TYPE-2 D I A B E T E S a Collision between Genes and Environment - - PowerPoint PPT Presentation

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TYPE-2 D I A B E T E S a Collision between Genes and Environment - - PowerPoint PPT Presentation

Aug 23, 2023 433 likes •616 views

TYPE-2 D I A B E T E S a Collision between Genes and Environment Patrik Rorsman OCDEM, Oxford (UK) Human pancretic islets Glucagon Insulin Low blood glucose Glucose production (catabolism) Exercise Normoglycaemia Feeding Glucose

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Patrik Rorsman OCDEM, Oxford (UK)

TYPE-2 D I A B E T E S – a Collision between Genes and Environment

Human pancretic islets

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Low blood glucose Glucagon Insulin Glucose production (catabolism) Normoglycaemia Exercise Insulin Glucagon Feeding High blood glucose Glucose storage (anabolism)

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SLIDE 3

Architecture of the human pancreatic islet

β β β β δ δ δ δ α α α α 50% β β β β-cells, 40% α α α α-cells, 10% δ δ δ δ-cells

Man: 1 million islets (1% of the pancreas volume/1 g of tissue)

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“Rodent diabetes is not a major clinical problem”

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Human islets

  • Transplantation to

treat some type-1 diabetics (OXford Clinical Islet Isolation and Transplantation Centre)

  • Quality assessment
  • Opportunity to

characterise human islet cells

  • >200 pancreases

analyzed since 2006

  • Genotypes known for

some of the donors

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SLIDE 6

T2DM associated with reduced GSIS

1 mM 20 mM Human islets Isolated islets

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Glucose-dependent effects on β β β β-cell electrical activity in intact human islets

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SLIDE 8

Consensus model of insulin secretion in human β β β β-cells

Sulphonylureas (1950-)

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SLIDE 9

Pancreatic islet function: Of mice and men

≠

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Diabetes: a collision between genes and lifestyle?

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Obesity and diabetes risk

Nurses’ Health Study, Carey et al., 1997

* *Body weight/(height)2

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Diabetes incidence in Norway 1925-55: benefits of German occupation?

Ashcroft & Rorsman 2012 Westlund 1966 (redrawn)

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Long-term exposure to FFAs mimics effects of diabetes

Reduced insulin granule fusion

Human islets

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Obesity, diabetes risk and insulin secretion

Nurses’ Health Study, Carey et al., 1997

Hypothesis: Obesity Chronic elevation of plasma FFA Reduced GSIS T2DM Chronic elevation of plasma FFA?

Karpe et al., Diabetes, 2011

Diabetes

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SLIDE 15

Plasma NEFA after meal (<0.1 mM)

K Frayn (redrawn)

Plasma FFAs become elevated during fasting

  • FFA-induced suppression of GSIS is an

evolutionarily preserved mechanism to protect against hypoglycaemia during starvation

  • This mechanism becomes erroneously

activated in diabetes GSIS ↓

  • Pathology = Physiology?
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Diabetes – ‘Starvation in the midst of plenty?’

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Lord Carnarvon and Howard Carter

“I see wonderful things”