1 million islets of Langerhans Insulin, the storage and
anabolic hormone of the body Islet amyloid polypeptide (IAPP, or
amylin), which modulates appetite, gastric emptying, and glucagon
and insulin secretion Glucagon, the hyperglycemic factor that
mobilizes glycogen stores somatostatin, a universal inhibitor of
secretory cells Pancreatic peptide, a small protein that
facilitates digestive processes by a mechanism not yet
clarified
Slide 4
Table. Pancreatic islet cells and their secretory products.
Cell Types Approximate Percent of Islet Mass Secretory Products A
cell (alpha)20Glucagon, proglucagon B cell (beta)75 Insulin,
C-peptide, proinsulin, amylin D cell (delta)3-5Somatostatin F cell
(PP cell) 1 < 2Pancreatic polypeptide (PP) 1 Within pancreatic
polypeptide-rich lobules of adult islets, located only in the
posterior portion of the head of the human pancreas, glucagon cells
are scarce (< 0.5%) and F cells make up as much as 80% of the
cells.
Slide 5
type 1, insulin-dependent diabetes severe or absolute insulin
deficiency immune and idiopathic causes type 2,
noninsulin-dependent diabetes tissue resistance combined with a
relative deficiency in insulin secretion Affects fat metabolism FFA
& TG, HDL) 30% or more will benefit from insulin therapy 10-20%
of individuals actually have both type 1 and type 2 ketoacidosis
may occur as the result of stress (infection), corticosteroids,
nonketotic hyperosmolar coma type 3, other multiple other specific
causes of an elevated blood glucose: nonpancreatic diseases, drug
therapy, etc. type 4, gestational diabetes mellitus (GDM) Noted
first time in the pregnancy In 4% of all pregnancies most
pronounced in the last trimester placenta and placental hormones
create an insulin resistance
Slide 6
51 amino acids arranged in two chains (A and B) linked by
disulfide bridges Proinsulin C-peptide crystals consisting of two
atoms of zinc and six molecules of insulin The entire human
pancreas contains up to 8 mg of insulin ~ 200 biologic units 28
units per milligram
Slide 7
Slide 8
Glucose Other sugars (eg, mannose) Certain amino acids (eg,
leucine, arginine) Glucagon-like polypeptide-1 Vagal activity
Slide 9
The liver (60%) and kidney (35-40%) in insulin-treated
diabetics receiving subcutaneous insulin injections, this ratio is
reversed The half-life of circulating insulin is 35 minutes.
Slide 10
Basal insulin values of 5-15 U/mL (30-90 pmol/L) Peak rise to
60-90 U/mL (360-540 pmol/L) during meals
Slide 11
Translocation of glucose transporters Increased glycogen
formation Protein synthesis, lipolysis, and lipogenesis Cell growth
and division Glucocorticoids lower the affinity of insulin
receptors for insulin
Slide 12
Table. Glucose transporters. Transport er Tissues Glucose K m
(mmol/L) Function GLUT 1 All tissues, especially red cells, brain
1-2 Basal uptake of glucose; transport across the blood- brain
barrier GLUT 2 B cells of pancreas; liver, kidney; gut 15-20
Regulation of insulin release, other aspects of glucose homeostasis
GLUT 3 Brain, kidney, placenta, other tissues < 1 Uptake into
neurons, other tissues GLUT 4Muscle, adipose 5 Insulin-mediated
uptake of glucose GLUT 5Gut, kidney1-2Absorption of fructose
Slide 13
Slide 14
Reversal of catabolic features of insulin deficiency Inhibits
glycogenolysis Inhibits conversion of fatty acids and amino acids
to keto acids Inhibits conversion of amino acids to glucose
Anabolic action Promotes glucose storage as glycogen (induces
glucokinase and glycogen synthase, inhibits phosphorylase)
Increases triglyceride synthesis and very- low-density lipoprotein
formation
Slide 15
Increased protein synthesis Increases amino acid transport
Increases ribosomal protein synthesis Increased glycogen synthesis
Increases glucose transport Induces glycogen synthase and inhibits
phosphorylase
Slide 16
Increased triglyceride storage Lipoprotein lipase is induced
and activated by insulin to hydrolyze triglycerides from
lipoproteins Glucose transport into cell provides glycerol
phosphate to permit esterification of fatty acids supplied by
lipoprotein transport Intracellular lipase is inhibited by
insulin
Slide 17
Frederick G. Banting Student assistant Charles H. Best and
Frederick G. Banting are standing on the roof of the medical
building with one of the diabetic dogs used in their experiments
with insulin.
