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
autonomous
(tumors)
insufficiency
lacking h. activity
(inflammation)
changes in insulin secretion/action
Hypopituitary gland - adrenal axis
related 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
GS: insulin resistance in the liver and peripheral
tissues at postreceptor level
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
Hypocorticalism and diabetes mellitus
Ethiology:
- 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)
Hypoglycemia !
Corticoid substitution:
- increased insulin needs
- decreased hypoglycemia episodes
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:
(adrenergic)
sweating, palpitations, tachycardia,
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
INSULIN ACTION
12
8
HOMA
MCRG (ml/kg/min)
10
6
4
2
0
K1
K2
DM
INS
PHA
PCOS
MCRG
HOMA
MCRG/I (ml/kg/min/mU/lx100, HOMA
INSULIN ACTION IN INSULINOMA AND
PRIMARY HYPERALDOSTERONISM
*
12
10
8
*
6
4
2
0
INS
PHA
MCRG/I
HOMA
K
Ich danke für Ihre Aufmerksamkeit