The glucolipotoxicity hypothesis:
postulates that chronically elevated levels of
glucose and fatty acids adversely affect
pancreatic beta-cell function and thereby
contribute to the deterioration of insulin
secretion in Type 2 diabetes.
Side Effects of Insulin:
1. Hypoglycemia. Initial signs are
autonomic (sweating, hunger, anxiety,
tremor, palpitations). More severe
symptoms are central (difficulty
concentrating, weakness, drowsiness,
dizziness, blurred vision, loss of
consciousness)
2. Weight gain. No longer leaking
calories.
3. Allergic reactions to insulin or other
injection ingredients: Skin reactions
including hive-like or wheal formation,
system allergic reactions e.g.,
angioedema, anaphylaxis (rare)
4. Atrophy or hypertophy of
subcutanenous fat at injections site
5. Insulin resistance (immune antibody
based or obesity)
6. Inhaled insulin induces cough and
reduces lung function-significance is
not yet known. Not recommended for
use in smokers, COPD patients etc.
Insulin preparations: required for Type I Diabetes
• 4 injectable categories available based
upon onset and duration of action
CATEGORY
APPEARANCE
ONSET
(HR)
MAXIMUM (HR)
DURATION
(HR)
clear
0.25
0.5 – 1.5
3–4
clear
0.5
2–3
4–8
cloudy
2–4
4 – 12
10 – 20
Ultralente Insulin
cloudy
6 – 10
small peak at 10-16 hrs
16 – 20
Glargine Insulin
clear
1–2
no peak
18 – 24
Detemir Insulin
clear
1-2
relatively flat
18 - 24
Exubera®
Powder
0.25
0.5 – 1.5
3-4
PREPARATION
Lispro Insulin
Rapid Acting
Aspart Insulin
Glulisine Insulin
Short Acting
Regular Insulin
Intermediate
Acting
NPH Insulin
Long Acting
Inhalation
Lente Insulin
Page 1
Becky Stepan
Rose-Hellekant – Insulin, Hypoglycemia
Insulin Injection Sites – self administered insulin is injected or infused into the fatty tissue just under the skin.
The body areas most commonly used for insulin injection are the abdomen, buttocks, and thighs. The backs of the
upper arms may be used as well. The avoid skin problems, inject at least a finger’s width away from your last
injection. To avoid absorption problems, do not inject near moles, scars or your navel.
Insulin Administration modes
• Insulin pen
• Insulin infusion set and pump
• Insulin inhaler
• Oral preparations are under development
− Primary roadblock is GI breakdown.
• Dermal patch under development
Recombinant Insulins
Insulin is 51 Amino Acids
• Aspart (rapid)
• Lispro (rapid)
• Glargine (long-acting)
Hypoglycemic Drugs – the goal is to decrease hyperglycemia
• Secretagogues are medicines that stimulate beta cell secretion of insulin.
• Secretagogues include the sulfonylureas, include glinides (meglitinides), GLP-1 analags and dipeptidase
inhibitors.
• Dipeptidases breakdown the incretins (GIP and GLP-1). Inhibitors of dipeptidases promote GLP-1 action
Pancreas
Increase Insulin Secretion
Sulfonylureas
Meglitinides
GLP-1 Analogs
Dipeptidase inhibitors
Sulfonylureas
First Generation
− Tolbutamide
− Chlorpropamide
•
•
•
Liver
Decrease Hepatic Glucose
Production
Biguanides
Amylinamimetics
GLP-1 Analogs
Dipeptidase inhibitors
t 1/2
4-7h
24-48h
Intestines
Decrease Carbohydrate
absorption
Alpha-Glucosidase
Inhibitors
Amylinamimetics
GLP-1 Analogs
Dipeptidase inhibitors
Skeletal Muscle
Increase Insulin
Sensitivity
Thiazolidinediones
Second Generation
~100x more potent and fewer side effects
− Glyburide
3-5h
− Glipizide
(but effects 12-24h)
− Glimepiride
(but effects 12-24h)
Food, hyperglycemia (which inhibits gastric
emptying/intestinal motility)inhibits absorption
so give 30 minutes prior to meal.
