Diabetes mellitus and insulin resistance

The hall mark of diabetes mellitus is the sweet smelling of urine. Egyptian Ebers paperus as far back as 1500 B.C. shows early clinical description of diabetes. In A.D. 96 in Greece Aritaeus of Cappadocia describe the disease as “Melting down of limbs and flesh into urine.”

In 1880, diabetes mellitus was considered to be caused by excessive sex or alcohol. In 1921, a link between diabetes mellitus and insulin was established by Sir Frederick Grant Banting and Charles Herbert Best of Canada.

Pancreas is a compound recemose gland situated between spleen and small intestine. It’s acini secret digestive juices but Islets of Langerhans of endocrine pancreas by mainly 4 types of cells secret:

β cells – Insulin and Amyline which opposes insulin

α cells - Glucagon

δ cells – Somatostatin

 PP cells- Pancreatic polypeptide

Insulin is a small protein (not active orally as it is digested by proteolytic enzyme) and human insulin has a molecular weight of 5808. It stimulates the cells to take up glucose. Glucagone breaks down Glycogen to yield glucose and Somatostatin regulates the production of insulin and glucagone. Lack of insulin or inability to utilise it leads to Diabetes Mellitus. There are 2 types of diabetes mellitus:

a)    Type 1 – i.e. Insulin Dependent Diabetes (IDDM): over 50% cases heritability contributed by HLA class II (i.e. D loci on the short arm of chromosome 6)

b)    Type 2 – i.e. Non-Insulin Dependent Diabetes (NIDDM). It is commonly associated with obesity, hypertension and hyperlipidemia.

After release of insulin  β cell it binds  to a receptor on the surface of the muscle or fat cell. Insulin controls metabolism of carbohydrate, protein and fat:

Cellular potassium uptake    

Insulin resistance is a condition in which cells fail to respond to normal action of insulin. The body produces insulin but the cells in body become resistant and unable to use it effectively leading to hyprglycaemia. Beta cells therefore produce more insulin leading to hyperinsulinaemia. It is a promonent defect in type 2 diabetes. Patient with insulin resistance has high triglyceride, low HDL and increase risk of cardiovascular disease. The condition is a impaired biological response to either exogenous or endogenous insulin.

When blood sugar rise after food insulin secreted from pancreas shuttle glucose in cells where it is stored as glycogen or used as energy. For this purpose insulin should fit like a key in a lock into receptor outside the cell. Each has about 20,000 or more insulin receptors. After insertion insulin activates tyrosine kinase i.e. an enzyme in the receptor. This causes a series of process by which glucose enters the cell. In case of insulin resistance the cell resists the process so instead of entering the cell the glucose builds up in the blood and pancreas pumps higher than normal amount of insulin in an attempt to nomalise the blood glucose level.

Patient with insulin resistance develops:

Actions Insulin Increase    Decrease (Anabolic effects)    (Catabolic effects) Carbohydrate Metabolism Glucose transport    Gluconeogenesis (Muscle, adipose tissue) Glucose phosphorylation    Glycogenolysis Glycogenesis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt Lipid Metabolism Tryglyceride synthesis    Lypolysis Fatty acid synthesis (Liver)    Lypoprotein lipase (Muscle) Lipoprotein lipase (adipose tissue activity)    Ketogenesis Fatty acid oxidation (liver)     Protein Metabolism Amino acid transport    Protein degradation Protein synthesis Electrolysis

Brain fogginess

High blood sugar

Intestinal bloating

Sleepiness

Increased triglyceride

High blood pressure

Increased cardio-vascular disease and increased pro-inflammatory cytokins.

Depression

Acanthosis nigricans

Increased hunger

The various causes and associated conditions of insulin resistance are as follows:

1.Diet

2.Obesity

3.Ageing

4.Genetics:In about 50% cases there occur genetic abnormalities of insulin receptor gene with genetic abnormalities of pro-insulin and insulin.

5.Type 2 diabetes

6.Medications: Cortcosteroid and ACTH especially in large doses. Besides these Thiazide diuretics and contraceptive pills have little effect on induction of diabetes.

7.Sedentary life style.

8.Hypertension

9.Dyslipidemia

10.After burns and other severe illness. However the condition is temporary.

11.Polycystic ovary syndrome

12.Hormone induced conditions: e.g. Acromegaly, Cushing syndrome, Pheochromocytoma, Glucagunoma etc.

