GLUCOSE METABOLISM AND DIABETES MELLITUS

Carbohydrates are the preferred source of energy for the body.

Final products of carbohydrate digestion in the digestive tract are monosaccharides (glucose [80%], fructose and galactose)

Much of fructose and all galactose are converted to glucose in the liver and released back into the blood.

Glucose is a large molecule that must be broken down into a form of energy usable by the cell (ATP).

Glucose: The Preferred Nutrient

A P P P

Adenosine Phosphate groups

High-energy bondsStructure of ATP: Adenosine Triphosphate

A P P P

Glucose is broken down into many molecules of ATP (higher # if O2 present)

A P P P+

C6H12O6

When bond is broken, energy is released to do cellular work

AdenosineDiphosphate

CATABOLISM: Molecule Breakdown

The process of glucose metabolism involves

Glycolysis The citric acid cycle (Krebs cycle) Electron transport.

Glucose Metabolism

Only 40% of the energy released through catabolism of glucose is captured in ATP.

The remaining 60% escapes as heat that warms the interior of the cells and the surrounding tissues.

If cells have inadequate amounts of glucose to catabolize, the immediately shift to the catabolism of fats for energy.

In starvation, proteins are used for energy after carbohydrate and fats are depleted.

Only enough ATP for immediate cellular requirements is made at any one time

Glucose that is NOT needed for ATP is ANABOLIZED into glycogen and stored for later use in the liver and in muscles.

GLYCOGENESIS: synthesis of glycogen from glucose molecules

Insulin ◦stimulates glycogenesis (glycogen anabolism) ◦ inhibits glycogenolysis (glycogen catabolism)

Glucose Storage

Glucose is in liquid form. As the number of glucose molecules increases, the pressure inside the cell increases.

Converting glucose to glycogen (in solid form) relieves pressure inside the cell.

Why is glucose stored as glycogen?

When cells are saturated with glycogen (liver cells store 5 to 8% of their weight as glycogen, muscle cells 1 to 3%) additional glucose is converted to fat in the liver and stored as fat in adipose cells.

Glucose Conversion to Fat

Excess glucose is preferentially stored as glycogen BUT

Without insulin, glucose transport into the cells will be insufficient.

Lacking glucose, cells will have to rely on protein and fat catabolism for fuel.

Also, when there is not enough insulin, excess glucose cannot be stored in the liver and muscle tissue.

Instead,glucose accumulates in the blood-- above normal levels.

Importance of Insulin

The high concentration of glucose in the blood (resulting from the lack of insulin) is called hyperglycemia, or high blood sugar.

Hyperglycemia, or High Blood Sugar.

Consists of 3 types:1) Type 1 diabetes2) Type 2 diabetes3) Gestational diabetes

a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both

¨ Complications :- Stroke- Heart attack- Kidney disease- Eye Disease- Nerve Damage

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)

Diabetes Mellitus

Gestational Diabetes 3-5% of pregnant women in the US develop gestational diabetes

In 1921, Dr. Frederick Banting discovered insulin, enabling people with diabetes to live long and healthy lives. 

Consist of A & B chains linked by 2 disulfide bonds

(plus additional disulfide in A)A = 21amino acids B = 30 amino acids

Insulin

~ ~ ~ ~

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

Insulin(synthesis, storage, secretion)

Zn

Insulin(Biochemical Role)

- Tyrosine Kinase receptors are the locks in which the insulin key fits

- Involved in signal transduction (insulin hormone being1stmessenger)

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.

• In the case of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulin

Types

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 somatostatingamma cells, which secrete a polypeptide.

Pancreatic Hormones Insulin Glucagon Somatostatin Pancreatic Polypeptide Amylin

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.

glucoseuptake

glycogen synthesis

protein synthesis

amino acids uptake

enzymeproduction

glycogenbreaking

fat synthesis

Biguanides:(Glucophage-metformin) lowers the production of glucose made in the liver

Well accepted as the drug of first choice in Type II Major side effects are GI Lactic acidosis rare but serious side effect

Diabetes Medications Oral

Oldest of oral meds Until 1995 the only meds available 1st gen- Orinase,Tolinase,Diabinese 2nd gen-Glucotrol(glipizide), Micronase or

Diabeta(glyburide) 3rd gen- Amaryl(glimeperide) Stimulate the pancreas to release more insulin,

hypoglycemia can be side effect

Sulfonylureas

Prandin(repaglinide) Starlix(nateglitinide) Stimulate insulin secretion when there is glucose

present in the blood stream Used with meals

Meglitinides

Precose(acarbose) Glyset(miglitol) Delay the conversion of carbohydrates into

glucose during digestion Major side effect gas/bloating limits use

Alpha-Glucosidase Inhibitors

Avandia(rosiglitazone) Actos(pioglitazone) Sensitizes muscle and fat cells to accept insulin

more easily FDA warning in May 2007 that Avandia may be

associated with possibility of heart attacks or other CV events

Cause or exacerbate CHF, watch closely for edema

Thiazolidinediones(TZDs)

Byetta(exenatide)-originally isolated from the saliva of Gila monster Lizard

Shares several of the coregulatory effects of the incretin glucagon-like peptide-1(GLP-1)

Improves glucose dependent insulin secretion Restores first phase insulin response Suppresses inappropriate glucagon secretion Slows rate of gastric emptying Increases satiety BID injection, main side effect nausea/weight

loss

Incretin Mimetics

Dipepityl Peptidase 4 inhibitor-slows the inactivation of GLP-1 and GIP (glucose-dependent insulinotropic polypeptide)

Januvia(sitagliptin) Very minimal side effects, weight neutral Most effective when used with metformin

DPP-4 Inhibitor

Each type different onset, peak, and duration Rapid Acting:Novolog(aspart) Apidra(glulisine) Humalog(lispro) Onset-15 min Peak- 30-90 min Duration- 3-5 hrs Take at the beginning of meals

Insulin

Humulin R and Novolin R (regular) Onset- 30-60 min Peak- 2-4 hrs Duration- 5-8 hrs Take 30 minutes before meals

Insulin Short acting

Humulin N and Novolin N (NPH) Onset- 1-3 hrs Peak- 8 hrs Duration- 12-16 hrs Usually twice a day

Insulin Intermediate Acting

Levemir (detemir) and Lantus (glargine) Also referred to as basal insulins Onset- 1 hr Peak- none Duration- 20-26hrs Usually once a day, may need bid as dose

increases

Insulin Long Acting

Humulin 70/30 Novolin 70/30 Humulin 50/50 Onset 30-60 min Peak- variable Duration- 10-16 hrs Typically bid

Insulin Premixed N and R

Humalog Mix 75/25 and 50/50 Intermediate and rapid-acting Onset- 15min Peak- variable Duration- 10-16 hrs Typically bid

Insulin Pre-mix lispro protamine and lispro

Novolog Mix 70/30 Intermediate and rapid-acting Onset- 15min Peak- variable Duration- 10-16 hrs

InsulinPre-mix aspart protamine and aspart

Think Diabetes- Who to screen! Good History and Physical Educate, educate, educate! Monitor Be aggressive- don’t be afraid to use insulin!

Summary