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Pathophysiology of carbohydrates and proteins metabolism

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By M.D., PhD, Marta R. Gerasymchuk Pathophysiology department, Ivano-Frankivsk National Medical University

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Page 1: Pathophysiology of carbohydrates and proteins metabolism
Page 2: Pathophysiology of carbohydrates and proteins metabolism

1. Regulation of protein metabolism.2. Starvation.3. Kwashiorkor.4. Marasmus.5. Regulation of glucose metabolism.6. Diabetus mellitus.7. Types of diabetus mellitus.8. Complications of diabetus mellitus.

Page 3: Pathophysiology of carbohydrates and proteins metabolism

• Disorders related to malnutritionmalnutrition, while potentially preventable, produce moderate to severe disabilities.

• Nearly 800 million people in the world do not have enough to eat, most of them living in developing countries. In these regions, inadequate amounts of food (causing conditions such as child malnutrition and retarded growth) and inadequate diversity of food (causing micronutrient deficiencies) continue to be priority health problems.

• MalnutritionMalnutrition increases the risk of disease and early death and affects all age groups, but it is especially common among poor people and those with inadequate access to health education, clean water, and sanitation.

• Diabetes mellitus Diabetes mellitus is a disease resulting from absolute or relative insulin insufficiency and accompanying by disturbance of metabolism mainly, carbohydrate one.

• The main manifestation of diabetes mellitus is hyperglycemia, sometimes reaching 25 mrnol/1, glucosuria with glucose in urine up to 555-666 mmol/1 (100-200 g/day), polyuria (to 10-12 L of urine per day), polyphagia and

polydipsia.

Page 4: Pathophysiology of carbohydrates and proteins metabolism

ProteinsProteins from the diet must be from the diet must be broken into amino acidsbroken into amino acids to be absorbed. to be absorbed. Protein digestion begins in the stomach Protein digestion begins in the stomach with the action of with the action of pepsinpepsin. . PepsinogenPepsinogen, the enzyme precursor of pepsin, is secreted , the enzyme precursor of pepsin, is secreted by the chief cells by the chief cells in response to a meal and acid pH.in response to a meal and acid pH.

Acid in the stomach Acid in the stomach is required for the conversion of is required for the conversion of pepsinogen to pepsinpepsinogen to pepsin. . Pepsin is inactivated Pepsin is inactivated when it enters the intestine by the when it enters the intestine by the alkaline pHalkaline pH..

Proteins are broken down further by pancreatic enzymes, such as trypsin, Proteins are broken down further by pancreatic enzymes, such as trypsin, chymotrypsin, carboxypeptidase, and elastase.chymotrypsin, carboxypeptidase, and elastase.

As with pepsin, the pancreatic enzymes are secreted as precursor As with pepsin, the pancreatic enzymes are secreted as precursor molecules. Trypsinogen, which lacks enzymatic activity, is activated by an molecules. Trypsinogen, which lacks enzymatic activity, is activated by an enzyme located on the brush border cells of the duodenal enterocytes. enzyme located on the brush border cells of the duodenal enterocytes. Activated trypsin activates additional trypsinogen molecules and other Activated trypsin activates additional trypsinogen molecules and other pancreatic precursor proteolytic enzymes. pancreatic precursor proteolytic enzymes.

The amino acids are liberated intramurally or on the surface of the villi by The amino acids are liberated intramurally or on the surface of the villi by brush border enzymes that degrade proteins into peptides that are one, two, brush border enzymes that degrade proteins into peptides that are one, two, or three amino acids long. Similar to glucose, many amino acids are or three amino acids long. Similar to glucose, many amino acids are transported across the mucosal membrane in a sodium-linked process that transported across the mucosal membrane in a sodium-linked process that uses the Na+/K+- ATPase pump as an energy source.uses the Na+/K+- ATPase pump as an energy source.

Page 5: Pathophysiology of carbohydrates and proteins metabolism

Starvation Starvation is a state of overall is a state of overall deprivation of nutrients. Its causes may deprivation of nutrients. Its causes may be the following:be the following:

I) deliberate fastingI) deliberate fasting—religious or political;—religious or political; II) famine conditions in a country or II) famine conditions in a country or

communitycommunity; ; III) secondary undernutrition III) secondary undernutrition such as due such as due

to chronic wasting diseases (infections, to chronic wasting diseases (infections, inflammatory conditions, liver disease), inflammatory conditions, liver disease), cancer etc. cancer etc.

Cancer Cancer results in malignant results in malignant cachexiacachexia as as a result of which cytokines are a result of which cytokines are elaborated e.g. elaborated e.g. tumour necrosis factor-tumour necrosis factor-α, α, elastases, proteases etcelastases, proteases etc..

