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RACP Written 2018 > Endocrine - Diabetes and Hyperglycaemia > Flashcards

Endocrine - Diabetes and Hyperglycaemia Flashcards

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

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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
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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

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4
Q

Increased insulin does what to glucagon levels?

A

Increased insulin DECREASES glucagon

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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

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6
Q

Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- identical twin?

A

30 - 40%

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7
Q

Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- parent and sibling?

A

25%

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8
Q

Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- HLA identical sibling?

A

16%

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9
Q

Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- Sibling

A

7%

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10
Q

Genetic Predisposition to T1DM?
Lifetime risk for T1DM in 1st degree relative <25 years old:
- Child

A

5%

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11
Q

Geographical impact on incidence of T1DM?

A

Increased in Finland

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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

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13
Q

Which genes are PROTECTIVE for T1DM?

A

HLA DR2

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14
Q

Which chromosome is HLA-DQ and DR3 and DR4 located?

A

Chromosome 6

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15
Q

Which chromosome is VNTR on?

A

VNTR is on Ch 11

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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)
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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
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18
Q

Pathodevelopment of T1DM?

A

T cell mediated autoimmunity, predominantly CD8+

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19
Q

Which T cells is predominantly involved in T1DM?

A

CD8+ T cells

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20
Q

What four antibodies are involved in pathodevelopment of T1DM?

A

(pro)insulin Ab
Anti-GAD
Anti-IA2
Anti-Zn Transporter 8 (ZnT8)

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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

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22
Q

What is fulminant DM?

A 
Severe onset suddenly
Antibody negative
Pancreatic enzymes positive
BUT no pancreatitis
Usually Asian
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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
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24
Q

Five features more frequent in LADA at diagnosis?

A
  • Age <50yrs
  • Acute symptoms
  • BMI <25
  • Personal hx of autoimmunity
  • FHx of autoimmunity
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25
Q

Importance of LADA?

A
  • theoretical risk of ketoacidosis
  • preference for basal-bolus regime
  • screen for associated autoimmune conditions (ie thyroid / coeliac)
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26
Q

Definition of MODY?

Features?

A

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

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27
Q

Inheritance pattern of MODY

What are the two most genetic causes?

A

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

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28
Q

MODY 3 underlying genetic defect?

A

defect in the HNF-1 alpha gene

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29
Q

MODY 3 underlying genetic defect?

A

defect in the glucokinase gene

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30
Q

HbA1c target in T1DM?

A

General: <=7%
Pregnancy: <=7%
Hypoglycaemia recurrence or unawareness <=8%

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31
Q

What was the DCCT Trial?

A

Intensive vs convensional sugar control in T1DM.

- reduced risk of retinopathy, micro and macro albuminaemia, and neuropathy

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32
Q

In the DCCT Trial which subgroups were NOT supported?

A
  • Recurrent hypoglycaemia
  • Macrovascular complications
  • Young children <13 years old
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33
Q

What was the EDIC Study?

A

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
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34
Q

Diagnostic Criteria for T2DM?

A

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

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35
Q

Diagnosing T2DM:

Fasting glucose BSL 5.5 - 6.9?

A

need OGTT

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36
Q

Diagnosing T2DM:

Fasting glucose BSL >7

A

Likely diabetes, need to repeat test if asymptomatic

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37
Q

Diagnosing T2DM:

If fasting glucose 6-7 and 2hr glucose <7.8

A

–> impaired fasting glucose (IFG)

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38
Q

Diagnosing T2DM:

If fasting glucose 6-7 and 2hr glucose 7.8-11

A

–> impaired glucose tolerance (IGT)

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39
Q

Diagnosing T2DM:

If fasting glucose >7 and 2hr glucose >11

A

–> Diabetes

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40
Q

Diagnosing T2DM:

Impaired fasting glucose (IFG)

A

If fasting glucose 6-7 and 2hr glucose <7.8

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41
Q

Diagnosing T2DM:

Impaired glucose tolerance (IGT)

A

If fasting glucose 6-7 and 2hr glucose 7.8-11

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42
Q

Diagnosing T2DM:

Diabetes

A

If fasting glucose >7 and 2hr glucose >11

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43
Q

Diagnosing T2DM with HbA1c?

A

If HbA1c >=6.5 and confirmed on repeat test

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44
Q

Treatment goals in T2DM?

A

Newly diagnosed early disease: <6.5%

Target HbA1c <7% in general

Except:

  • if no insulin –> target <6.5%
  • if hypoglycaemia –> target <8%
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45
Q

Treatment goal in T2DM in newly diagnosed early disease?

A

Target HbA1c <6.5%

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46
Q

Treatment goal in T2DM in general?

A

Target HbA1c <7%

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47
Q

Treatment goal in T2DM if no insulin?

A

Target HbA1c <6.5%

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48
Q

Treatment goal in T2DM if hypoglycaemia?

A

Target HbA1c <8%

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49
Q

Treatment algorithm for treating diabetes?

