PATHOPHYSIOLOGY OFDIABETES MELLITUS

MUDr. Pavel Maruna

Diabetes mellitus

= chronic endocrine - metabolic disorder,the result of insufficient insulin influence saccharide, lipid, protein metabolism, both water and mineral

dysbalance

Chronic hyperglycemia glykosuria osmotic diuresis

= endocrine active part of pancreas1-2,5 mil. islets, 1-2 g, 1-2% mass of pancreas

B cells (β cells) ... 60-80 %, insulinA cells (α cells) ... 15-20 % glukagonD cells ... 5 % somatostatinG cells ... gastrinOther cells ... VIP, PP, serotonin ...

Islets of Langerhans

Islets of Langerhans

Insulin synthesis

preproinsulin (linear chain, 107 AA)A - C - B chain, terminal fragment

cleavage of terminal fragment

proinsulinA - C - B chain

transport to Golgi complex-SS- bridgesEncapsulationRelease after stimulus

Islets of Langerhans

Insulin secretion

insulin + C peptide (in equal amount)• C peptide – a minimal extraction in liver• hINS a pINS - 1 AA difference on position 30

(treonin x serin)• insulin - 50% extraction in liver during the first pass• half-life of insulin in circulation 4-5 min.• specific membrane bound receptors on target cells

Islets of Langerhans

Insulin secretion

basal secretion(plasma levels 5-30 mU/l)

after stimulus glcsome AA, glucagon ...sulphonylurea

Islets of Langerhans

Islets of Langerhans

Islets of Langerhans

Insulin effects

Liver - inhibition of glycogenolysis- inhibition of gluconeogenesis- stimulation of glycogenogenesis

Other cells (muscles, fat, fibroblasts, brain)- Glc. uptake and utilization- stimulation of anabolic actions- inhibition of catabolic actions

(e.g. inhibition of LP lipase)- transport of AA and K+ do cells

Islets of Langerhans

Insulin effects

GLUT4

Insulin dependent Glc uptake into cells

Islets of Langerhans

Contraregulatory activities

Glucagon - activation of hepatic glycogenolysis, activation of ketogenesis

Epinephrine - activation of glycogenolysis in liver and muscles, lipid catabolism

GH - activation of glycogenolysis in muscles, lipid catabolism

Cortisol - stimulation of gluconeogenesis

T3, T4 - intestinal resorption of Glc, stimulation of both gluconeogenesis and glycogenolysis in liver

Somatostatin - inhibition of insulin, glucagon, PP, GH secretion

Islets of Langerhans

Insulin insufficiency

- absolute- relative

CausesInsulin is not composed in B cells of islets ........ !!

Insulin is composed in defect shapeInsulin is composed OK, but is not released from B cellsInsulin is eliminated from circulation (auto-Ab)Insulin receptor or post-receptor insufficiency ........ !!! effect of contraregulatory hormones ........ !

Symptoms of insufficient insulin activity

Glc uptake to cells (fat, muscles) gluconeogenesis in liver and kidneys glycogenolysis

... glycaemia, plasma osmolarity

... glycosuria due to overrun of renal threshold

... osmotic diuresis, dehydration, Na and K loss lipolysis lipogenesis ketoacids production in liver

(overpassing and utilising capacity of tissues)... ketoacidosis, acetonuria

... acute and chronic diabetic complications

Insulin insufficiency

Classification

DM 1st type (= insulin-dependent)defect insulin secretion, absolute insulinodeficiency

DM 2nd type (± non-insulin dependent)Inzulinoresistance + relative insulinodeficiency(impaired dynamics of secretion, delayed secretion ...)

Secondary DM - in endocrinopathy (Cushing sy, acromegaly, thyrotoxicosis, feochromocytoma)

Malnutrition-related DM(rare) hereditary syndromes

Drugs (diuretics, corticoids)Gestatory DMDM in pancreatic disorders (inflammation, tumors, surgery...)

