Endocrine - Diabetes and Hyperglycaemia Flashcards
(121 cards)
1
Q
GLP-1 is secreted by which cells and in response to what?
A
L cells in the jejunum and ileum when food enters
2
Q
What does GLP-1 do?
A
- stimulates insulin secretion (glucose dependent)
- suppresses glucagon secretion
- slows gastric emptying
- improves insulin sensitivity
- reduces food intake
3
Q
What is the incretin effect?
A
Amplification of insulin response in ORAL compared to intravenous glucose
There is a diminished effect in diabetes
4
Q
Increased insulin does what to glucagon levels?
A
Increased insulin DECREASES glucagon
5
Q
Difference in glucagon levels between early and late diabetes
A
Usually low BSL –> decreased insulin –> increased glucagon BUT in T1DM glucagon doesn’t get this signal as there is already no insulin.
Early DM: high glucagon
Late DM with recurrent hypos: low glucagon, cortisol, GH and adrenaline
6
Q
Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- identical twin?
A
30 - 40%
7
Q
Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- parent and sibling?
A
25%
8
Q
Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- HLA identical sibling?
A
16%
9
Q
Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- Sibling
A
7%
10
Q
Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- Child
A
5%
11
Q
Geographical impact on incidence of T1DM?
A
Increased in Finland
12
Q
Which genes are SUSCEPTIBLE to T1DM?
A
HLA-DQ
HLA DR3 and DR4 (MOST diabetogenic)
(Both are on Chromosome 6)
Insulin VNTR on Ch 11
13
Q
Which genes are PROTECTIVE for T1DM?
A
HLA DR2
14
Q
Which chromosome is HLA-DQ and DR3 and DR4 located?
A
Chromosome 6
15
Q
Which chromosome is VNTR on?
A
VNTR is on Ch 11
16
Q
What perinatal factors increase risk of T1DM?
A
- Infections (congential rubella)
- maternal age >25yrs
- pre-eclampsia
- neonatal respiratory disease
- c-section
- neonatal jaundice (esp ASO incompatibility)
17
Q
What non-perinatal factors increase risk of T1DM?
A
Viral infection: children with T1DM are 10x more likely to have ENTEROVIRUS
- Vitamin D deficiency
- Early gluten exposure in infancy
- adiposity
18
Q
Pathodevelopment of T1DM?
A
T cell mediated autoimmunity, predominantly CD8+
19
Q
Which T cells is predominantly involved in T1DM?
A
CD8+ T cells
20
Q
What four antibodies are involved in pathodevelopment of T1DM?
A
(pro)insulin Ab
Anti-GAD
Anti-IA2
Anti-Zn Transporter 8 (ZnT8)
21
Q
Importance of Anti-ZnT8?
A
Anti-Zn Transporter 8 (Anti-ZnT8) is a beta-cell specific antigen.
ZnT8 is positive in 5% of patients with NEGATIVE GAD/IA2/insulin
22
Q
What is fulminant DM?
A
Severe onset suddenly Antibody negative Pancreatic enzymes positive BUT no pancreatitis Usually Asian
23
Q
Diagnostic criteria of LADA?
A
LADA = Latent Autoimmune Diabetes of Adulthood - Adult 30 - 75yrs - Diabetes diagnosis - Evidence of islet autoimmunity (anti-GD >5) - Period of insulin dependence
24
Q
Five features more frequent in LADA at diagnosis?
A
- Age <50yrs
- Acute symptoms
- BMI <25
- Personal hx of autoimmunity
- FHx of autoimmunity
25
Importance of LADA?
- theoretical risk of ketoacidosis
- preference for basal-bolus regime
- screen for associated autoimmune conditions (ie thyroid / coeliac)
26
Definition of MODY?
| Features?
Maturity-onset diabetes of the young (MODY) is characterised by the development of type 2 diabetes mellitus in patients < 25 years old.
Features of MODY
typically develops in patients < 25 years
a family history of early onset diabetes is often present
ketosis is NOT a feature at presentation
patients with the most common form are very sensitive to sulfonylureas, insulin is not usually necessary
27
Inheritance pattern of MODY
| What are the two most genetic causes?
