1. Diabetes Mellitus Overview and Treatments
Andrew P. Vogt
Chemistry 6116

2. Diabetes Mellitus : a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both
20.8 million in US ( 7% of population)
estimated 14.6 million diagnosed (only 2/3)
Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes
Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage

3. (resulting in insulin dependence)
Diabetes Mellitus
Type 1 Diabetes
- cells that produce insulin are destroyed
- results in insulin dependence
- commonly detected before 30
Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin production
2) Insufficient insulin action (resistant cells)
- commonly detected after 40
- effects > 90%
- eventually leads to β-cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US develop gestational diabetes

4. Testing : Fasting Plasma Glucose Test Oral Glucose Tolerance Test
(FPG) - (cheap, fast)
*fasting B.G.L mg/dl signals pre-diabetes
*>126 mg/dl signals diabetes
Oral Glucose Tolerance Test
(OGTT)
*tested for 2 hrs after glucose-
rich drink
* mg/dl signals pre-
diabetes
*>200 mg/dl signals diabetes
A.K.A.: Glycated Hemoglobin tests
A1C
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.

5. Diabetes - Insulin Discovered in 1921 by Banting and Best
Consist of A & B chains linked by 2 disulfide bonds
(plus additional disulfide in A) ~ ~ ~ ~
A = 21amino acids B = 30 amino acids

6. Diabetes – Insulin (synthesis, storage, secretion)
Produced within the pancreas by β cells  islets of Langerhans
insulin mRNA is translated as a single chain precursor called preproinsulin
removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin
Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin
Stored as β granules Zn
This light micrograph of a section of the human pancreas shows one of the islets of Langerhans, center, a group of modified glandular cells. These cells secrete insulin, a hormone that helps the body metabolize sugars, fats, and starches. The blue and white lines in the islets of Langerhans are blood vessels that carry the insulin to the rest of the body.

7. Diabetes – Insulin (Biochemical Role)
Tyrosine Kinase
receptors are the locks
in which the insulin
key fits
- Involved in signal
transduction
(insulin hormone being 1st messenger)

8. Diabetes – Oral Medications
6 Classes :
Sulfonylureas
Biguanides
Sulfonylureas and biguanide combination drugs
Thiazolidinediones
Alpha-glycosidase inhibitors
Meglitinides

9. Sulfonylureas : stimulate β cells to produce more insulin
1st generation
(1)Orinase (tolbutamide)
(3)Tolinase (tolazamide)
(6)Diabinese (chlorpropamide)
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940’s  hypoglycemia
Currently > 12,000
 may become dislodged  delayed activity
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

10. Biguanides : improves insulin’s ability to move glucose into cells (esp. muscle)
Metformin
- Glucophage®, Fortamet®,
Riomet®
- 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.
*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).

11. Sulfonylurea & Biguanide Combo drugs/ Cocktails
Glucovance® (Glyburide & Metformine HCl)
&
&

12. Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp
Thiazolidinediones (TZD’s) : make cells more sensitive to insulin (esp. fatty cells)
Pioglitazone
- Actos®, Avandia®
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ).
- PPARγ 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,
PPARγ–ligand 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
PPAR - γ

13. Αlpha – glycosidase inhibitors : Block enzymes that help digest starches  slowing the rise in B.G.L.
AGI’s
- Precose ® (acarbose),
- Glyset ® (miglitol)

14. Meglitinides : Stimulate more insulin production ; dependant upon level of glucose present
- Prandin ® (repaglinide)
- Starlix ® (nateglinide)

15. Diabetes – Oral Medications Summary
6 Classes :
Sulfonylureas stimulate β cells
Biguanides improves insulin’s 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
Meglitinides stimulate β cells (dependant upon glucose conc.)

16. In Conclusion : 2 major types of diabetes (3 with Gestational)
Type 1 => insulin dependant (5-10%)
Type 2 => may treat with oral medication which may alter insulin production &/or sensitivity ; disease often succumbs to insulin dependence (>90%)

17. References: http://www.webmd.com/content/article/59/66840