LSC 432 Basic Pharmacology April 1, 2003 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

This presentation is made possible by a grant entitled “Shortcourses in Endocrinology at Minority Undergraduate Institutions” from the National Institute of General Medical Sciences (NIGMS) to The Minority Affairs Committee of the Endocrine Society

The Medical Problems of Diabetes & Obesity Over 16 million in the US have clinically diagnosed diabetes mellitus; about 8% of the population. Of these, 91% have type 2 diabetes (strongly linked to obesity) & 9% have type 1 diabetes (autoimmune & genetic origin). Up to 16% of US whites have diabetes by age 70. Prevalences are often higher in other ethnic groups. > 65% of the US population is > 20% over the healthy body weight for their height, age, & gender & at risk for diabetes, cardiovascular disease (heart attack, stroke), & high blood pressure

Acute Problems in Diabetes Hyperglycemia: leads to hyperosmolality of serum, polyuria, dehydration, Na + & K + imbalances, weakness/fatigue, polyphagia with weight loss, glycosylation of proteins Ketoacidosis: decreases blood pH, HCO 3 -2, Hb avidity for O 2 ; leads to hypoxic coma &/or tachycardia Hypoglycemia (especially in treated diabetics): lack of brain glucose leads to neuropathy & coma, autonomic hyperactivity

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Glucose Homeostasis The body must control glucose levels because all cells use glucose to make ATP, the energy currency of cells. Some tissues like brain almost never burn any other fuel molecule. But too much glucose damages cells by getting attached to certain proteins and changing their function. Key tissues in this balancing act are: Liver Fat Muscle Brain Pancreas (endocrine cells)

The Liver is Central to Processing of Sugars. Converts many simple sugars, several amino acids, acetate & glycerol to glucose ( = gluconeogenesis) then secretes it into blood. Stores glucose as a macromolecule, glycogen, & hydrolyzes glycogen to glucose. Makes fat from fatty acids & glycerol, & breaks fat down to acetate & glycerol. Stores amino acids as protein, & can break proteins down to amino acids.

After meals glucose from liver is mainly stored as glycogen in liver & muscle & as fat in fat cells. When more energy is needed between meals, glycogen, fat & protein (last) are broken down & liver uses the parts to make glucose. Hormones (insulin, glucagon, adrenalin, cortisol) signal the change from storage to synthesis.

Glucagon acts on liver to stimulate glucose production & release, & on fat to cause fat breakdown. Glucagon rises when glucose falls. Adrenaline, cortisol, & growth hormone also make blood glucose rise. But insulin-like- growth factor I acts like insulin. Pancreas Hormones Control the Glucose Balance Insulin acts on body cells to allow them to take in circulating glucose. Insulin levels rise when glucose rises. InsulinGlucagon Islets of Langerhans

αlpha cells, red, lie at the outer edges of islets along with D & F cells. Blood flow is away from ß cells toward the outer cells. Insulin may block glucagon release. / IHCimage/1422.jpg.../ Julian_Thorpe/tem26r.jpg ß cell / Julian_Thorpe/tem20.jpg αlpha cell

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Mechanism of Action of Insulin graduate/pancreas19.gif

Diagnosis & Monitoring of Diabetes Thirst, polyuria, unexplained weight loss Hyperglycemia, random test > 200 mg/dL Elevated fasting glucose > 126 mg/dL Elevated glucose tolerance curve Glycosuria Ketonuria Tests for capillary blood glucose Tests for ketonuria Tests for glycosylated hemoglobin, HbA 1c

