Typical disorders of metabolism

Pathophysiological pathways in carbohydrate metabolisms disorders

Navasardyan G.A. Professor of Pathophysiology department The faculty of Stomatology 2010 1

Plan of the lecture

1. 2. 3. 4.

General etiopathogenesis of metabolic disorders Disorders of carbohydrate metabolism Hyper-, hypoglycemic states Diabetes mellitus as a model of metabolic disorders

5.
6. 7. 8. 9.

Types of diabetes mellitus (DM)

DM type 1: etiopathogenesis. DM type 2: etiopahtogenesis. Manifestations and complications of DM. DM and impairment in oral cavity.
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General etiopathogenesis of metabolic disorders

1. Genetic disorders (enzymopathy)
impairment of intracellular regulation

2. Damage to membrane and intracellular receptors signal pathology 3. Impairment in endocrine (humoral) regulation
impairment in enzyme synthesis and activation
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General etiopathogenesis of metabolic disorders (contd)

4. Impairment of neural control a) Impairment of trophic function (via axoplasmic influence) b) emotional stress impairment of limbic-cortical regulation c) impairment in secretion of hypothalamic releasing hormones d) disorders of vegetative nervous system

5. Dietary and digestive disorders

6. Other organ disorders
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Typical disorders of carbohydrates

Memory check!

Blood Glucose & Hormones

Hormone Insulin Glucortocoids Glucagon Growth Hormone Epinephrine Action Glucose Glucose Glucose Glucose Glucose
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Memory Check!
Blood glucose homeostasis (balance) regulation
inhibition activation

Permeability

of

cellular membranes glucokinase reaction rate

synthesis of

Insulin

glycolytic enzymes
gluconeogenesis

Counter-insulin hormones (glucagon, adrenaline, thyroids, glucocorticoids growth hormone, ACTH)

glucose-6phosphate production
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Impairments of glucose balance

Normal glucose level in the blood

75 -110 mg/% 3.85 - 6.05 mmol/L

Hypoglycemia (less than 2.5 mmol/L results in coma) Hyperglycemia

3.85
Hypoglycemia

6.05
NORM
Hyperglycemia

GLUCOSE
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Hypoglycemia
Exogenous Endogenous

Functional

Exogenous hypoglycemia

Insulin injection Alcohol (develops 6-36 hours after heavy

consumption)

Some drugs (e.g. salicylates, pentamidine) Long term and intense physical exercise
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Endogenous hypoglycemia
insulinoma (hyperplasia of -cells) glycogenosis (glycogen storage disease) hereditary fructose intolerance

insufficiency in phosphoenolpyruvate carboxykinase hepatocellular insufficiency

Impaired absorption
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Functional Hypoglycemia (Dysfunction) 1. Alimentary (after gastrectomy, dumping syndrome)

2. Spontaneous reactive (cause is not known diarrhea, tachycardia, tremor, headache, weakness) 3. Alcohol promoted (consumption in hungry state)-drinking on an empty stomach 4. Endocrine insufficiency (decrease in counter-insulin hormone ) 5. Hepatic failure 6. Malnutrition (lack of body stores for protein, fat, carbohydrates) 7. Heavy physical load (without carbohydrate uptake) 8. Transient functional hypoglycemia of children (in infancy) Neonatal (10% of live births, during first 3 days of life) Maternal diabetes (caused by B-cell hyperplasia) Erythroblastosis fetalis (incompatibility between maternal 11

Manifestations of hypoglycemia Starvation Tremor Excessive sweating Tachycardia Headache, dizziness-term for describing various symptoms (faintness, giddiness, unsteadiness) Impaired vision Anxiety, fear Impaired cognition

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Hyperglycemia

1. Excessive carbohydrate (glucose) intake (may lead to obesity)

Causes of hyperglycemia (excessive glucose in the blood)

