diabetes mellitus part-1

Diabetes Mellitus

Biochemistry for medics www.namrata.co

(Part-1)

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Contents

• General Introduction• Classification• Gross differences between Type 1 and Type 2

Diabetes Mellitus• Etiology and pathophysiology• Genetic considerations• Metabolic alterations

10/30/2013 2Biochemistry for medics

Diabetes mellitus

Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or a combination of insulin resistance and inadequate insulin secretion to compensate.


Classification of Diabetes MellitusDM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy .The two broad categories of DM are designated type 1 and type 2. Both types of diabetes are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progresses.


Diabetes MellitusThe terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia. Age is not a criterion in the classification system. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.


Etiological Classification of Diabetes MellitusI. Type 1 diabetes (β-cell

destruction, usually leading to absolute insulin deficiency)

A. Immune-mediatedB. IdiopathicII. Type 2 diabetes (may range from

predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance)


Etiological Classification of Diabetes Mellitus (contd.)

III. Other specific types of diabetesA. Genetic defects of β cell function (MODY 1-6)B. Genetic defects in insulin action

(Characterized by Insulin resistance)C. Diseases of the exocrine pancreaso Pancreatitiso Pancreatectomyo Neoplasiao Cystic fibrosiso Hemochromatosiso Fibrocalculous pancreatopathy


Etiological Classification of Diabetes Mellitus (contd.)

F. Infectionso Congenital rubellao Cytomegaloviruso CoxsackieG. Uncommon forms of immune-mediated diabeteso “Stiff-person" syndromeo Anti-insulin receptor antibodies H. Other genetic syndromes sometimes associated with diabeteso Down's syndromeo Klinefelter's syndromeo Turner's syndrome, o Laurence-Moon-Biedl syndromeo PorphyriaIV. Gestational diabetes mellitus (GDM)

[MODY, maturity onset of diabetes of the young].Source: Adapted from American Diabetes Association, 2007.


Gross differences between Type 1 and Type 2 Diabetes mellitusS.N. Feature Type 1 DM Type 2 DM

1 Previous names Insulin Dependent diabetes mellitus(IDDM) , also called Juvenile onset DM

Non insulin dependent Diabetes mellitus (NIDDM), also called Maturity onset diabetes mellitus

2. Age of Onset Usually during childhood or puberty (Exception- LADA- Latent auto immune Diabetes mellitus of adults )

Frequently after the age of 35( Exceptions- can be observed in children and adolescents , MODY- Maturity onset diabetes of young )

3. Pattern of onset Abrupt- Symptoms develop rapidly

Slow – Symptoms appear gradually


Gross differences between Type 1 and Type 2 Diabetes mellitus (contd.)

S.N. Feature Type 1 DM Type 2 DM

4. Prevalence 10% of the diagnosed cases

90 % of the diagnosed cases

5. Genetic predisposition

Moderate Very strong

6. Nutritional state at the time of onset

Undernourished Mostly obese

7. Biochemical defect Auto immune destruction of β cells in 90 % of the cases, in remaining 10% cause is not known. Thus there is impaired production of insulin

Insulin resistance combined with inability of β cells to produce appropriate amount of insulin

8. Plasma insulin Low to absent High in the early stage, low in the disease of long duration10/30/2013 10Biochemistry for medics

Gross differences between Type 1 and Type 2 Diabetes mellitus (contd.)

S.N. Feature Type 1 DM Type 2 DM

9. Acute Complications Hypoglycemia and ketoacidosis

Hyperosmolar non ketotic coma

10. Frequency of ketosis Very common Rare

11. Treatment Insulin is always needed, oral hypoglycemic drugs are ineffective.

Diet, exercise, oral hypoglycemic drugs and insulin in severe cases


Etiology of Type 1 DiabetesThis form of diabetes is immune-mediated in over 90% of

cases and idiopathic in less than 10%. Immune-mediated o The rate of pancreatic B cell destruction is quite variable,

being rapid in some individuals and slow in others.o Approximately one-third of the disease susceptibility in

immune mediated type is due to genes and two-thirds to environmental factors.

