ENDOCRINE DISORDERS

AND

DIABETES MELLITUS

Prof. Dr. Jan Škrha

3rd Department of Internal Medicine, First Faculty of Medicine,

Charles University, Prague

47. Jahrestagung DDG, Stuttgart

Hormone influence on glucose metabolism

Hormone

overproduction insufficiency

autonomous lacking h. activity (tumors) (inflammation)

changes in insulin secretion/action

Hypopituitary gland - adrenal axisrelated to diabetes

• Acromegaly

• GH deficiency

• Hypercortisolism (Cushing´s sy)

• Cortisol deficiency

• Primary hyperaldosteronism

• Feochromocytoma

GH & Insulin resistance GH IR in the liver and muscle

- increased gluconeogenesis and glycogenolysis in the liver - decreased glucose uptake and utilisation in the muscles - lipolysis stimulation – FFA elevation - aggravated

insulin resistance in the liver and muscle by Randle cycle

- GH effect at postreceptor level

Acromegaly and diabetes mellitus

GH causes insulin resistance (related to IGF-I)

IGT – in 15 – 36 % acromegalic patients

DM (usually NIDDM) – in 15 – 30 % (56%) pts with acromegaly

When DM diagnosed - acromegaly lasts 5-10 yrs

GH suppression – decreasing IR, IRI,

improved glucose tolerance

GH defficiency and glucose regulation

Especially children with GHD are prone to severe hypoglycemia

In insulin treated diabetic patients : newly developed GHD is associated with hypoglycemic episodes

GH treatment in GHD adults – causes limited changes in plasma glucose and insulin levels

Hypercortisolism

A. Endogenous 1. ACTH dependent - central - ectopic 2. ACTH independent - adenoma,

carcinoma, bilateral hyperplasia

B. Iatrogenous (the most frequent)

daily and cummulative dose of corticoids

GC effects on glucose metabolism

1. decreased glucose transportation into cells, decreased glucose utilisation

2. increased gluconeogenesis in the liver

- induction of key gluconeogenic enzymes increased protein catabolism in muscles increased lipolysis in adipose tissue

- increase of gluconeogenic substrates

3. increased glycogen synthesis and decreased glycogenolysis

GS: insulin resistance in the liver and peripheral tissues at postreceptor level

Hypocorticalism and diabetes mellitusEthiology:

- peripheral – Addison´s disease (in 80 %

autoimmune, TBC, tumors, adrenex)

- central (in hypopituitarism)

Autoimmune Addison´s disease (AAD):

- 2.5x more frequent in women, between 20.- 50. yrs - in 40 – 50 % APS II - Schmidt syndrome

(+Hashimoto tyreoiditis, gonadal failure, - IDDM in 10 %, vitiligo, perniciose anemia, coeliac

sprue)

In 50 % AAD pts – in families tyreoiditis or IDDM

Hypocorticalism developed in IDDM patient

- increased insulin sensitivity,

decreased insulin needs

decreased blood glucose levels

(decreased gluconeogenesis)

Corticoid substitution: - increased insulin needs - decreased hypoglycemia episodes

Hypoglycemia !

Primary hyperaldosteronism and glucose metabolism

• In about 50 %: mild impaired glucose tolerance, DM is rare

• Insulin secretion in OGTT is delayed and subnormal – caused by low serum potassium level

• K+ improvement – improved insulin secretion

Pheochromocytoma

Hyperglycemia: IGT in 30 up to 75 %

Catecholamines:•Inhibit insulin secretion by stimulated α2- adrenergic receptors on B cells•Insulin resistance in peripheral tissue – impaired glucose utilisation (β-adrenergic receptors, at postreceptor level) increased FFA

Pheochromocytoma and glucose metabolism

Catecholamines:

• Glycogenolysis stimulation in the liver and muscles Gluconeogenesis stimulation - adrenalin• Lipolysis stimulation in adipose tissue - substrate for gluconeogenesis in the liver • Stimulation of glucagon secretion

Pheochromocytoma treatment

• Surgical removal

– improved IGT to normal

• Blockade of α – adrenergic receptors – improved glucose tolerance and insulin secretion

Thyreotoxicosis

Thyroxin: increases glucose production and release by the liver(glycogenolysis, gluconeogenesis, lipolysis, ketogenesis, proteolysis)

increased insulin secretion

peripheral insulin action: x x 0

IGT: 30-50 % DM: worsening of glucose control, increased lability and prone to ketoacidosis

Hyperandrogenism (PCOS)

plasma testosterone plasma SHBG

PCOS: insulin insensitivity dependent on weight

a) normal weight - normal insulin sensitivity b) overweight and obese

increased insulin secretion

IGT or DM dependent on PCOS duration and individual genetic disposition

Insulinoma and diabetes

Extremely rare

-association with T2DM-newly occuring severe hypoglycemia especially in the fasting state (morning!)-exclusion of the influence of diabetes treatment (oral agents)

HYPOGLYCEMIC SYMPTOMS

1) neurogenic: sweating, palpitations, tachycardia,

(adrenergic) anxiety

2) neuroglycopenic:

a) neurologic: headache, impaired or double vision,

decreased abbility to concentrate,

impaired speech and consciousness,

cramps, epilepsy

b) psychiatric: unusual hesitation, temper changes

(depression, euphory)

impaired thinking

Algorithm of diagnosis in endocrine tumors

Clinical suspition

Biochemical examination

Diagnosis confirmed Diagnosis unconfirmed

Topographic localisation

CT Angiography Endosonography

Localisation confirmed Localisation unconfirmed

Surgery

Tumor removed Tumor unremoved

Conservative treatment

Clinical background

• < 1 % patients with DM or IGT have primarily

other endocrinopathy

• DM may help to disclose other endocrinopathy

Treatment of endocrinopathy may improve

diabetes control

Clinical remarks- endocrinopathies are associated with

changes in insulin action

- IGT developes earlier than DM

- screening of glucose changes has to be done in patients with endocrinopathies

- improvement of insulin action is the main task for treatment

- normalization of hormonal activity has to be associated with appropriate treatment of glucose metabolism

INSULIN RESISTANCE DETERMINATION

Insulin action measurement (IR)

A) „Gold standard“Isoglycemic and euglycemic hyperinsulinemic

clamps(M, M/I, MCRG)

B) Index

IRIB x GlucoseB

HOMA =

22.5

0

2

4

6

8

10

12

MC

RG

(m

l/kg

/min

)

K1 K2 DM INS PHA PCOS

INSULIN ACTION

MCRG

HOMA

HO

MA

INSULIN ACTION IN INSULINOMA AND PRIMARY HYPERALDOSTERONISM

0

2

4

6

8

10

12

INS PHA K

MCRG/I HOMA

MC

RG

/I (m

l/kg

/min

/mU

/lx10

0, H

OM

A

*

*

Ich danke für Ihre Aufmerksamkeit