Diabetes mellitus

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Diabetes mellitus
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DM Definition, Prevalence

• chronic metabolic disease caused by absolute or
  relative insufficiency of insulin (or their
  combination)
• in the world approximately 270 million diabetic
  patients
• raising incidence, mainly DM type 2

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Classification DM

• DM type 1
• DM type 2
• Gestational DM
• Other specific types of DM (e.g. MODY-hereditary
  forms linked to mitochondrias, drug induced DM -
  glucocorticoids, ß-blockers, thiazides)

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Acute Complications of DM

• diabetic ketoacidosis (typical for DM type 1, but
  can also occur at DM type 2)
• hyperosmolar coma (typical for DM type 2)
• hypoglycaemic coma

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Chronic Complications of DM

• diabetic macroangiopathy acceleration of
  atherosclerosis
• diabetic microangiopathy damage of retinal and
  renal vessels
• diabetic nephropathy
• diabetic neuropathy senzo-motoric affection

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Prevention of Complications

• good long-term diabetes controll
• complex treatment of concomitant risk factors
  (hypertension, dyslipidemia, obesity...)

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DM type 1

• most often among children
• genetically determined (allele DQ8, DR3,4)
• autoimune destruction of B-cells in pancreas by
  Tc lymphocytes
• absolute insufficiency of insulin
• requires whole-life treatment with insulin

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DM type 1 - Diagnosis

• clinically polyuria, polydypsia, loosing of
  weight, acetone foetor ex ore
• biochemically
• ? fasting glycemia gt7 mmol/l
• ? oGTT - glycemia 120 min. gt11mmol/l
• ? C-peptide ? or 0
• ? urine ketonuria, glucose

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DM type 1 - Treatment

• nowadays exclusively only human insulins
• effort to imitate diurnal secretion of insulin
  (basal postprandial)
• important education of parents and also children
  (selfmonitoring, regimen precaution)

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Insulins According to Origin

• 1. Semisynthetic from porcine insulin
• by the change of AA (Insuman)
• 2. Prepared by recombinant
• DNA method (Humulin - HM)
• 3. Insulin analogues (exchange, change of
• sequence or type of AA) better
• pharmacocinetic

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Insulins according to Length of Action

• A. Short acting
• ? fast beginning of the effect
• (15 - 30 min.)
• ? acting 3 - 6 hours
• ? water soluable
• ? s.c. or i.v. administration (acute
• states require i.v. administration
  !!!)

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Insulins according to Length of Action

• B. Intermediate acting (NPH)
• ? slower beginning of the effect
• (1 - 3 hours)
• ? acting 4 - 12 hours
• ? suspensions
• ? only s.c. administration (after i.v.
• administration risk of embolisation
  !!)

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Insulins according to Lenght of Action

• B. Insulins with prolonged action
• ? slow beginning of the effect
  (3 - 4 hours)
• ? acting 10 - 24 hours
• ? suspensions
• ? only s.c. administration

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Insulin Analogues

• Insulins lispro aspart
• ? beginning of the effect till 15 min.,
  lasts
• shortly (cca 1 hour)
• ? possible to administer right before meal
• Insulins glargine detemir
• ? act 16 24 hours
• ? usually enough to administer one time
• per day

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Adverse Effects of Insulin

• hypoglycemia ? dose, insufficient food income,
  interaction with alcohol
• lipodystrophy at human ins. rarely
• weight gain at ? daily doses of insul. at DM
  type 2
• local allergy rarely

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Insulin Regimens

• the conventional regimen 1-2 s.c. injections/day
• ? at DM type 2 after failure of treatment
  
• with PAD or PAD
• intensified regimen (basal bolus)
• ? standard at DM type 1
• ? at DM type 2 after failure of PAD

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Intensified Regimen

• the best imitation of physiologic insulin
  secretion
• Important is patient education (selfmonitoring)
• most often 4-5 s.c. injections/day
• intermediate ins. only at evening or in morning
  at evening (basal), short-acting ins. before
  main meal morning-noon-evening (bolus)

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Insulin Pump

• continual s.c. administration of insulin
• only for good cooperating patients after adequate
  education
• the best compensation of diabetes
• in case of combination with sensor to monitor
  glycemia, automatic adjustment of doses

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Aplication Forms of Insulin

• injection
• insulin pens
• ins. pump
• inhaled insulin (powder)
• peroral forms in development

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Indications of Insulin Therapy

• DM type 1
• DM type 2
• ? loss of PAD effectiveness
• ? surgery, intercurrent diseases
• gestational DM
• states after pancreatectomia, pankreatitis

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Goals of DM Type 1 Therapy

• prevention of chronic complications
• by good diabetes compensation
• ? long-term glycemia 7 mmol/l
• ? HbA1c (glykosyled Hb) lt 7
• keeping stabilized glycemia
• ? without frequent
• hypo-hyperglycemias
• keeping the best possible quality of patients
  lives

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DM Type 2

• insulin resistance at postreceptor level
  relative insulin deficiency, later also absolute
• the same CV risk as patients after MI !!!
• marked therefore as also CV disease
• frequently part of metabolic syndrome

