Diabetes

Charith Kumara Group-14 KSMU.

Diabetes Mellitus
Disease in which the body doesnt produce or properly use insulin, leading to hyperglycemia.

Carbohydrate Digestion

Insulin Secretion

What goes wrong in diabetes?

Multitude of mechanisms

Insulin
Regulation Secretion Uptake or breakdown

Beta cells

damage

Action of Insulin on the Cell Metabolism

Action of Insulin on Carbohydrate, Protein and Fat Metabolism

Carbohydrate

Facilitates the transport of glucose into muscle and adipose cells Facilitates the conversion of glucose to glycogen for storage in the liver and muscle. Decreases the breakdown and release of glucose from glycogen by the liver

Action of Insulin on Carbohydrate, Protein and Fat Metabolism

Protein

Stimulates protein synthesis Inhibits protein breakdown; diminishes gluconeogenesis

Action of Insulin on Carbohydrate, Protein and Fat Metabolism

Fat

Stimulates lipogenesis- the transport of triglycerides to adipose tissue Inhibits lipolysis prevents excessive production of ketones or ketoacidosis

Type I Diabetes
Low or absent endogenous insulin Dependent on exogenous insulin for life Onset generally < 30 years 5-10% of cases of diabetes Onset sudden

Symptoms: 3 Ps: polyuria, polydypsia, polyphagia

Type I Diabetes Cell

Type I Diabetes

Genetic component to disease

Type II Diabetes

Insulin levels may be normal, elevated or depressed

Characterized by insulin resistance, diminished tissue sensitivity to insulin, and impaired beta cell function (delayed or inadequate insulin release)

Often occurs >40 years

Type II Diabetes

Type II Diabetes

Risk factors: family history, sedentary lifestyle, obesity and aging Controlled by weight loss, oral hypoglycemic agents and or insulin

Screening for Diabetes

Fasting Significance Action Blood Glucose < 110 Normal Retest in 3 years >110 & <126 IGT

1. Additional
testing 2. Check risk factors 3. MNT 1. Confirm by 2nd FBG 2. Treat DM

> 126

Diabetes Likely

Management of Diabetes Mellitus

Nutrition Blood

glucose Medications Physical activity/exercise Behavior modification

Medical Nutrition Therapy

Primary
Blood

Goal improve metabolic control

glucose Lipid (cholesterol) levels

Medical Nutrition Therapy

Maintain short and long term body weight Reach and maintain normal growth and development Prevent or treat complications Improve and maintain nutritional status Provide optimal nutrition for pregnancy

Nutritional Management for Type I Diabetes

Consistency

of meals Timing of insulin Monitor blood glucose regularly

and timing

Nutritional Management for Type II Diabetes

Weight loss Smaller meals and snacks Physical activity Monitor blood glucose and medications

Diabetes Control and Complications Trial

10 year randomized, controlled, clinical trial Determine the effects of glucose control on the development of long term microvascular and neurologic complications in persons with type I diabetes. 1441 participants, ages 13 to 39

Diabetes Control and Complications Trial

Conventional therapy:

1 - 2 insulin injections, self monitoring B.G routine contact with MD and case manager 4X/year. 3 or more insulin injections, with adjustments in dose according to B.G monitoring, planned dietary intake and anticipated exercise.

Intensive therapy:

Diabetes Control and Complications Trial

Results:

76% 60% 54% 39%

reduction reduction reduction reduction

in in in in

retinopathy neuropathy albuminuria microalbuminuria

Implication: Improved blood glucose control also applies to person with type II diabetes.

Nutrition Recommendations

Carbohydrate

60-70% calories from carbohydrates and monounsaturated fats 10-20% total calories

Protein

Nutrition Recommendations

Fat

<10% calories from saturated fat 10% calories from PUFA <300 mg cholesterol 20-35 grams/day Type I limit to 2 drinks/day, with meals Type II substitute for fat calories

Fiber

Alcohol

Types of Insulins

Short peptide mimics

Regular insulins Insulin analogs Pre-mixed insulin

Regular insulins:

Human insulin: Humulin (from E.coli), Novalin (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed. Lente insulin / Ultralente insullinzinc added

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

Achai n Position
Source/ Type Human Aspart Lispro Glulisin e Glargine A21 Asn Asn Asn Asn Gly Lys B3 Asn

B- chain Position

B28 Pro Aspartic acid Lys Pro Pro

B29 Lys Lys Pro Glu Lys

B30 Thr Thr Thr Thr Thr

B31 And B32

rapid-acting

Arg

Detemir

Lys

Myristic acid

long-acting

Diabetes Oral Medications

6 Classes :

Sulfonylureas Biguanides Sulfonylureas and biguanide combination drugs Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides

Sulfonylureas : stimulate cells to

produce more insulin

1st generation
bind to protein

(1)Orinase

(tolbutamide) thiadiazole (IPTD) was used in treatment of typhoid fever in 1940s hypoglycemia Currently > 12,000 (3)Tolinase (tolazamide) (6)Diabinese (chlorpropamide)

2-(p-aminobenzenesulfonamido)-5-isopropyl -

may become dislodged delayed activity

Rel. Potency

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 insulins ability to

move glucose into cells (esp. muscle)
R N R N
H

R N

R R

N R

Metformin

N H N H N H

N N H

- Glucophage, Fortamet, + HCl 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).

Thiazolidinediones (TZDs) : make

cells more sensitive to insulin (esp. fatty cells)
O

Pioglitazone
- Actos, Avandia

O S NH

O 5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

- binds to and activates the gamma isoform of the peroxisome proliferator-activated rec

- PPAR is a member of the steroid hormone nuclear receptor superfamily, and is found cardiac and skeletal muscle, liver and placenta

- upon activation of this nuclear receptor by a ligand such as a TZD, PPARligand 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 -

lpha glycosidase inhibitors :

Block enzymes that help digest starches slowing the rise in B.G.L.

AGIs
- Precose (acarbose),

- Glyset (miglitol)
H O H O N O H

H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol

Meglitinides : Stimulate more insulin

production ; dependant upon level of glucose present

Meglitinides
O

- Prandin (repaglinide)

N NH

O O

OH

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

- Starlix (nateglinide)
NH O O OH 2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

Diabetes Oral Medications

Summary

6 Classes :

Sulfonylureas stimulate cells Biguanides improves insulins 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 conc.)

Meglitinides stimulate cells (dependant upon glucose

In Conclusion :

2 major types of diabetes (3 with Gestational) Type 1 => insulin dependant (510%) Type 2 => may treat with oral medication which may alter insulin production &/or sensitivity ; disease often succumbs to insulin dependence (>90%)