Diabetes Mellitus Overview and Treatments Andrew P. Vogt

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

(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

Testing : Fasting Plasma Glucose Test Oral Glucose Tolerance 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 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.

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

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.

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)

In the case of type 1 diabetes, insulin levels are grossly deficient In the case of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulin Type 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance. A number of treatment options may be employed.

Animation showing overview of diabetes: http://www.healthscout.com/animation/1/34/main.html Animation showing mechanism of action of insulin: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html

Pancreatic Hormones and Insulin Receptor Agonists Hongmei Li Mar. 21th, 2006

The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. Inside the pancreas are millions of clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are: beta cells, which secrete insulin and amylin; alpha cells, which secrete glucagon; delta cells, which secrete somatostatin gamma cells, which secrete a polypeptide.

Pancreatic Hormones Insulin Amylin Glucagon Somatostatin Pancreatic Polypeptide

Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (S—S) bridges to a B chain of 30 amino acids. A chain Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose. B chain

Insulin affects many organs: It stimulates skeletal muscle fibers. It stimulates liver cells. It acts on fat cells It inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor. protein synthesis amino acids uptake glucose uptake glycogen synthesis fat synthesis enzyme production glycogen breaking

The insulin receptor (IR) is a transmembrane glycoprotein, composed of 2α and 2β domains. Its intracellular tyrosine kinase domain is activated by binding of insulin, leading to a cascade of signaling events.

Who need insulin medicine Type I (insulin dependent) diabetes patients whose body produces no insulin. Type 2 diabetes patients that do not always produce enough insulin. Treatment subcutaneous injection

Insulin drug evolution Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) 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 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 (trade name = Novolin®) (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 Insulin analogs Pre-mixed insulin Short peptide mimics

Regular insulins: Human insulin: Humulin® (from E.coli), Novalin® (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed. Lente® insulin / Ultralente® insullin- zinc added

Types of insulin Regular insulins Insulin analogs Pre-mixed insulin Short peptide mimics

Insulin Analogs: Fatty Acid Acylated insulins Insulin Lispro (Humalog®) (1996) Insulin Aspart (NovoLog®) (2000) Insulin Glargine (Lantus®) (2002) Insulin Detemir (Levemir®) (Jun.,2005) Insulin Glulisine (Apidra®) (Jan., 2006)

Amino Acid Substitutons A- chain Position B- chain Position Source/ Type A21 B3 B28 B29 B30 B31 And B32 Human Asn Pro Lys Thr Aspart Aspartic acid Lispro Glulisine Glu Glargine Gly Arg Detemir Myristic rapid-acting long-acting

References Renuka C. P. et.al (2002) J. Biol. Chem. 277, 22590–4 Zoltan V. AND William C. D. (2001) Pharm. Rev. 52, 1-9 Lauge S. et. Al (2003) PNAS 100, 4435-9 Mark R. B. (1997) J. of Clin. Endoc.& Met. 82, 3-7 Gianni C. (1992) FEBS 307, 66-70 Irl B. H., (2001) Clin. Diabetes 19, 146-7 BRUCE W. B. and POUL S. (2001) Diabetes care 24,69-72 http://www.indstate.edu/thcme/mwking/diabetes.html

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

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

Mechanism of Action 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

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. 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).

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

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

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

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

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.)

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%)

References: http://www.webmd.com/content/article/59/66840   http://hms.harvard.edu/public/disease/diabetes/diabetes.html http://focus.hms.harvard.edu/2005/May20_2005/immunology.shtml http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/surface.html http://www.cancure.org/insulin_potentiation_therapy.htm http://www.diabetes.org/about-diabetes.jsp http://www.diabetesnet.com/diabetes_treatments/sulfonylureas.php http://www.people.vcu.edu/~urdesai/sulf.htm http://en.wikipedia.org/wiki/Glucohexal http://www.drkoop.com/druglibrary/93/glucovance-warnings_precautions.html http://en.wikipedia.org/wiki/Actos   http://www.answers.com/topic/peroxisome-proliferator-activated-receptor http://www.mja.com.au/public/issues/176_08_150402/omo10828_fm.html http://www.univgraph.com/bayer/inserts/precose.pdf http://www.drugs.com/pdr/ACARBOSE.html http://www.pfizer.com/pfizer/download/uspi_glyset.pdf http://www.rxlist.com/cgi/generic2/miglitol.htm http://en.wikipedia.org/wiki/Prandin http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00593.txt