1. Diabetes mellitus

2. DM – Definition, Prevalence
chronic metabolic disease caused by absolute or relative insufficiency of insulin (or their combination)
in the world approximately 370 million diabetic patients
raising incidence, mainly DM type 2

3. 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, β-blockers, thiazides)

4. Acute Complications of DM
diabetic ketoacidosis (typical for DM type 1, but can also occur at DM type 2; breakdown of amino acids and fatty acids in liver to provide energy – ketone bodies)
hyperosmolar coma (typical for DM type 2)
hypoglycaemic coma

5. Chronic Complications of DM
diabetic macroangiopathy = acceleration of atherosclerosis
diabetic microangiopathy = damage of retinal and renal vessels
diabetic nephropathy
diabetic neuropathy = senzo-motoric affection

6. Diabetic foot

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

8. DM type 1 most often among children
genetically determined (allele DQ8, DR3,4)
autoimune destruction of ß-cells in pancreas by Tc lymphocytes
absolute insufficiency of insulin
requires whole-life treatment with insulin

9. DM type 1 - Diagnosis
clinically: feeling tired and unwell, polyuria, polydypsia, loosing of weight, acetone foetor ex ore
biochemically:
 fasting glycemia >7 mmol/l
 oGTT - glycemia 120 min. >11mmol/l
 C-peptide ↓ or 0
 urine: + ketonuria, glucose

10. 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)

11. Goals of DM Type 1 Therapy
prevention of chronic complications
by good diabetes compensation
 long-term glycemia ≤ 7 mmol/l
 HbA1c (glykosyled Hb) < 7%
keeping stabilized glycemia
 without frequent hypo-hyperglycemias
keeping the best possible quality of patient´s lives

12. Indications of Insulin Therapy
DM type 1
DM type 2
 loss of PAD effectiveness
 surgery, intercurrent diseases
gestational DM
states after pancreatectomia, pankreatitis

13. Insulin Protein secreted from ß-cells of the islets of Langerhans
Secretion induced by a rise in blood glucose and inhibited by a fall in blood glucose
Consists of 2 peptid chains (A and B), connected by 2 disulphide bridges
Incretins (hormones released from intestine cells in the presence of food) induce insulin secretion

15. Insulin Metabolic effects – anabolic:
Glucose – increasing glycogen storage: active transport of glucose into cells (mostly sceletal muscle, adipose tissue); storage of glucose in the form of glycogen (liver, muscle); inhibits glycogenolysis; inhibits gluconeogenesis in liver.
Lipids – reduces plasma free fatty acids and increases adipocyte triglyceride storage.
Proteins – inhibition of catabolism of amino acids in liver; increased transport of amino acids into muscle and increased protein synthesis
Anabolic effects are inhibited with glucagon, growth hormone, cortisol, catecholamines

16. Insulins According to Origin
1. Prepared by recombinant DNA method
(Humulin - HM) using bacteria or yeast
2. Insulin analogs (exchange, change of sequenceor type of AA) = better pharmacocinetic properties

17. ;

18. Insulins according to Length of Action
A. Short-acting insulins:
Fast beginning of the effect ( min.), acting hours
Has a slower onset and longer duration of action than rapid- acting insulin analogues after s.c. administration
Consists of insulin hexamers crystallized around a zinc molecule
Water soluable
s.c. or i.v. administration (acute states require i.v. administration !!!)
i.v. administration only at units equipped to monitor the patient and must be performed by trained personnel; change of therapy only by trained personnel
Can be available in biphasic formulations (e.g. regular + NPH)

19. Insulins according to Lenght of Action
B. Insulins with prolonged action:
To generate intermediate-acting or long-acting formulations, insulin is complexed with:
Protamine
Zinc
Protamine and zinc

20. Insulins according to Length of Action
B. Intermediate acting (NPH = Neutral Protamine Hagedorn):
Slower beginning of the effect (1 - 2 hours), peak ( hours), duration (18 – 24 hours)
Suspensions, must be gently rolled or inverted before each use to ensure uniform dosage
Contains particles of insulin combined with zinc and protamine that slowly dissolve after s.c. administration
Is more prone to erratic absorption and intrapatient variability than the long-acting insulin analogues
Only s.c. administration (after i.v. administration risk of embolisation !!)

