Professional Documents
Culture Documents
Carbohydrate
Incretins
(GLP-1,
GIP, etc.)
Pancreas
Blood
Glucose
Adipose
tissue
Insulin Inhibition of
hepatic glucose
production
Muscle
Insulinstimulated
glucose uptake
InsulinInhibition of
lipolysis
Glucose
Lab data:
Serum Na+: 130 mEq/L (normal: 135-145)
K+: 5.1 mEq/L (normal: 3.5-5.1)
Serum glucose: 479 mg/dL
Serum Cl: 104 mEq/L
Arterial pH: 7.0 (normal: 7.35-7.45)
Arterial pO2: 92 mm Hg (normal: 80-105)
Urine & serum ketones: ++++
Case 1
What is your diagnosis?
A) Starvation ketosis
B) Diabetic ketoacidosis
D) Food poisoning
Case 1
What type of diabetes mellitus does she most
likely have?
Antidiabetic Agents
Insulin & insulin
analogue
preparations
Oral hypoglycemic
agents (OHAs)
Others
Glucose
Amino acids
Triglycerides
Glycogen
Protein
Adipose tissue
Liver
Muscle
Fatty acids
Stimulated by insulin
Increased by feeding
Inhibited by insulin
Increased by fasting & in diabetes
Insulin Secretion
Insulin is released from pancreatic beta
cells at:
a) a low basal rate and
b) in response to variety of stimuli esp.
glucose
Other stimulants of insulin secretion:
Other sugars (mannose)
Certain amino acids (leucine, arginine)
Vagal activity
Incretins (GLP-1; glucose-dependent)
80
60
40
20
0600
0800
1200
1800
2400
Time of day
B=breakfast; L=lunch; D=dinner
0600
Insulin Degradation
Insulin degraded by insulinase;
removed from circulation by:
Liver (60% endogenous insulin; 3040% exogenous insulin)
Kidney (35-40% endogenous insulin;
60% exogenous insulin)
Case 1
What type of insulin would you give her?
A) Ultralente insulin
B) Insulin glargine
C) Regular insulin
D) NPH insulin
Insulin Preparations
Insulin
Human, Porcine, Bovine
Examples: Neutral Protamine
Hagedorn (NPH), Regular, Lente,
Ultralente
Mixture of different types of
insulin: 70% NPH + 30% Regular
Insulin analogues
Insulin analogues
Ultra-rapid-acting
Very rapid onset & short
duration of action
E.g., Lispro, Aspart
Long-acting
Slow onset & long
duration of action
E.g., Glargine, Detemir
Question:
Intermediate-acting insulin that is protaminated to
have an onset of action of 1-2 hours, peak action at
5-7 hours and duration of action of 13-18 hours
when injected subcutaneously:
B. Insulin glargine
C. Regular insulin
D. Insulin Lispro
E. Insulin Aspart
Type
Preparation
Appearance
Ultra-shortacting
Aspart
Glulisine
(hours)
Onset
Peak
Duration
Clear
0.25
0.67-1
3-5
Lispro
Clear
0.25
0.5-1.5
2-5
Short-acting
Regular
soluble
(crystalline)
Clear
0.5-0.7
1.5-4
5-8
Intermediateacting
NPH
(isophane)
Cloudy
1-2
6-12
18-24
Long-acting
Detemir
Clear
6-8
20-22
Glargine
Clear
2-5
5-24
18-24
*Subcutaneous administration
Glargine 24 hours
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours
Lispro
Insulin analogue in which proline at B28 has been
interchanged with lysine at position B29.
Case 1
How would you administer it to her?
A) Via inhalation
Human Insulin
21 amino acids
A-chain
B-chain
30 amino acids
Monomers
Dimers
Zn++
Zn++
Hexamers
Self-aggregation
in solution
The hexameric
formulation of
human insulin takes
2 to 3x longer to
dissociate &
become absorbed
when injected SQ.
Short-acting Insulin
Regular insulin
Soluble crystalline zinc*
insulin
Less costly than lispro or
aspart
Instantly converted to
monomeric form when
given intravenously.
Intermediate-acting Insulin
NPH
Onset of action is delayed by combining
appropriate amounts of insulin and protamine so
that neither is present in an uncomplexed form
(isophane)
Long-acting Insulin
Detemir
Glargine
Peakless (i.e., having broad plasma
concentration plateau) ultra-long-acting insulin
analogue
Case 1
She was subsequently discharged on NPH 12 units at bedtime
and insulin lispro 5 units immediately before breakfast, lunch
and dinner. She then noted that she would feel faint and get
palpitations, cold sweats, tremors, hunger pangs before
bedtime. Her blood sugar levels during these episodes were
noted to be low. What should she do?
