2. NORMOGLYCEMIA (WHO)NORMOGLYCEMIA (WHO)
Fasting glucose:Fasting glucose:
3.83.8−−6.1 mmol/l6.1 mmol/l
HbAHbA1C1C: 4.7–6.0%: 4.7–6.0%
GlucoseGlucose occupies a central position
in metabolism as the predominant
substrate for energy productionenergy production.
3. RandomRandom
blood glucoseblood glucose
<7.8 mmol/l<7.8 mmol/l 7.8–11.1 mmol/l7.8–11.1 mmol/l ≥≥11.1 mmol/l11.1 mmol/l
NormalNormal
Impaired GlucoseImpaired Glucose
Tolerance (IGT)Tolerance (IGT)
Diabetes mellitusDiabetes mellitus
Suspected diabetes mellitusSuspected diabetes mellitus
75 g glucose p.o.:75 g glucose p.o.: 2 h later2 h later
6. HbAHbA1C1C is a lab test that showsis a lab test that shows
the average amount of sugarthe average amount of sugar
in blood over 2–3 months. It showsin blood over 2–3 months. It shows
how well you are controlling DM.how well you are controlling DM.
An HbAAn HbA1C1C of 6% or less is normal.of 6% or less is normal.
The following are the resultsThe following are the results
when the HbAwhen the HbA1C1C is being usedis being used
to diagnose diabetes:to diagnose diabetes:
•NormalNormal: Less than 5.7%: Less than 5.7%
•Pre-diabetesPre-diabetes: 5.7% to 6.4%: 5.7% to 6.4%
•DMDM: 6.5% or higher: 6.5% or higher
Values of HbA 1C1C ≥ 7% are a signal
for emergency change in treatment.
9. ype 1 DM(beta-cell destruction) – about 10% of all patients.
Autoimmune DM (the so called insulin-dependent DM – IDDM
juvenile-onset diabetes). It results from autoimmune mediated
estruction of the beta cells of the pancreas. The rate of destruction
quite variable (and may reach 80% of the beta- cells of the Langerhans
ets), being rapid in some individuals and slow in others. The
pidly progressive form is commonly observed in children, but also may
ccur in adults. The slowly progressive form generally occurs in adults
nd is sometimes referred to as latent autoimmune DM in adults (LADA).
Idiopathic type 1 DM, which has no known etiology (has no
vidence of autoimmunity). This form is more common among
dividuals of African and Asian origin. Patients periodically
evelop ketoacidosis.
Diabetes mellitus (DM)
10. Type 2 DM (predominantly insulin resistance with relative insulin
deficiency or predominantly an insulin secretory defect with/without
insulin resistance). DM of this type previously encompassed non-
insulin-dependent diabetes (NIDDM), or adult-onset diabetes. It is
a term used for individuals who have relative (rather than absolute)
insulin deficiency. People with this type of diabetes (> 80% of
patients with DM) frequently are resistant to the action of insulin.
Other specific types of DM
•Genetic defects of beta-cell function (mutations on chromo-
some 12 in a hepatic nuclear transcription factor referred to as
HNF13. A second form is associated with mutations in
the glucokinase gene on chromosome 7p.
11. •Genetic defects in insulin action (It is connected with
some pediatric syndromes that have mutations in the insulin
receptor gene with subsequent alterations in the insulin receptor
function and extreme insulin resistance).
•Diseases of the exocrine pancreas (pancreatitis, trauma, cancer)
•Endocrinopathies (acromegaly, Cushing’s syndrome,
glucagonoma, and pheochromocytoma).
•Drug- or chemical-induced (pentamidine, glucocorticoids, etc.).
•Viral infections may cause beta-cell destruction (e.g. mumps,
adenovirus, cytomegalovirus, Coxsackie B, congenital rubella).
•Other genetic syndromes sometimes associated with
DM (Down’s, Klinefelter’s and Turner’s syndromes, etc.).
•Gestational diabetes includes the former categories
of gestational impaired glucose tolerance.
12. >> 52520 000 patients0 000 patients
with DMwith DM
17. •Diet
– weight control
– low fat intake
– normal protein intake
– carbohydrates ~ 50% of total energy
•Control blood
pressure (120/80 mm)
BMI
18.5–24.9
•Motor activity and compliance!
!
18. Insulin is a protein, secreted
from the β-cells of the islets of
Langerhans in the pancreas
in response to a rise in blood
glucose, and inhibited by a fall.
t1/2: 5–6 min
molecule mass: 5734 Da
t1/2: 5–6 min
molecule mass: 5734 DaI. InsulinI. Insulin
20. Amylin (Islet Amyloid Polypeptide – IAPP)
reperesents a 37-residue peptide hormone.
It is cosecreted with insulin from the pancreatic
β-cells in the ratio of approximately 100:1.
Amylin plays a role in glycemic regulation by
slowing gastric emptying and promoting satiety,
thereby preventing post-prandial spikes
in blood glucose levels.
21. Mechanism of action
•Insulin acts via receptors that
are transmembrane
glycoproteins.
•Each receptors has two binding
sites. Receptor occupancy
results in:
22. 1. Activation of insulin-dependent
glucose transport processes in
adipose tissue and muscle.
2. Inhibition of adenylyl cyclase-
dependent processes (lipolysis,
proteolysis, glycogenolysis).
24. 4. Intracellular accumulation of
potassium and phosphate
(which are linked to glucose
transport in some tissue).
5. Increased cellular amino acid
uptake, DNA and RNA synthesis.
6. Increased oxidative
phosphorylation.
25.
26. Insulin is extracted either
from cattle or pig pancreas.