21. Insulins according to Length of Action
C. Rapid-acting insulin analogs:
Insulins lispro, aspart, glulisine
Very fast beginning of the effect ( min.), peak (1 hour), acting (less than 3 hours)
Usually given right before meal, but can be given immediately after eating
Can be available in biphasic formulations (insulin aspart + insulin aspart protamine; insulin lispro + insulin lispro protamine)
s.c. or i.v. administration
i.v. administration only at units equipped to monitor the patient and must be performed by trained personnel
Can be available in biphasic formulations (e.g. insulin aspart + insulin aspart protamine) – only s.c. administration

22. Insulins according to Length of Action
D. Long-acting insulin analogs:
Insulins glargine, detemir, deglutec
Beginning of the effect (1 - 2 hours), acting (up to 24 hours)
Usually enough to administer one time per day
Are slowly absorbed after s.c. administration, which avoids plasma insulin peaks
They should not be administered i.v.

23. Adverse Effects of Insulin
Hypoglycemia: the main problem; most people experience warning symptoms, those who not are prone to sudden attack with loss of consciousness, reasons: ↑ dose, insufficient food income, interaction with alcohol
Rebound hyperglycaemia: can occur after episode of hypoglycaemia, especially at night (Somogyi effect – compensatory release of hormones, e.g. adrenaline)
Insulin resistance: due to production of circulating antibodies, human insulins rarely
Weight gain: at ↑ daily doses of insul. at DM type 2
Local allergy: rarely
Local fat hypertrophy: can be minimized by rotating the site of injection

24. Aplication Forms of Insulin
injection
insulin pens
ins. pump
inhaled insulin – rapid onset of action, effect lasts 5 – 10 hours (can be used in place of short or rapid-acting insulins)
peroral forms = in development

25. Insulin Regimens the conventional regimen 1-2 s.c. injections/day
in some cases at DM 2 after failure of treatment with
PAD or + PAD
the most commonly application of monophasic or
biphasic insulin 1/day (usually in the morning) or 2 x/day
(morning and evening)
intensified regimen 3-5 s.c. injections/day
 standard at DM type 1
 at DM type 2 after failure of PAD, special situations (severe infection, surgery, metabolic acidosis)

26. Intensified Regimen
the best imitation of physiologic insulin secretion
important is patient education (selfmonitoring)
most often 3-5 s.c. injections/day
administration of prandial insulin (regular, analog) before a meal in combination with basal insulin (NPH, analog)

27. Insulin Pump continuous s.c. administration of insulin
only for good cooperating patients after adequate education
the best compensation of diabetes
is used if there is a problem with recurrent hypoglycaemia, unpredictable daily lives or hyperglycaemia before breakfast
in case of combination with sensor to monitor glycemia, automatic adjustment of doses

29. Inhaled insulin lower-than-expected sales Exubera
problem - the bioavailability 10-15%, is used exclusively for type 2 diabetes, ADR -  vital capacity (!), Ca lungs?
was withdrawn from the U.S. market in 2007 due to lack of consumer demand for the product
Afrezza
FDA 2014
DM type 1 or 2, adults only, non-smokers, not COPD, not lung Ca
lower-than-expected sales

31. Pancreatic cell transplantation
necessity of life-long immunosuppression - daclizumab (Zenapax), sirolimus (Rapamune), tacrolimus (Prograf)
Edmonton protocol
Stem cells,
genetic engineering

32. DM Type 2
occurs in middle and older age (usually after 40yrs of age), it is often associated with overweight
the onset of the disease is usually slow, diabetes is often only diagnosed incidentally during tests for other health problems

33. DM Type 2 A significant proportion of a genetic predisposition
Other factors: obesity, stress, low physical activity, inadequate diet composition
It can lead to recurrent urinary tract inflammations, badly healing wounds, skin infections, fungal diseases of the genital area, retinopathy

34. DM Type 2
insulin resistance at postreceptor level = relative insulin deficiency, later also absolute
impaired release (secretion) of insulin
the same CV risk as patients after MI !!!
often part of the metabolic syndrome

