endocrine disorders and diabetes mellitus prof. dr. jan Škrha 3rd department of internal medicine,...
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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