Diabetes mellitus

Characteristics

• Absolute insulin insufficiency• Tendency to ketoacidosis• Insulin-dependent = insulin therapy is necessary• Revealed in children or young age (juvenile diabetes)• Quick progression of signs ketoacidotic coma

1st type DM

Etiology, pathogenesis

genetic dispositions + acquired factors (viral infection)? autoantigenic presentation of β-cells lymphocyte immune control β-cell destruction

Genes disposing for DM 1st type are localized in MHC on 6p chromosome. These genes encode antigens, regulating T-lymphocyte immune supervision (a discernment of own cells)

1st Class HLA (HLA-A,B,C,D) - expressed on almost all cells2nd Class HLA (HLA-DP,DQ,DR) expressed on immune cells and (possible) on islets

cellsE.g. HLA-DR3,DR4,DR1,DR8,DR16 ... higher risk of DM,

HLA-DR11,DR15 protection against DM

Prediction of 1st type DM – quantification of risk:Auto-Ab against β-cells, insulin, GAD (glutamate-decarboxylase)

1st type DM

Insulitis

= disappearance of β-cells, inflammatory infiltration, degranulation, hydropic changes, fibrosis

– in young diabetics

1st type DM

Insulitis

1st type DM

LADA

= latent autoimmune diabetes in adults(diabetes of the 1 1/2 type)

DM 1st type with manifestation in later age (>30 r.)

• similarity to DM 2nd type (but without obesity),• however both C-peptide and insulin levels are lower 0• due to destruction of β-cells• ! auto-Ab presented: anti-GAD, ICAs auto-Ab• tendency to ketoacidosis

1st type DM

Characteristics

The most frequent type of DM (80-90 %)

• Relative lack of insulin• x ketoacidosis• Usually non-insulin-dependent• Manifestation in middle or older patients• Slow progression, tendency to chronic complications

2nd type DM

Etiology, pathogenesis

Genetic dispositions (15-20% population)(marked hereditary dependence, often familiar presence, evidently polygenic transmission)

Acquired factors - links to obesity (80 %)(overeating, obesity, stress, age, inactivity)

type 2a) without obesity, type 2b) with obesity

1. Inzulinoresistance = lower sensitivity of muscles, liver and fat to insulin ( receptors, affinity of receptors, or post-receptor blockade)

2. Inzulinodeficiency = insufficient maximal insulin secretion (absolute or relative, manifesting together with insulinoresistance)

2nd type DM

MODY

= Maturity Onset Diabetes of the Young

An early manifestation of NIDDM in young patients

2nd type DM

MODY

2nd type DM

= Transition between DM and normal glucose metabolism

Diagnostics: oGTT

Prognosis: normalization x long-term persistence x progress to DM

Observation is necessary

Impaired glucose tolerance

= PGT or DM manifested firstly in pregnancy

During pregnancy - physiologically sensitivity to insulin compensatory insulinaemia

Gestatory DM reveals in women with insufficient compensatory insulinaemia

After delivery, glucose tolerance is normalized, but there is a risk of DM in future

Diff. dg.: first manifestation of latent IGT or 1st type DM

Gestatory DM

Glycaemia

fasting / postprandial / glycaemic profile

< 5 mmol/l fasting excludes DM

> 10 mmol/l in blood (11 mmol/l in plasma) confirms DM7 - 10 mmol/l in blood (8 mmol/l in plasma) repeatedly + typical features suspect DM5 - 7 (8) mmol/l oGTT

Laboratory markers of DM

oGTT (oral glucose tolerance test)

75 g Glc per os0 1 2 h

DM >7 >10 >10 mmol / l in venous bloodIGT <7 >10 7-10

(unconvincing results ? ... decisive fasting glycemia or glycemia after 2 h)

Laboratory markers of DM

Glycated albuminGlycated hemoglobin (normal levels below 4 %)

Products of non-enzymatic glycation of proteins

Glc + H2N-protein Schiff´s base ketoamine glycated protein

Irreversible, non-enzymatic process, dependent on- concentrations of glucose and proteins- half-life of glycated protein

(colagens, lens x hemoglobin, albumin)Importance

- pathogenesis- diagnostics (markers of long-term compensation of DM)

Laboratory markers of DM

C peptide above 70-80 pmol/l

Insulin (IRI = immunoreactive insulin)

To distinguish 1st type x 2nd type DM

Laboratory markers of DM

Urine

• glycosuria55 mmol/l Glc = 1%account of glucose tolerance

• aceton• proteinuria

microalbuminuria (physiologically 10-20 mg/24 h)• U-glucosaminidase

an early marker of kidney disease

Laboratory markers of DM

Autoantibodies

ICAs = against β cells (against various cytoplasmic compounds)non-specific (founded in polyglandular syndromes, e.g.)

