
16
Q
Number 2 evidence for insulin resistance? Think glucose progression
A
in progression through increasing glucose levels to diabetes insulin resistance precedes insulin deficiency
17
Q
Number 3 evidence for insulin resistance? Think direct comparison
A
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
18
Q
Number 4 IR, think Blood glucose.
A
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
19
Q
Number 5 IR think family
A
- Normoglycaemic relatives of patients with T2DM are insulin resistant but not insulin deficient
20
Q
Number 5 IR think prediction
A
- 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
21
Q
Number 6 IR think transition
A
- Insulin resistance is what changes in the transition from normoglycaemia to hyperglycaemia
22
Q
Number 7 IR think prevention
A
- T2DM can be prevented by strategies that alleviate insulin resistance such as diet, exercise and metformin
23
Q
What is the time scale between diabetes and insulin resistance?
A
Insulin resistance precedes diabetes by many years
24
Q
How does insulin secretion occur?
A
It is made from pro-insulin with an alpha chain, beta chain and c peptide chain.
25
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
26
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: +
```
27
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)
28
Evidence 1 ID? Think families
1. 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.
29
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
30
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
31
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
32
Evidence 4 ID. Think post meal
The initial response to glucose is reduced. Draw graph of what happens post meal
33
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
34
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.
35
Evidence 5 ID think predictors
the great majority of genetic predictors of Type 2 diabetes concern insulin beta cell function •
36
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
37
For insulin secretion, what is the most accurate in terms of surrogate to most precise?
homeostasis model assessment•the insulinogenic index•IVGTT acute insulin response•IVGTT modelling: glucose C-peptide minimal model•IVGTT modelling: insulin C-peptide combined model•OG/MTT modelling: glucose C-peptide modelling•hyperglycaemic clamp•C-peptide deconvolution analysis (reference method)
38
What is it does insulin's metabolism allow?
Plasma half life of insulin is very short meaning that different phases in insulin secretion can very clearly be monitored. Use c peptide as not taken up by liver metabolism and produced in equimolar quantities.
39
What is HOMA? Pros and Cons
Provides a model of insulin resistance as well as beta cell dysfunction. Just need fasting glucose and insulin/c peptide.
It assumes that insulin resistance causes higher basal insulin concentrations and that beta cell dysfunction causes higher basal glucose production. FOR A GIVEN COMBINATION OF INSULIN RESISTANCE AND BETA DEFICIENCY THERE WILL BE A UNIQUE COMBINATION OF BASAL GLUCOSE AND INSULIN LEVELS. If there is impaired beta cell function, fasting glucose will rise in proportion to this.
It's a computer based, mathematical stimulation model.
PROS: simple to measure basal glucose and insulin and easy to carry out calculation. It correlates with the glycaemic clamp and finally provides index of insulin resistance and secretion.
CONS: from experimental data and only provides relative insulin resistance and secretion
40
What is the euglycaemia hyperinsulinaemic clamp? What value is given
1) THE EUGLYCAEMIC HYPERINSULINAEMIC CLAMP – gold standard for insulin resistance
Measure blood glucose every 5 minutes for 2 hours and then give a constant infusion of insulin to make hyperinsulinaemic. See what rate that glucose has to be given to maintain normoglycaemia. STEADY STATE (M VALUE) glucose infusion rate equals glucose disappearance rate (both suppression of endogenous glucose production and stimulation of uptake into tissues). Then get STANDARD CURVE so can see if receptor defect is before or after the receptor. The higher the m value the more sensitive that cells are to insulin.
To distinguish between production and uptake give isotopically labelled glucose at constant rate before and during the clamp. Difference between pre clamp and steady state gives dilution rate. The glucose production rate is the rate of entry of glucose into the system minus the m value.
Clamp based variants can be used for measuring other insulin dependent processes such as suppression of lipolysis, amino acid metabolism or can be used in conjunction with other techniques such as indirect calorimetery or tissue biopsy studies. There are also hyper and hypo glycaemic variants.
PROS: reference procedure that provides measure of true insulin sensitivity and is highly versatile.
CONS: complex procedure and sustained hyperinsulinaemia is not physiological
41
What is the gold standard for measure insulin secretion?
Insulin / C-peptide secretion by deconvolution (1). give a bolus C-peptide injection and measure C-peptide concentrations to derive a C-peptide decay profile. the reference method for measuring insulin secretion•determine the C-peptide kinetic rate constants, k01, k12, k21, and volume of distribution, Vd, for an individual volunteer•use the rate constants and volume of distribution, plus the equations of C-peptide kinetics to determine the insulin secretion profile that can give rise to any observed C-peptide profile in that individual volunteer
42
What is the IGVTT minimal model?
What does it assume?
What does it rely on?
Pros and COns
Measure first phase insulin after glucose load, iv. Area under graph is equal to insulin secretion. Mathematical model of beta cell function.
ASSUMPTIONS: the injected glucose distributes instantly into a single compartment. The glucose disappearance rate depends on the plasma glucose concentration and glucose sensitivity. The activity of insulin in a remote compartment which then depends on insulin sensitivity.
RELIES on there being enough change in plasma insulin concentration in which to relate the change in plasma glucose.
For patients with limited insulin production: inject glucose, then 20mins later tolbutamide and insulin. Then phase 1 insulin secretion can be measured.
For normoglycaemia patients use 0.5 g/kg approach for glucose.
Then forms complicated equation.
PROS it's a relatively simple procedure that allows simultaneous evaluation of insulin secretion
CONS it requires complex mathematical analysis with simplifying equations necessary, need specialist models and takes 3 hours
43
What is the short insulin test?
5) SHORT INSULIN TOLERANCE TEST
Inject insulin and calculate the rate of fall of glucose levels.
Simple and easy to carry out but risk of hypoglycaemia and there may be counter regulatory responses. Dose standardised?
44
Very generally, what investigation for insulin secretion in epidemiological investigations
HOMA or OGTT
45
For insulin secretion, what for small to large scale for investigation of secretion and sensitivity
IVGTT insulin (AIRg or model-derived measures) for small to large scale investigations with evaluation of both insulin sensitivity and secretion
46
When do you use bolus c peptide/ convolution measurements?
Bolus C-peptide injection / deconvolution analysis for small, intensive investigations involving a high degree of precision
47
For insulin sensitivity, what is the surrogate to best investigation?
```
fasting plasma insulin
fasting insulin and glucose-derived indices
OGTT insulin
OGTT insulin and glucose–derived indices
short insulin tolerance test
minimal model analysis of the IVGTT
euglycaemic, hyperinsulinaemic clamp
```
48
For the euglycaemic hyperinsulinaemic clamp, what value do you get?
The steady state value when glucose infusion rate is constant. The higher the m value is, the more insulin sensitive the tissues are.
49
What are the various blots used for?
Northern blot -mRNA
Western blot -protein
Southern blot DNA
South Western post translational modification
50
How to quantify levels of peptide in the brain?
radio immuno assay, however won't measure in cells particularly well.
51
What is the difference between in situ hybridisation and immunohistochemistry
How to locate precisely: IN SITU HYBRIDISATION (mRNA) which uses radiation.
Or IMMUNOHISTOCHEMISTRY for proteins using specific ANTIBODIES
52
How do you see which neuronal pathway is activated?
C-fos
53
How do you establish the role of a peptide?
optogenetics or knock out mice models or carry out cell lines
54
For conducting studies, for ethics whose approval do you need?
ethics board- central office for research ethics committee (COREC). Home office for animal studies. MHRA medicines healthcare regulatory agency
55
What do you have to do to test in humans?
3 species for 3 months administration, then take hormones out for histology. Give dose higher than would give humans to see the effect. CAL (?) test for bacteria as clots when comes into contact with bacteria.
56
How can you see which food is being metabolised?
Respiratory quotient
57
How do you determine lactose breakdown?
Hydrogen breath test for lactose broken down.
58
How do you test gastric motility?
Give paracetamol and see how quickly it appears in the blood
59
What should graphs always have?
Error bars
60
What is the difference between the different stages of a clinical trial?
Phase 0: for safety only, healthy volunteers
Phase 1: small number of healthy volunteers to test safety and dosage- pharmacokinetics and pharmacodynamics (20-80)
Phase 2: small number of patients with condition, 20-30. Stage that normally fail at
Phase 3: RCT. Need 2 successful for regulatory agents
Phase 4: long term side effects
61
How do you test for nausea in rats?
Conditioned taste aversion
62
How do you test for syndromic forms of obesity?
EG prader willi and Bader biedel. DO PCR
63
What happens in case controlled?
Case controlled: those who already have the disease matched to those who don't
64
What is the difference between came controlled and cohort?
Eg Cohort (longitudinal, control vs risk factor, better for rare risk factor) vs case control (Observed, looking back, outcome not determined by researcher, better for rare outcomes
65
What are four types of bias?
* LITERATURE REVIEW: reporting bias, avoid by doing comprehensive search
* RECRUITMENT: selection bias, avoid by randomization and allocation concealment
* Whilst running the study, there may be performance bias, overcome by blinding
* COLLECTING INFORMATION: observation bias, avoided by blinding outcome assessment
66
What should you look for in statistics?
are the appropriate? Confidence intervals? P values? Was a power calculation performed?
67
What is external validity?
Can the findings be justified to the general population
68
What do you look for when you look at a paper?
1) PICO – Patient, Intervention, Comparison and Outcome. Is it a relevant/important question? Adding anything new?
2) study design appropriate
3) bias
4) findings justify conclusion
5) external validity
6) Surrogate endpoints – may correlate with a real clinical endpoint but may not correlate with a guaranteed relationship (eg no point In measuring less pain from a drug if more people just dying as have not measured death as an outcome)
7) Conflicts of interest
69
What is used to assess association and causation?
Bradford Hill Criteria
1 Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal.
2 Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.
3 Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.
4 Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).
5 Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.
6 Plausibility: A plausible mechanism between cause and effect is helpful
7 Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect.
8 Experiment: "Occasionally it is possible to appeal to experimental evidence"
9 Analogy: The effect of similar factors may be considered.
70
What is the difference between type 1 and 2 errors?
