Docstoc

DIABETES MELLITUS DIABETES MELLITUS Insulin Glucagon β cells INSULIN α

Document Sample
DIABETES MELLITUS DIABETES MELLITUS Insulin Glucagon β cells INSULIN α Powered By Docstoc
					DIABETES MELLITUS
                        Insulin      Glucagon

β-cells INSULIN
α-cells Glucagon
δ-cells Somatostatin
PP-cells Pancreatic polypeptide
D1-cells       VIP
Enterochromaffin cells - serotonin
                  Insulin synthesis and secretion




                                            Brain
                                            Nerves
                                            Lens
                                            Kidneys
                                            Blood vessels


                                            glucose uptake- insulin
                                            independent

Skeletal muscle
Fibroblasts
Fat cells
                     DM
 Main symptoms:
    Hyperglycaemia     While the
    Glucosuria         cells are „starving”

 Absolute or relative insulin deficiency

       The most frequent metabolic
                 disorder

    Occurrence is consistantly raising
           Blood glucose level
Hypoglycaemia
  ≤3 mmol/l

          Normal
        3-6,4 mmol/l
                   Provocation test

                       6,4-8mmol/l
                                      Pathologic
 Postprandial glucose level           ≥ 8mmol/l
    Reverts to normal in 2-3 hours
    Diabetic patients: ≥ 11 mmol/l
        Healthy – Latent - Manifest
                  Diabetes
          (Oral Glucose ToleranceTest - OGTT)


14


                                          Diabetes


7
                                              IGT


4,5
                                              Normal

75 g Glucose                                        Min
               30    60       90        120
0 min 3.9–5.8 mmol/L     0 min 70–105 mg/dl
60 min 6.7–9.4 mmol/L    60 min 120–170 mg/dl
90 min 5.6–7.8 mmol/L    90 min 100–140 mg/dl
120 min 3.9–6.7 mmol/L   120 min 70–120 mg/dl
             Diagnosis of DM
 A random glucose concentration greater than
  200mg/dl, with classical signs and sy-s

 Fasting glucose concentration grater than
  126mg/dl on more than one occasion

 Abnormal oral glucose tolerance test in
  which glucose concentration is greater than
  200mg/dl 2 hours after a standard
  carbohydrate load
          Glucose in urine
Normal: 0,01-0,02 %

> 9-10 mmol/l glucose level: Glucosuria

Plasma concentration is higher than the
  threshold of the tubules
IGT (Impaired
  Glucose Tolerance)
  / Latent Diabetes
                          Manifest Diabetes
  – 6,4-8 mmol/l
                            – ≥8 mmol/l twice
  But
                            or
  – OGTT: 120 Min: 8-11
    mmol/l                  – OGGT: 120 Min: ≥11
  or                          mmol/l
  – once ≥11 mmol/l
               Causes of glucosuria
1. DM

2. Renal : primary tubular, Fanconi syndr., Multiple
   Myeloma, Wilson

3. Postprandial: meal rich in carbohydrates, Dumping
   syndrome, Hyperthyreosis

4. Stress: Steroid, trauma, burns,AMI, Pancreatitis,
   Tumor, cirrhosis, CNS diseases

5. Others: Phaeochromocytoma (Adrenalin), Acromegalia
   (STH), Glucagonoma (α-cell tumor), Asphyxia
 Praediabetes: disease before clinical
  manifestation
   Both parents are diabetic

 LatentDiabetes
   Impaired insulin secretion on provocation
   tests

 Manifest Diabetes
   type I. : (Juvenile) Diabetes
   type II. : (Adult) Diabetes
         Diabetes mellitus – WHO
               classification
 Type I- juvenile DM: 4,5%
    (IDDM)

 Type II- – „Adult”-Diabetes: (NIDDM)

 (95%)

 Type III- (MODY) – juvenile NIDDM

   (Mature Onset Diabetes of the Young)
1.   Type 1 diabetes (β-cell destruction, leads to absolute
     insulin deficiency)
       Immune-mediated
       Idiopathic


2.   Type 2 diabetes (insulin resistance with relative
     insulin deficiency)


3.   Genetic defects of β-cell function
      Maturity-onset diabetes of the young (MODY),
     caused by mutations in:
       Hepatocyte nuclear factor 4α[HNF-4α] (MODY1)
       Glucokinase (MODY2)
       Hepatocyte nuclear factor 1α[HNF-1α] (MODY3)
       Insulin promoter factor [IPF-1] (MODY4)
       Hepatocyte nuclear factor 1β[HNF-1β] (MODY5)
       Neurogenic differentiation factor 1 [Neuro D1]
     (MODY6)
      Mitochondrial DNA mutations
4.   Genetic defects in insulin processing or insulin action
      Defects in proinsulin conversion
      Insulin gene mutations
      Insulin receptor mutations