Common
multidose
insulin
regimens
Immunologic:
Allergy
Insulin resistance
Weight gain
Incessant thirst
Polyphagia
Polyuria
5-lb weight loss over the last 2
months
His wife also notes the presence of
ants on the urinal.
Acanthosis nigricans
Case 2
Whats your diagnosis?
D) Normoglycemia
Pathogenesis of Type 2 DM
Resistance to the action of insulin in
peripheral tissues (muscle, fat, liver)
Defective insulin secretion
Increased hepatic glucose production
Insulin deficiency
Pancreas
Excess
glucagon
Diminished
insulin
Alpha cell
produces
excess
glucagon
Beta cell
produces
less insulin
Diminished
insulin
Hyperglycemia
Liver
Excess glucose output
Insulin resistance
(decreased glucose uptake)
Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin
Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:21522180;
Rhodes CJ Science 2005;307:380384.
Sulfonylureas
Meglitinides
DPP4
inhibitors
Insulin deficiency
Pancreas
Excess
glucagon
Islet
Alpha cell
produces
excess
glucagon
Beta cell
produces
less insulin
Diminished
insulin
Diminished
insulin
Hyperglycemia
Liver
Excess glucose output
Metformin
TZDs
Insulin resistance
(decreased glucose uptake)
Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin
Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:21522180;
Rhodes CJ Science 2005;307:380384.
Case 2
Despite lifestyle modifications such as diet and
exercise, his fasting blood sugar remains quite
elevated. Which of the following oral medications
would you choose to treat him and would most likely
not result in weight gain?
A) Glibenclamide
B) Metformin
C) Repaglinide
D) Rosiglitazone
E) Exenatide
Question:
Hypoglycemia is most likely to result from
which of the following agents?
A. Metformin
B. Rosiglitazone
C. Acarbose
D. Glibenclamide
Second Generation
Glipizide
Glibenclamide
/Glyburide
Gliclazide
Glimepiride
Sulfonylureas:
Mechanism of Action
Stimulate insulin
release from
pancreatic beta cells
Administered OD or
BID depending on
formulation
CA++
SUR1
K+
GLUT2
Glucose
K pump
Ca channel
ATP
Metabolism
Insulin
Beta Cell
Sulfonylureas: Characteristics
Generic Name
Daily Dose
Range (g)
Duration
of action
(h)
Metabolism
0.5-3.0
6-12
By liver to inactive
product
Up to 60
First Generation
Tolbutamide
Chlorpropamide 0.10-0.5
2nd Generation
Glipizide
5.0-40 (mg)
10-24
Glyburide/
2.5-20 (mg)
10-24
Glibenclamide
Gliclazide
Glimepiride
1-8 (mg)
12-24
By liver to inert
products; renal
excretion
Sulfonylureas:
Side effects
Hypoglycemia - all agents but especially chlorpropamide
Insulin secretagogues:
Meglitinides
Repaglinide, nateglinide
Stimulate insulin release by
closing ATP-dependent K+
channels in pancreatic beta
cells
Short half-life: ~ 1h
Usually administered TID
before meals; reduces mostly
postprandial blood sugars
Less incidence of
hypoglycemia compared to
SUs
Biguanides:
Metformin
Euglycemic rather than
hypoglycemic agent (does not
cause hypoglycemia with
monotherapy)
Does not cause weight gain
Half-life 1.5-3h
Not metabolized
Excreted by kidneys as active
compound
Metformin:
Mechanism of Action
Insulin sensitizer via:
Reduced hepatic glucose
production (esp.
gluconeogenesis)
Increased peripheral uptake
of glucose
Activates AMP-activated
protein kinase (AMPK) - liver
enzyme with important role in
insulin signaling, whole body
energy balance, and
metabolism of glucose and fats
Metformin: Uses
First-line T2DM
therapy (ADA, EASD)
Also used to treat
polycystic ovary
syndrome
Question:
Metformin is contraindicated in patients with renal
insufficiency because:
Metformin:
Adverse and other reactions
Gastrointestinal:
anorexia, nausea,
vomiting, abdominal
discomfort, diarrhea
(often transient)
Lactic acidosis
Does not cause wt.