Liver metabolism, kidney excretion
Site of Action: the pancreatic Beta cell (which has GLUT 2 transporters)
Side Effects of Sulfonylureas
• Hypoglycemia  especially in individuals w/impaired liver/kidney function
• Weight Gain
• Disulfirmam-like reactions  blocks the oxidation of alcohol at the acetaldehyde stage
• May potentiate effects of ADH – hyponatremia
• Primary failure (never respond) & secondary failure (fail after short term treatment)
• Drug Interactions
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Becky Stepan
Rose-Hellekant – Insulin, Hypoglycemia
Meglitinides/Glinides [Repaglinide & Nateglinide ]
• Enhance glucose-induced insulin release - K+-channel blocker similar to sulfonylureas
• Increased insulin production
• Rapid onset, short duration of action- taken with meal; liver metabolism
• Side effects
− Weight gain
− Hypoglycemia
Biguanides – [Metformin]
− GI, tremor, dizziness
• Reduce glucose production
− Decrease hepatic
Thiazolidinediones - [Rosiglitazone & Pioglitazone]
gluconeogenesis
• Insulin Sensitizer-primarily skeletal muscle & adipose
− not hypoglycemic, but
− Increase glucose uptake and utilization by
antihyperglycemic
Increasing synthesis and transport of
• Orally effective, excreted unchanged
GLUT4 and GLUT2 transporters in muscle,
• Max at 1-3 hours, duration 8-12 hours
adipose and liver.
• Side effects
− PPARg receptor agonist so upregulate insulin
− GI, metallic taste, anorexia,
responsive genes in liver cells that regulate
− diarrhea
CHO & lipid metabolism
− Decreased weight
− Require Insulin presence for action.
− Lactic acidosis
• Side effects
− Weight gain
− Edema
− Upper respiratory infections, headache
− Hepatotoxic?; metabolized by liver CYP450s earlier versions were taken off the market.
− 10 failure
Amylinomimetics: Pramlintide
• Mechanism of Action: decreases carbohydrate
absorption, decreases glucose production by the liver
• Effects
− Inhibits glucagon synthesis
− Inhibits glucose synthesis in the liver
− Delays gastric emptying
− Increases satiety
• Pharmacokinetics
− SC administration
− Peak concentration in 30 min, t1/2 = 50 min
− Excreted by kidney
− GI side effects most common
• Can induce severe hypoglycemia in combination
with insulin
• Reduces absorption of other drugs
• This drug needs to be injected
• Birth defects (?)
a-Glucosidase Inhibitors [Acarbose &
Miglitol]
• Glucosidases hydrolyze
carbohydrates to monosaccharides.
• Glucosidase inhibitors therefore
interferes with hydrolysis of
disaccharides and complex
carbohydrates to monsaccharides
• Taken with meals.
• Slows digestion
• Acarbose is not absorbed
• Side effects predominantly GI
• Can be used with other oral
hypoglycemic to lower
postprandial glucose levels
The “Incretins” GIP and GLP-1
GI hormones that ENHANCE INSULIN secretion (i.e. these are insulin secretagogues) Mediators of Intestinal
Phase of Insulin Secretion
• GIP: gastric inhibitory peptide; AKA glucose dependent insulinotropic peptide
− 42 amino acid peptide produced by K cells of duodenum and jejunum
− in Type 2 diabetic, secretion is normal but response to endogenous peptide is impaired
− Rapidly metabolism: half-life minutes
• GLP-1: glucagon like peptide 1
− 30/31 amino acid peptide produced by lower small intestine and colon
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Becky Stepan
Rose-Hellekant – Insulin, Hypoglycemia
−
−
−
−
−
−
−
Product of alternative splicing of the proglucagon gene (vs. in pancreas which splices so that
glucagon is secreted).
Stimulates insulin and inhibits glucagon secretion
delays gastric emptying
induces satiety
in Type 2 diabetic secretion is impaired but response to endogenous peptide is normal
Half-life: minutes
rapid degradation by the enzyme dipeptidyl peptidase-4.
Incretin Analogs: EXENATIDE (GLP-1 analog)
• Effects
− Increases insulin and decreases glucagon secretion
− Delays gastric emptying
− Increases satiety
− Administered sc before meal, peak concentration about 2 hrs, excreted by kidney
• GI side effects most common
• Increased hypoglycemia with sulfonylureas
• Low incidence of pancreatitis
• Birth defects in preclinical studies with animals
DDP-IV Inhibitors: [Sitagliptin (Januvia®)]
• Dipeptidyl peptidase-4 is responsible for the degradation of incretins such as GLP-1 and GIP.
• Inhibits Dipeptidyl Peptidase-IV
• Increases GLP-1 levels
• Decreases glucagon and glucose
• Orally effective
• Well tolerated, not associated with hypoglycemia or weight gain
• Long term use must be assessed
GLP-1: glucagon like peptide 1: made by distal small bowel and colon in response to glucose presence. Receptors
in beta pancreatic cells and in brain. Receptor presence in alpha cells is controversial. GLP-1 affects on glucagon
may be mediated via nervous system.
Amylin: co-secreted with insulin in beta cells; controls nutrient intake as well as nutrient influx to the blood by an
inhibition of food intake, gastric emptying, and glucagon secretion
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Becky Stepan
Rose-Hellekant – Insulin, Hypoglycemia