2. Insulin (diabetes mellitus)

3. Glucagon glycogenolysis and mobilization of fatty acids

4. Epinephrine
5.ACTH

Mechanisms:
A. release of corticosteroids liver gluconeogenesis & glycogenolysis

B. Inhibition of peripheral glucose utilization

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Hyperglycemia
Causes of hyperglycemia (excessive glucose in the blood)

6. Psychological stress, pain

7. Growth hormone

Free fatty acids and proteins gluconeogenesis

Inhibition of peripheral glucose utilization

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Manifestations of hyperglycemia
Glucosuria

Polyuria
Polydypsia Hypohydration of the organism

Arterial hypotension
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Diabetes mellitus
The term diabetes mellitus (DM, from going through and honey, sweet) is used to describe a syndrome characterized by chronic hyperglycemia and other disturbances of carbohydrate, fat, and protein metabolism.

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Diabetes Mellitus characteristics

Insulin insufficiency: absolute or relative
(characteristics)

Impairment in carbohydrate, lipid, protein metabolism Hyperglycemia

Non-enzymatic glycosylation
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Regulation of carbohydrate metabolism

Role of

1. I N S U LI N

1. Increase in permeability of myocyte and adipocyte membranes for glucose (Glut-4) 2. Increase in activity of glucokinase, glycogensythetase, aerobic glycolysis, pentose-phosphate shunt and Krebs cycle enzymes 3. Increased rate of glycogen synthesis in liver 4. Increase in synthesis of lipids from glucose 5. Inhibition of gluconeogenesis

All the mentioned mechanisms are impaired with insulin 18 deficiency in DM and cause hyperglycemia.

2. Counter-insulin hormones A CTH, growth hormone, cortisol, thyroid hormone, glucagon, adrenaline
1.Stimulate absorption of carbohydrates (cortisol, thyroid hormone) 2. Increase glycogenolysis in liver and muscles, inhibit glycogenesis ( adrenaline, cortisol, thyroid) 3. Inhibit hexokinase activity and therefore its utilization (cortisol, growth hormone) 4.Stimulate gluconeogenesis (cortisol, thyroid, glucagon) 5. Activate insulinase (growth hormone, thyroid)

Activation of these hormones in DM lead to hyperglycemia.

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Classification of diabetes mellitus

1. Type 1 diabetes (-cell destruction, usually leading to absolute insulin deficiency)

Immune-mediated
Idiopathic

2. Type 2 diabetes (combination of insulin resistance and -cell dysfunction)

3. Genetic defects of -cell function (MODY included here),

4. Genetic defects in insulin action (Type A insulin resistance) 5. Exocrine pancreatic defects
(Chronic pancreatitis, Pancreatectomy etc.)

6. Endocrinopathies (Acromegaly, Cushing syndrome, etc.)

7. Infections
(Cytomegalovirus, Coxsackie B virus Congenital rubella)

8. Drugs (Glucocorticoids, Thyroid hormone etc.)

9. Genetic syndromes associated with diabetes

10. Gestational diabetes mellitus

(e.g. Down syndrome)

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Classification of DM Most common are: 1: -cell defect or failure Juvenile, Insulin-dependent diabetes mellitus (IDDM)
Type Type

2: Insulin resistance with inadequate Insulin secretion-Adult onset diabetes mellitus Non insulin dependent diabetes mellitus (NIDDM)
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Pancreatic islet

The beta-cells of pancreas synthesize:

INSULIN
1. Preproinsulin 2. Proinsulin (A and B peptides connected by a C peptide) 3. Insulin (circulates freely in the plasma) Secretion of insulin is regulated by chemical and neural control.
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COMPARISON Type-1 DM Type-2

1. 2. 3. 4. 5.
6.

Frequency Age at onset Name Onset Complications

Presence of antibody

1.
2.

Less common Insulin- Dependent Weeks Acute Metabolic Yes

1. 3.

More common (90%)

< 30 Years (peak 11-13y.)2. >25 Years (peak 40-50y.)