Autosomal Dominant
MODY 3
60% of cases
due to a defect in the HNF-1 alpha gene
MODY 2
20% of cases
due to a defect in the glucokinase gene
28
MODY 3 underlying genetic defect?
defect in the HNF-1 alpha gene
29
MODY 3 underlying genetic defect?
defect in the glucokinase gene
30
HbA1c target in T1DM?
General: <=7%
Pregnancy: <=7%
Hypoglycaemia recurrence or unawareness <=8%
31
What was the DCCT Trial?
Intensive vs convensional sugar control in T1DM.
| - reduced risk of retinopathy, micro and macro albuminaemia, and neuropathy
32
In the DCCT Trial which subgroups were NOT supported?
- Recurrent hypoglycaemia
- Macrovascular complications
- Young children <13 years old
33
What was the EDIC Study?
Follow on from DCCT Trial, over the next 8 years HbA1c became the same but in the INTESNIVE treatment:
- reduced macro and micro albuminaemia
- reduced neuropathy
- nonfatal MI/stroke/CVS and cardiac mortaliy
34
Diagnostic Criteria for T2DM?
FASTING Glucose:
BSL 5.5 - 6.9 (--> needs OGTT)
BSL >7 (likely diabetes, need to repeat test if asymptomatic)
OGTT:
If fasting glucose 6-7 and 2hr glucose <7.8
--> impaired fasting glucose (IFG)
If fasting glucose 6-7 and 2hr glucose 7.8-11
--> impaired glucose tolerance (IGT)
If fasting glucose >7 and 2hr glucose >11
--> diabetes
If HbA1c >=6.5 and confirmed on repeat test
35
Diagnosing T2DM:
| Fasting glucose BSL 5.5 - 6.9?
need OGTT
36
Diagnosing T2DM:
| Fasting glucose BSL >7
Likely diabetes, need to repeat test if asymptomatic
37
Diagnosing T2DM:
| If fasting glucose 6-7 and 2hr glucose <7.8
--> impaired fasting glucose (IFG)
38
Diagnosing T2DM:
| If fasting glucose 6-7 and 2hr glucose 7.8-11
--> impaired glucose tolerance (IGT)
39
Diagnosing T2DM:
| If fasting glucose >7 and 2hr glucose >11
--> Diabetes
40
Diagnosing T2DM:
| Impaired fasting glucose (IFG)
If fasting glucose 6-7 and 2hr glucose <7.8
41
Diagnosing T2DM:
| Impaired glucose tolerance (IGT)
If fasting glucose 6-7 and 2hr glucose 7.8-11
42
Diagnosing T2DM:
| Diabetes
If fasting glucose >7 and 2hr glucose >11
43
Diagnosing T2DM with HbA1c?
If HbA1c >=6.5 and confirmed on repeat test
44
Treatment goals in T2DM?
Newly diagnosed early disease: <6.5%
Target HbA1c <7% in general
Except:
- if no insulin --> target <6.5%
- if hypoglycaemia --> target <8%
45
Treatment goal in T2DM in newly diagnosed early disease?
Target HbA1c <6.5%
46
Treatment goal in T2DM in general?
Target HbA1c <7%
47
Treatment goal in T2DM if no insulin?
Target HbA1c <6.5%
48
Treatment goal in T2DM if hypoglycaemia?
Target HbA1c <8%
49
Treatment algorithm for treating diabetes?
1st line is metformin
2nd line add in:
- sulfonylureas
- DPP4-inhibitor
- SGLT2 inhibitor
Then add:
3rd agent
OR add GLP-IRA or insulin
50
Which diabetes medications provide weight loss?
1st: GLP-1
2nd: SGLT2
3rd: Metformin
51
Metformin: Action?
Activates AMP-kinase
| Reduces hepatic glucose output and increases peripheral utilisation of glucose
52
Metformin: effect?