Diabetes is a hot illness (characterized by vasodilation & a high metabolic rate). Various remedies are used: nopal (or cactus), aloe vera juice, bitter gourd. In some areas in Texas & Mexico treatment is started with maturique root infusion for about 1 week if the person is extremely hyper- glycemic. Then, for maintenance therapy, trumpet flower- herb or root infusion (tronadora), brickle bush (prodigiosa) tea, or sage tea (salvia) are used. Proven safety & efficacy of maturique, trumpet flower, or bricklebush are not known. Aloe vera juice is reasonably safe but aloe vera latex is a powerful purgative. Sage tea taken chronically can lower the seizure threshold & has been reported to cause mental & physical deterioration because it contains thujones & tannins. [Nancy Neff, Dept. of Community Medicine, Baylor College of Medicine Module VII, Folk Medicine in Hispanics in the Southwestern United States, ww.rice.edu/projects/HispanicHealth/Courses/ mod7/mod7.html] Traditional Treatments in the Southwest

Drugs for Diabetes Type 1 Insulin Multiple preparations available Differ in multimerization of insulin, up to hexamers, & resulting speed of absorption, action, & clearance Ultra-short acting, 5-15’ = lispro Short acting, 15-30’ = regular Intermediate acting, 2-4 h = NPH, Lente Long acting, 4-5 h = Ultralente Idea in Rx is to provide basal insulin + peaks after meals chemcases.com/olestra/ images/insulin.jpg

How fast is the insulin response to glucose?

Antidiabetic (Hypoglycemic) Drugs  Intestinal brush border α glucosidase inhibitors  Stimulants of insulin release: sulfonylureas, meglitinide analogs  Blockers of gluoneogenesis: Biguanides  Insulin mimics or PPARγ activators: thiazolidinediones Possibilities  Endogenous insulin secretagogues: glucagon-like peptide 1  Glucagon antagonists

Sulfonylureas Stimulate insulin release from ß cells via binding to the SU receptor = K + ATP channel Mostly long metabolic T 1/2 After

Sulfonylurea Actions on ß Cells After

Meglitinide Analogs Bind to ß cells via SU receptor Rapid absorption, metabolism & clearance, T 1/2 < 1 h After

Biguanides Act by inhibiting liver gluconeogenesis & increasing insulin sensitivity in other tissues Metformin is not metabolized, but excreted intact in 2-5 h After

Thiazolindinediones Partial mimics of isulin actions, may bind insulin receptor or act through the peroxisomal proliferator activated receptor γ Metabolized with a long half life After /cmc9-1/kecskemeti/fig10.gif

Counterindications for Drug Use Compromised liver function Renal impairment Cardiovascular problems Advanced age Concurrent use of contraceptive steroids or other medications

After

Troglitazone Metabolites Kecskemeti 1*, V., Z. Bagi 1, P. Pacher 1, I. Posa 2, E. Kocsis 2 & M. Zs. Koltai 2 (~2000) New Trends in the Development of Oral Antidiabetic Drugs, /cmc9-1/kecskemeti/Kecskemeti-ms.htm

Prospects for Long-Term Cures pumps implants gene therapies

Body Mass Homeostasis: Our New Understanding / images/jpg/adipocytes.jpg

A Little About the Central Players

Summary: Diabetes is a group of pathologies. Type 1 is due to autoimmunity to pancreatic ß cells & demonstrates genetic predispositions. Type 2 seems due to chronic overwork of ß cells & often appears during old age, especially in the chronically overweight. Monitoring tools are available as are drugs and therapies. ß cell implants are being tested. Prevention of Type 2 is often accessible by control of life-style. Prevention of Type 1 will only be possible when causes are identified.

Fats are often broken down after being absorbed by the small intestine. They are moved as complexes wrapped in specific proteins. The earliest complexes have the most fat relative to protein and are the least dense. hsc.usf.edu/2005/ lipoprotmet.jpg

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Modified from Diabetes/Alpha.gif

Definition of Diabetes

What kinds of hormone are there? Known Hormonal Classes Proteins & peptides Lipids (steroids, eicosanoids) Amino acid derived (thyronines, neurotransmitters) Gases (NO, CO) chemcases.com/olestra/ images/insulin.jpg chem.pdx.edu/~wamserc/ ChemWorkshops/ gifs/W25_1.gif website.lineone.net/~dave.cushman/ epinephrine.gif