Insulin and other antidiabetic agents
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Distribution, degradation and excretion of
insulin
Volume of insulin distribution - volume of
extracellular fluids
At fast:
Concentration of insulin in portal blood 50-100 U/ml.
Concentration of insulin in the peripheral
circulation - 12 U/ml.
After meal
Rapid rise in insulin concentration in
portal blood, followed by parallel but smaller rise
in the peripheral circulation
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Degradation of insulin: in the liver, kidneys and
muscles.
Excretion of insulin – kidneys.
Molecular mechanisms of insulin action
• rapid effects - seconds to minutes –
transport activation
• intermediate effects - 3 to 6 hours – genes
expression
• long-term effects - hours or several days –
cells proliferation and differentiation
Pharmacokinetics: rapid-acting insulins, shortacting insulins, intermediate-acting insulins, longacting insulins, premixed insulins
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Variation in insulin secretion in response
to physiologic and psychologic stress.
Substrate - mediated insulin secretion.
Substrate - related cessation of insulin
secretion as plasma glucose falls.
Continious basal insulin secretion in the
postabsorptive state: between meals and
overnight.
Diurnal variation is the basal insulin
secretory rate with glucose nadir arround
3-4 a.m. and glucose rise between 5-8 a.m.
Initial insulin dose
Daily insulin production in healthy, thin persons
0.2-0.5 /kg
Newly diagnosed diabetics 0.5 U/kg/day
„Honeymoon" period 0.4 U/kg/day
Pregnant women, 1st 20 weeks of gestation 0.6
U/kg/day
Established diabetics previously treated with 0.70.9 U/kg/day - 0.7 U/kg/day
Established diabetics previously treated with less
than 0.7 U/kg/day - Previous dose unless
obviously inadequate
Established diabetics previously treated with
greater than 0.9 U/kg/day - Reduce previous dose
by 20-25%
Insulin – therapeutic regimens
CONVENTIONAL INSULIN THERAPY
Insulin in inhalation = rapid-acting insulin
Dose in inhalation is 10x  than given s.c
Pre-prandial bolusem together with intermediateacting or long-acting insulin given s.c.
Contraindicated: smokers, patients with
bronchoobturation, below age 18, pregnancy,
liver/renal insufficiency ?
Species; bovine insulin, porcine insulin, „human
insulin”, insulin analog
Degree of purity: „standard insulins” –
nonpurified, "purified" insulins ["Single - peak"
insulins (SPI), "Single-component
(monocomponent) insulins]
Physiologic insulin secretion
• Insulin secretion into hepatic portal
circulation. Hepatic portal insulin levels
are significantly higher than systemic
insulin levels.
The morning pre-breakfast dose should usually be
composed
in 1/3 as regular insulin
in 2/3 as intermediate-acting insulin
1/2 of the evening dose should be given as
intermediate-acting insulin
hypoglycemic agents have failed to
maintain satisfactory blood glucose
concentrations.
4. Patients with diabetes type 2 in terms of
surgery, fever, infections, serious renal or
hepatic dysfunction, and other metabolic
disturbances.
5. Pregnant women with pregestational and
gestational diabetes.
INTENSIVE INSULIN THERAPY
1/2 of the total daily dose should be given as basal
insulin dose (ultralente, glargine, detemir, NPH,
lente)
Pre-prandial insulin (regular, lispro, aspart) should
be divided as:
30-45%before breakfast
25-30% before lunch
25-30% before supper
Correction factor
• It determines how far the blood glucose
drops per U of rapid acting/regular insulin
given
• 1800 Rule (1500 Rule for regular)
• 1800/TDD = point drop (1500/TDD)
• TDD = 30 U, correction factor = 1800/30
= 60mg/dl. Patients expects 60mg/dl drop
in blood glucose for every 1U rapidinsulin administered
Indications for insulin treatment
1. All patients with Type I diabetes mellitus
regardless of age.
2. Patients with ketoacidosis or hyperosmolar
coma.
3. Patients with diabetes type 2 when diet
restriction, exercise, and oral
Insulin-adverse reactions
Hypoglycemia, local and systemic allergic
reactions, lipoatrophy and lipohypertrophy,
insulin resistance (immune-dependent),
hyperglycemic rebound, insulin edema.