3. 4. 5.

6.

Insulin Independent * 4. Months to years 5. Chronic Vascular 6. No Yes 8. Normal or high * 9. Normal / Exhaustion 10.60-80% in twins 11.No
7.
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7. 8.

9.
10. 11.

Hereditary Insulin levels Islets Concordance Association with HLA

No 8. Very low or no 9. Insulitis 10. 50% in twins 11. HLA-DR3, DR4

7.

Type 1 DM results from autoimmune destruction of -cells and is related to genetic susceptibility, autoimmunity and environmental factors. Autoimmunity is resulted by -cell antibodies and antibodies to insulin, glutamic acid decarboxylase that participate in damage of -cell. Clinical manifestations and mechanisms for DM-1: Hyperglycemia- see previous information. Polyuria - hyperglycemia acts as an osmotic diuretic. Glucosuria - the glucose filtration exceeds reabsorption by the renal tubules. Polydipsia - elevated blood sugar level is resulted in water loss (osmotically attraction) from body cells dehydration stimulation of thirst in hypothalamus. Polyphagia - depletion of cellular stores of carbohydrates, fats and proteins cellular starvation increase in hunger. Proteins and fats break down weight loss. Ketoacidosis is caused by increased metabolism of fats and proteins 26 ketones pH metabolic acidosis.

Type 1 DM

Type 1 diabetes mellitus

Autoimmune (type 1A) 90% Non-immune (type 1B, far less common than immune, 10%)

1.

Enviromental-genetic Factors trigger cellmediated destruction of -cells

Genetic-susceptibilty is strongest associated with MHC (hystocompatibility (HLA) leukocyte antigen) class II allels - HLA-DR)

2.

It occurs secondary to other diseases (such as pancreatitis or to a more fulminate disorder termed idiopathic (type 1B) DM)

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Pathophysiological pathways in DM-1

Genetic predisposition Environmental factors

Autoantigens on -cells
Circulate in blood stream and lymphatics

Presentation of autoantigen
Activation of Th1 lymphocytes
IFN-

Activation of Th2 lymphocytes

IL-2

Activation of macrophages with release of IL-1 and TNF

Activation of B lymphocytes production of autoantibodies

IL-12

Note! In DM-1 absolute deficiency of insulin.

Activation of T cytotoxic (CD8) specific cells

Destruction of -cells Decrease insulin secretion

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Genetic HLA-DR3/4

Pathogenesis of Type 1 DM
Environment Viral infe..? Autoimmune Insulitis Ab to cells/insulin

1. Drugs, chemicals (streptozotocin, alloxan, pentamidine) 2. Dietary (cow milk, high nitrosamine levels) 3. Viruses (Coxsackie, measles, rubella, cytomegalovirus) (molecular mymicry)

Activation of cytotoxic T-cells

cell Destruction
Insulin deficiency

Type 1 / IDDM

By lymphocytes islet cell autoantibodies and/or autoantibodies to insulin, glutamic acid decarboxylase (GAD) and tyrosine 29 - phosphatase.

Type 2 DM
Type 2 DM results from a combination of genetic and environmental factors: Genetic involves genes that influence cellular responses to insulin or -cell function, or both. Decreased -cell responsiveness to plasma glucose levels. Islet dysfunction due to decrease in -cell mass and abnormal function, amyloid deposits cell destruction.

