Fasting Plasma Glucose Test (FPG) - (cheap, fast) *fasting B.G.L. 100-125 mg/dl signals pre-diabetes *>126 mg/dl signals diabetes
Oral Glucose Tolerance Test (OGTT) *tested for 2 hrs after glucose-rich drink *140-199 mg/dl signals prediabetes *>200 mg/dl signals diabetes
80 to 90 mg per 100 ml, is the normal fasting blood glucose concentration in humans and most mammals which is associated with very low levels of insulin secretion.
Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.
Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin). Yeast is also used to produce insulin. (1987).
Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog and NovoLog) or slower (Lantus) than regular human insulin.
Types of insulin
Regular insulins:
Human insulin: Humulin (from E.coli), Novalin (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed. Lente insulin / Ultralente insullinzinc added
Types of insulin
Insulin Analogs:
Fatty Acid Acylated insulins Insulin Lispro (Humalog) (1996) Insulin Aspart (NovoLog) (2000) Insulin Glargine (Lantus) (2002)
B- chain Position
rapid-acting
Arg
Detemir
Lys
Myristic acid
long-acting
6 Classes :
Sulfonylureas Biguanides Sulfonylureas and biguanide combination drugs Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides
Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels This, in turn, leads to opening of calcium channels Which leads to the production of insulin
1st generation
bind to protein
(1)Orinase
Rel. Potency
2nd generation
(75)Glucotrol
(glipizide) (150)Glucotrol XL (ex. rel. glipizide) (150)Micronase, Diabeta (glyburide) (250)Glynase (micronized glyburide)
3rd generation
(350)Amaryl
(glimepiride)
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway *Hydroxylated derivatives have much lower hypoglycemic activity
Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels This, in turn, leads to opening of calcium channels Which leads to the production of insulin
R R R N R N
H H +
Metformin
H N H N N N N
N R N
N R
HCl
- mechanism improves insulin sensitivity by increasing peripheral glucose uptake and utilization. - Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase - Metformin was first described in the scientific literature in 1957 (Unger et al). - It was first marketed in France in 1979 but did not receive FDA approval for Type 2 diabetes until 1994. Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).
NH
&
O S
NH O O
H N H N N H + N H H
&
O O NH
HCl
Pioglitazone
O S NH
O 5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR). - PPAR is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta
- upon activation of this nuclear receptor by a ligand such as a TZD, PPARligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism. - Marketed in USA in August of 1999
AGIs - acarbose
- miglitol
O H O N
H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol
Meglitinides
O
- repaglinide
N NH
O O
OH
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
NH
- nateglinide
O O OH 2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
6 Classes :
Sulfonylureas stimulate cells Biguanides improves insulins ability to move glucose Sulfonylureas and biguanide combination drugs BOTH Thiazolidinediones cells more sensitive to insulin Alpha-glycosidase inhibitors Block enzymes that help digest
starches
ADIPOSE TISSUE
MUSCLE
INTESTINE
INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide