Biol 300-M5 Applied Biochemistry, Barry University April 1, 2005 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of Biology University of Massachusetts.

Biol 300-M5 Applied Biochemistry, Barry University

April 1, 2005

Diabetes: Basics & Drugs

Kenneth L. CampbellProfessor 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

www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld019.htm

www.telemedicine.org/ dm/dg.jpg

www.telemedicine.org

/ dm/dd.jpg

www.michiganeye.com/images

/ retinopathy/pic2.gif


Obtaining & Processing Nutrients

What are nutrients? Why are they being extracted?

Nutrients are those parts of food that provide sources of energy, molecular building blocks,

or ions and small molecules needed to support biochemical functions.

•Amino acids•Fats•Sugars•Nucleic Acid Components•Minerals•Vitamins

Teeth: break food into smaller particles & mix in saliva

Saliva: adds water, buffer salts & often enzymes that

begin sugar digestion

Stomach: adds HCl & pepsin, a proteolytic enzyme

Apocrine pancreas & bile: add enzymes & detergents

for degrading protein, fats, sugars, & nucleic acids

Small intestine: absorbs simple sugars, amino acids,

fats, nucleosides, vitamins, & ions

Cecum: often acts as a fermenter allowing bacteria to

break down complex sugars

Large intestine: absorbs water, ions, & small molecules

Colon: absorbs water, stores feces

Where does this occur?

www.iun.edu/~biologyn/P262%20Web%20Pages/EX-14%20Digestive%20Histology/aa.GIF

www.le.ac.uk/pathology/teach/ va/anatomy/case6/gi4.gif

Smoothmusclelayers

Mucosa:HCl & pepsin

StomachHistology

Small IntestineHistology

www.uoguelph.ca/zoology/devobio/ miller/013634fig8-24.gif

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

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.

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:

LiverFatMuscleBrainPancreas (endocrine cells)

Hormones Play Key Roles in Controlling Blood Glucose

But what are hormones?

Hormones are distinct molecules that act as intercellular chemical

messages.

Hormone Functions

• Maintain Internal Homeostasis

• Support Cell Growth

• Coordinate Development

• Coordinate Reproduction

• Facilitate Responses to External Stimuli

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

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 theGlucose Balance

Insulin acts on body cells to allow them to take in circulating glucose. Insulin levels rise when glucose rises.

InsulinGlucagon

Islets of Langerhanshttp://medlib.med.utah.edu/WebPath/jpeg4/ENDO039.jpg

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.

www.labvision.com/images/ IHCimage/1422.jpg

.../ Julian_Thorpe/tem26r.jpg

ß cell

www.biols.susx.ac.uk/home/ Julian_Thorpe/tem20.jpg

αlpha cell

www.umanitoba.ca/dnalab/ graduate/pancreas13.gif

Mechanism of Action of Insulin

www.umanitoba.ca/dnalab/ graduate/pancreas19.gif


Diagnosis & Monitoring of Diabetes

Thirst, polyuria, unexplained weight lossHyperglycemia, random test > 200 mg/dLElevated fasting glucose > 126 mg/dLElevated glucose tolerance curveGlycosuriaKetonuria

Tests for capillary blood glucoseTests for ketonuriaTests for glycosylated hemoglobin, HbA1c


www.umanitoba.ca/dnalab/graduate/pancreas28.gif

Drugs for Diabetes Type 1

Insulin

Multiple preparations availableDiffer 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

SulfonylureasStimulate insulin release from ß cells via binding to the SU receptor = K+

ATP channelMostly long metabolic T1/2

After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig-1.gif

Sulfonylurea Actions on ß Cells

After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig3.gif

SU closes KATP channels causing membrane depolarization & opening of voltage - dependent, L - type Ca+2 channels.

Meglitinide AnalogsBind to ß cells via SU receptor

Rapid absorption, metabolism & clearance, T1/2 < 1 h


Biguanides Act by inhibiting liver gluconeogenesis & increasing insulin sensitivity in other tissues

Metformin is not metabolized, but excreted intact in 2-5 h


Thiazolindinediones

Partial mimics of insulin actions, may bind insulin receptor or act through the peroxisomal proliferator activated receptor γ

Metabolized with a long half life


www.diabetes-mellitus.org/slidesho/slide5.gif

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

Prospects for Long-Term Cures

pumps

implants

gene therapies

Body Mass Homeostasis:

Our New Understanding

www.garvan.org.au/library/ 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.

Counterindications for Drug Use

Compromised liver function

Renal impairment

Cardiovascular problems

Advanced age

Concurrent use of contraceptive steroids or other medications

After www.diabetes-mellitus.org/slidesho/slide22.gif

Troglitazone MetabolitesKecskemeti1*, V., Z. Bagi1, P. Pacher1, I. Posa2, E. Kocsis2 & M. Zs. Koltai2

(~2000) New Trends in the Development of Oral Antidiabetic Drugs,

www.bentham.org/sample-issues/cmc9-1/kecskemeti/Kecskemeti-ms.htm



users.cybercity.dk/.../diabetes/ billeder/glut2.JPG

Modified from www.pharmacology2000.com/Endocrine/ Diabetes/Alpha.gif

Definition of Diabetes

Review:What do each ofthese organs do?

Stomach

SmallIntestine

ColonCecum

LargeIntestine

Pancreas& Bile

Saliva

Teeth

Relation of Animal Body Evolution to Digestion

Evolutionary Adaptations for Digestion

Form & function of the gut.

Shape & arrangement of teeth:From Wessells & Hopson, Biology, (Random House:1988), 817, 822, 819.

Carnivore Omnivore Herbivore

Contents of saliva:Contains amylases in cloven hoofed animals, rodents, rabbits, dogs, & primates. High content of HCO3

-2 & PO4

-3 in herbivores.Venoms & proteases in some reptiles & invertebrates.

Digestive Tracts of Carnivores:

Simple stomach, short small intestine, simple, short large intestine for extraction of high quality foods.

Digestive Tracts of Herbivores:Ruminants, efficiently extract nutrients from low quality foods by symbiosis with bacteria in complex stomach.

On similar feed, equids extract easily digested materials in foregut, & get more calories by fermentation in complex hindgut.

Digestive Tracts of Omnivores:

These are hybrid, systems: simple stomachs, moderately long small intestines, & well-developed, but simple, large intestines.

Digestion is an extraction & breakdown process optimized to provide metabolic building blocks & energy source molecules.

Evolutionary adaptations match each animal’s anatomy & physiology to it’s food sources & quality.

Summary:

Biol 300-M5 Applied Biochemistry, Barry University April 1, 2005 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of Biology University of Massachusetts.

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