With regard to insulin resistance we must remember diabetes is the result of abnormal insulin function i.e. a defect at any point in the synthesis or functioning of insulin. This may occur in the pancreatic cells. If the insulin producing cells are absent or cannot synthesize or secrete proper insulin diabetes results. After releasing from the cell insulin must travel to receptor cell but it can be destroyed enroute by antibodies. Diabetes can also result from deficient or structurally abnormally receptors because after reaching target cell insulin must bind to receptor. Again when insulin binds to receptor cell membrane allows glucose to enter by facilitated transport and then glucose is either metabolized to generate energy or stored as glycogen as already stated. Defects in glucose uptake and utilization can also produce diabetes mellitus.

Insulin resistance may be mainly due to anyone of the following causes:

a) An abnormal insulin molecule

b) An excessive amount of circulating antagonist

c) Target tissue defects: specially seen in both obese and non-obese patients with NIDDM.

So in insulin resistance there may occur receptor abnormalities -  lipoatrophic diabetes, acanthosis nigricans, antibodies to insulin receptors, abnormalities of insulin receptor gene. Antibodies to specific proteins have been identified recently which includes antibodies to glutamic acid decarboxylase (GAD, the 64-k Da antigen), an even closer association is found in the presence of antibodies to tyrosin phosphatase (37-k Da, 1A-2). The presence in a non-diabetic person of 3 or more antibodies (Islets cell antibodies, antiGAD antibodies, anti1A-2 antibodies, anti-insulin antibodies) indicate an 88% chance of developing diabetes within 10 years.

In NIDDM there are more than likely relationship between reduced insulin secretion and  increased insulin resistance:

It may be mentioned that obesity is the commonest cause of insulin resistance. In obese with distorted waist-hip ratio (Apple shaped android obesity with waist-hip ratio>0.9 more prone to NIDDM than pear shaped gynoid obesity with waist-hip ratio <0.7) insulin resistance is perhaps because of down regulation of insulin receptors due to circulatory hyperinsulinaemia. Recent studies suggest that there is a relation between low birth weight and development of insulin resistance, NIDDM, coronary artery disease in middle age.

Patients with insulin resistance are treated with exercise, weight loss, low carb-diet. Metformin and Thiazolidinediones improve their condition.  (Reprint)

 