5.   Exocrine pancreatic defects
      Chronic pancreatitis
      Pancreatectomy
      Neoplasia
      Cystic fibrosis
      Hemachromatosis
      Fibrocalculous pancreatopathy


6.   Endocrinopathies
      Acromegaly
      Cushing syndrome
      Hyperthyroidism
      Pheochromocytoma
      Glucagonoma
7.    Infections
       Cytomegalovirus
       Coxsackie virus B


8.    Drugs
       Glucocorticoids
       Thyroid hormone
       α-interferon
       Protease inhibitors
       β-adrenergic agonists
       Thiazides
       Nicotinic acid
       Phenytoin


9.    Genetic syndromes associated with diabetes
       Down syndrome
       Klinefelter syndrome
       Turner syndrome


10.   Gestational diabetes mellitus
Acute symptoms
 Hyperglycaemia:
   elevated blood glucose
 Glucosuria
 Polyuria
 Polydipsia (thirst)
 Polyphagia
 Muscle weakness
 Secondary
     hyperlipoproteinaemia
 Warm, wet skin, flush
 Coma diabeticum
   -Ketoacidotic coma
   -Hyperosmolar-hyperglycaemic
 Acute, life theratening
complications of diabetes

     Ketoacidosis

     Infections

     Hyperosmolarity

     Coma
Ketoacidotic coma: IDDM
  -Insuline deficiency: elevated
     lipolysis
  -Free fatty acids in circulation

  -Ketone bodies;
  Aceto Acitic Acid, Hydroxy butiric acid

  -Acidosis
                               Coma
 Ketoacidotic coma: IDDM
  -Insuline deficiency: elevated lipolysis
     (lipoprotein lipase activation)
  -Free fatty acids in circulation
     liver, esterification to fatty acyl CoA
  -Ketone bodies;Aceto acitic acid, β-hydroxy butiric acid
  -Ketonaemia , (ketonuria)
  - Acidosis (Kussmaul breath)

 Hyperosmolar coma: NIDDM:
     elevated water secretion
     (insulin in the portal circulation prevents unrestricted fatty
       acid oxidation)
Patomechanisms of Late complications

 Formation of Advanced Glycation End
  products (AGE)

 Activation of Protein Kinase C

 Intracellular hyperglycemia
  – Polyol pathway disturbancies
Patomechanisms of Late complications

 Formation of Advanced Glycation End
  products (AGE)
         AGE binds to receptors (R) on

     Macrophages,
     T cells,
     Endothelial cells, and
     Vascular SMC -s
 Patomechanisms of Late complications
 AGE-RAGE binding results in

- proinflammatory cytokine formation

- reactive oxygen species in EndC-s

- Increased procoagulant activity on EndC-s and MA-s

- Enhanced proliferative and secretory activity of VSMC-s


Result: severe vascular wall thickening,
 thrombosis Advanced, accelerated AS
Effects of Advanced Glycation End Products (AGEs)
           Non-enzymatic glycosylation




                     HgB 1 AC
 Effects of Advanced Glycation End Products (AGEs)
Extracellular Matrix Components

Abnormal matrix-matrix and matrix-cell interactions


Cross-linking of polypeptides of same protein (e.g., collagen)


Trapping of nonglycated proteins (e.g., LDL, albumin)


Resistance to proteolytic digestion
Patomechanisms of Late complications

 Formation of Advanced Glycation End
  products (AGE)

 Activation of Protein Kinase C

 Intracellular hyperglycemia
  – Polyol pathway disturbancies
                        VEGF production -
                             neovascularisation
                        Endothelin-1 elevation
                        with NO decrease
                        TGF-β formation - BM
                             thickening, EM
                             production
                        PAI-1 production –
DAG = diacyl glycerol         reduced fibrinolysis
                        Proinflammatory
                        cytokines   by
                              endothelium
Patomechanisms of Late complications

 Formation of Advanced Glycation End
  products (AGE)