The other mechanisms and key terms

Fat adipose tissue is active physiological system! Adipokines are hormones produced in adipose tissue
a)

Glossary

b)
c)

Leptin decrease insulin sensitivity Resistin Adiponectin Amylin-is a hormone co-secreted with insulin by the -cells, inhibits glucagon secretion (deficiency of amylin in type 1, type 2 DM). Incretins-are a class of peptides released from the gastrointestinal tract in response to food intake, bind to receptors on -cells and increase secretion of insulin in response to glucose level. Ghrelin-is a peptide produced in the stomach and pancreatic islets that stimulates GH receptors. Decreased level of ghrelin is associated with insulin resistance. Fatty acids increase in DM attenuates insulin signaling. 31

Obesity

Insulin resistance

Diabetes

Type 2 DM
How obesity is related with DM-2?
Obesity
lipid accumulation in islets. excess fat in muscle insulin resistance. fat infiltration in the liver

-cells

are sensitive to high levels of glucose and free fatty acids and undergo apoptosis. Cytokines (TNF, IL-1) also are toxic to -cells. Amylin is decreased.
Down

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regulation of insulin receptors. Postreceptor insulin signaling is impaired. Disrupt insulin signaling insulin resistance hyperinsulinemia.

Pathogenesis of Type 2 DM
Genetic / cell defect Obesity / Life style ? Abnor. Secretion Insulin Resistance

Note! In type 2 DM combination of insulin resistance and -cell dysfunction relative insulin deficiency.

IDDM

Relative Insulin Def. Type 2 NIDDM

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cell exhaustion

Pathogenesis of Type 2 DM
Genetic predisposition
activity of genes that code amylin

Obesity

Diet, physical inactivity

insulin receptor density - down regulation

adipokines, free fatty acids, -cell mass inflamm. cytokines (TNF-, IL-1), and function ghrelin activity activity of
incretins

toxic to cell apoptosis

Insulin resistance Demand for insulin synthesis

Hyperinsulinemia

Hypoinsulinemia Glucagon (antagonist)tissue

effects and hyperglycemia (type 2 DM) Tissue effects without hyperglycemia (insulin resistance without diabetes)
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MAIN IMPAIRMENT IN DM
HYPERGLYCEMIA
(mechanisms - see effects of insulin) Hyperglycemia is a main underlying characteristic for all metabolic disorders and damage of multiple organs in DM.
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PATHOGENESIS OF DIABETES MELLITUS AND MANIFESTATIONS

Insulin insufficiency
Fatty acids

Ketone bodies
- hydroxybutirate, acetoacetate accumulation in blood
Metabolic acidosis

Blood glucose level

glucosuria polyuri a dehydration Poly thirst dipsia

Hypovolemia
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Ketonuria

Kussmaul's respiration

CNS depression
SHOCK

PATHOGENESIS OF DIABETES MELLITUS (contd)

Stress hormones
Catecholamines, cortisol, growth hormone, glucagon Hyperglycemia

Diuresis polyuria Hyperosmolarity Thirst

Polydipsy

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Complications of diabetes mellitus

I. Acute:

Coma

Keto-acidotic
Hyperosmolar, Hyperglycemic

Lactate-acidotic

Hypoglycemia (insulin shock )

II. Late (chronic) complications

1) Microangiopathy

Retinopathy Nephropathy Other forms of microangiopathy

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2) Macroangiopathy

Macroangiopathy
Macroangiopathy - result of atherosclerotic

damage to great vessels

The mechanisms include the following:

a) Growth hormone smooth muscle

proliferation

b) Thromboxane A2 mitogenic effect

c) Increase in low and very low lipoproteins
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Chronic complications of diabetes mellitus

Microvascular (retinopathy and nephropathy) Macrovascular (Coronary artery disease, stroke, peripheral artery disease) Infection

Neuropathies

Are associated with hyperglycemia due to three metabolic events: non enzymatic glucosylation, polyol pathway and protein kinase C activation.
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Other specific types of diabetes include:

Genetic defects in -cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemical-induced -cell dysfunction Infections Other uncommon autoimmune and inherited disorders The most well-described of these DM is termed maturityonset diabetes of youth (MODY) include 6 specific 42 autosomal dominant mutations.

Diabetes mellitus and disorders in oral cavity.