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DM Type 2 - Treatment

• must be complex (hypertension, dyslipidemia,
  obesity...)
• important regimen precautions
• ? loss of weight
• ? reduction diet
• ? physical activity

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Peroral Antidiabetics

• 1. Stimulators of insulin secretion
• a. derivates of sulfonylurea
• b. derivates of meglitinides
• 2. Insulin sensitisers
• a. biguanines
• b. thiazolidindiones (glitazones)
• 3. Inhibitors of intestine glukosidases
• 4. New antidiabetics

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Derivates of Sulfonylurea

• stimulation of endogenous insulin secretion
• effect depends on the functional B-cells of
  pancr.
• in monotherapy or in combination
• binding to albumin gt 90 interactions !!!
• AE - hypoglycemia (carefull, interactions with
• NSA, alcohol, warfarin)
• risk of hypoglycemia mainly glibenclamid, less
  glipizid and gliklazid

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Derivates of Meglitinide

• short-lasting stimulation of insulin secretion
  influencing postprandial glycemia
• taking before the main meal
• metabolism in liver possibility to give to
  patients with renal insufficiency
• mostly in combination with metformin
• AE - hypoglycemia
• repaglinid, nateglinid

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Biguanines - Metformin

• insulin sensitisers increase sensitivity of
  tissues to insulin, ? level of TAG, anorectic and
  antabus effect
• drug of the 1st choice in the treatment of DM
  type 2
• after treatment failure combination with other
  PAD
• AE - GIT intollerance, lactic acidosis (? risk
  among alkoholitics and at chronic renal, hepatal
  and respiratory diseases)

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Thiazolidindions (Glitazons) Rosiglitazone,
Pioglitazone

• activators of nuclear receptor PPARy
  (transkriptional factor) increase sensitivity
  of tissues to insulin, ? TAG, ? HDL
• AE - ? weight (fat redistribution), fluid
  retention oedemas, heart failure, among risk
  patients ? CV mortality !!
• not the 1st choice, only in combination with
  other PAD

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Inhibitors of Intestine Glukosidases (Akarbose)

• inhibition of disacharidases in small intestine
  slowing down of composite sacharides hydrolysis
• influencing only postprandial glycemia
• oft AE - flattulence, diarrhoea, stomach pain
• less used, only in combination

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New Antidiabetics

• on the ground of GLP-1 (glucagon-like peptide 1)
• incretin, released in small intestine
• after stimulation with food, degraded by
• DPP-4 (dipeptidyl peptidáza 4)
• ? stimulates insulin secretion from
  B-cells
• ? decreases glucagon secretion
• ? has anorectic effect
• low risk of hypoglycemia
• dont lead to weight gain
• in combination with metformin

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New Antidiabetics

• 1. Analogues of GLP-1 liraglutid, exenatid
• ? s.c. aplication
• 2. Inhibitors of DPP-4 (gliptins) sitagliptine
• ? p.o. aplication
• AE - nasopharyngeal urinary infections

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DM Type 2 as the part of Metabolic Syndrome

• metabolic sy ??? CV risk
• ? insulin resistance ( DM type 2)
• ? abdominal obesity (weist circumference)
• ? hypertension
• ? dyslipidemia
• ? protrombotic state
• ? hyperuricaemia

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DM Type 2 as the part of Metabolic Syndrome

• need of complex therapy of all risk factors
• hypertension - ACEI, Sartans, CaCB (telmisartan
  PPARy agonist)
• protrombotic state - aspirin, clopidogrel
• dyslipidemia - statins
• obesity - diet, excercise, antiobesitic drugs

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Obesity

• key etiologic factor of metabolic sy (ins.
  resistance)
• CV risk mainly abdominal obesity (weist
  circumference gt 102 cm men, gt 88 cm women)
• without weight loss is good compensation of DM
  type 2 almost impossible !!!

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Antiobezitiká

• 1. Sibutramin
• ? inhibits reuptake of norepinephrine
• serotonin
• ? central anorectic effec
• 2. Orlistat
• ? inhibitor of intestine lipase
• ? less effective ass sibutramin

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Antiobezitiká

• 3. Rimonabant
• ? blockator of canabinoid recep. (CB1
• receptors hypothalamus, limbic system,
  
• visceral region)
• ? anorectic effect
• ? ? adiponectin (antiatterogenically,
  antidiabetically)
• ? makes better lipid profile (TAG, HDL)
• ? lowers insulin resistance
• ? help at quiting of smoking

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Case

• 13 year old boy, last days is feeling more tired,
  urinates several times per day also at night,
  permanently feels thirst despite of drinking more
  than 2 l fluids per day, fainted at school,
  before cramp pain of stomach
• Anamnesis not seriously ill before, family
  history without no remarkable
• Objectively at admission skin pale,
  intensificated breathing, signs of dehydration,
  foetor ex ore after fruit, BP 90/60, P 95/min.
  

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Case

• 1. What is susspicious diagnosis?
• 2. What examinations would you recommend ?
• 3. What is pseudoperitonitis diabetica?
• 4. Make pharmacoterapeutic plan