In inhalation – cough, pharyngitis, dry mouth,
sinusistis
Hypoglycemic reactions can be results of:
• to high dose of insulin/to small content of
carbohydrates in a meal
• mismatch between the time of peak
delivery of insulin and food intake
• physical effort
Mechanisms of SU action
1. Stimulate insulin release (not production)
2. Reduce serum glucagon concentration
3. Potentiate insulin action on target tissues
increase binding of insulin to its receptors
increase number of insulin receptors
stimulate of glycogen synthetase in
skeletal muscles
stimulate synthesis of glucose transporters
inhibit hepatic gluconeogenesis
SU adverse effects: hypoglycaemia, nausea and
vomiting, cholestatic jaundice, agranulocytosis,
aplastic or hemolytic anemias, generalized allergy
reaction, alcohol-induced flash
Meglitinides: Stimulate insulin release
repaglinide, nateglinide
Adverse effects: hypoglycaemia, allergy
Acarbose, miglitol – adverse reactions;
flatulence, abdominal pain, diarrhoea
Contraindications: diabetic children and
adolescents under 18 years, pregnant and breastfeeding women, patients with malabsorption
syndrome
Biguanides – metformin
Mechanism of action
• Disorganise oxidative phoshorylation and
 ATP synthesis
• ATP deficient activates AMP kinase
(AMPK)
• AMPK counteracts with insulin
intracellular signal net and  insulin
sensitivity
Pharmacological effects:
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slow GI absorption of glucose
enhance the insulin-induced peripheral
glucose uptake
• suppress hepatic gluconeogenesis
• reduce of plasma glucagon levels
• increase insulin binding to insulin
receptors
• decrease plasma concentration of
triglycerides and cholesterol
Biguanides – adverse reactions; lactic acidosis,
diarrhoea, nausea, vomiting
Thiazolidinediones - pharmacological effects
(rosiglitazone, pioglitazone)
Addipose tissue
• stimulate preadipocytes differentiation and
maturation (insulin sensitivity)
• FFA uptake and utilization -  insulin
resistance
• lipogenesis (only subcutaneous fat, not in
visceral)
•  GLUT4
•  TNF-alpha and other cytokines secretion
from visceral adipose tissue - insulin
resistance
Liver
• reduce gluconeogenesis and lipogenesis
•  FFA oxidation
•  small dense LDL and TG concentration
Skeletal muscle
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insulin binding to plasma membranes,
increase glucose uptake and glycogen
synthesis
 expression of Glut 1 and 4
prevent inhibition of insulin receptor
kinase induced by high glucose levels
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Thiazolidionodines –adverse effects: GI events,
edema, asthenia ? weight gain, haeadache,
dizziness
Exacerbation of coronary heart disease?
Incretin agents
• Incretins – intestinal hormones:
GLP-1 (glucagon like peptide – 1)
GIP – (glucose-dependent insulinotropic peptide 1)
• GLP-1 (glucagon-like peptide-1) physiology
stimulates insulin secretion,
inhibits glucagon secretion,
decreases gastric motility,
decreases rate of gluconeogenesis,
decreases appetite
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DM type 1 – no GLP-1
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DM type 2 -  GLP-1, sometimes in DM
type 2 - paradoxical gastric emptying
Incretins mimetics - GLP-1 analogs
• native glp-1 – short t1/2
• exenatide, liraglutide – longer t1/2
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when therapy with su or metformin
exenatide is added as the 3rd agent
given s.c. 2 daily (morning-evening)
before meals
contraindications: acute diabetic
complications, renal/hepatic insufficiency,
pregnancy, gastroparesis
adverse effects: nausea, when given with
su - hypoglycaemia
Incretins mimetics - dipeptidylpeptidase IV
inhibitors
• dipeptidylpeptidase IV – degrade GLP-1
• sitagliptine, vildagliptine
• given orally
• diabetes type 2
• therapeutic effects and adverse effects –
like GLP-1 analog
The Kidneys Play an Important
Role in Glucose Control
Normal Renal Glucose Physiology
• 180 g of glucose is filtered
each day
• Virtually all glucose
reabsorbed in the proximal
tubules & reenters the
circulation
• SGLT2 reabsorbs about
90% of the glucose
• SGLT1 reabsorbs about
10% of the glucose
• Virtually no glucose
excreted in urine
Altered Renal Glucose Control in Diabetes
• Gluconeogenesis is increased in
postprandial and postabsorptive
states in patients with Type 2 DM
– Renal contribution to
hyperglycemia
– 3-fold increase relative to
patients without diabetes
• Glucose reabsorption
– Increased SGLT-2
expression and activity in
renal epithelial cells from
patients with diabetes vs.
normoglycemic individuals
SGLT2 Inhibitors – dapagliflozin
Increase insulin sensitivity in muscle, liver
Improve beta-cells function
 Can be taken orally once daily at
any time of day with or without
food
 Indicated in adults aged 18 years
and older with type 2 diabetes
mellitus:
• Monotherapy
When diet and exercise alone do not
provide adequate glycaemic control in
patients for whom use of metformin is
considered inappropriate due to
intolerance.
• Add-on combination therapy
In combination with other glucoselowering medicinal products including
insulin, when these, together with diet and
exercise, do not provide adequate
glycaemic control
• increase diuresis associated with a
modest decrease in blood pressure,
which may be more pronounced in
patients with very high blood
glucose concentrations.
• are not recommended for use in
patients receiving loop diuretics or
who are volume depleted, e.g. due
to acute illness (such as
gastrointestinal illness).
• caution should be exercised in
patients with known cardiovascular
disease, patients on antihypertensive therapy with a history
of hypotension or elderly patients.