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Diabetes Mellitus Flashcards

1
Q

Diabetes definition

A

Chronic non-communicable disease characterised by hyperglycaemia
Usually irreversible
Late complications

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2
Q

Diabetes cause

A

Relative insulin deficiency or resistance to both

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3
Q

How many people diagnosed in UK

A

3.7 million

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4
Q

How many deaths 2015

A

1.6 million

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5
Q

Type 1 Diabetes

A

Chronic autoimmune
Immune (T cell) mediated disruption of the pancreatic Beta cells within the islets of Langerhans
Insulin deficiency- constant need for injections

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6
Q

Type 1 as immune-mediated disease

A

Infiltration of pancreas islets by mononuclear cells (insulitis)
90% newly presenting patients possess autoantibodies against islet constituents

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7
Q

Type 1 hereditary

A

Prominent as disease of childhood or young patients <30
Any age
Increased susceptibility may be inherited

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8
Q

Type 2

A 
Most common - 80-95%
Chronic, progressive disease
Abnormal insulin action + secretion
More present in older, but now increasing in young population
Genetic components to disease
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9
Q

Genes that may be responsible for Type 2

A

GKRP

PPARG

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10
Q

RF Type 2

A 
Obesity
Family history
Age
Ethnicity
Environment
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11
Q

Obesity BMI

A

Greater than 31 –> 40x increased risk

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12
Q

Fam history RF

A

1st generation - lean + otherwise healthy relatives often develop skeletal muscle insulin resistance

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13
Q

Monozygotic twins

A

If 1 has diabetes, other has 60-90% increase chance of diabetes

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14
Q

Obesity- Intrinsic effects

A

Mitochondrial dysfunction
Oxidative stress
ER stress

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15
Q

Obesity- Extrinsic effects

A

Accumulation of lipids + their metabolites
Increased conc. of circulating free FAs
Chronic inflammation
Altered adipokine levels

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16
Q

Obesity- hyperinsulinaemia

A

Increases lipid synthesis + exacerbates insulin resistance

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17
Q

Most common alterations that lead to insulin resistance

A

Decrease in no. insulin receptors
Decrease in catalytic activity of receptor
Increased activity Tyr phosphatases
Increased Ser/Thr phosphorylation of receptor or of IRS
Decreased PI3K/Akt activity
Decreased levels + functions GLUT4

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18
Q

Serine/Threonine kinase activation

A

Activated by pro-inflammatory cytokines, saturated FFAs + amino acids
Phosphorylate IRS, reducing its Tyr phosphorylation + increasing its degradation

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19
Q

Insulin resistance in healthy individuals

A

Body can generate new Beta cells in response to insulin resistance associated with obesity or pregnancy

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20
Q

Insulin compensation in insulin resistance

A

Islets increase both in size + number due to beta cell increasing in size and number
Increased Beta cell function