Slide 18
Slide 19
Slide 20
Intensive regimens involving multiple daily injections (MDI)
use long-acting insulin analogs to provide basal or background
coverage, and rapid-acting insulin analogs to meet the mealtime
requirements. Conventional therapy consists of split- dose
injections of mixtures of rapid- or shortacting and
intermediate-acting insulins.
Slide 21
Slide 22
Slide 23
Binding, activity, half-life, immunogenicity & mitogenicity
are similar to human regular insulin Their duration of action is
rarely more than 45 hours, which decreases the risk of late
postmeal hypoglycemia. The lowest variability of absorption
(approximately 5%) compared with 25% for regular insulin and 25% to
over 50% for long-acting analog formulations and intermediate
insulin, respectively Insulin lispro, the first monomeric insulin
analog Low tendency to dimers formation To enhance the shelf life
of insulin in vials, insulin lispro is stabilized into hexamers by
a cresol Onset of action within 515 minutes and peak activity as
early as 1 hour.
Slide 24
Its effect appears within 30 minutes, peaks between 2 and 3
hours after subcutaneous injection, and generally lasts 58 hours.
Regular insulin (crystal) Dimers hexamers (Zn) 3 rates of
absorption Risk of late postprandial hypoglycemia It should be
injected 3045 or more minutes before the meal to minimize the
mismatching. Onset, duration, peak increase with the size of the
dose S.c. & i.v (i.v. in DKA, after surgery, acute
infection)
Slide 25
NPH (neutral protamine Hagedorn, or isophane) insulin Isophane
1:10 ratio Protamin proteolyzed after s.c. inj. NPH insulin has an
onset of approximately 25 hours and duration of 412 hours Mixed
with regular, lispro, aspart and glulisine given 2-4 times
daily
Slide 26
Glargine Peakless Insulin Glargine has a slow onset of action
(1 1.5 hours) and achieves a maximum effect after 46 hours. This
maximum activity is maintained for 1124 hours or longer. Some very
insulin-sensitive or insulin- resistant individuals benefit from
split (twice a day) dosing. Soluble in acidic pH Should not mixed
Separate syringes Less immunogenic No mitogen 6-7 fold greater
binding affinity to IGF-1 receptor
Slide 27
Detemir Myristic acid Increasing both self- aggregation in
subcutaneous tissue and reversible albumin binding. Less
hypoglycemia than NPH Dose-dependent onset of action of 12 hours
and duration of action of more than 12 hours. It is given twice
daily to obtain a smooth background insulin level.
Slide 28
Insulin lispro, aspart, and glulisine can be acutely mixed (ie,
just before injection) with NPH insulin without affecting their
rapid absorption. NPH = NPL & NPA NPL/Lispro (50/50 &
75/25) NPA/Aspart (70/30) Glargin & Detemir as separate inj.,
and syringes.
Slide 29
Regular, lispro, aspart, glulisine In pregnancy
Slide 30
TIGHT GLYCEMIC CONTROL HbA 1c of 7.2% (normal
colesevelam hydrochloride Persons with type 2 diabetes who are
taking other medications or have not achieved adequate control with
diet and exercise. Interruption of the enterohepatic circulation
and a decrease in farnesoid X receptor (FXR) activation. The drug
may impair glucose absorption Colesevelam is administered as a pill
or an oral suspension in a dosage of 1875 mg twice daily or 3750 mg
once daily. It lowered HbA 1c about 0.5%, and LDL > 15% AE:
constipation, indigestion, flatulence Impair absorption of drugs
Should not be used in individuals with hypertriglyceridemia, a
history of pancreatitis secondary to hypertriglyceridemia, or
esophageal, gastric, or intestinal disorders
Slide 54
Pramlintide Approved for preprandial use in persons with type 1
and type 2 diabetes. Pramlintide suppresses glucagon release via
undetermined mechanisms, delays gastric emptying, and has central
nervous system mediated anorectic effects. Rapidly absorbed after
SC; peak within 20 min., and the duration of action is not more
than 150 minutes. Pramlintide is renally metabolized and excreted
The most reliable absorption is from the abdomen and thigh
Pramlintide should be injected immediately before eating Initiated
with the lowest dose and titrated upward Concurrent rapid- or
short-acting mealtime insulin doses should be decreased by 50% or
more. It cannot be mixed with insulin AE: hypoglycemia and
gastrointestinal symptoms, including nausea, vomiting, and
anorexia.