Decreases HbA1c by 15-22mmol (1.5-2%)
53
Metformin benefits?
Weight neutral
| Decreases CVS events
54
Metformin S/E:
GIT effects
B12 deficiency
lactic acidosis
Acute hepatitis
55
Metformin contraindications?
Renal, hepatic or cardiac failure
56
Is metformin an insulin SENSITSER or STIMULATOR?
Sensitiser
57
Sulfonylureas: name them
Gliclazide, glipizide, glibenclamide, glimepiride
58
Sulfonylureas: Action?
Closes k-ATP channels on beta cell plasma membranes
| Binds to beta cell receptor to stimulate glucose-independent insulin release
59
Sulfonylureas: effect?
Decreases HbA1c by 0.6 - 1.15% when added to metformin
60
Sulfonylureas: benefits?
Glibenclamide and gliclazide reduce incidence of microvascular complications
61
Sulfonylureas: S/E
Weight gain
Hypoglycaemia
Low durability
62
Sulfonylureas: contraindicated?
Hx of hypoglycaemia
Increased risk hypoglycaemia in renal disease
Avoid in hepatic failure
63
Are sulfonylureas an insulin SENSITSER or STIMULATOR?
STIMULATOR
64
DPP4 Inhibitors: what are they called?
Sitagliptin and the other '-gliptins'
65
DPP4 Inhibitors: action?
Reversible competitive inhibitor of DPP4 active site to inhibit inactivation of GLP-1
--> so increased GLP-1 available
Increases postprandial active incretin concentrations resulting in:
- improved beta cell function + insulin secretion
- decreased glucagon secretion
- slows gastric emptying
66
DPP4 Inhibitors: effect?
HbA1c decreases by 0.6 - 0.7%
67
DPP4 Inhibitors: benefits
Weight neutral
No hypoglycaemia (unless combined with sulfonylureas)
Decreased postprandial hyperglycaemia
68
DPP4 Inhibitors: S/E
```
GIT effects
Nasopharyngitis (transient)
Angioedema and immunologiclal derm effects
Pancreatitis (rare)
Back pain
```
Saxagliptin: increased CCF hospitalisaitons
69
DPP4 Inhibitors: contraindications
Vidogliptin has increased risk ACE-i angioedema --> so DON'T use with ACEi
Ala-, Sita- and Saxa- all need renal dose adjustment
Avoid Saxa in heart failure
70
Are the increased CVS events with DPP4 inhibitors?
No
But increased heart failure hospitalisations with saxagliptin
71
Thiazolidinediones: name them
Pioglitazone and Rosiglitazone
72
Thiazolidinediones: are they an insulin SENSITSER or STIMULATOR?
SENSITISOR
73
Thiazolidinediones: Action?
- Agonist of peroxisome proliferated activated receptor gamma (PPAR-gamma) (regulates genes involved in lipid and glucose metabolism)
- Lowers BSLs by increased insulin sensitivity
- decreases hepatic glucose output
- stimulates GLUT4 expression
74
Thiazolidinediones: Benefits?
No hypoglycaemia
Increases HDL-C
Pioglitazone decreases triglycerides and CVS events (Proactive trial)
75
Thiazolidinediones: S/E
```
Weight GAIN
Anaemia
Peripheral oedema
Fractures
Increased CK
LFT derangement
Increased bladder cancer risk (pioglitazone)
Increased LDL-C (rosiglitazone)
Increased myocardial infarcts (rosiglitazone)
```
76
PROACTIVE Trial vs RECORD Trial
PROACTIVE: pioglitazone
- decreased macrovascular outcomes in high risk patients
RECORD: rosiglitazone
- NO reduction in CVS deaths/MI/stroke
- increased CCF and nonvertebral fractures
77
Thiazolidinediones: Contraindications
Don't use in CCF or IHD
78
Acarbose: Action?
Alpha glucosidase inhibitor to slow intestinal carbohydrate absorption.
Reduce postprandial hyperglycaemia
79
Acarbose: Benefits?
