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WHY IS DIABETES
SUCHA PROBLEM?
(THATMONASHNEEDEDANEWDEPARTMENT)
IDF Diabetes Atlas, 7th edition
Greatest epidemic in all human historyPaul Zimmet
1 2 3 4 5 6
7 8 9 11
Diabetes
One in every eleven adults
400,000 adults +40,000 in 2017
1981 1983 1990 1995 2000
AusDiab
Busselton
0.2
0.4
1.0
0.6
0.75
2017
Millions withdiabetes
Diabetes is the fourth largest
...
What’s the difference betweenType 1 andType 2 diabetes?
No insulin signal No response to insulin
TYPE 1 DIABETES STATISTICS
•Type 1 diabetes is one of the most common chronic diseases in
children, it occurs more frequen...
Incidence and Prevalence of T1D Increasing and
Occurring at Earlier Age
Cases/100,000/yr in Children 0–14 yr
0
10
20
30
40...
T1D Natural History: A Framework for Prevention
Adapted from Eisenbarth
100%
0%
FunctionalBetaCell
Mass
At Risk Pre-Sympto...
WHAT CAUSES
TYPE 2 DIABETES?
0.4
1.6
0.4
1.4
0.4
1.5
0.0
0.4
0.8
1.2
1.6
2.0
Normal Obese
Males Females All
Incidenceofdiabetes
(%peryear)
< 94 cm for ...
Our fat stores are like our pantry
Thin Fat Obese
No where to put the groceries
so spill over into other places
ectopos (o...
Sjöström L et al.JAMA 2014; 311: 2297-304
Losefatearlywithgastricbypassanddiabetescangoaway?
>90% remission
WHAT IS THE PROBLEM
WITH HAVING DIABETES?
Life expectancy is reduced in patients with T2D ✝1
No T2D
60 End of life
years
T2D –6 years
1. The Emerging Risk Factors C...
0
5
10
15
20
25
30
35
NON-DIABETIC
DIABETES
RATIO 2.5 RATIO 2.2 RATIO 2.1
WHITEHALL
STUDY
MORTALITYRATE
(DEATHSPER1,000PAT...
Annual impact of diabetes in Australia
22
HOPE CARDS
HPS PERHAPSTHE
GREATEST SUCCESS
STORY IN MEDICINE
SINCEVACCINES
MI
STROKE
AMPUTEE
RENAL
FAILURE
Diseased mouse retina treated with immunosuppressiveT cells
WHY THE
KIDNEY MATTERS
IN TYPE 2 DIABETES…
The kidney is like a sieve
AlbuminuriaAlbumin Leakage
Diabetes can lead to holes in that sieve…
Coronary heart disease
Coronary death
Non-fatal MI
Cerebrovascular disease
Ischaemic stroke
Haemorrhagic stroke
Unclassifi...
ISN’T THERE A TREATMENT
FOR TYPE 2 DIABETES?
Managing Diabetes
Multifactorial intervention in type 2 diabetes
Diabetes: the last hundred years
no longer available
still going strong
the recent
explosion
King of the sedentary lifestyle
AMPLIFIER
SIGNAL AMPLIFICATION OUTPUT
GLUCOSE GLP-1 increase
FOOD AMPLIFICATION INSULIN
(incret-ins)of glucose/food stimul...
From Lizard Saliva to Diabetes Drugs
“I want some of that (adaptation) for my patients”
glomerulus 360g/d
Glucose
11mM
proximal tubule
SGLT2 SGLT1
120ml/min
GLUT1GLUT2
Increased sodium
reabsorbed with glucose ...
glomerulus 360g/d
Glucose
11mM
proximal tubule
SGLT2 SGLT1
120ml/min
GLUT1GLUT2
Na
Macula
densa
Tubuloglomerular feedbac...
DCCT
6.5 years
10
8
6
4
2
0
Risk of heart attack or stroke
or death from either
still reduced by 32%
twenty+ years later?
...
0.5 1.0 2.0Makes it
better
Makes it
worseAdapted from Boussageon et al. BMJ (2011)
STENO-2
7.8 years 7.9 years
Gæde, et al Diabetologia (2016)
Intensive
Standard
Years since randomisation
BAD KARMA: Every ...
• ACCUMULATED MODIFICATIONS?
• EPIGENETIC PROGRAMMING?
