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Treatment of Diabetes by jonathanscott

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									         Treatment of Diabetes
•Type 1(IDDM)
  Tight control of blood sugar levels

Regular monitoring of:
Blood sugar
Caloric intake
•Prevents primary effects of low insulin (ketosis)
And reduces secondary effects…vascular disease etc.

• Type 2
  Diet
  Oral antidiabetics….sulphonylureas, phenylalanine
  abnalogues, biguanides, alpha-glucosidase inhibitors,
  thiazolidinediones
  Insulin
     Insulin Preparations
Porcine or bovine insulin still available but
recombinant insulin usually used (safety?)

Soluble insulin (acetate buffered)
Rapid acting and short-lived action (IV)

Protamine or zinc-precipitated insulin
Poorly soluble
Slower absorption and longer action (IM,sub-cutaneous)

Insulin pumps
       Insulin treatment
•2 or more daily injections
  short or intermediate acting preps
• Usually before meals

• For patients with more uncontrolled blood sugar then
  multiple injections required or continuous perfusion

• IV infusion in emergency
..hyperglycemic coma
..diabetic ketoacidosis
National Post June 7th 2000
     The Edmonton Protocol
•Potential cure for type 1 diabetes
•Injection of purified islets into the hepatic portal vein
•Liver acts as a surrogate endocrine pancreas
•Low levels of immunosuppressants required all the time
•Patients have virtually normal lives
(>600 patients worldwide so far)

Downside……
•Require 2 fresh donor pancreas for one transplant and two
  transplants are usually required for success
• Islets are rejected over time
•Only used in 24+ age group <90 kgs and BMIs <25
•Only for severe diabetics
•Needs to be developed for juveniles
•Cost….>$50,000 per procedure
        Oral antidiabetics
The sulphonylureas:
• Sulphonamide antibiotic derivatives
• Showed marked reduction in blood glucose
• Been in use for diabetes for over 40 years
• All prone to cause post prandial hypoglycemia

• Tolbutamide: (Orinase) was the first one used
• Glibenclamide (Diabeta)
• Chlorpropamide (Diabenese)
• Effective, not to be used in patients >65 or with renal
  complications

•New derivatives……Glipizide, Gliclazide
                                    Sulphonylurea
                                      structures
       Thiosulphonylurea group


                                  Compound       Brand name
Benzamido group

                                 Glibenclamide   DiaBeta,
                                   (Glyburide)   Micronase,
                                                 Glynase.

                                 Tolbutamide     Orinase.

                                 Glimepiride     Amaryl.
         Sulphonylurea group
                                 Glipizide       Glucotrol (XL).
KATP channels, sulfonylureas and
       beta cell function




                                 sulfonylureas




          Low glucose   High glucose             Low glucose




 -70 mV                  1 min
Molecular makeup of
 the KATP channel




       SUR             Kir6.2




         NBF1   NBF2     ATP
      The sulfonylurea receptor

• SUR is a member of the ABC family of proteins
  (CFTR, P-glycoprotein, multidrug resistance protein)

• SUR subunit bestows pharmacology on channel

• 3 major isoforms, SUR1, 2A, 2B

• SUR1 and Kir6.2 genes mapped to chromosome
  11p15.1
  Sulphonylureas bind
   to the SUR subunit
                  SUR            Kir6.2



     Cytoplasmic loops 3 and 7


Sulphonylureas bind SUR with high affinity
-the SUR isoforms display different sensitivity

clinically important……
    Clinical efficacy of
     Sulfonylureas

Pros: Effective….yes
      Safe….?

Cons:
post-prandial hypoglycemia
Cardiovascular side effects
               Biguanides
Action independent of insulin
Increase glucose uptake into skeletal muscle
Some effects on glucose absorption and hepatic glucose
Production

Examples:
Phenformin, use discontinued because of lactic acidosis
Metformin (glucophage)…better tolerated

Increases glucose uptake
Decrease appetite (useful in type 2 NIDDM)
Decreases plasma LDL, VLDL

Increases beta-cell glucose-responsiveness
Alpha-Glucosidase Inhibitors
Example: acarbose

Oligosaccaride that slows the rate of absorption of
Carbohydrates such as starch, dextrin, maltose, sucrose

Binds ~ 100-fold more potently to disaccharidases

Prevent the initial “glucose-spike” that occurs after food
Ingestion

Principal side effect is flatulence
       (this discourages overconsumption of carbos!)
        Insulin-Sensitizers
Oral hypoglycemic agents that improve the action
of insulin.
PPAR-alpha/gamma ligands
Alpha- fenofibrate
Gamma- piogliazone, rosiglitazone

Actions on liver, skeletal muscle and adipose tissue

Corrects hyperglycemia in obese and non-obese
Type 2 diabetics

Also lowers blood pressure (vasodilatory effects)
Only recently become available
Side effects, mild weight gain, fluid retention
Contra-indicated in CHF and hepatic disease
Phenylalanine analogs
                                          Nateglinide

N-(cyclohexylcarbonyl)-D-phenylalanines
Eg. Nateglinide (Starlix, Novartis)
    Repaglinide (Prandin, Novo Nordisk)

FDA approved
Target the beta-cell KATP channel, fast acting
and readily metabolized
No side effects documented
Glucagon-like Peptide-1




   Endocrine Reviews 20(6) 876 1999
         Glucagon-Like Peptide-1




•Excellent glucose-management profile
•GLP-1 rapidly cleaved by serine protease dipeptidyl peptidase IV.
 non-hydrolysable analogues of exendin now in market
(exenatide….. Byella). But only administered sub-cutaneously
at the moment…need for oral adminstration route

DPPIV inhibitors also in market (Sitagliptin….Januvia)
• Exenatide
•   Exenatide, a synthetic version of exendin-4, a hormone in the saliva of
    the Gila monster, a lizard native to several Southwestern American
    states, displays properties similar to human GLP-1.

•   The lizard eats only four times a year and turns its pancreas off the rest
    of the time. When it eats, it secretes exendin-4 to turn its pancreas on
    again.

•   Research suggests that Exenatide exerts its effects through the GLP-1
    receptor, is much more potent than GLP-1, and has all of the actions of
    GLP-1 -- stimulating insulin secretion, slowing gastric emptying and
    inhibiting production of glucagon by the alpha cells of the pancreas.

•   Byetta (exenatide) is now now in market

								
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