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21
Q

Glucose tolerance can be maintained by…

A

Increased insulin resistance

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22
Q

Impaired islet compensation

A

In Type 2, number of islets decreases

–> significant reduction in number of Beta cells per islet

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23
Q

Reduced pancreatic beta cell mass/increased death

A

Reduced pancreatic Beta cell function

–> reduced insulin synthesis + secretion

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24
Q

Susceptibility genes associated with Type 2 diabetes

A

Most are regulators of cell turnover or regeneration

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25
Glucagon deregulation
Excessive circulating glucagon levels reported in all diabetes forms
26
Beta cell adaptation to insulin resistance
Increased glucokinase activity Increased malonyl-CoA --> inhibition of CPT1 + increase in DAG levels Fatty acids bind to GPR40 GLP1 binding to its receptor Release of Ach from parasympathetic nerve terminals
27
Mechanisms in insulin resistance
Impaired islet compensation Reduced pancreatic Beta cell mass + increased death Pancreatic Beta cell loss of function
28
Impaired islet compensation - Type 2
Number of islets decrease | Significant reduction in number of Beta cells per islet
29
Type 2- Reduce pancreatic Beta cell mass + increased death
Many susceptibility genes associated with type 2 diabetes are regulators of cell turnover or regeneration
30
Type 2- Beta cell loss of function
Most risk variants for type 2 diabetes in healthy pop. act through impairing insulin secretion rather than action Inherited abnormalities of Beta cell function or mass --> further enhances insulin resistance
31
Mature onset diabetes of young (MODY)
Autosomal dominant inheritance Present at birth, but often detected only later in life Pancreatic Beta cell dysfunction
32
Gestational diabetes
Occurs 2-6% pregnancies European women Insulin resistance not compensated Increased complications 2nd half pregnancy Increased risk subsequent development type 2
33
Latent autoimmune diabetes of adults (LADA)
5-10% phenotypic type 2 diabetics have markers of autoimmunity Progression to insulin dependency faster than normal type 2
34
Diagnosis
``` One abnormal plasma glucose Random >11.1mmol/L Fasting >7mmol/L Thirst Increased pee Recurrent infections Weight loss Drowsiness Coma ```
35
Asymptomatic ppl diagnosis
Two fasting venous plasma glucose samples in abnormal range
36
Oral glucose tolerance test
Normal fasting <6.1 | Normal after 2h <7.8
37
HbA1c advantages
Reliable measure HbA1c levels relatively stable vs glucose Ease of sample collection No need for 8h fast- convenient
38
HbA1c limitations
Cost Influence of Hb traits Conditions affecting RBC turnover
39
HbA1c cut off point diagnosis
48mmol/mol (6.5%)
40
Treatment aim
Lower blood glucose levels
41
Treatment drugs
Biguanides (Metformin) Sulfonylureas TZDs others
42
Treatment pathways
``` Enhance insulin activity Inhibit gluconeogenesis Stimulation of insulin secretion Enhance GLP1 activity Reduce DDP4 activity ```
43
Enhancement of insulin sensitivity- drug
Biguanides (Metformin)
44
Inhibition of gluconeogenesis- drug
Biguanides (Metformin)
45
Stimulation of insulin secretion- drug
Sulfonylureas Meglitinides --> act on ATP sensitive potassium channel, closing it
46
Enhancement GLP1 action- drug
Biguanides (metformin)
47
GLP 1 actions
Inhibits glucagon secretion + hepatic glucose production Augments glucose induced insulin secretion Slows gastric emptying Promotes satiety Restores beta cell function Increases insulin biosynthesis Promotes Beta cell differentiation
48
Inhibition of DDP-4 action- drug
DDP 4 inhibitors | --> block DDP4 and decrease glucose (DDP4 enzyme inactivates GLP 1)
49
Acute complications of diabetes
Ketoacidosis | Hypoglycaemia
50
Ketoacidosis
Continual use of FAs for energy --> ketone body production Blood + urine acid levels rise, dehydration, coma, death Potentially life threatening More common type 1
51
Ketoacidosis emergency treatment
Fluids Electrolytes Insulin
52
Hypoglycaemia
<70mg/dL (<3.9mmol/L) | Presence of Whipple triad
53
Whipple triad
Low blood glucose Symptoms + signs associated with low blood glucose Resolution of symptoms + signs by carbohydrate ingestion
54
Hypoglycaemia causes
``` Alcohol excess Insulinoma Excessive exercise Reactive hypoglycaemia Type 1 diabetes ```
55
Chronic complications of diabetes
Hyperglycaemia | Dyslipidaemia
56
Hyperglycaemia- Macrovascular
Atherosclerosis
57
Hyperglycaemia- Microvascular
Kidney disease Nerve disease Blindness Amputation
58
Dyslipidaemia
Ectopic fat deposition in skeletal muscle + liver in exacerbation of insulin resistance Macrovascular complications
59
Hyperglycaemia Pathophysiology
Excess glucose diverted into other pathways
60
Hyperglycaemia- hyperactivation of PKCs
``` Can damage blood vessels Increased permeability Increased occlusion Increased reactive O2 species levels Increased inflammation Mitochondrial dysfunction ```
61
Diabetic retinopathy- Non-Proliferative
Dilation of retina veins + microaneurysms Can cause internal haemorrhaging + oedema in retina Oedema in central retina is main cause of vision loss in this case
62
Diabetic retinopathy- Proliferative
Fragile, new blood vessels form near optic disk Grow on vitreous chamber and elsewhere in retina Can bleed, reduce vision + lead to separation + detachment of areas in retina
63
Diabetic retinopathy occurrence
20 years poorly controlled diabetes
64
Diabetic nephropathy
Damage to BVs in glomerulus - -> proteinuria, glomerular hypertrophy, decreased GFR, renal fibrosis - -> 1/3 patients affected
65
Diabetic neuropathy
Damage to nerve vessels + blood vessels supplying nerves Peripheral- pain or loss in hands, arms, feet, legs Autonomic- changes in digestion, bowel + bladder control, erectile dysfunction, nerves supplying heart Proximal- pain in thighs + hips, weakness in legs Focal- any nerve in body
66
Atherosclerosis mechanism
AGE modification of oxidised LDL receptor --> enhanced LDL uptake into atherosclerotic plaques AGE-LDL induces pro-inflammatory cytokine production Glycation of apolipoprotein --> impaired cholesterol efflux from atherosclerotic plaques Glycation of LDLR and LDL --> impaired cholesterol clearance
67
Atherosclerosis effect
Tissue nutrient + O2 supply to heart, brain + extremities compromised
68
Most common cause of death for patients with diabetes
Atherosclerosis | 70%

Metabolism CC (29 decks)

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