Transcript Document

The Endocrine Pancreas
1 million islets of Langerhans
Cell Types
Approximate
Percent of Islet Mass
Secretory Products
A cells (Alpha)
20
Glucagon
Proglucagon
B cells (Beta)
75
D cells (Delta)
3-5
Somatostatin
F cells (PP
cells)
<2
Pancreatic
polypeptide
Insulin, C-peptide,
proinsulin, islet
amyloid
polypeptide (IAPP)
or amylin
Different Forms of Diabetes Mellitus
General – genetic and other factors not precisely defined
Type 1 (Insulin-Dependent Diabetes Mellitus)
Autoimmune type 1 DM type 1A)
Non-autoimmune or idiopathic type 1 DM (type 1B)
Type 2 (Non-insulin Dependent Diabetes Mellitus)
Specific – defined gene mutations
Maturity-onset diabetes of youth (MODY)
MODY 1 hepatic nuclear factor 4α (HNF4A) gene mutations
MODY 2 glucokinase (GCK) gene mutations
MODY 3 hepatic nuclear factor 1α (TCF1) gene mutations
MODY 4 insulin promoter factor 1 (IPF1) gene mutations
MODY 5 hepatic nuclear factor 1β (HNF1β) gene mutations
MODY 6 neurogenic differentiation 1 (NEUROD1) gene mutation
MODY X unidentified gene mutation(s)
Maternally inherited diabetes and deafness (MIDD)
Mitochomdrial leucine tRNA gene mutations
Insulin gene mutations
Insulin receptor gene mutations
Diabetes secondary to pancreatic disease
Chronic pnacreatitis
Surgery
Tropical diabetes (chronic pancreatitis asst’d with nutritional and/or toxic factors)
Diabetes secondary to other endocrinopathies
Cushing’s disease
Glucocorticoids administration
Acromegaly
Diabetes secondary to immune suppression
Diabetes associated with genetic syndrome (Prader-Willi syndrome)
Diabetes associated with drug therapy
Some Drugs That Cause Hypoglycemia or Hyperglycemia
Drugs with Hypoglycemic Effects:
Beta-adrenergic receptor antagonists
Salicylates
Indomethacin
Naproxen
Ethanol
Clofibrate
ACE inhibitors
Li+
Theophyllin
Ca++
Bromocriptine
Mebendazole
Sulfonamides
Sulbactam-ampicillin
Tetracycline
Pyridoxine
Pentamidine
Drugs with Hyperglycemic Effects:
Epinephrine
Glucocorticoids
Diuretics
Atypical antipsychotic
HIV-1 protease inhibitors
Diazoxide
Beta2 adrenergic agonists
Ca++ channel blockers
Phenytoin
Clonidine
H2-receptor blockers
Pentamidine
Morphine
Heparin
Nalidixic acid
Sulfinpyrazone
Marijuana
Nicotine
Insulin:
Chemistry:
* a small protein with molecular weight of 5808
* contains 51 amino acids
* arranged in 2 chains ( A & B ) linked by disulfide
bonds/bridges
* stored crystals consisting of 2 atoms of zinc & 6
molecules of insulin
* contain 8mg of insulin/human pancreas (=200 units)
ivity)
Insulin secretion:
- respond to a variety of stimuli ( glucose, mannose, leucine, arginine & vagal
-
Insulin Degradation:
2 main organs: liver – 60%
kidney – 35-40%
hydrolysis of the disulfide bonds  glutathione insulin
transhydrogenase (insulinase )
half-life: 3-5 minutes
-
Measurement of Circulating Insulin:
radioimmunoassay permits detecton of insulin in picomolar quantities
basal insulin values: 5-15uU/ml (30-90pmol/L)
peak rise: 60-90uU/ml (360-540pmol/L)
-
The Insulin Receptor:
Effects of Insulin on its Targets
A. Action of Insulin on Glucose Transporters:
Transporters
Tissues
GlucoseKm
(Mmo/L)
Function
GLUT 1
All tissues, esp.red
cells, brain
1-2
Basal uptake of glucose;
Transport across the BBB
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
GLUT 4
Muscle, adipose
GLUT 5
Gut, kidney
< 1
Uptake into neurons, other
tissues
5
Insulin-mediated uptake of
glucose
1-2
Absorption of fructose
B. Action of Insulin on Liver
- inhibits hepatic glucose production (decreases gluconeogenesis & glycogenolysis)
- stimulates hepatic glucose uptake
C. Effect of Insulin on Muscle
- stimulates glucose uptake
- inhibits flow of gluconeogenic precursors to the liver (alanine, lactate & pyruvate)
D. Effect of insulin on Adipose Tissue
- stimulate glucose uptake (amount is small compared to muscle)
- inhibits flow of gluconeogenic precursor to liver (glycerol) and reduces energy
substrate for hepatic gluconeogenesis (non-esterified fatty acids)
A. Principal
Types and Duration of Action
1. Short- and Rapid-acting insulins:
= Regular insulin ( soluble crystalline zinc )
= Insulin lispro, Insulin aspart, insulin glulysine
= Permit more physiologic prandial insulin replacement
= Taken immediately before meal without sacrificing glucose
control
= With very fast onset (5-15 min, 10-20 min. & 30 minutes after
SQ) and short duration (3-5 hours & 5-8 hours)
= Peak serum values: 1 hour & 2 & 3 hours
= The only type that should be administered intravenously
= Useful in the management of diabetic ketoacidosis, surgery or
during acute infection, and when the insulin requirement is
changing rapidly
1. Intermediate-acting
a. LENTE INSULIN (insulin zinc suspension)
 mixture of 30% semilente with 70% ultralente insulin  provide a combination of
relatively rapid absorption with sustained long action
b.NEUTRAL PROTAMINE HAGEDORN or Isophane Insulin
 absorption & onset of action is delayed by combining appropriate amounts of insulin &
protamine
 6 molecules of insulin per molecule of protamine
3. Long-acting insulins
a. ULTRALENTE INSULIN (extended insulin zinc suspension)
b. PROTAMINE ZINC INSULIN SUSPENSION
 they have slower onset and a prolonged peak of action
 recommended dose be split into 2 or more doses
c. INSULIN GLARGINE
 soluble, “peakless, ultra-long-acting insulin analog