Diabetes mellitus and insulin resistance

The hall mark of diabetes mellitus is the sweet smelling of urine. Egyptian Ebers paperus as far back as 1500 B.C. shows early clinical description of diabetes. In A.D. 96 in Greece Aritaeus of Cappadocia describe the disease as Melting down of limbs and flesh into urine. In 1880, diabetes mellitus was considered to be caused by excessive sex or alcohol. In 1921, a link between diabetes mellitus and insulin was established by Sir Frederick Grant Banting and Charles Herbert Best of Canada. Pancreas is a compound recemose gland situated between spleen and small intestine. Its acini secret digestive juices but Islets of Langerhans of endocrine pancreas by mainly 4 types of cells secret: cells Insulin and Amyline which opposes insulin cells - Glucagon cells Somatostatin PP cells- Pancreatic polypeptide Insulin is a small protein (not active orally as it is digested by proteolytic enzyme) and human insulin has a molecular weight of 5808. It stimulates the cells to take up glucose. Glucagone breaks down Glycogen to yield glucose and Somatostatin regulates the production of insulin and glucagone. Lack of insulin or inability to utilise it leads to Diabetes Mellitus. There are 2 types of diabetes mellitus: a) Type 1 i.e. Insulin Dependent Diabetes (IDDM): over 50% cases heritability contributed by HLA class II (i.e. D loci on the short arm of chromosome 6) b) Type 2 i.e. Non-Insulin Dependent Diabetes (NIDDM). It is commonly associated with obesity, hypertension and hyperlipidemia. After release of insulin cell it binds to a receptor on the surface of the muscle or fat cell. Insulin controls metabolism of carbohydrate, protein and fat: Cellular potassium uptake Insulin resistance is a condition in which cells fail to respond to normal action of insulin. The body produces insulin but the cells in body become resistant and unable to use it effectively leading to hyprglycaemia. Beta cells therefore produce more insulin leading to hyperinsulinaemia. It is a promonent defect in type 2 diabetes. Patient with insulin resistance has high triglyceride, low HDL and increase risk of cardiovascular disease. The condition is a impaired biological response to either exogenous or endogenous insulin. When blood sugar rise after food insulin secreted from pancreas shuttle glucose in cells where it is stored as glycogen or used as energy. For this purpose insulin should fit like a key in a lock into receptor outside the cell. Each has about 20,000 or more insulin receptors. After insertion insulin activates tyrosine kinase i.e. an enzyme in the receptor. This causes a series of process by which glucose enters the cell. In case of insulin resistance the cell resists the process so instead of entering the cell the glucose builds up in the blood and pancreas pumps higher than normal amount of insulin in an attempt to nomalise the blood glucose level. Patient with insulin resistance develops: Actions Insulin Increase Decrease (Anabolic effects) (Catabolic effects) Carbohydrate Metabolism Glucose transport Gluconeogenesis (Muscle, adipose tissue) Glucose phosphorylation Glycogenolysis Glycogenesis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt Lipid Metabolism Tryglyceride synthesis Lypolysis Fatty acid synthesis (Liver) Lypoprotein lipase (Muscle) Lipoprotein lipase (adipose tissue activity) Ketogenesis Fatty acid oxidation (liver) Protein Metabolism Amino acid transport Protein degradation Protein synthesis Electrolysis Brain fogginess High blood sugar Intestinal bloating Sleepiness Increased triglyceride High blood pressure Increased cardio-vascular disease and increased pro-inflammatory cytokins. Depression Acanthosis nigricans Increased hunger The various causes and associated conditions of insulin resistance are as follows: 1.Diet 2.Obesity 3.Ageing 4.Genetics:In about 50% cases there occur genetic abnormalities of insulin receptor gene with genetic abnormalities of pro-insulin and insulin. 5.Type 2 diabetes 6.Medications: Cortcosteroid and ACTH especially in large doses. Besides these Thiazide diuretics and contraceptive pills have little effect on induction of diabetes. 7.Sedentary life style. 8.Hypertension 9.Dyslipidemia 10.After burns and other severe illness. However the condition is temporary. 11.Polycystic ovary syndrome 12.Hormone induced conditions: e.g. Acromegaly, Cushing syndrome, Pheochromocytoma, Glucagunoma etc. With regard to insulin resistance we must remember diabetes is the result of abnormal insulin function i.e. a defect at any point in the synthesis or functioning of insulin. This may occur in the pancreatic cells. If the insulin producing cells are absent or cannot synthesize or secrete proper insulin diabetes results. After releasing from the cell insulin must travel to receptor cell but it can be destroyed enroute by antibodies. Diabetes can also result from deficient or structurally abnormally receptors because after reaching target cell insulin must bind to receptor. Again when insulin binds to receptor cell membrane allows glucose to enter by facilitated transport and then glucose is either metabolized to generate energy or stored as glycogen as already stated. Defects in glucose uptake and utilization can also produce diabetes mellitus. Insulin resistance may be mainly due to anyone of the following causes: a) An abnormal insulin molecule b) An excessive amount of circulating antagonist c) Target tissue defects: specially seen in both obese and non-obese patients with NIDDM. So in insulin resistance there may occur receptor abnormalities - lipoatrophic diabetes, acanthosis nigricans, antibodies to insulin receptors, abnormalities of insulin receptor gene. Antibodies to specific proteins have been identified recently which includes antibodies to glutamic acid decarboxylase (GAD, the 64-k Da antigen), an even closer association is found in the presence of antibodies to tyrosin phosphatase (37-k Da, 1A-2). The presence in a non-diabetic person of 3 or more antibodies (Islets cell antibodies, antiGAD antibodies, anti1A-2 antibodies, anti-insulin antibodies) indicate an 88% chance of developing diabetes within 10 years. In NIDDM there are more than likely relationship between reduced insulin secretion and increased insulin resistance: It may be mentioned that obesity is the commonest cause of insulin resistance. In obese with distorted waist-hip ratio (Apple shaped android obesity with waist-hip ratio0.9 more prone to NIDDM than pear shaped gynoid obesity with waist-hip ratio 0.7) insulin resistance is perhaps because of down regulation of insulin receptors due to circulatory hyperinsulinaemia. Recent studies suggest that there is a relation between low birth weight and development of insulin resistance, NIDDM, coronary artery disease in middle age. Patients with insulin resistance are treated with exercise, weight loss, low carb-diet. Metformin and Thiazolidinediones improve their condition. (Reprint)