IAAs = against insulinrevealed mostly during insulin therapy,low prognostic impact

Anti-GAD = against decarboxylase of glutamate (enzyme for GABA production)

highly specific to DM 1 typetheir detection means risk of DM 1st type

Anti-37kD = against 37 kD chain of GADstill higher specificity than anti-GAD

Anti-BSA = against bovine albuminwhich has (similarly as coxsackie viruses) sequences similar to cytoplasmic antigens of β cells

Laboratory markers of DM

Markers of DM microangiopathy

= markers of endothelium activation (beforeclinical signs of angiopathy revealed)

tPA (tissue plasminogen activator) - marker of fibrinolysis, cleavage of fibronectin

PAI-1 (plasminogen activator inhibitor) - antifibrinolytic activity

von Willebrand factor

NAG (N-acetyl-β-glucosaminidase)

30 kD N-terminal fibronektin

- better than total fibronectin, it reflects an activity of tPA

Laboratory markers of DM

1. Acute

a) Hypoglycemia … PAD, insulinb) hyperosmolar hyperglycemic coma ... 2nd type DMc) ketoacidotic coma ... 1st type DM d) lactoacidotic coma … biguanids

DM complications

2. Chronic

a) Specific for DM

- microangiopathy (diabetic leg)- neuropathy

(peripheral symmetric (low extr.), asymmetric (head, extremities), amyotrophy, autonomic visceral)

- eye complications (cataracta, glaucoma, paresis, retinopathy)- renal complications (diabetic glomerulosclerosis)

Bell´s form (diffuse) x nodular form Kimmelstiehl-Wilsonmicroalbuminuria proteinuria renal failure+ renal hypertension

- cardiomyopathy (hypertrophy, cardiac dilation)

DM complications

2. Chronic

a) Specific for DM

Diabetic retinopathy

I rare microaneurysma, small hemorrhages with exsudateII more frequent hemorrhages, central edemaIII frequent retinal hemorrhages vascular intraretinal

proliferationIV total retinal destruction

DM complications

2. Chronic

a) Nonspecific

- macroangiopathy (arteriosclerosis)- liver steatosis- TIN

3. Immunoallergic

a) Allergy to insulinb) Resistance to insulin

DM complications

Komplikace DM

DM - diet mistake, insulin therapy, sulphonylurea therapy

Insulinoma

Postprandial (Dumping sy, alcohol)

Alcohol - inhibition of gluconeogenesis + stimulation of insulin synthesis in β cells

Tumors - consumption of Glc or production of insulin-like factors

Liver failure - only terminal phase

Glycogenoses I, III, VI, VII type...

Differ. diagnostics of hypoglycemia

1988 Reaven´s syndromesyndrome X(pluri)metabolic syndromesyndrome of 5 H

Former definition: Combination of main metabolic risk factors of atherosclerosis and ischemic heart diseases

• obesity (central type)• diabetes mellitus II type• HLP IV type ( TG )• hypertension• hyperurikaemia• atherosclerosis, coronary disease

Syndrome ofSyndrome ofinsulinoresistanceinsulinoresistance

Prof. Gerald Reaven

New definition: Metabolic and clinical links of postreceptor insulinoresistance

Prevalence:25 % of adult population (mainly asymptotic course)

Etiology:Postreceptor blockade of insulin influence in musculature

(muscles = acceptors of 80 % of glucose)

• defect of phosphorylation ?• IRS-1 ?• membrane transport of glucose ?,• glycogenogenesis ?

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Pathogenesis

Postreceptor blockade of insulin effects

Low uptake of glucose, hyperglycaemia

Stimulation of beta cells

Compensatory hyperinsulinaemia

A. Partial blockade of insulin effectsB. Partial overexpression of insulin effects

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Pathogenesis

(relativ.) low uptake of glucosehyperglycaemia

... Diabetes mellitus II type

DHEA (syndrome of low DHEA) PAI - 1proliferation of vessel smooth musclenatrium retention ET 1central stimulation of sympathetic nervous system vasoconstrictioninhibition of NO (inhibition of vasodilatation)

... Hypertension

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Pathogenesis

Dyslipidemia (HDL, LDL, TG)... Atherosclerosis

(via IGF-1 receptor) Ovarial hyperandrogenism... Stein-Leventhal syndrome... Achard-Thiers syndrome (diabetes II + hirsutism)

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Clinical features

* Type 2 DM

* Central type of obesity

* Hyperlipidemia

* Hypercoagulation

* Hypertension

* ... Atherosclerosis

Syndrome of insulinoresistanceSyndrome of insulinoresistance

Syndrome of insulinoresistanceSyndrome of insulinoresistance

? FFA? TNFα? leptin? β3 adrenergic receptor? cortizol, DHEA

Insulinorezistance obesity interactions

Polygenic dispositions+ acquired factors

Syndrome of insulinoresistanceSyndrome of insulinoresistance