“Depression and type 2 diabetes: Cortisol pathway

implication and investigational needs”

Claudia Gragnoli

Journal Club 3

The Paper

• Why this one?• Psychiatry

– Depression• Atypical• Major Depression

• Endocrinology– T2DM– HPA axis

• What is known and what links are there?

The HPA axis

CRH receptors

• CRHR2– Sustaining HPA

function– Recovery Phase of

HPA response

Brainstem to release catecholamines/ adrenaline

Anxiety

• CRHR1•HPA axis Development•Initiation of HPA axis response•Behaviour/Anxiety•(Limbic) HPA feedback

T2DM and cortisol

Chronic Stress

↑ Cortisol

↑ visceral fat/ ↑ portal/ peripheral

FFA

↓ insulin action on GLUT4

translocation

↑ hepatic gluconeogenesis

↓ insulin production

(CRHR1 in beta cells)

Depression and cortisol

Major

Depression

•↑ Cortisol, ↑CRH (despite high cortisol)

•↓ ACTH response to CRH BUT normal cortisol response•?

Adrenal Hypersensitivity

Hypothesis

•Functional HPA axis

•?Dysfunction above the level of the hypothalamus•?

CRHR dysfunction

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

SecretionT2DM

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 ResistanceT2DM