Idiopathic o Less than 10% of subjects have no evidence of pancreatic

B cell autoimmunity to explain their insulinopenia and ketoacidosis.

o This subgroup has been classified as "idiopathic type 1 diabetes" and designated as "type 1B."

o Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin.


Pathophysiology of Type 1 Diabeteso Auto Immune destruction Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). o After all beta cells are destroyed, the inflammatory process abates, the islets become atrophicoThe autoimmune destruction of pancreatic β-cells leads to a deficiency of insulin secretion. oIt is this loss of insulin secretion that leads to the metabolic derangements associated with IDDM.


Pathophysiology of Type 1 Diabetes Mellitus (contd.)

oIn addition to the loss of insulin secretion, the function of pancreatic α-cells is also abnormal. oThere is excessive secretion of glucagon in IDDM patients. Normally, hyperglycemia leads to reduced glucagon secretion. oHowever, in patients with IDDM, glucagon secretion is not suppressed by hyperglycemia. oThe resultant inappropriately elevated glucagon levels exacerbate the metabolic defects due to insulin deficiency .


Genetic considerations in Type 1 DMo Children of diabetic parents are at increased lifetime risk for developing type 1 diabetes. o A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child's father has it. oThe risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic parent.o If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%oThe highest risk is for identical twins, where the concordance rate is 25–50%.


Type 1 Diabetes Mellitus- An Overview of Etiology


Etiology of Type 2 Diabetes MellitusType 2 Diabetes mellitus (formerly called non - insulin - dependent diabetes mellitus (NIDDM) or adult - onset diabetes mellitus) is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity (insulin resistance).Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss.The disease is polygenic and multifactorial since in addition to genetic susceptibility, environmental factors (such as obesity, nutrition, and physical activity) modulate the phenotype.The mechanisms by which these genetic alterations increase the susceptibility to type 2 diabetes are not clear.


Pathophysiology of Type 2 Diabetes Mellitus• Type 2 DM is characterized by impaired insulin secretion,

insulin resistance, excessive hepatic glucose production, and abnormal fat metabolism.

• In the early stages of the disorder, glucose tolerance remains near-normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output .

• As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemia state.

• IGT, characterized by elevations in postprandial glucose, then develops.

• A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia.

• Ultimately, beta cell failure may ensue.


Pathophysiology of Type 2 DM


Insulin resistanceoInsulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. oInsulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis.oInsulin resistance results from inherited and acquired influences.


Causes of Insulin resistance• Pre receptor

– Abnormal insulin (mutations)– Anti-insulin antibodies

• Receptor– Decreased number of receptors (mainly, failure to activate tyrosine

kinase)– Reduced binding of insulin– Insulin receptor mutations– Insulin receptor – blocking antibodies

• Postreceptor– Defective signal transduction– Mutations of GLUT4 (In theory, these mutations could cause insulin

resistance, but polymorphisms in the GLUT4 gene are rare.)


Causes of Insulin resistance(contd.)

• Combinations of defects Obesity is associated mainly with post receptor abnormality and is also associated with a decreased number of insulin receptors. Obesity is the most common cause of insulin resistance.

• Aging - This may cause insulin resistance through a decreased production of GLUT-4 transporters


Causes of Insulin resistance (contd.)Increased production of insulin antagonists - A number of disorders are associated with increased production of insulin antagonists, such as -oCushing syndromeoAcromegalyoStress states, such as trauma, surgery, diabetes ketoacidosis, severe infection, uremia, and liver cirrhosis.


Causes of Insulin resistance (contd.)•Medications include glucocorticoids (Cushing syndrome), cyclosporine, niacin, and protease inhibitors.•Human immunodeficiency virus (HIV)- Protease inhibitor – associated lipodystrophy is a recognized entity.

Nucleoside analogues have also been implicated in the development of insulin resistance.


Causes of Insulin resistance(contd.)