A

1st line is metformin

2nd line add in:

  • sulfonylureas
  • DPP4-inhibitor
  • SGLT2 inhibitor

Then add:
3rd agent
OR add GLP-IRA or insulin

50
Q

Which diabetes medications provide weight loss?

A

1st: GLP-1
2nd: SGLT2
3rd: Metformin

51
Q

Metformin: Action?

A

Activates AMP-kinase

Reduces hepatic glucose output and increases peripheral utilisation of glucose

52
Q

Metformin: effect?

A

Decreases HbA1c by 15-22mmol (1.5-2%)

53
Q

Metformin benefits?

A

Weight neutral

Decreases CVS events

54
Q

Metformin S/E:

A

GIT effects
B12 deficiency
lactic acidosis
Acute hepatitis

55
Q

Metformin contraindications?

A

Renal, hepatic or cardiac failure

56
Q

Is metformin an insulin SENSITSER or STIMULATOR?

A

Sensitiser

57
Q

Sulfonylureas: name them

A

Gliclazide, glipizide, glibenclamide, glimepiride

58
Q

Sulfonylureas: Action?

A

Closes k-ATP channels on beta cell plasma membranes

Binds to beta cell receptor to stimulate glucose-independent insulin release

59
Q

Sulfonylureas: effect?

A

Decreases HbA1c by 0.6 - 1.15% when added to metformin

60
Q

Sulfonylureas: benefits?

A

Glibenclamide and gliclazide reduce incidence of microvascular complications

61
Q

Sulfonylureas: S/E

A

Weight gain
Hypoglycaemia
Low durability

62
Q

Sulfonylureas: contraindicated?

A

Hx of hypoglycaemia
Increased risk hypoglycaemia in renal disease
Avoid in hepatic failure

63
Q

Are sulfonylureas an insulin SENSITSER or STIMULATOR?

A

STIMULATOR

64
Q

DPP4 Inhibitors: what are they called?

A

Sitagliptin and the other ‘-gliptins’

65
Q

DPP4 Inhibitors: action?

A

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
Q

DPP4 Inhibitors: effect?

A

HbA1c decreases by 0.6 - 0.7%

67
Q

DPP4 Inhibitors: benefits

A

Weight neutral
No hypoglycaemia (unless combined with sulfonylureas)
Decreased postprandial hyperglycaemia

68
Q

DPP4 Inhibitors: S/E

A 
GIT effects
Nasopharyngitis (transient)
Angioedema and immunologiclal derm effects
Pancreatitis (rare)
Back pain

Saxagliptin: increased CCF hospitalisaitons

69
Q

DPP4 Inhibitors: contraindications

A

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
Q

Are the increased CVS events with DPP4 inhibitors?

A

No

But increased heart failure hospitalisations with saxagliptin

71
Q

Thiazolidinediones: name them

A

Pioglitazone and Rosiglitazone

72
Q

Thiazolidinediones: are they an insulin SENSITSER or STIMULATOR?

A

SENSITISOR

73
Q

Thiazolidinediones: Action?

A
  • 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
Q

Thiazolidinediones: Benefits?

A

No hypoglycaemia
Increases HDL-C

Pioglitazone decreases triglycerides and CVS events (Proactive trial)

75
Q

Thiazolidinediones: S/E

A 
Weight GAIN
Anaemia
Peripheral oedema
Fractures
Increased CK
LFT derangement
Increased bladder cancer risk (pioglitazone)
Increased LDL-C (rosiglitazone)
Increased myocardial infarcts (rosiglitazone)
76
Q

PROACTIVE Trial vs RECORD Trial

A

PROACTIVE: pioglitazone
- decreased macrovascular outcomes in high risk patients

RECORD: rosiglitazone

  • NO reduction in CVS deaths/MI/stroke
  • increased CCF and nonvertebral fractures
77
Q

Thiazolidinediones: Contraindications

A

Don’t use in CCF or IHD

78
Q

Acarbose: Action?

A

Alpha glucosidase inhibitor to slow intestinal carbohydrate absorption.
Reduce postprandial hyperglycaemia

79
Q

Acarbose: Benefits?

A 
Weight neutral
No hypoglycaemia
Decreased postprandial glucose excursions
Nonsystemic
\+/- decreased CVS events (STOP-NIDDM)
80
Q

Acarbose: S/E

A

Bloating
Ileus
Hepatotoxic

81
Q

SGLT2 Inhibitors: name them

A

Canagliflozin
Dapagliflozin
Empagliflozin

82
Q

SGLT2 Inhibitors: Action

A

Inhibits renal SGLT2 transporter in proximal tubule encoded by SCL5A2

83
Q

What gene encodes the SGLT2 transporter?

A

SCL5A2

84
Q

SGLT2 Inhibitors: Benefits?