AGE
Articular cartilage
GETTING
CRUSTY
As we get older?
Faster in those
with diabetes?
Reducing AGEs in diabetes associated atherosclerosis
Forbes JM et al. Diabetes 2004;53:1813-1823
NH2-
Arginine
N-C-
NHH3C
...
Second
messengers
Oxidative
stress
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
RAGE
COMPL...
Genetic deletion of RAGE protects against diabetes
associated atherosclerosis in apoE KO mice
Control Diabetes
Soro-Paarvo...
0
1
2
3
4
5
Control Diabetes C+GKT D+GKT
Nox1 Nox2 Nox4 hNox5
Optimalinhibitionofpro-oxidantNoxenzymes
withGKT
X X X
0
50
...
GKT137831 in patients with type 1 diabetes & CKD
GKT137831
200mg bd
Placebo
Change in mean kidney albumin
leakage after 48...
Understanding the legacy or memory effect
• ACCUMULATED MODIFICATIONS?
• EPIGENETIC PROGRAMMING?
DNA
2 metres long
Needs to be condensed >10,000 fold to fit into a nucleus
<10m long
chromatin
If genes were ‘words’
Epigenetics instructs how to
access and read the words
“The structural adaptation of chromosomal reg...
Gene is
Open for
transcription
(e.g.H3K4me)
Gene is
Closed for
transcription
(e.g.H3K9me)
Understanding the histone code
s...
0
0.5
1
1.5
2
2.5
3
LG (16h) HG (16h) 6 days post HG 6 days post LG
H3K4mChIp(foldchange)
wild type Set7KD
Knockdown of hi...
New targets
Glucose
BP
Fat
HEART
ATTACKS
STROKES
BLINDNESS
AMPUTATION
DIALYSIS
DEATH
PRIMARY PREVENTION
The Diabetes Translational research laboratory was
established in 2017 with the generous support of
Elias and Coleen Jreis...
Changing the way we treat diabetes and its complications: Public lecture
Changing the way we treat diabetes and its complications: Public lecture
Changing the way we treat diabetes and its complications: Public lecture
Changing the way we treat diabetes and its complications: Public lecture
Changing the way we treat diabetes and its complications: Public lecture
Changing the way we treat diabetes and its complications: Public lecture
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Changing the way we treat diabetes and its complications: Public lecture

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Professor Mark Cooper AO presented Central Clinical School's annual public lecture for 2017. Prof Cooper is the inaugural head of the new Department of Diabetes, the first of its kind in Australia. He explained the physiological mechanisms of diabetes and how the recently emerging classes of drugs are targeting the various issues in complications caused by diabetes.

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Changing the way we treat diabetes and its complications: Public lecture

  1. 1. WHY IS DIABETES SUCHA PROBLEM? (THATMONASHNEEDEDANEWDEPARTMENT)
  2. 2. IDF Diabetes Atlas, 7th edition Greatest epidemic in all human historyPaul Zimmet
  3. 3. 1 2 3 4 5 6 7 8 9 11 Diabetes One in every eleven adults
  4. 4. 400,000 adults +40,000 in 2017
  5. 5. 1981 1983 1990 1995 2000 AusDiab Busselton 0.2 0.4 1.0 0.6 0.75 2017 Millions withdiabetes Diabetes is the fourth largest contributor to overall disease burden in Australia. >2 million? + another 400 cases every day
  6. 6. What’s the difference betweenType 1 andType 2 diabetes? No insulin signal No response to insulin
  7. 7. TYPE 1 DIABETES STATISTICS •Type 1 diabetes is one of the most common chronic diseases in children, it occurs more frequently than cancer, cystic fibrosis, multiple sclerosis and muscular dystrophy •Approximately 2400 Australians are diagnosed with type 1 diabetes every year •10-14 years is the peak age of diagnosis but many are diagnosed after 20 yrs of age, can even occur in middle aged and elderly people •In Australia, around 95% of the diabetes found in children is type 1 diabetes but this situation is changing especially in indigenous Australians
  8. 8. Incidence and Prevalence of T1D Increasing and Occurring at Earlier Age Cases/100,000/yr in Children 0–14 yr 0 10 20 30 40 50 60 70 1950 1960 1970 1980 1990 2000 Finland Sweden Colorado Germany
  9. 9. T1D Natural History: A Framework for Prevention Adapted from Eisenbarth 100% 0% FunctionalBetaCell Mass At Risk Pre-Symptomatic Recent Onset Established Diabetes Time Genetic Risk Environmental Etiologies Beta Cell Autoimmunity Beta Cell Loss Glucose Intolerance Clinical Symptoms  Risk of developing T1D can be identified  T1D develops with a relatively predictable course with a variable rate of progression  Interventions can be developed to arrest progression
  10. 10. WHAT CAUSES TYPE 2 DIABETES?