```
Weight neutral
No hypoglycaemia
Decreased postprandial glucose excursions
Nonsystemic
+/- decreased CVS events (STOP-NIDDM)
```
80
Acarbose: S/E
Bloating
Ileus
Hepatotoxic
81
SGLT2 Inhibitors: name them
Canagliflozin
Dapagliflozin
Empagliflozin
82
SGLT2 Inhibitors: Action
Inhibits renal SGLT2 transporter in proximal tubule encoded by SCL5A2
83
What gene encodes the SGLT2 transporter?
SCL5A2
84
SGLT2 Inhibitors: Benefits?
No hypoglycaemia
Weight loss
Decreased BP
Decreased serum urate (by 10%)
Empagliflozen: reduced CVS mortality and HF
Dapagliflozin: decreased albuminuria with no change to eGFR in hypertensive T2DM on stable ACEi/ARB
85
SGLT2 Inhibitor: S/E
```
UTI
Dehydration
Avoid use with loop diuretics
Euglycaemic ketoacidosis
Increased LDL-C
Canagliflozen --> fracture risk
Dapagliflozen --> bladder cancer risk
```
86
What renal precautions in SGLT2 Inhibitors?
Avoid dapagliflozin if eGFR<60
| Avoid canagliflozin and empagliflozin if eGFR<45
87
Why are dapagliflozin and empagliflozin good to add onto insulin?
Add onto insulin
| Less likely to cause hypoglycaemia as they are insulin independent
88
GLP-1 Receptor Agonists: name them
Exenatide
| Liraglutide
89
GLP-1 Receptor Agonists: Action
Stimulate Beta cell insulin release
| Slow gastric emptying
90
GLP-1 Receptor Agonists: Benefits
Weight loss
No hypoglycaemia
Decreased postprandial excursions
Beneficial effect on BP independent of weight loss
91
GLP-1 Receptor Agonists: S/E
n+v
Increased risk pancreatitis
Increased risk medullary c-cells thyroid cancer
92
Which diabetes drugs are insulin SENSITISERS?
Thiazolidinediones
| Metformin
93
Which diabetes drugs are insulin STIMULATORS?
Sulfonylureas
94
Which diabetes drugs are INCRETINS?
GLP-1 Receptor Agonists
| DPP4 Inhibitors
95
In insulin secretion what is the characteristic feature of insulin secretion phases seen in diabetes?
Loss of first phase insulin response
First phase: peaks at 2-4 minutes
2nd phase: plateaus at 2-3 hours
96
Insulin synthesis?
Synthesised in beta cells of islets
C-peptide and insulin are stored together and cosecreted
97
Describe the secretion of insulin
Glucose is transported into Beta Cell by GLUT1 or GLUT2
Glucose phosphorylation by glucokinase (rate limiting step) to Glucose-6-Phosphate
Glucose-6-Phosphate then via glycolysis makes ATP --> which inhibits ATP-sensitive K channels (** target of sulphonylureas)
Inhibiting K channels --> depolarisation --> OPENS voltage dependent calcium channels resulting in influx of calcium.
Influx of calcium stimulates release of secretory granules containing insulin and CCP
98
Action of insulin
Insulin binds to ALPHA-subunit of transmembrane receptors causing auto-phosphorylation of BETA-subunit leading to:
1) PI-3K pathway --> recruitment of GLUT4 to membrane
2) MAP kinase signalling pathway leading to cell growth, proliferation and gene expression
99
Which are the ULTRA SHORT insulins? How fast do they act?
```
Lispro insulin (humalog)
Aspart insulin (novorapid)
Glulisine insulin (Apidra)
```
0 - 4 hours
100
Which are the SHORT insulins? How fast do they act?
Regular insulin (Actrapid or Humilin R)
0 - 6 hours
101
Which are the INTERMEDIATE insulins? How fast do they act?
Isophane insulin (Protaphane and Humilin NPH)
0-14 hours
102
Which are the LONG insulins? How fast do they act?