 Activation of Protein Kinase C

 Intracellular hyperglycemia
  – Polyol pathway disturbancies
NAD consumption, reduced glutathione,
Oxidative stress susceptibility
   Diabetes – late complications
1. Microangiopathy               2. Macroangiopathy
BM thickening, intima fibrosis     Atherosclerosis
microaneurysms                        - Infarctions: heart, brain
                                      - Peripheral circulatory
   - Retinopathy
                                             disturbancies :
   - Glomerulosclerosis
                                             Gangrene
                                 Hypertension:
 3. Neuropathy                     - Arteriosclerosis
 4. Nephropathy                    - Nephrosclerosis
 5. Infections                     - Apoplexy
 6. Glaucoma
 7. Cataracta
                                  !!!!!!!
                Infections
 Impaired granulocyte functions, impaired
  wound healing

 Furuncules, Pyelonephritis, Papillanecrosis,
  Pneumonia

 Fungal infections (Candidiasis)

 Insuline need is elevated in cases of
  infection or operation
             Skin (diabetic foot)
Necrobiosis lipoidica diabeticorum (granuloma anulare)

 Diabetic ulcers (neuropathy, trophic disturbancies)




                                    Confluating granulomas
       Diabetic nephropathy

 1. Kimmelstiel-Wilson-disease
  10-15%-of the cases
  Mesangial matrix
  Proteinuria, renal failure


 2. Pyelonephritis

 3. Nephrosclerosis

 4. Papilla-necrosis
 Diabetic nephropathy

 Cause: non enzymatic glycolysation

 BM collagene thickening

 Mesangial proliferation, Sclerosis

 Diffuse Glomerulosclerosis and/ or
 Nodular Glomerulosclerosis - pathognomic
  Kimmelstiel-Wilson - PAS + hyaline globules
       Diabetic retinopathy
 50%, Progressive microangiopathy
 Blindness
 Microinfarctions: Haemorrhage,
  Exudation, Microaneurysms
 Forms:
  – Exudative : Lipid rich exudate,
    haemorrhage
  – Proliferative vasc. Prolif.
  – Ablatio retinae
            Neuropathia diabetica
              sensory / motor
 Paraesthesia / Hypaesthesia

 Hypotension

 Diarrhea / Obstipation

 Difficulties in swallowing

 Urination problems

 Orthostatic hypotension

 Erectile dysfunctions
        Embriopathy / Fetopathy
 Latent diabetes manifests during
  pregnancy
 Giant babies: > 4,5 kg
   IRDS
   Perinatal mortality is increased
   Transient Hypoglycaemia for β-cell hpl
   Developmental abnormalities
Therapy

1. Diet
2. Oral anti-
     diabetics
3. Insuline

Blood
glucose level
control
     Type I-Diabetes
          No β cells


Failure of self T-tolerance
               Type I-Diabetes
            Pathogenesis: Autoimmune
                   No β cells
GENETICAL          Exogeneous Injury
PRAEDISPOSITION
                    Virus (Rubeola/Pikorna/Coxsackie)
6. CHR.
HLA – DR3          Cow-milk (AB-s cross-reacting with βcells)
                                           Viral mimicry
HLA – DR4
                                           Bystander damage
                                           Viral déjá vu


               Β cell autoimmune injury


             Lowered glucose consumption
Autoreactive lymphocytes – Genetic
– cytotoxic T lymphocytes injurious to β-cells

–Failure of self T-tolerance
Autoantibodies
– AB-s to glucose transport protein
– AB-s to islet cells
– AB-s to insuline

    When 80% of       β   cells injured:

           DM becomes manifest
              Type I –DM:
      Initially : lymphocytic Insulitis
End stage : almost complete loss of β cells




               Insulitis
        Type II - Diabetes
 Obesity in the pathogenesis :
  relative hyperinsulinism


 Β-cells are almost normal in number,
  serum insuline is frequently still normal

 Failure of the elevation of the serum
     insuline, after Glucose administration
        Type II - Diabetes
 Non esterified fatty acids –intracellular
  accumulation promotes serine phosphorylation,
  which attenuates insulin signaling
 Adipokines (adipose cytokines) (low level of
  leptin, adiponectin, which promotes fatty acid
  oxidation in liver and muscle by AMPK activation)
 Inflammation (proinflammatory cytokines formed
  by fat cells) reduces insulin sensitivity
 Peroxisome proliferator-activated receptor
  stimulate insulin sensitivity – target for drugs
Predisposing factors :