Individuals with diabetes are at risk for a variety of infections related to sensory impairment, vascular complications, impaired white blood cells, and suppressed immunity, rapid proliferation of pathogens, and delayed wound healing. All these cause destruction of parodentium and inflammation periodontitis and other disorders.
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Chronic Polyneuropathy
Claw foot Dermopathy & Neuropathy

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Diabetic Neuropathic ulcer

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Neuropathic ulcer
Etiology: peripheral sensory neuropathy, Trauma & deformity. Factors: Ischemia, callus formation, and edema.

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Typical tests 1. Choose the exogenous cause of hypoglycemia 1) Glycogenosis 2) Hyperplasia of -sells 3) High doses of insulin 4) Defficiency of phosphoenolpyruvatee carboxy-kynase 2. Hypoglycemia is a characteristic finding in: a) gastrinoma, b) insulinoma, c) glucagonoma, d) VIPoma. 3. The following statements are true concerning insulin-dependent diabetes, EXCEPT: a) there is association with HLA-DR3, HLA-DR4, b) there is autoimmune disease association, c) there is more than 90% concordance for monozygotic twins to develop diabetes d) viral infection may precede type I diabetes. 47

4. The following are correct statements for type II diabetes, EXCEPT: a) It is more than common than IDDM, b) These patients are generally obese. c) Insulin resistance plays an important role. d) There is presence of insulitis. 5. The following complication is almost exclusive for type I diabetes (IDDM): a) hyperosmolar coma, b) atherosclerosis, c) diabetic ketoacidosis, d) diabetic nephropathy. 6. The most reliable assessment of diabetes is provided by the following investigation. a) whole blood glucose estimation, b) plasma glucose estimation, c) capillary method of glucose estimation, d) glycosylated hemoglobin.
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7. Which of the following is not an acute complication of diabetes: 1) hypoglycemic coma, 2) ketoacidotic coma, 3) hyperglycemic coma, 4) retinopathy. 8. Choose the chronic (late) complications of diabetes: a) neuropathy, b) nephropathy c) hypoglycemic coma, d) atherosclerosis, e) hyperosmolar coma. Choose the correct answer: 1-a,b,d 2-a,d,e 3-c,d,e

4-a,b

9. Which statement is the most correct: 1) Diabetes mellitus is a chronic systemic disease which is characterized by hyperglycemia. 2) Diabetes mellitus is a hyperglycemic state is caused by an autoimmune reaction triggered by an infection. 3) Diabetes mellitus is a chronic systemic disease which is characterized by insulin deficiency or peripheral resistance, resulting in hyperglycemia, disorders of 49 carbohydrates, protein, lipid metabolism.

10. Choose the typical presentations of type I diabetes mellitus: a) polydipsia, polyuria and polyphagia, b) dehydration, c) obesity, d) hyperosmolar coma, e) metabolic ketoacidosis. Choose the correct answer: 1-a,b,c 2-a,d,e 3-a,b,e 4-a,d,c 11. All of the following are characteristics of type II diabetes mellitus (DM),EXCEPT: 1) Represents 90% of causes DM, 2) Affects obese adults usually older than 30 years, 3) Relative insulin insufficiency, 4) Metabolic ketoacidosis, 5) Hyperglycemia. 12. Which of the following disorders in oral cavity is associated with DM? a) Delayed wound healing b) Destruction of parodentium c) Activation of infections d) All of the above.

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ADDITIONAL SLIDES

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Lack of insulin and increase of glucagon

Pathogenesis of type 1 DM Pancreatic -cell destruction

Decrease glucose utilization

Adipose tissue

Liver

Muscle

Lypolysis Ketogenesis Glucogen Synthesis FFA Gluconeogenesis Glycerol Protein catabolism Hyperglycemia LDL cholesterol Aminoacids Glucosuria HDL Ketoacidosis Muscle wasting Osmotic diures Loss of water and electrolytes Hypovolemia
Hyperventilation

Hypotension

Death

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Pathophysiology of Type 2 DM
central obesity
Genetic predisposition Diet, physical inactivity