  11. 11. 0.4 1.6 0.4 1.4 0.4 1.5 0.0 0.4 0.8 1.2 1.6 2.0 Normal Obese Males Females All Incidenceofdiabetes (%peryear) < 94 cm for males < 80 cm for females  102 cm for males  88 cm for females People who are obese are over 4 times more likely to develop diabetes than people of a healthier weight. Today ~40% of Australians are obese Annual incidence of Type 2 Diabetes in Australia Adiposity can account for up to half of all risk for type 2 diabetes
  12. 12. Our fat stores are like our pantry Thin Fat Obese No where to put the groceries so spill over into other places ectopos (out of place)
  13. 13. Sjöström L et al.JAMA 2014; 311: 2297-304 Losefatearlywithgastricbypassanddiabetescangoaway? >90% remission
  14. 14. WHAT IS THE PROBLEM WITH HAVING DIABETES?
  15. 15. Life expectancy is reduced in patients with T2D ✝1 No T2D 60 End of life years T2D –6 years 1. The Emerging Risk Factors Collaboration. JAMA 2015;314:52 Mostly due to Cardiovascular Disease
  16. 16. 0 5 10 15 20 25 30 35 NON-DIABETIC DIABETES RATIO 2.5 RATIO 2.2 RATIO 2.1 WHITEHALL STUDY MORTALITYRATE (DEATHSPER1,000PATIENT-YEARS) PARIS PROSPECTIVE STUDY HELSINKI POLICEMEN STUDY RATIO 2.5 AUSDIAB STUDY Diabetes doubles premature mortality
  17. 17. Annual impact of diabetes in Australia
  18. 18. 22 HOPE CARDS HPS PERHAPSTHE GREATEST SUCCESS STORY IN MEDICINE SINCEVACCINES MI STROKE AMPUTEE RENAL FAILURE
  19. 19. Diseased mouse retina treated with immunosuppressiveT cells
  20. 20. WHY THE KIDNEY MATTERS IN TYPE 2 DIABETES…
  21. 21. The kidney is like a sieve
  22. 22. AlbuminuriaAlbumin Leakage Diabetes can lead to holes in that sieve…
  23. 23. Coronary heart disease Coronary death Non-fatal MI Cerebrovascular disease Ischaemic stroke Haemorrhagic stroke Unclassified stroke Other vascular deaths 2.00 (1.83–2.19) 2.31 (2.05–2.60) 1.82 (1.64–2.03) 2.27 (1.95–2.65) 1.56 (1.19–2.05) 1.84 (1.59–2.13) 1.73 (1.51–1.98) HR (95% CI) 26,505 11,556 14,741 3799 1183 4973 3826 Number of cases 11 2 4 Hazard ratio (diabetes vs no diabetes) Outcome Diabetes doubles the risk of vascular events 2
  24. 24. ISN’T THERE A TREATMENT FOR TYPE 2 DIABETES?