35. INSULIN RESISTANCE

36. DM Type 2 - Treatment  loss of weight  reduction diet
must be complex (hypertension, dyslipidemia, obesity...)
important regimen precautions
 loss of weight
 reduction diet
 physical activity
quit smoking and drinking alcohol

37. Peroral Antidiabetics
1. Stimulators of insulin secretion („hypoglycemic agents“)
a. sulfonylureas
b. meglitinides (glinides)
2. Insulin sensitisers („antihyperglycemic agents“)
a. biguanides
b. thiazolidindiones (glitazones)
3. Inhibitors of intestine glukosidase („antihyperglycemic agents“)
4. New antidiabetics

38. Sulfonylureas stimulation of endogenous insulin secretion
effect depends on the functional ß-cells of pancreas
in monotherapy or in combination
binding to albumin > 90% = interactions !!!
AE:
the effect increased by: NSAIDs, alcohol, warfarin
the effect decreased by: thiazide diuretics, glucocorticoids, β2-agonists, estrogens
risk of hypoglycaemia (especially in older patients using preparations with long action)
weight gain
not suitable for patients with severe renal, hepatic, cardiovascular and respiratory system disorder
risk of hypoglycemia mainly glibenclamide (longer duration of action), less glipizide,gliklazide,glimepiride, gliquidon (shorter duration of action).

39. Sulfonylureas effective – only if functional ß-cells
 problem – treatment failure:
primary – genet. polymorphisms
secondary – loss of pancreatic fuction after treatment
reduced basal (prandial) and postprandial blood glucose level and some of them (e.g. gliclazide) have additional beneficial extrapancreatic effects, e.g. antioxidant, anti-atherogenic, resp. increase of insulin sensitivity

40. Sulfonylureas
block of ATP sensitive kallium channels by binding to specific receptors (increase the release of insulin from ß-cells in response to stimulation by glucose)
high affinity binding to SUR receptors depolarization - Ca2+ entry  insulin secretion

41. SU RECEPTOR
belongs to a family of transmembrane proteins – a group of ABC transporters (ATP-Binding Cassette transporter), is only a regulator of ion channels
ATP sensitive kallium channels - KATP channels:
ß-cells of pancreas (SUR1)
smooth muscle cells – vessels (SUR2B)
cardiomyocytes (SUR2A)
(animals – slowdown myocardial repolarization, vasoconstriction)
Selecitivity of SUR1- the highest gliclazide and meglitinides

42. Meglitinides
drugs with similar mechanisms of action and the resulting effects as sulphonylureas
short-lasting stimulation of insulin secretion = influencing postprandial glycemia
taking before the main meal
mostly in combination with metformin
AE - hypoglycemia
repaglinide, nateglinide, mitiglinide

43. Biguanides (Metformin)
insulin sensitisers = increase sensitivity of tissues to insulin (muscles, adipose tissue), ↓ level of TAG, no weight gain and antabus effect, no hypoglycaemia
drug of the 1st choice in the treatment of DM type 2
after treatment failure combination with other PAD
AE - GIT intollerance (often), lactic acidosis (potentially fatal; ↑ risk among alkoholitics and at chronic renal, hepatal and respiratory diseases, heart failure)

44. Thiazolidindiones (Glitazons) – Rosiglitazone, Pioglitazone
agonists of nuclear peroxisome proliferator- activated receptor-γ (PPARy) = 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

46. Rosiglitazone
EMEA: suspension of registration for the potential risk of ischemic CV events (acute myocardial infarction, stroke!!!)
FDA: only restriction on the use

47. Inhibitors of Intestine Glukosidase (Acarbose)
inhibition of disacharidases in small intestine = slowing down of composite sacharides hydrolysis
influencing only postprandial glycemia
reduce postprandial blood glucose without the risk of hypoglycaemia
AE - flattulence, diarrhoea, stomach pain
effectiveness in reducing HbA1c is lower than that with other antidiabetic drugs
less used, only in combination

48. New antidiabetics
Analogues of GLP-1 (incretin mimetics) and the DPP-4 inhibitors (gliptins)
Glucuretics/ SGLT2 inhibitors/Gliflozins
Others – only FDA:
D2-receptor agonist (bromocryptine with quick-release)
bile acid sequestrant (colesevelam)
analogue of human amylin (pramlintide)

49. Incretin mimetics and gliptins
Incretins:
polypeptides – hormones, secreted by intestinal cells
plasmatic half-life 2-7 minutes
GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide)
Glukagon like peptid (GLP-1):
Increases insulin secretion
Decreases gastric emptying
Increases satiety (weight loss)
Stimulates neogenesis of beta-cells
Enzyme (DPP-4 dipeptidyl peptidase-4)  inhibits the degradation of the incretins (GLP-1 and GIP).