Glargine (lantus)
| Detemir (levemir)
103
Which are the PREMIXED insulins? How fast do they act?
Regular/Isophane (mixtard)
Aspart/Isophane (Novomix)
Lispro/Isophane (Humalog)
104
Complications of inpatient hyperglycaemia
Metabolic: ketoacidosis, lactic acidosis, electrolyte disturbances and dehydration
Infection: ESPECIALLY deep sternal wound infection
CVS mortality and morbidity
** new onset hyperglycaemia has strong mortality association, but known diabetes does not **
105
Diabetes Treatment:
| BP targets
Aim SBP <140, DBP <90
ACCORD STUDY: in T2DM dropping BP <120/80 had NO change to total mortality, or nonfatal MI/stroke or CV death
106
Diabetes Treatment:
| Pharmacology
ACEi or ARB
ACCOMPLISH study: In T2DM ACEi/amlo has decreased CV events compared to ACEi/thiazide
At least one CVS med in evening lowers event rate
107
Diabetes Treatment:
| Lipid targets
Triglycerides <1.7
HDL >1.0 (or >1.3 in women)
Add fenofibrate if DIABETIC DYSLIPIDAEMIA
(increased triglyceride, low HDL)
ATORVASTATIN reduced CV events irrespective of lipid profile
108
Diabetes Treatment:
| Antiplatelets?
```
For primary prevention if 10yr risk >10%
includes men >50 or women >60yrs
with AT LEAST ONE OF:
- FHx CVD
- HTN
- smoking
- dyslipidaemia
- albuminaemia
```
109
Diabetes Complications:
| Pathology of diabetic nephropathy?
Initially glom. hyperfiltration and renal hypertrophy
Then thickened BM, glom hypertrophy and mesangial expansion
After 5-10yrs microalbuminuria (50% then get macroalbuminuria over next 10 years)
110
Diabetes Complications:
| Management of diabetic nephropathy?
- optimise glucose control to slow onset
- use ACEi/ARB only once albumin appears
- aim SBP <130-140
- captopril reduces incidence ONLY in advanced CKD and prevents ESRF
111
Diabetes Complications:
| Features of NONPROLIFERATIVE retinopathy?
- Late in first decade or early in 2nd decade
- Retinal vascular microaneurysms
- Blot haemorrhages
- Cotton wool spots
112
Diabetes Complications:
| Features of PROLIFERATIVE retinopathy?
Neovascularisation in response to retinal hypoxaemia
- vitreous haemorrhage
- fibrosis
- retinal detachment
113
Which tuning fork is most sensitive for early peripheral neuropathy?
128Hz
BUT less predictive of ulceration than a monofilament
114
Features of POLYRADICULOPATHY syndrome?
Severe disabling pain >1 nerve root
Can have lumbar or femoral involvement with associated hip flexor / extensor weakness (= DIABETIC AMYOTROPHY)
Usually self limited <12 months
115
What is diabetic dermopathy?
= pigmented pretibial papules
Begins as erythematous area with circular hyperpigmentation
More commonly older diabetic men
116
What is bullosa diabeticorum?
= shallow ulcerations in pretibial area
117
What is necrobiosis lipoidica diabeticorum
- rare (0.3-1.2% of diabetes)
- mainly young women with T1DM
- chronic granulomatous disorder of the skin
- may be painful
- lower limbs most commonly affected
- often develop ulcerations
118
What is diabetic cheiroarthropathy?
- positive prayer sign and tabletop sign
- waxy skin over dorsum
- restricted PIPs and MCP extension and 5th DIP
119
SHORT TERM Complications of Gestational Diabetes
- Macrosomia
- Pre-eclampsia
- Polyhydramnios
- Stillbirth (if poor BSLs)
- Neonatal morbidity
120
LONG TERM Complications of Gestational Diabetes
Infant: obesity, impaired glucose tolerance, metabolic syndrome
Mum: T2DM and diabetic vascular disease
121
Good glycaemic control in GDM?
Reduces:
- preeclampsia
- macrosomia
- shoulder dystocia