  25. 25. Managing Diabetes Multifactorial intervention in type 2 diabetes
  26. 26. Diabetes: the last hundred years no longer available still going strong the recent explosion
  27. 27. King of the sedentary lifestyle
  28. 28. AMPLIFIER SIGNAL AMPLIFICATION OUTPUT GLUCOSE GLP-1 increase FOOD AMPLIFICATION INSULIN (incret-ins)of glucose/food stimulated insulin secretion
  29. 29. From Lizard Saliva to Diabetes Drugs “I want some of that (adaptation) for my patients”
  30. 30. glomerulus 360g/d Glucose 11mM proximal tubule SGLT2 SGLT1 120ml/min GLUT1GLUT2 Increased sodium reabsorbed with glucose Na Macula densa Tubuloglomerular feedback Sodium glucose co-transport ↑eGFR ↑ Pressure ↑ Flow Hypertrophy Energy expenditure Glucose toxicity Glucose reabsorption makes the kidney work harder? Injury
  31. 31. glomerulus 360g/d Glucose 11mM proximal tubule SGLT2 SGLT1 120ml/min GLUT1GLUT2 Na Macula densa Tubuloglomerular feedback SGLT2 inhibition in Diabetes Hypertrophy Energy expenditure Glucose toxicity eGFR  Pressure  Flow glucose Injury
  32. 32. DCCT 6.5 years 10 8 6 4 2 0 Risk of heart attack or stroke or death from either still reduced by 32% twenty+ years later? BAD KARMA: Still suffering the outcomes of poor control twenty+ years later? STANDARD INTENSIVE 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 years since entry DCCT/EDIC Diabetes Care (2016) Glucose lowering Diabetes Complications and ControlTrial
  33. 33. 0.5 1.0 2.0Makes it better Makes it worseAdapted from Boussageon et al. BMJ (2011)
  34. 34. STENO-2 7.8 years 7.9 years Gæde, et al Diabetologia (2016) Intensive Standard Years since randomisation BAD KARMA: Every year of suboptimal control efforts is a year off your life? GOOD KARMA: Every year of intensive control efforts is a year on your life?
  35. 35. • ACCUMULATED MODIFICATIONS? • EPIGENETIC PROGRAMMING?
  36. 36. AGE Articular cartilage
  37. 37. GETTING CRUSTY As we get older? Faster in those with diabetes?
  38. 38. Reducing AGEs in diabetes associated atherosclerosis Forbes JM et al. Diabetes 2004;53:1813-1823 NH2- Arginine N-C- NHH3C H3C Aminoguanidine (AG) Metformin dicarbonyl AGE-modification . Control Diabetes D+ALT D+AG
  39. 39. Second messengers Oxidative stress ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ RAGE COMPLICATIONS S100 HMGB1 AGEs Non-AGE ligands AGE-ligands Ligand-dependent activation of RAGE in Diabetes Lysine-CEL Arginine-MGH1 Histidine-AGE Cysteine-AGE autoinduction
  40. 40. Genetic deletion of RAGE protects against diabetes associated atherosclerosis in apoE KO mice Control Diabetes Soro-Paarvonen et al. Diabetes 2010 Diabetic RAGE KO Arch Arch Arch Thoracic Abdominal Thoracic Abdominal Thoracic Abdominal
  41. 41. 0 1 2 3 4 5 Control Diabetes C+GKT D+GKT Nox1 Nox2 Nox4 hNox5 Optimalinhibitionofpro-oxidantNoxenzymes withGKT X X X 0 50 100 150 200 250 300 Control Diabetes C+GKT D+GKT Kidney damagePlaque area (%) 
  42. 42. GKT137831 in patients with type 1 diabetes & CKD GKT137831 200mg bd Placebo Change in mean kidney albumin leakage after 48 weeks Type 1 diabetes + micro/macroalbuminuria n=142
  43. 43. Understanding the legacy or memory effect • ACCUMULATED MODIFICATIONS? • EPIGENETIC PROGRAMMING?
  44. 44. DNA 2 metres long Needs to be condensed >10,000 fold to fit into a nucleus <10m long chromatin
  45. 45. If genes were ‘words’ Epigenetics instructs how to access and read the words “The structural adaptation of chromosomal regions so as to store, retain, and recall past experiences in a way to shape present and future behaviour
  46. 46. Gene is Open for transcription (e.g.H3K4me) Gene is Closed for transcription (e.g.H3K9me) Understanding the histone code signal
  47. 47. 0 0.5 1 1.5 2 2.5 3 LG (16h) HG (16h) 6 days post HG 6 days post LG H3K4mChIp(foldchange) wild type Set7KD Knockdown of histone code by blocking the Set7 enzyme Brasacchio, et al. Diabetes (2009) persistent No bad memories= Eternal Sunshine?
  48. 48. New targets Glucose BP Fat HEART ATTACKS STROKES BLINDNESS AMPUTATION DIALYSIS DEATH PRIMARY PREVENTION
  49. 49. The Diabetes Translational research laboratory was established in 2017 with the generous support of Elias and Coleen Jreissati and their family TheTranslational Research Hub for Diabetes Complications was established in 2017 with the generous support of Moshe Meydan and family foundation

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