1. “Depression and type 2 diabetes: Cortisol pathway implication and investigational needs” Claudia Gragnoli Journal Club 3

2. The Paper Why this one? Psychiatry –Depression Atypical Major Depression Endocrinology –T2DM –HPA axis What is known and what links are there?

3. The HPA axis

4. CRH receptors CRHR2 –Sustaining HPA function –Recovery Phase of HPA response Brainstem to release catecholamines/ adrenaline Anxiety CRHR1CRHR1 HPA axis DevelopmentHPA axis Development Initiation of HPA axis responseInitiation of HPA axis response Behaviour/AnxietyBehaviour/Anxiety (Limbic) HPA feedback(Limbic) HPA feedback

5. T2DM and cortisol Chronic Stress ↑ Cortisol ↑ visceral fat/ ↑ portal/ peripheral FFA ↓ insulin action on GLUT4 translocation ↑ hepatic gluconeogenesis ↓ insulin production (CRHR1 in beta cells)

6. Depression and cortisol Major Depression ↑ Cortisol, ↑CRH (despite high cortisol)↑ Cortisol, ↑CRH (despite high cortisol) ↓ ACTH response to CRH BUT normal cortisol response↓ ACTH response to CRH BUT normal cortisol response ? Adrenal Hypersensitivity? Adrenal Hypersensitivity Hypothesis Functional HPA axisFunctional HPA axis ?Dysfunction above the level of the hypothalamus?Dysfunction above the level of the hypothalamus ?CRHR dysfunction?CRHR dysfunction

7. T2DM and Depression 60% risk of diabetes if you have major depression –No known link but... Melancholic Depression CRH Receptor Hypofunction ↑ HPA, ↑CRH, ↑Cortisol Insulin Resistance and ↓Insulin Secretion T2DM

8. T2DM and Depression Atypical Depression patients so no raise in cortisol but still are at risk of T2DM Atypical Depression CRH Receptor Hyperfunction ↓ HPA, ↓CRH, ↓Cortisol ↑Insulin Secretion & ↑ Food Intake Insulin Resistance T2DM