Glucose-stimulated insulin release from pancreas B cell

Diabetes Mellitus and Starvation Similarity: Lack of intracellular energy

Difference: What causes the problem

Cause of the problem

DM: Deficient mechanism to obtain energy from glucose - Starvation: Lack of nutrients input for the provision of fuel substances

Alternative to obtain energy in DM and Starvation a. Switch from carbohydrate to fat metabolism b. Switch from gluconeogenesis to ketone production Consequences (what are they?) have to be monitored.

Diabetes Mellitus type1 - Less common than type 2 - Autoimmune destruction of pancreatic B cells - Severe insulin deficiency - Diabetic ketoacidosis

Diabetes Mellitus type 2 - Insulin resistance - Do not require insulin treatment - Managed with diet alone or diet plus medications

Purpose of medications: - Enhance endogenous insulin secretion (sulfonylureas)

- Decrease insulin resistance

- Decrease intestinal carbohydrate absorption (-glycosidase inhibitors)

Explain biochemical aspects of: 1. Hyperglycaemia 2. Glucosuria 3. Decreased glycogenesis 4. Decreased fatty acid synthesis 5. Increased lypolysis

6. Increased fatty acids in blood 7. Ketonaemia 8. Ketonuria 9. Metabolic acidosis 10. Negative Nitrogen Balance

Explanation of 1-4

Actions of insulin on target tissues

Hyperglycaemia - Decreased glucose uptake by insulin dependent glucose transporter (Glut 4, muscle, adipose tiss) - Decreased glycogenesis Not sufficient insulin to activate phosphodiesterase, enzyme for conversion of cAMP to AMP, meaning to decrease cAMP concentration cAMP inhibiting factor in glycogenesis

Explanation of 5 6 Due to a switch from utilization of glucose to fat for source of energy. Low levels of oxaloacetate (OAA) in liver Ketone body production increases

Explanation of 7 8
Increased production of ketone bodies Less utilization in muscle (low OAA)

Develops ketonaemia in type 1 DM and

type 2 DM with insulinopenia.

Type 2 DM: Deficient control of insulin secretion

Glucose is insulin secretagogue for insulin secretion

Explanation 9 - 10
In severe cases of DM, tissue protein utilized for energy Cysteine sulphates acid urine Negative N-balance due to ineffective amino acid metabolism.

Complications and Therapy

Advanced glycation end products (AGEs)

A serious complication of diabetes
Glycoprotein = covalent linkage of sugar to protein

Can occur nonenzymatically

Glycation causes change to protein function

Circulation, joint and vision problems.

Nonenzymatic glycation of Hb (glycated Hb) is

Used to estimate blood glucose over past several months

Chronic Complications

Microvascular complications induced by:

1. Polyol pathway 2. AGE formation

3. Protein kinase C (PKC)

4. Hexosamine Pathway

ad 1. Aldose reductase converts glucose to sorbitol In hyperglycemia: accumulation of sorbitol osmotic stress in nerves, endothelial cells, eye lens (cataract)

ad 2. AGEs can cause : - Microvascular damage - Formation of glycated HbA (= HbA1c) Used as index of glycemic control over preceding 2-3 months

ad 3. Intracellular hyperglycemia in endothelium increased DAG (diacylglycerol) activates protein kinase C (PKC) effects on blood flow and endothelial permeability.

ad 4. Increase of glucose entering hexosamine pathway produces substrates that

can bind covalently to transcription

factors stimulate protein expression e.g. transforming growth factor, enhancing microvascular damage

Gluconeogenesis Inhibitors
Metformin improves sensitivity to insulin in type 2 DM Stimulates glucose uptake by glucose transporters in peripheral tissues Increases binding of insulin to insulin receptors Stimulates tyrosine kinase activity of insulin reseptor Inhibits glukoneogenesis in liver

REFERENCES 1. Medical Biochemistry (MASTER MEDICINE) Brownie, A.C., Kernohan, J.C. 2nd ed. 2005 2. BIOCHEMISTRY Garrett, R.H., Grisham, C.M. 3rd ed. 2005 3. Pathophysiology of Disease McPhee, S.J., Ganong, W.F. 5th ed. 2006