Bovine (B) insulin differs
from human insulin in three
amino acid residues, and
porcine (S) insulin in one,
but their action is very
similar to human. Nobel prize
(1923)
27. More recently, recombinant
DNA technology has allowed
in vitro manufacturing of insulin
with the same structure as
human (H) insulin.
All current insulin preparations
have a low content of impurities.
28. Insulin is initially purified by
protein extraction to form a
crystalline product. It may then
undergo either gel filtration to
produce a single peak (SP)
insulin or gel filtration and ion
exchange chromatography
which generates:
29. •monocomponent (MC),
•single component (SC) and
•rarely immunogenic (RI) insulin.
Other abbreviations
which are used for insulins are:
•Hum- and -man (for human ),
•PP (purified preparation)
30. MAIN TYPES OF
INSULIN PREPARATIONS
•Short-acting
•Intermediate-acting
(they contain protamin or Zn)
•Long-acting
(they contain both protamin & Zn)
Injectors (with cartridge):
OptiPen, OptiSet, Penfill, etc.
31. Comparisons among insulins
Type Onset of Peak Duration
action activity
Short-
acting 10–20 min 1–2 h 5–7 h
Interme-
diate-act. 1–2 h 5–7 h 13–18 h
Long-act. 2–4 h 8–14 h 18–36 h
32. Insulins are used mainly in type 1 DM.
Patients with type 2 DM use
insulins in the following cases too:
•acute infections
•pregnancy
•surgical operations
•burn
•myocardial infarction
•ketoacidosis
33. Therapy of DMTherapy of DM
with insulin iswith insulin is
a replacementa replacement
therapy.therapy.
s.c.:
6 sec
s.c.:
6 sec
High compliance!
35. Insulin pumps:Insulin pumps:
They infuseThey infuse
subcutaneouslysubcutaneously
fast-actingfast-acting
insulin throughinsulin through
small cathetersmall catheter
(very handy(very handy
and veryand very
expensive).expensive).
36. a) Insulins: Actrapid®
, Humulin R®
b) Analogues: Insulin aspart, Insulin lispro
1. Short-acting insulins
and analogues
s.c. 15 min before meal 4 times daily
chronobiologically (4:3:2:1)
40. 3. Long-acting insulins
s.c. 20 min
before meal
once daily
•Insulin detemir
(Levemir®
)
•Insulin glargine
(Lantus®
)
41. Adverse effects of insulins
•hypoglycemia/coma
•allergic reactions
•insulin resistance
•lipodystrophia of subcutane-
ous fat at or near injection
•local fibrosis
42. II. Oral hypoglycemic andII. Oral hypoglycemic and
other drugs, usedother drugs, used
in DM type 2in DM type 2
43. 1. Biguanides:
Metformin
•usually first line drug for type 2 DM
•reduces intestinal glucose absorption
•stimulates anaerobic glycolysis
•stimulates glucose uptake
•enhances insulin receptor binding
44. •excreted exclusively
by the kidney
•does not increase weight
and preferable in the obesepreferable in the obese
•GI side effectsGI side effects
•rarely
lactic acidosislactic acidosis
MetforminMetformin
46. Unwanted effects
•Hypoglycemia, weight gain
•facial flushing following
alcohol ingestion
Mechanism of action
•promote enhanced insulin release
from the pancreas
•leads to a reduction in hepatic
glucose production
47. •displacement from protein binding sites
– salicylates and sulphonamides
•interference with hepatic metabolism
– inducers: rifampicin, phenytoin
– inhibitors: cimetidine
•reduction of renal elimination
– allopurinol, salicylates
Sulfonylureas –
important drug interactions:
48. •Inhibits intestinal alpha-glucosidase
•Decreases intestinal absorption
of the mono- and polysaccharides.
•Produces flatulence and diarrhoeaflatulence and diarrhoea.
- Acarbose (Gluco Bay®
): p.o.
4. Glucosidase inhibitors
3. Meglitinides: stimulate the release of insulin
from pancreas by closing ATP-dependent
potassium channels.
- Nateglinide
- Repaglinide
49. 5. Thiazolidinediones (TZDs)
They increase tissue insulin sensitivity
but have serious ADRs and the EMAbut have serious ADRs and the EMA
recommended in Sept (2010) that theyrecommended in Sept (2010) that they
be suspended from the EU marketbe suspended from the EU market:
- Rosiglitazone (Avandia®
)
has high cardiovascular riskshigh cardiovascular risks.
- Pioglitazone causes bladder tumorsbladder tumors.
- Troglitazone causes hepatitishepatitis.
50. 6. Glucagon-like peptide-1 (GLP-1)6. Glucagon-like peptide-1 (GLP-1)
agonists (in type 2 DM):agonists (in type 2 DM): increase
pancreatic secretion of insulin:
Exenatide
Bydureon (s.c./7 days):Bydureon (s.c./7 days):
$323/4 doses, resp.$323/4 doses, resp.
$4200 per year$4200 per year
52. 7. Inhibitors of Dipeptidil7. Inhibitors of Dipeptidil
peptidase-4 (DPP-4):peptidase-4 (DPP-4): prevent
degradation of incretin GLP-1
Sitagliptin (p.o.)
Vildagliptin (p.o.)
53. 8. Inhibitors of reabsorption
of glucose (SGLT2 inhibitors): p.o.
•Canagliflozin blocks in renal proximal
tubule sodium / glucose co-transporter
protein 2 (SGLT2), which re-absorbed
90% of the filtrated glucose.
The result is increased glucosuria and
plasma glucose levels are lowered.
ADRs: Hypoglycaemia, vulvovaginal candidiasis
urinary tract infections, polyuria, frequent urination.