Slide 55
Exenatide and liraglutide Potentiation of glucose mediated
insulin secretion, suppression of postprandial glucagon release,
slowed gastric emptying, and a central loss of appetite, decreased
beta-cell apoptosis, increased beta-cell formation. Exenatide is
approved as an injectable, adjunctive therapy in persons with type
2 diabetes treated with metformin or metformin plus sulfonylureas
who still have suboptimal glycemic control. Exenatide peak 2 hrs.
duration of action of up to 10 hrs.
Slide 56
Exenatide is injected subcutaneously within 60 minutes before a
meal; therapy is initiated at 5 g twice daily, with a maximum
dosage of 10 g twice daily. It undergoes glomerular filtration, and
dosage adjustment is required only when the creatinine clearance
< 30 mL/min. The oral hypoglycemic dosage may need to be
decreased HbA 1c reductions from 0.2% to 1.2%. SE: nausea (about
44% of users) and vomiting and diarrhea. necrotizing and
hemorrhagic pancreatitis.
Slide 57
Slide 58
Liraglutide Liraglutide is approved for the treatment of type 2
diabetes as an injectable therapy in patients who achieve
inadequate control with diet and exercise, and are receiving
concurrent treatment with metformin, sulfonylureas, or Tzds. It is
not recommended as a first-line therapy or for use with insulin.
Treatment is initiated at 0.6 mg and is titrated in weekly
increments of 0.6 mg as needed, and as tolerated, to achieve
glycemic goals. Peak in 812 hrs., T 1/2 is about 13 hrs.
Slide 59
Reduction of HbA1c from 0.8% to 1.5%; Weight loss ranges from
nominal to 3.2 kg. AE: headache, nausea, and diarrhea; antibody
formation, urticaria, and other immune reactions also are observed
Hypoglycemia can occur with concomitant sulfonylurea use and may
require a dose reduction of the oral hypoglycemic agent.
Pancreatitis is another serious adverse effect CI: liraglutide is
contraindicated in individuals with a history of pancreatitis and
should be permanently discontinued if pancreatitis develops. in
individuals with a personal or family history of medullary cancer
or multiple endocrine neoplasia type 2.
Slide 60
Although they require injection, the GLP- 1 receptor ligands
have gained popularity because of the improved glucose control and
associated anorexia and weight loss in some users. Safety issues,
however, may determine future use.
Slide 61
Sitagliptin, saxagliptin, and linagliptin Inhibitors of DPP-4,
the enzyme that degrades incretin hormones. Increase GLP-1 and GIP,
which ultimately decreases postprandial glucose excursions by
increasing glucose-mediated insulin secretion and decreasing
glucagon levels. Approved as adjunctive therapy to diet and
exercise in the treatment of individuals with type 2 diabetes who
have failed to achieve glycemic goals.
Slide 62
Sitagliptin usual dosage is 100 mg orally once daily.
Bioavailability > 85%, peak within 14 hrs, and T 1/2 12 hrs. It
is primarily (87%) excreted in the urine. Sitagliptin has been
studied as monotherapy and in combination with metformin,
sulfonylureas, and Tzds. HbA 1c reductions of between 0.5% and
1.0%. AE: nasopharyngitis, upper respiratory infections, headaches,
and hypoglycemia when the drug is combined with insulin
secretagogues or insulin. PMS reports of acute pancreatitis (fatal
and nonfatal) and severe allergic and hypersensitivity
reactions.
Slide 63
Saxagliptin Saxagliptin is given orally as 2.55 mg daily The
drug reaches maximal concentrations within 2 hours (4 hours for its
active metabolite). The terminal plasma half-life is 2.5 hours for
saxagliptin and 3.1 hours for its active metabolite. Dosage
adjustment is recommended for individuals with renal impairment and
concurrent use of strong CYP3A4/5 inhibitors Saxagliptin is
approved as monotherapy and in combination with biguanides,
sulfonylureas, and Tzds. HbA 1c reduction in the range of 0.40.9%.
AE: an increased rate of infections (upper respiratory tract and
urinary tract), headaches, peripheral edema (when combined with a
Tzd), hypoglycemia (when combined with a sulfonylurea), and
hypersensitivity reactions (urticaria, facial edema).