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Printable Handouts
Navigable Slide Index
- Introduction
- Making treatment decisions in diabetes
- A simple approach to diabetes treatment
- Hyperglycaemia & diabetes treatment
- MODY in the pre-genetic era
- MODY in the post-genetic era
- Glucokinase – the pancreatic glucose sensor
- Glucokinase patients-mildly raised blood glucose
- Blood glucose does not change with treatment
- MODY patients do not benefit from treatment
- HNF1A diabetes deteriorating glycaemia with age
- Sulfonylurea sensitivity (HNF1A mutation MODY)
- HNF1A MODY vs. T2D patients & sulfonylurea (SU)
- Insulin secretion with SUs (mutated HNF1A)
- Patient with renal cysts and gestational diabetes
- HNF-1B mutations/deletions- the RCAD syndrome
- HNF1B in early pancreatic development
- Treatments for different MODY-genetic subtypes
- MODY prevalence in clinics (Sweden, USA & UK)
- 80-90% MODY diabetes - not diagnosed in the UK
- 94% of MODY are incorrectly diagnosed (USA)
- Diagnosis of MODY - a real problem
- Diagnosing of MODY is difficult
- Ab's & C peptide improve diagnosis
- MODY probability calculator
- Conclusions - MODY
- Treatment in neonatal diabetes (ND)
- Insulin-treated diabetes diagnosed at 3 mo
- Diagnosis under 6 mo is neonatal diabetes
- Neonatal diabetes - in the pre-genetic era
- Neonatal diabetes - activating mutations in Kir6.2
- Kir6.2 - glucose sensing & insulin secretion
- ABCC8 (SUR1) mutations also cause ND
- Potential treatment with SU
- Kir6.2 diabetics secrete insulin in response to SU
- Kir6.2 diabetics can be treated with SU
- Kir6.2 diabetics can transfer from insulin to SU
- Glycaemia control is improved with SU
- Glucose fluctuate less on glibenclamide treatment
- Excellent response preserved at 5 yrs
- Glucose control is responsive to food intake
- Free rapid testing worldwide for neonatal diabetes
- Conclusions - potassium channel neonatal diabetes
- Treatment in ND and gene discovery
- ~50% of Referrals are monogenic diabetes
- Increasing gene discovery in ND (18 genes)
- Finding known genes in neonatal diabetes
- Genetic cause found in about 70% PNDM
- Pancreatic development - lessons from mice
- Human validation of mice knockout models
- Pancreatic agenesis is a rare human condition
- Finding new causes of pancreatic aplasia
- Strategy - look for de novo mutations
- GATA6 mutations cause pancreatic agenesis
- Mutations in GATA6 result in haploinsufficency
- GATA6 role in pancreatic development (man)
- Isolated pancreatic agenesis (recessive mutation)
- Homozygosity mapping on chr. 10
- Whole genome sequencing
- Identifying putative developing beta-cell enhancers
- Human epigenome maps used to prioritise variants
- Shared variant near PFT1A is highly conserved
- Recessive mutations in putative enhancer
- Confirmed mutations in novel PTF1A enhancer
- Monogenic causes of pancreatic agenesis in man
- Conclusions - pancreas agenesis
- Making treatment decisions in diabetes
- Acknowledgements
Topics Covered
- Approaches to diabetes treatment
- Maturity onset diabetes of the young (MODY) in the pre-genetic era
- MODY in the pre-genetic era
- Treatment in glucokinase MODY
- Treatment in HNF1a MODY
- Renal cysts and diabetes (RCAD) syndrome and its treatment
- The diagnosis of MODY in pediatric clinics
- MODY probability calculator
- Neonatal diabetes (ND)
- The role of Kir6.2 and SUR1 mutation in ND
- Testing for ND
- Using Mice model to learn on pancreatic development and ND
- Pancreatic agenesis and patients' genetics
- Mutations in PTF1A mutations and pancreatic agenesis
Links
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Talk Citation
Hattersley, A. (2015, January 19). Changing lives: stratified medicine in monogenic diabetes [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 21, 2024, from https://doi.org/10.69645/UJEL3565.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Andrew Hattersley has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Clinical Practice
Transcript
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0:00
Hello, I'm Andrew Hattersley from the University of Exeter.
What I'd like to do is to talk about how in
diabetes genetics has really made a dramatic difference for treatment,
and really to show how genetic technology and
genetic techniques have changed
treatment for a considerable number of people with diabetes.
0:22
I think for many diabetologists,
the idea that a genetic sequencer should be involved in the decisions about
what treatment a patient should have would seem ridiculous and far-fetched.
0:35
Indeed, if we think about treatment in diabetes in general,
many people would say that actually the approach that
most diabetes consultants take is a very simple one.
But it's basically the more severe the blood glucose,
the more treatment we give.
At one extreme, we're treating with diet and exercise,
and at the others we're treating with insulin.
But the key thing about this approach is it is all based on how
high the blood glucose is and not what is the cause of the blood glucose.
1:09
The big question is whether actually we can
start to make diabetes treatment be based on the cause.
Graeme Bell in 1998 said that he thought that one day physicians would be able to tailor
their treatment of diabetes depending on
the nature of the underlying molecular defect or defects.
Really, if you want to do that,
the place to do it is in monogenic diabetes,
where a single gene mutation results in the person having diabetes.
Because what that means is that if you can find that mutation,
you can make a diagnosis.
But crucially, you can then define
the etiology of what's wrong with the insulin produced in Beta cell.
I think the big question is whether this can
actually then be used to define the treatment response.