Insulin treatmentoLow titer IgG anti-insulin antibody levels are present in most patients who receive insulin. oEnhanced destruction of insulin at the site of subcutaneous injection has also been implicated.Other conditions that are categorized as receptor or post

receptor insulin-resistant stateo Leprechaunismo Lipodystrophic stateso Ataxia-telangiectasiao Werner syndrome


Risk factors for type 2 Diabetes mellitus• Family history of diabetes (i.e., parent or sibling with type 2

diabetes) • Obesity (BMI >25 kg/m2) • Habitual physical inactivity • Race/ethnicity (e.g., African American, Latino, Native American,

Asian American, Pacific Islander) • Previously identified IFG or IGT • History of GDM or delivery of baby >4 kg (>9 lb) • Hypertension (blood pressure >140/90 mmHg) • HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a

triglyceride level >250 mg/dL (2.82 mmol/L) • Polycystic ovary syndrome or acanthosis nigricans • History of vascular disease


Obesity and Type 2 Diabetes Mellitus

•The increased adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products •The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver. •For example, free fatty acids impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair beta cell function.


Obesity and Type 2 Diabetes Mellitus (contd.)• Adipocytes secrete a number of biologic products

(nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-α, resistin, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity.

• The production by adipocytes of adiponectin, an insulin-sensitizing peptide, is reduced in obesity and this may contribute to hepatic insulin resistance.

• Adipocyte products and adipokines also produce an inflammatory state and may explain why markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 DM.


Genetic considerations in Type 2 DM• Genetic and environmental factors combine to cause both

the insulin resistance and the beta cell loss. • In monozygotic twins over 40 years of age, concordance

develops in over 70% of cases within a year whenever type 2 diabetes develops in one twin.

• Individuals with a parent with type 2 DM have an increased risk of diabetes; if both parents have type 2 DM, the risk approaches 40%.

• The disease is polygenic and multifactorial since in addition to genetic susceptibility, environmental factors (such as obesity, nutrition, and physical activity) modulate the phenotype.

• The mechanisms by which genetic alterations increase the susceptibility to type 2 diabetes are not clear. 10/30/2013 29Biochemistry for medics

Metabolic alterations in Diabetes Mellitus

A) Glucose metabolism- Increased hepatic output and decreased glucose utilizationo Peripheral uptake- Reduced uptake of glucose in skeletal muscle, cardiac muscle and adipose tissue (GLUT- 4 receptors are insulin dependent)oGlycolysis Reduced rate of phosphorylation in liver cells (Glucokinase is insulin dependent)Glycolytic enzymes are covalently modified by glucagon mediated c AMP cascade.Reduced availability of Fr 2,6 bisphosphate, reduced activity of PFK-1Reduced rate of glycolysis


Glucose metabolism in diabetes mellitus (contd.)

Gluconeogenesis- Increased rate of gluconeogenesis due to -o Increased availability of substrateso Increased activity and concentration of enzymes of pathway

of gluconeogenesis under the effect of glucagonGlycogen Metabolism- Enzyme activities are altered by

glucagon triggered phosphorylation cascadeGlycogenesis- Inhibited due to reduced activity of glycogen

synthase (Phosphorylated form is inactive form)Glycogenolysis- Stimulated due to increased activity of

phosphorylase (Phosphorylated form is active form)


TCA cycle- suppressed due to non availability of oxaloacetate as it is channeled towards glucose productionHMP Pathway- Suppressed due to reduced activity of glucose-6-P dehydrogenase enzyme as that is under the influence of insulin.Net effect-The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels.

Glucose metabolism in diabetes mellitus (contd.)


Implications of altered carbohydrate metabolism• The net effect of altered carbohydrate metabolism is

hyperglycemia• When the capacity of the kidneys to absorb glucose is

surpassed, Glycosuria ensues. • Glucose is an osmotic diuretic and an increase in renal

loss of glucose is accompanied by loss of water and electrolytes, termed polyuria.

• The result of the loss of water (and overall volume) leads to the activation of the thirst mechanism (polydipsia).

• The negative caloric balance which results from the glucosuria and tissue catabolism leads to an increase in appetite and food intake (polyphagia).


Lipid metabolism in Diabetes MellitusA) Adipolysis•There is a rapid mobilization of triglycerides from adipose tissue leading to increased levels of plasma free fatty acids. •The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. •Free fatty acids are also taken up by the liver.


Lipid metabolism in Diabetes Mellitus (contd.)