designed to provide reproducible, convenient, background insulin replacement

has a slow onset of action (1-1.5 hours)

achieves a maximum effect after 4-5 hours and maintained for 11-24 hours or longer
 given once a day
A Species of Insulin
1. Beef and pork insulins

The beef insulin differs by 3 amino acids, pork differs by 1
amino acid

The beef hormone is most antigenic
2.


Human insulins
Less expensive, less immunogenic
Production by recombinant DNA techniques
B.

Purity of Insulin
Chromatography
C.
Concentration
100 units/ml, 500 units/ml
Insulin Delivery Systems
A. Portable Pen Injectors
 to facilitate multiple SQ injections
B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin
Pumps)
 encouraged for individuals who are unable to obtain target control
while on multiple injection regimens & where excellent glycemic control
is desired, such as during pregnancy
 velosulin (reg. insulin) & insulin aspart and lispro
C.



Inhaled Insulin
have a rapid route and a relatively short duration of action
used to cover mealtime insulin requirements
to correct high glucose levels
Factors that Affect Insulin Absorption:
site of injection: abdomen, buttock, anterior thigh, or dorsal
arm
type of insulin
subcutaneous blood flow: massage, hot baths, or exercise
smoking
regional muscular activity at the site of the injection
volume & concentration of injected insulin
depth of injection
Treatment With Insulin
 Type 1 patients
 Type 2
 Contraindication: advanced renal disease
Elderly
Complications of Insulin Therapy
A. Hypoglycemia
1. Mechanisms and diagnosis
 result from a delay in taking a meal
 unusual physical exertion
 dosage error

CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea,
convulsion, coma
 Treatment: glucose administration
Glucagons 1 mg SQ or IM
Honey or syrup
B. Immunopathology of Insulin Therapy
1. Insulin allergy
 an immediate type of hypersensitivity (IgE-antibodies)
 Tx: antihistamines, corticosteroids & desensitization
2. Immune insulin resistance (IgG antibodies)
 + circulating antibodies that neutralize the action of insulin to a small extent
 Tx: switching to a lesser antigenic purified insulin
C. Lipodystrophy at injection sites
 corrected by avoidance of that specific injection site or with liposuction –
hypertrophy
Oral Anti-diabetic Agents
4 Categories:
Insulin secretagogues (sulfonylureas, meglitinides,
D-phenylalanine derivatives)
b. Biguanides
c. Thiazolidinediones
d. Alpha-glucosidase inhibitors
a.
Insulin Secretagogues:
A. Sulfonylureas
Mechanism of Action:
 to increase insulin release from pancreatic B cells
Sulfonylureas
bind
to
S
receptorinhibits
efflux
of
K+depolarizationopens a voltage-gated Ca++ channelresults in Ca++
influx and the release of preformed insulin

reduction of serum glucagon concentrations
Chronic adm’n of sulfonylureas to type 2 diabetics reduces serum glucagon
levels