Type 1 Errors
Detecting an effect which is not present: Rejecting the hypothesis when it is true. Can occur if you do enough statistical tests
Eg after conducting a study, there is p<0.05 when in fact there is no real difference. There is either a difference or it is due to chance.
Type 2 Errors
Failing to detect a study when it is present. Rejecting the hypothesis when it is false. This is due to the power of the study often.
71
How does glucose secretion occur?
* Glucose enters the cell through Glut 2
* It is converted to glucose 6 phosphate by glucokinase
* Then converted to ATP
* This causes the membrane to depolarize and the ATP dependent K+ channels to shut
* This causes calcium to enter through voltage dependent calcium channel
* Leads to insulin granules to be secreted
* Insulin acts on its receptor and leads to the activation of the PI3K pathway and gene transcription
72
What is MODY?
• MODY2 have a mutation in glucokinase so that cell cannot sense glucose as effectively (less conversion to ATP). Have a higher glucose set point 5-5.8, less insulin post prandially and usually do not need Insulin treatment. Not particularly associated with any complications
73
How do thiazolidinediones work?
Thiazolidinediones or TZDs act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors, with greatest specificity for PPARγ (gamma). The endogenous ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing transcription of a number of specific genes and decreasing transcription of others.
74
How do thiazolidinediones work?
The activated PPAR/RXR heterodimer binds to peroxisome proliferator hormone response elements upstream of target genes in complex with a number of coactivators such as nuclear receptor coactivator 1 and CREB binding protein, this causes upregulation of genes (f):
Insulin resistance is decreased
Adipocyte differentiation is modified[1]
VEGF-induced angiogenesis is inhibited[2]
Leptin levels decrease (leading to an increased appetite)
Levels of certain interleukins (e.g. IL-6) fall
Antiproliferative action[citation needed]
Adiponectin levels rise
75
A very high blood glucose is likely to indicate what?
• If have very high blood glucose 30+ mmol/mol then most likely T2DM as takes a long time to build up
76
Why is BMI not that useful in diagnosis?
• BMI not that useful at diagnosis as whole population slightly obese
77
What role do ketones have in diagnosis?
• Ketones may not differentiate T1DM from T2 as may eventually get in T2DM when there is no insulin being produced from beta cells. FFA converted to ketones through lipolysis is suppressed by insulin.
78
When can you not use HbAIc?
in pregnancy or in blood conditions
79
What can happen immediately after the diagnosis of T1DM?
• In t1dm may have honeymoon period when still produce enough insulin. Especially at diagnosis can have antibodies to islet cells
80
What is the role of antibodies in diagnosis?
• If have antibodies can confirm T1DM but lack does not exclude since titres naturally drop anyway
81
What happens in DKA?
Occurs when in starvation body switches from carbohydrate metabolism to fat metabolism. FFA are produced in adipocytes and transported in the liver bound to albumin. Broken down into acetate and then turned into ketoacids which are then transported into peripheral tissue for oxidation.
82
What is the treatment in DKA?
Give IV fluids and insulin, potassium supplements, anti coagulation prophylaxis, monitor fluid balance, screen for infection
83
What is LADA?
* Academic definition of t1dm (latent autoimmune diabetes in adults)
* Diagnosis above 35 years and not requiring insulin for at least 6 months.
* Is slow autoimmune beta cell failure
* If GAD antibody and islet cell antibody present then likely to progress to complete beta cell failure within five years
84
Characteristics of MODY?
* 2% of all DM, often misdiagnosed
* genetic defect in glucose homeostasis, often only diagnosed in teenage years
* not initially insulin dependent usually
* very commonly has a family history
85
What happens in MODY2?
• MODY2 have a mutation in glucokinase so that cell cannot sense glucose as effectively (less conversion to ATP). Have a higher glucose set point 5-5.8, less insulin post prandially and usually do not need Insulin treatment. Not particularly associated with any complications
86
What is the other type of MODY? What is the problem with giving insulin
• 70% nuclear factor 1 alpha HNF, a TF. As there is a mutation, less insulin is coded for. Give sulphonylurea which closes ATP dependent k+ channel and leads to insulin being released
- hnf4a similar but more rare, older onset, Macrosomia and renal
• If give insulin treatment to such patients they may become hypoglycaemic
87
What are the final two types of diabetes
• There are also 2 forms of mitochondrial diabetes(maternal transmission and will need insulin): MELAS and MIDD. Maternal transmission, any degree of insulinopaenia and often accompanied by hearing loss
88
What did the Finish study show?
)FINNISH STUDY intensive lifestyle interventions reduced the risk oft2dm
89
What did the Nurses Health study show?
NURSES HEALTH STUDY :body fat is the largest determinant of t2dm risk. Best is lifestyle advice and metformin.
90
What is the key diabetes study
A key study is the UKPDS which ran over 20 years and 23 clinical sites (5000 patients) which showed that microvascular and macrovascular complications of T2DM could be improved by IMPROVING BLOOD GLUCOSE AND BLOOD PRESSURE. Evidence base for metformin
