MODY 3 - Yorkshire and the Humber Deanery

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Michael Mansfield
Diabetes Consultant
Leeds Teaching Hospitals
New units for HbA1c
Diabetes is relevant to in-patient care
NHS diabetes resource
Gliptins & GLP-1 analogs & SGLT-2 inhibitors
End of life
Sodium
type 1 diabetes
type 2 diabetes
gestational diabetes
diabetes secondary to pancreatic disease
unknown / unclear
genetic diabetes
other
MODY 3
Mutations of the hepatocyte nuclear factor 1α gene
Disordered insulin release
Autosomal dominant pedigree over 2, ideally 3 generations
Age of onset < 25 years in at least one family member
No need for insulin (or detectable C-peptide) in first 2-5 years after diagnosis
Progressive rise in glucose levels through life
Low renal threshold for glucose
Often very sensitive to sulphonylurea therapy
Permanent neonatal diabetes mellitus
Activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit
of the beta cell K-ATP channel.
Congenital impairment of insulin release
Mostly new mutations
Onset in first 3 (- 6) months of life but no immune markers of type 1 diabetes
Often responds well to sulphonylurea therapy
New units for glycated haemoglobin
DCCT
HbA1c
IFCC
HbA1c
%
mmol/mol
6.0
42
6.5
48
7.0
53
7.5
59
8.0
64
9.0
75
Umpierrez et al JCEM 2002, Memphis, Tennessee and Atlanta Georgia
Baker et al Thorax 2006 St George’s Hospital London
The Think Glucose programme provides a package of tried and
tested products, learning and support to improve awareness and
remove the obstacles to the treatment of patients with diabetes as
a secondary diagnosis.
Implementing a clinical pathway will improve the patient
experience and the quality of their care.
Training of staff
Links to and alerting of diabetes team
New and NHS-wide documentation
Importance of careful medicines reconciliation
IV insulin infusion safety
cannula
IV fluid
Insulin storage and insulin syringes
National or local guidelines for:
DKA, HHS hypoglycaemia
surgery, endoscopy
hyperkalaemia
end of life
tube feeding
labour
steroids for fetal lung maturation
Capillary glucose monitoring and recording
Patient self-management/admin of insulin
“Sliding scales” and other insulin prescribing
www.diabetes.nhs.uk
withdrawn
(USA)
withdrawn
withdrawn
SGLT-2 inhibitors
oral
2012
The incretin effect
oral glucose
IV glucose
oral glucose
IV glucose
Satiety effect
reduced food intake
Increased
glucose uptake
& glycogenesis
Slowed gastric emptying
Increased insulin release
Reduced glucagon release
Site of GLP-1 synthesis
Secretion increased after meals
Overview of GLP-1 physiology
DPP4 inhibitors
NICE 2009
The problem with…..
Metformin
is bowel side effects, risk of lactic acidosis when eGFR decreased
Sulphonylureas weight gain and risk of hypoglycaemia
Insulin
is weight gain, risk of hypoglycaemia, some driving restrictions
injections
Glitazones
take weeks to start working, expensive, very marked weight gain,
fluid retention and heart failure, distal bone fracture risk
Gliptins (DPP4 inhibitors) expensive, no long-term safety record
weak pancreatitis signal
Exenatide
expensive, nausea and vomiting in first months
injected, no long-term safety record, pancreatitis signal
Liraglutide
even more expensive, nausea and vomiting in first months
injected, no long-term safety record
pancreatitis signal, v weak thyroid malignancy signal
Dapaglifozin
expensive, genital thrush, no long-term safety record
glucose control in diabetes at the end of life
altered nutrition
negative energy balance
weight reduction
reduction in physical activity
systemic humoral stress response
pancreatic destruction
renal impairment
liver destruction
loss of fat and muscle
steroids
psychological stress
mental illness
July 2012
Key principles
Aims for glucose levels:
1. No glucose level less than 6 mmol/L
2. No glucose level higher than about 15 mmol/L
Breaks down care in to 4 scenarios:
1. End of life but prognosis of more than 1 year
2. Prognosis in months
3. Prognosis in weeks
4. Prognosis in days
A few words on hyponatraemia
Always check for hyperglycaemia:
For every 3.5 mmol/L the glucose is high, sodium falls by 1 mmol/L
It’s all about the brain
Always look for timescale of sodium fall
Brain tolerates slow changes (up or down) remarkably well
SIADH is not the only cause, dehydration is common too
Assessment of patient’s circulating volume status is key
A cause for appropriate ADH release/activity excludes SIADH
If patient has been on steroids then suppressed HPA axis possible
Low circulating volume (NB intact thirst)
acute medical emergency including sepsis
surgical abdomen
hypoadrenalism (Addisons or suppressed HPA axis)
diuretics
ascites
nephrosis
congestive cardiac failure
Normal or increased circulating volume
syndromes of inappropriate ADH activity (secretion or receptor)
sick cell syndrome
Redistribution of body water
hyperglycaemia
Management
Usually not urgent unless the cause itself is emergency
Treatment obviously depends on the cause
In practice it often seems to self correct
May need treatment anyway if brain function impaired by
sudden and/or severe fall:
ie neurological signs / seizures / reduced GCS
IV saline and in some exceptional circumstances hypertonic
saline appropriate.
Aim for slow improvement in Na 5mmol/L in 12 hours.
Not much improvement needed to reverse brain dysfunction
Read this article:
Adrogue 2000 NEJM 342: 1851
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