potentiation of insulin action on target tissues
First Generation Sulfonylureas
Tolbutamide:
 well absorbed but rapidly metabolized in the liver
 duration of action: 6-12 hours
 elimination half-life: 4-5 hours
 toxic reactions: skin rash
hypoglycemia
 drug interactions: dicumarol, phenylbutazone,
sulfonamides
Chlorpropamide:
 duration of action: up to 60 hours
 half-life: 32 hours
 slowly metabolized in the liver
 20-30% is excreted unchanged in the urine
 SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia,
thrombocytopenia, jaundice
 CI: hepatic & renal insufficiency
 Dosage: 250mg daily
Tolazamide:
 duration of action: 10-14 hours
 more slowly absorbed
 half-life: 7 hours
 SE: hypoglycemia
Second Generation Sulfonylureas
Glyburide:
 metabolized in the liver
 short plasma half-life
 duration of action: 10-24 hours
 SE: flushing, hypoglycemia
 Contraindication: hepatic & renal insufficiency
 Dosage: 5-10mg as single morning dose
Glipizide:
 has the shortest half-life: 2-4 hours
 duration of action: 10-24 hours
 90% is metabolized in the liver
 10% excreted unchanged in the urine
 SE: hypoglycemia
 Contraindication: renal & hepatic insufficiency
 Dosage: 5-20mg as a single dose, 30 minutes before breakfast
Glimepiride:
 duration of action: 12-24 hours
 half-life: 5 hours
 available as once-daily dosing
 completely metabolized by the liver
 dosage: 1 mg daily
B. Meglitinides
Repaglinide:
 modulate B cell insulin release by regulating K+ efflux through the K+ channels
 no direct effect on insulin exocytosis
 peak conc & peak effect: within 1 hour
 fast onset & duration of action (5-8 hrs.)
 hepatically cleared by CYP3A4
 half-life: 1 hour
 indication: controlling postprandial glucose excursions
 Dosage: 0.25-4 mg
 SE; hypoglycemia
 Caution: hepatic & renal impairment
C. D-phenylalanine derivative
Nateglinide:
 stimulates very rapid and transient release of insulin from B cells through the
closure of ATP-sensitive K+ channel
 may suppress glucagons release early in the meal and result in less endogenous or
hepatic glucose production
 has minimal effect on overnight or fasting blood glucose levels
 ingested just prior to meals
 absorbed within 20 minutes after oral administration
 time to peak concentration: < 1 hour
 hepatically metabolized by CYP2C9 & CYP3A4
 half-life: 1.5 hours
 duration of action: < 4 hours
 SE: hypoglycemia but lowest of all the secretagogues
Biguanides
Mechanism of action:
- direct stimulation of glycolysis in tissues, with increased glucose removal from blood
- reduced hepatic & renal gluconeogenesis
slowing of glucose absorption from the GIT, with increased glucose to lactate
conversion by enterocytes
- reduction of plasma glucagon levels
Metabolism & Excretion:
Metformin:
 half-life: 1.5-3 hours
 duration of action: 10-12 hours
 not bound to plasma proteins
 not metabolized
 excreted by the kidneys as active compound
 may impair the hepatic metabolism of lactic acid
Clinical Uses:
- refractory obesity whose BS is due to ineffective insulin action (insulin resistance
syndrome)
use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in
whom
oral monotherapy is inadequate
- dosage: 500mg TID
Toxic Effects:
 anorexia, nausea, vomiting, abdominal discomfort, diarrhea
 absorption of B12 appears to be reduced during long-term therapy
Containdications:
 renal disease, alcoholism
 hepatic disease
 chronic cardiopulmonary dysfunction
Thiazolidinediones
 Act to reduce insulin resistance
 Primary action: nuclear regulation of gene involved in glucose and lipid metabolism and
adipocyte differentiation
 Are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma)
 Have significant effects on vascular endothelium, the immune system, the ovaries and
tumor cells
 In diabetes, a major site of action is adipose tissue, where the drug promotes glucose
uptake and utilization and modulate synthesis of lipid hormones or cytokines and
other proteins involved in energy regulation
 Also regulate adipocyte apoptosis & differentiation
 Are considered “euglycemics”
 Have a slow onset and offset of activity
 SE: hypoglycemia in combination
Drop in triglyceride levels
Slight rise in HDL & LDL cholesterol values
Edema – fluid retention
Anemia
Dose-related weight gain (1-3 kg)
 CI: pregnancy
Significant liver disease
Heart failure
Pioglitazone:
 may have PPAR-alpha as well as PPAR-gamma activity
 absorbed within 2 hours of ingestion
 metabolized by CYP2C8 and CYP3A4 to active metabolites
 DI: estrogen-containing oral contraceptives
 Taken once daily
 Dosage: 15-30mg

Approved as monotherapy or in combination with metformin,
sulfonylureas, and insulin
Rosiglitazone:
 rapidly absorbed and highly protein bound
 metabolized in the liver by CYP2C8 & CYP2C9
 administered once or twice daily
 dosage: 4-8 mg

approved as monotherapy or in combination with biguanides &
sulfonylureas
Alpha-Glucosidase Inhibitors
- are competitive inhibitors of the intestinal alpha-glucosidases and
reduce the postprandial digestion and absorption of starch and
disaccharides--> lowering postmeal glycemic excursions (4560mg/dl) and creating an insulin-sparing effect
- members: acarbose & miglitol
- taken in doses of 25-100 mg just prior to ingesting the first
portion of each meal
- both are absorbed from the gut
- SE: flatulence, Diarrhea, Abdominal pain
- CI: Chronic or inflammatory bowel disease, Renal impairment,
Hepatic disease (acarbose)