51. Incretin mimetics and gliptins
1. Analogues of GLP-1 (incretins) = e.g. exenatide, liraglutide, dulaglutide
 s.c. aplication (no peroral antidiabetics)
2. Inhibitors of DPP-4 (gliptins) = e.g. sitagliptin, vidagliptin, alogliptin
 p.o. aplication
AE - nasopharyngeal + urinary infections

52. Incretin mimetics and gliptins
low risk of hypoglycaemia
don´t lead to weight gain
many other pleiotropic effects
ADRs:
nasopharyngeal + urinary infections
exenatide: acute pancreatitis !!

53. Gliflozins = Glucuretics = SGLT2 inhibitors
Selective inhibition - SGLT2 (sodium glucose co-transporter) = gliflozins
Inhibition of renal glucose transport  glycosuria
Phlorizin - the first non-selective
E.g.: Dapagliflozin, Canagliflozin, Empagliflozin
ADRs – urinary tract infections, fungal
Increased excretion of glucose in the urine leads to a reduction of body weight, decrease in blood pressure and also a lower risk of hypoglycaemia as with sulphonylureas

54. Analogue of human amylin (Pramlintide)
Injections s.c.
Analogue of human amylin –
neuroendocrine hormone
– is amyloidogenic, toxicity
 postprandial release of glucagon
 postprandial release of pancreatic enzymes
satiety (hypothamamus)

55. Dopamine agonists (Bromocriptine)
Has been used for many years in the treatment of hyperprolactinaemia and Parkinson´s disease
Research suggest that deficient dopamine neurotransmission in hypothalamus is associated with disturbances in circadian rhythm – it can lead to development of insulin resistance, obesity and diabetes

56. DM Type 2 as the part of Metabolic Syndrome
metabolic sy = ↑↑↑ CV risk
 abdominal obesity (weist circumference)
 insulin resistance (± DM type 2)
 hypertension
 dyslipidemia
 protrombotic state
 hyperuricaemia

57. 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

58. Obesity key etiologic factor of metabolic sy (ins. resistance)
CV risk mainly abdominal obesity (waist circumference > 102 cm men, > 88 cm women- USA; 94 cm and 80cm- Europe
without weight loss is good compensation of DM type 2 almost impossible !!!

60. Obesity therapy
the first line is a combination of a low calorie diet, increased physical activity and behavioral therapy
pharmacotherapy – in Slovakia available for the safety only OTC preparations
bariatric surgical treatment

61. Hormonal changes and obesity
Hypothyreosis
Cushing´s syndrome
Deficiency and excess of growth hormone
Polycystic ovary syndrome

62. Anti-Obesity Drugs
the possibility of effective pharmacotherapy remains at present limited
many new drugs are already at the stage of clinical trials, and many were withdrawn from the market due to adverse reactions
the promise to the future is the use of combination therapy

63. Anti-Obesity Drugs Sibutramine
inhibits reuptake of norepinephrine + serotonin
central anorectic effec
reported changes of mood, depressions, panic disorders, FDA doesn´t recommed use for the risk of acute CV events !!! (MI, stroke)

64. Anti-Obesity Drugs
2. Dexfenfluramine, fenfluramine, phentermine, sibutramine
centrally acting appetite suppressants, withdrawn for increased risk of valvular heart disease and pulmonary hypertension

65. Anti-Obesity Drugs 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
helps at quiting of smoking
psychic disturbances, increased risk of suicidal behavior !!!

66. Anti-Obesity Drugs 4. Orlistat inhibitor of intestine lipase
less effective as sibutramin
Impaired absorption of fat-soluble vitamins
not recommended to use more than for 2 years
increase incidence of hypothyroidism
liver damage?
in Slovakia not on market

67. 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.

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