gain (may induce minor
wt. loss)
Metformin:
Contraindications
Renal disease
Alcoholism
Liver disease
Conditions predisposing to anoxia (e.g.,
cardiopulmonary dysfunction)
Question:
Oral antidiabetic agent most likely to cause
edema and weight gain:
A. Metformin
B. Rosiglitazone
C. Acarbose
D. Insulin
E. Repaglinide
Thiazolidinediones: Pioglitazone
Metabolized via CYP450
Other effects:
Reduce visceral fat mass, increase
subcutaneous fat
Slight drop in triglycerides, increase in HDL,
increase (rosiglitazone) or decrease
(pioglitazone) in LDL
Thiazolidinediones:
Adverse reactions
Hepatotoxicity (troglitazone)
Edema (Fluid retention), CHF
Increased MI risk? (rosiglitazone)
Hypoglycemia in combination
with insulin, sulfonylureas
Weight gain
Dilutional anemia
Bone loss
Bladder CA? (pioglitazone)
Question:
Mechanism of action of acarbose:
Plasma Glucose
(mg/dL)
Duodenum
140
Jejunum
Ileum
Meal
Placebo
Acarbose
*
120
100
80
30 0
* P <.05
60
120
Time (min)
180
240
Alpha-glucosidase Inhibitors:
Adverse effects
Gastrointestinal: flatulence,
diarrhea, abdominal pain
Hepatic enzyme elevation
Contraindicated in bowel
disease, renal disease
Hypoglycemia unlikely with
monotherapy but may occur
with concurrent sulfonylurea,
insulin, other hypoglycemic
agents
Picture of flatulence
deodorizer
Glucagon
Pharmacologic effects
Hyperglycemic
factor
Mobilizes hepatic
glycogen stores
Inotropic,
chronotropic effects
on heart
Intestinal smooth
muscle relaxation
Glucagon
Clinical Uses
Treatment of severe
hypoglycemia
Endocrine dx (test for
pancreatic beta cell
reserve)
Treatment of betablocker poisoning
Bowel radiology
Incretin Mimetics
Incretin Enhancers
New antihyperglycemic agents
INCRETIN
INtestinal
Se CRET
ion
Of
INsulin
C-peptide (nmol/L)
2.0
*
200
Incretin Effect
1.5
1.0
100
0.5
0.0
0
0
60
120
180
60
Time (min)
Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498
120
180
Incretins
The GI tract is an endocrine organ.
Incretins are gut hormones that
enhance insulin secretion in response
to food ingestion (glucose-dependent)
Incretin effect: Ingested food causes a
more potent release of insulin than
intravenous glucose.
In type 2 DM, incretin effect greatly
reduced or absent.
Incretin GLP-1-secreted by L cells of
ileum and colon
Liver:
Reduces hepatic glucose
output by inhibiting
glucagon release
Alpha cell:
Inhibits glucagon
secretion
Flint A, et al. J Clin Invest. 1998;101:515-520.
Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.
Nauck MA, et al. Diabetologia. 1996;1546-1553.
Drucker DJ. Diabetes. 1998;47:159-169.
Beta cell:
Stimulates glucosedependent insulin
secretion
Stomach:
Slows gastric
emptying
Exenatide:
GLP-1 agonist action
Stimulates insulin secretion in
glucose-dependent fashion
Restores first-phase insulin
response (1st 10 min after food
ingestion) lost early in type 2
diabetes
Suppresses inappropriately
elevated glucagon secretion
decreased hepatic glucose output
and insulin demand
Slows gastric emptying
Reduces appetite/food intake
May promote beta cell health/
survival
Exenatide
Disadvantage: injected
(BID-exenatide, ODliraglutide), nausea,
vomiting, diarrhea,
pancreatitis?
Advantages:
Lack of hypoglycemia
with monotherapy;
May produce substantial
and sustained weight
loss.
DISCUSSION
Despite its favourable biological actions, the therapeutic potential of
GLP-1 is limited primarily by its rapid degradation by the ubiquitous
enzyme dipeptidyl peptidase-IV (DPP-IV).
The rapid inactivation of GLP-1, in addition to its rapid renal
clearance, contributes to a short half-life of less than two minutes.
Thus, sustaining plasma concentrations of GLP-1 long enough to
produce a therapeutic effect requires continuous administration.
As is typical of other peptides, GLP-1 requires administration by
injection.
Amylin Analog
Pramlintide
Pramlintide:
Mechanism of Action
Mimics the effects of amylin (which
is secreted with insulin by pancreatic
beta cells in response to food intake)
Slows gastric emptying (reduced rate
of glucose absorption)
Suppresses glucagon secretion
decreased hepatic glucose output
and insulin demand
Reduces food intake
Pramlintide
Disadvantages:
Hypoglycemia
Injected
Nausea
May delay absorption
of other medications
Case 2
Despite lifestyle modifications such as diet and exercise, his
fasting blood sugar remains quite elevated. Which of the
following medications would you choose to treat him with?
A) Glibenclamide
B) Metformin
C) Repaglinide
D) Rosiglitazone
E) Acarbose
F) Sitagliptin
G) Exenatide
5) In this particular patient, list the advantages and disadvantages
of your drug of choice.
6) Which medication would be appropriate to use in combination
with your drug of choice? Why?