Pancreatic -cell Apoptosis and Insulin

Adipose tissue Abnormal lipid synthesis LDL-cholesterol HDL Dislipidemia and atherogenesis Liver Lypolysis Adipokinses HyperinFFA sulinism Muscle Insulin resistance

Hyperglycemia Fatigue Glucosuria Osmotic diuresis

Cardiovascular disease

Hypovolemia and dehydratation Hypotension Death 53

PATHOGENESIS OF HYPERGLYCEMIC COMA

Insulin deficiency
Decreased glucose utilization Increased glucose production Hyperglycemia Glucosuria Osmotic diuresis

Hyperosmolarity and dehydration DIC syndrome COMA

DEATH

SHOCK

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IMPAIRMENT OF LIPID METABOLISM IN DIABETES MELLITUS Insulin deficiency

Decreased glucose utilization Decreased lipogenesis Mobilization of fats to depots

Hyperlipidemia
Metabolic acidosis Ketonemia and hypercholesterolem ia Keto-acidotic coma Increased ketogenesis and cholesterol productoin Ketonuria Loss of Na+
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IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES MELLITUS Insulin deficiency

Decreased glucose utilization Increase in proteolysis Aminoacidemia, increased uptake of aminoacids by the liver 1. Activation of gluconeogenesis 2. Increased removal of nitrogen via urea Loss of potassium and other ions by the cells Dehydration of Potassium loss the cells by the organism

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Whats New

Metabolic syndrome

The metabolic syndrome also has been called the Insulin resistance syndrome or syndrome X. It is a clustering of clinical traits occurring together that increase the risk for accelerated cardiovascular disease and type 2 DM. Metabolic syndrome was recently defined by the National Cholesterol Education Programs Adult Treatment Panel III as the identification of three of the following five traits: Increase waist circumference (>40 inches, > 35 woman) Plasma triglycerides >15mg/dl Plasma HDL cholesterol <40mg/dl , <50 mg/dl Blood pressure > 130/85 mm Hg Fasting plasma glucose > 100mg/dl
The syndrome is associated with insulin resistance and behaviorally modifiable risk factors, such as smoking, exercise and diet.
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hyperglycemia A) Non enzymatic glucosylation

Non enzymatic glucosylation
is the reversible attachment of glucose to proteins, lipids and nucleic acids without the action of enzymes.
With recurrent (persistent) hyperglycemia glucose becomes irreversibly bound to collagen and other proteins in RBCs, blood vessel walls and interstitial tissue leading to formation of Advanced Glucosylation End (AGE) products and tissue injury. 58

Non-Enzymatic glycosylation
Irreversible Advanced Glycosylation End products (AGE) formation. Non-enzymatic glycosylation is the reversible attachment of glucose to protein, lipid, nucleic acids, Hb, collagen, long life span proteins, without action of enzymes damage to interstitial space, vessels a) Basal membranes thickening b) Binding of different cell receptors (such as macrophages) c) Immune complex formation d) Increased production of endothelins, cytokines vasoconstriction, thrombosis e) Induction of oxidative stress (free radicals) f) Inactivation of NO (loss of vasodilation) g) Procoagulant changes on endothelial cells. 59
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hyperglycemia
B) Polyol pathway (alternate metabolic pathway of glucose)
Glucose is shunted and converted to sorbitol (a polyol) by aldose reductase and to fructose (by sorbitol dehydrogenase).
Accumulation of sorbitol and fructose Increase in intracellular osmotic pressure Water influx and swelling, cell injury

Usually develops in the eye lens, nerves, Shwann cells

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hyperglycemia
C) Protein kinase C (PKC) pathway activation
PKC is a family of different intercellular signaling proteins.

Consequences:
Insulin resistance
Production of extracellular matrix and cytokines Vascular cell proliferation Enhanced contractility Increased permeability

macro-, microneurological complacations61