B) Fatty acid oxidation- IncreasedBiochemical Basiso Normally, the levels of malonyl-CoA are high in the presence of insulin. oThese high levels of malonyl-CoA inhibit carnitine palmitoyl Transferase I, the enzyme required for the transport of fatty acyl-Co A's into the mitochondria where they are subject to oxidation for energy production. oThus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-Co A's into the mitochondria increases. oMitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle.


Lipid metabolism in Diabetes Mellitus (contd.)Implication of high rate of fatty acid oxidation1) KetosisoIn hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetone, Acetoacetate and β-hydroxybutyrate. oThese ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle.o In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. oProduction of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. oIn diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.10/30/2013 36Biochemistry for medics

Lipid metabolism in Diabetes Mellitus (contd.)Implication of high rate of fatty acid oxidation

2) Hypercholesterolemia- Excess Acetyl co A, the end product of fatty acid oxidation can enter the pathway of Cholesterol biosynthesis causing hypercholesterolemia, increasing the risk for atherosclerosis.


Lipid metabolism in Diabetes Mellitus (contd.) Serum Triglyceride levels o Normally, plasma triglycerides are acted upon

by lipoprotein lipase (LPL), an enzyme on the surface of the endothelial cells lining the vessels.

o In particular, LPL activity allows fatty acids to be taken from circulating triglycerides for storage in adipocytes.

o The activity of LPL requires insulin and in its absence a hypertriglyceridemia results.10/30/2013 38Biochemistry for medics

Lipid metabolism in Diabetes Mellitus (contd.)Net effect- Dyslipidemia (Atherogenic profile)oIncreased level of circulating free fatty acidsoKetoacidosisoHypercholesterolemiaoHypertriglyceridemiaoVLDL c and LDLC HighoHDLc low (Inverse relation with triglycerides)


Protein metabolism in Diabetes Mellitus• Insulin regulates the synthesis of many genes, either

positively or negatively that then affect overall metabolism.

• Insulin has a global effect on protein metabolism, increasing the rate of protein synthesis and decreasing the rate of protein degradation.

• Thus, insulin deficiency will lead to increased catabolism of protein.


Protein metabolism in Diabetes Mellitus (Net effect)

• The increased rate of proteolysis leads to elevated concentrations in plasma amino acids.

• These amino acids serve as precursors for hepatic and renal gluconeogenesis.

• In liver, the increased gluconeogenesis further contributes to the hyperglycemia seen in IDDM.


Advanced Glycosylation End Products

o Increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra- and extra cellular proteins. oNonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. o AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure. oThe serum level of AGEs correlates with the level of glycemia, and these products accumulate as glomerular filtration rate declines.10/30/2013 42Biochemistry for medics

Glycated hemoglobin (HbA1C)• Hemoglobin becomes glycated by ketoamine reactions between

glucose and other sugars and the free amino groups on the alpha and beta chains.

• Only glycation of the N-terminal valine of the beta chain imparts sufficient negative charge to the hemoglobin molecule to allow separation by charge dependent techniques.

• These charge separated hemoglobin are collectively referred to as hemoglobin A1 (HbA1).

• The major form of HbA1 is hemoglobin A1c (HbA1c) where glucose is the carbohydrate. HbA1c comprises 4–6% of total hemoglobin A1.

• The remaining HbA1 species contain fructose-1, 6 bisphosphate (HbA1a1); glucose-6-phosphate (HbA1a2); and unknown carbohydrate moiety (HbA1b).

• The hemoglobin A1c fraction is abnormally elevated in diabetic persons with chronic hyperglycemia.


Sorbitol Pathway

• Hyperglycemia increases glucose metabolism via the Sorbitol pathway.

• Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase.

• Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.

• Diabetic cataract is the result of osmolysis by sorbitol accumulation10/30/2013 44Biochemistry for medics

Water and Electrolyte imbalance in Diabetes mellitus

• Dehydration is a frequent finding , Polyuria is responsible for dehydration.

• Hypokalemia- total body K is low, but there be false hyperkalemia due to non functioning of Sodium Potassium ATPase pump. Caution is needed during Insulin administration.


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