A

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
Q

SGLT2 Inhibitor: S/E

A 
UTI
Dehydration
Avoid use with loop diuretics
Euglycaemic ketoacidosis
Increased LDL-C
Canagliflozen --> fracture risk
Dapagliflozen --> bladder cancer risk
86
Q

What renal precautions in SGLT2 Inhibitors?

A

Avoid dapagliflozin if eGFR<60

Avoid canagliflozin and empagliflozin if eGFR<45

87
Q

Why are dapagliflozin and empagliflozin good to add onto insulin?

A

Add onto insulin

Less likely to cause hypoglycaemia as they are insulin independent

88
Q

GLP-1 Receptor Agonists: name them

A

Exenatide

Liraglutide

89
Q

GLP-1 Receptor Agonists: Action

A

Stimulate Beta cell insulin release

Slow gastric emptying

90
Q

GLP-1 Receptor Agonists: Benefits

A

Weight loss
No hypoglycaemia
Decreased postprandial excursions
Beneficial effect on BP independent of weight loss

91
Q

GLP-1 Receptor Agonists: S/E

A

n+v
Increased risk pancreatitis
Increased risk medullary c-cells thyroid cancer

92
Q

Which diabetes drugs are insulin SENSITISERS?

A

Thiazolidinediones

Metformin

93
Q

Which diabetes drugs are insulin STIMULATORS?

A

Sulfonylureas

94
Q

Which diabetes drugs are INCRETINS?

A

GLP-1 Receptor Agonists

DPP4 Inhibitors

95
Q

In insulin secretion what is the characteristic feature of insulin secretion phases seen in diabetes?

A

Loss of first phase insulin response

First phase: peaks at 2-4 minutes
2nd phase: plateaus at 2-3 hours

96
Q

Insulin synthesis?

A

Synthesised in beta cells of islets

C-peptide and insulin are stored together and cosecreted

97
Q

Describe the secretion of insulin

A

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
Q

Action of insulin

A

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
Q

Which are the ULTRA SHORT insulins? How fast do they act?

A 
Lispro insulin (humalog)
Aspart insulin (novorapid)
Glulisine insulin (Apidra)

0 - 4 hours

100
Q

Which are the SHORT insulins? How fast do they act?

A

Regular insulin (Actrapid or Humilin R)

0 - 6 hours

101
Q

Which are the INTERMEDIATE insulins? How fast do they act?

A

Isophane insulin (Protaphane and Humilin NPH)

0-14 hours

102
Q

Which are the LONG insulins? How fast do they act?

A

Glargine (lantus)

Detemir (levemir)

103
Q

Which are the PREMIXED insulins? How fast do they act?

A

Regular/Isophane (mixtard)
Aspart/Isophane (Novomix)
Lispro/Isophane (Humalog)

104
Q

Complications of inpatient hyperglycaemia

A

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
Q

Diabetes Treatment:

BP targets

A

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
Q

Diabetes Treatment:

Pharmacology

A

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
Q

Diabetes Treatment:

Lipid targets

A

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
Q

Diabetes Treatment:

Antiplatelets?

A 
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
Q

Diabetes Complications:

Pathology of diabetic nephropathy?

A

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
Q

Diabetes Complications:

Management of diabetic nephropathy?

A
  • 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
Q

Diabetes Complications:

Features of NONPROLIFERATIVE retinopathy?

A
  • Late in first decade or early in 2nd decade
  • Retinal vascular microaneurysms
  • Blot haemorrhages
  • Cotton wool spots
112
Q

Diabetes Complications:

Features of PROLIFERATIVE retinopathy?

A

Neovascularisation in response to retinal hypoxaemia

  • vitreous haemorrhage
  • fibrosis
  • retinal detachment
113
Q

Which tuning fork is most sensitive for early peripheral neuropathy?

A

128Hz

BUT less predictive of ulceration than a monofilament

114
Q

Features of POLYRADICULOPATHY syndrome?

A

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
Q

What is diabetic dermopathy?

A

= pigmented pretibial papules

Begins as erythematous area with circular hyperpigmentation

More commonly older diabetic men

116
Q

What is bullosa diabeticorum?

A

= shallow ulcerations in pretibial area

117
Q

What is necrobiosis lipoidica diabeticorum

A
  • 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
Q

What is diabetic cheiroarthropathy?

A
  • positive prayer sign and tabletop sign
  • waxy skin over dorsum
  • restricted PIPs and MCP extension and 5th DIP
119
Q

SHORT TERM Complications of Gestational Diabetes

A
  • Macrosomia
  • Pre-eclampsia
  • Polyhydramnios
  • Stillbirth (if poor BSLs)
  • Neonatal morbidity
120
Q

LONG TERM Complications of Gestational Diabetes

A

Infant: obesity, impaired glucose tolerance, metabolic syndrome

Mum: T2DM and diabetic vascular disease

121
Q

Good glycaemic control in GDM?

A

Reduces:

  • preeclampsia
  • macrosomia
  • shoulder dystocia

RACP Written 2018 (167 decks)

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