 Obesity, pregnancy, stress, infections

                    TREATMENT

 Oral antidiabetics (Sulfonylurea) mobilise insulin
  reserve of the β cells

 Weight loss can ameliorate the situation

 Physical activity can lower insuline needs
 Type II- Diabetes Pathogenesis

 GENETICAL PRAEDISPOSITION
                                   Obesity
 Familiar genetical
 alterations

                                  Peripheral
Abnormal Insuline secretion   Insuline resistency


             Lowered glucose uptake
         Insulin resistency
„Down”-regulation of the insuline
  receptors:

 Postreceptor alterations

 Proteins, playing role in glycogene
  synthesis (glucose transporters,
  hexokinase II, glycogene synthetase)
        Type III. DM - MODY
„young patients develop „adult type” DM (NIDDM)

   Genetic defects (Kaukasus): parents are
   diabetics in 85% of the cases
   AD
   Age < 25
   Abnormal Insulin secretion
    Cells are normal
   No obesity
   Absence of β-cell autoantibodies
        Type III. DM - MODY
„young patients develop „adult type” DM (NIDDM)
„loss of function”
mutations
Eg: glucokinase (GK) -
catalyzes the transfer of
phosphat from ATP to
glucose
Mutation elevates the
threshold of glucose that
triggers insulin release
              Secondary Diabetes
 Pancreatic injury or insuline antagonist hormones

 Pancreatitis (acute,-necrotizing 10-30%-     chronic, viral)
 Cystic Pancreas fibrosis
 Heavy meals
 Tumors
 Chemical injuries
 Iron deposition (Haemochromatosis) (60% - bronze
      diabetes)
 Endocrine diseases (Insuline Antagonists):
      adrenal, hypophysis, thyroid
 Pregnancy
     Diabetes of pregnancy
 1-2% of pregnancies



 Serum glucose reverts to normal after
  delivery, but later diabetes might occur
         Hypoglycaemia
IDDM: high insuline

– „Quick” symptoms: Adrenalin:
  Vasoconstriction, tachycardy, sweat,

– „Slow” symptoms: Depression, bizarre
  behaviour, neurological signs
          Nesidioblastosis
       Hypoglycaemia with hyperinsulinism




Diffuse or focal reactive β-cell-Hyperplasia
                 Newborns
             Etiology unknown
Diffuse neuroendocrine system (DNES)
Gastro-entero-pancreatics (GEP) tumors
            (APUD-omas)
      MARKERS OF NEUROENDOCRINE
           DIFFERENTIATION
                 General markers
 Vesicles
   Chromogranin A, B
   Synaptophysin
 Cytosole
   NSE
   PGP 9.5 (protein gene product)
 Membrane bound
  (receptors for adhesion molecules)
     CD56, (N-CAM)
MARKERS OF NEUROENDOCRINE
     DIFFERENTIATION

      Specific markers
Hormones (cell type dependent)

                   Insulin
    NEUROENDOCRINE TUMORS OF THE
                  PANCREAS
 Insulinoma - β-cells- benign
 Gastrinoma- δ-cells - carcinoma –
    Zollinger-Ellison Syndrome: parietal cell hyperplasia, multiple ulcers

 Glucagonoma - α-cells - carcinoma
    Mild diabetes, skin rash, anaemia
 Somatostatinoma - δ-cells – carcinoma – slow
 bowel movements, steatorrhea
 VIPoma - PP-cells - carcinoma -               Werner-Morrison
 Syndrome (watery diarrhea, Hypokalaemia, Achlorhydria)
 Carcinoid - Enterochromaffine cells – carcinoid
 syndrome
         Endocrine system
„Neuroendocrine”
      Glands
         hypophysis, parathyroid, adrenal medulla, paraganglia
      Islands
         Pancreas
      Single cells
         C-cells


„Classic” endocrine
       Glands
         Thyroid, adrenal cortex
       Diffuse
         Stromal cells of the ovaries and testes
                 MEN1 Wermer sy   MEN 2A Sipple sy   MEN 2B

Hypophysis       Adenomas

Parathyroid      HPL +++          Hpl +
                 Adenoma +
Langerhans       HPL ++
islands          Adenoma ++
                 CC +++
Adrenal          HPL              Pheochromo-        Pheochromo-
                                  cytoma ++          cytoma +++
Thyroid                           C cell hpl +++     C cell hpl +++
                                  Medull. Cc +++     Medull. Cc +++
Extraendocrine                                       Mucocutan
organs                                               ganglioneuromas
                                                     Marfanoid
Genetics         MEN1 11q13       RET 10q11.1        RET ?

				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:81
posted:4/15/2011
language:English
pages:59