A starved individual has lax, dry skin, A starved individual has lax, dry skin, wasted muscles and atrophy of internal wasted muscles and atrophy of internal organs.organs.

Page 6: Pathophysiology of carbohydrates and proteins metabolism

Anorexia nervosaAnorexia nervosa 1. Pathogenesis1. Pathogenesis a. Self-induced starvation leading to PEM b. Distorted body image 2. Clinical findings:2. Clinical findings: a. Secondary amenorrhea 1) Decreased gonadotropin-releasing hormone • Caused by excessive loss of body fat and weight 2) Decreased serum gonadotropins produces

hypoestrinism. b. Osteoporosis 1) Caused by hypoestrinism • Estrogen normally enhances osteoblastic activity and

inhibits osteoclastic activity, 2) Lack of estrogen leads to decreased osteoblastic

activity and increased osteoclastic activity. c. Increased lanugo (fine, downy hair) d. Increased hormones associated with stress (e.g.,

cortisol, growth hormone) e. Most common cause of death is ventricular arrhythmia

French model French model and actress and actress

Isabelle Caro Isabelle Caro

Isabelle Caro Isabelle Caro

Page 7: Pathophysiology of carbohydrates and proteins metabolism

Ex-model Frail Jeremy Frail Jeremy GillitzerGillitzer has suffered from anorexia for 25 years.

He now weighes only 41.275 kg

Page 8: Pathophysiology of carbohydrates and proteins metabolism

Bulimia nervosaBulimia nervosa1. Pathogenesis• Bingeing with self-induced vomiting2. Clinical findings:2. Clinical findings:a. Complications of vomiting1) Acid injury to tooth enamel2) Hypokalemia and metabolic

alkalosisb. Ventricular arrhythmia is the

must common cause of death.

Page 9: Pathophysiology of carbohydrates and proteins metabolism

PROTEIN-ENERGY MALNUTRITIONPROTEIN-ENERGY MALNUTRITION The The inadequate consumption of protein and energy inadequate consumption of protein and energy as a as a

result of primary dietary deficiency or conditioned deficiency result of primary dietary deficiency or conditioned deficiency may cause loss of body mass and adipose tissuemay cause loss of body mass and adipose tissue, resulting , resulting in in protein energy or protein calorie malnutrition (PEM protein energy or protein calorie malnutrition (PEM or PCM).or PCM).

The primary deficiency is more frequent due to The primary deficiency is more frequent due to socioeconomic factors limiting the quantity and quality of socioeconomic factors limiting the quantity and quality of dietary intake, particularly prevalent in the developing dietary intake, particularly prevalent in the developing countries of Africa, Asia and South Americacountries of Africa, Asia and South America. The impact . The impact of of deficiency is marked in infants and childrendeficiency is marked in infants and children..

Page 10: Pathophysiology of carbohydrates and proteins metabolism

The spectrum of The spectrum of clinical syndromes produced as a result clinical syndromes produced as a result of PEM of PEM includes the followingincludes the following::

1. 1. KwashiorkorKwashiorkor which is related to protein deficiency though which is related to protein deficiency though calorie calorie intake may be sufficient.intake may be sufficient.

2. 2. MarasmusMarasmus is starvation in infants occurring due to overall is starvation in infants occurring due to overall lack of lack of calories.calories.

However, it must be remembered that mixed However, it must be remembered that mixed forms of forms of kwashiorkor-marasmuskwashiorkor-marasmus syndrome syndrome may also occur. may also occur. Marasmic Marasmic kwashiorkor (edematous, severe childhood malnutrition) is a kwashiorkor (edematous, severe childhood malnutrition) is a combination of chronic energy deficiency and chronic or combination of chronic energy deficiency and chronic or acute protein deficiency. acute protein deficiency.

Page 11: Pathophysiology of carbohydrates and proteins metabolism

1. Pathogenesis1. Pathogenesisa. Inadequate protein intakea. Inadequate protein intakeb. b. Adequate caloric intake consisting Adequate caloric intake consisting mainly of carbohydratesmainly of carbohydratesc. c. ProteinProtein in liver and other organs (i.e., visceral protein) is in liver and other organs (i.e., visceral protein) is

decreaseddecreased..d. d. Muscle protein Muscle protein (i.e., somatic protein) (i.e., somatic protein) is relatively is relatively unchanged.unchanged. 2. Clinical findings:2. Clinical findings:a. a. Pitting edema and ascitesPitting edema and ascites • • Caused by Caused by hypoalbuminemia hypoalbuminemia and and loss loss of plasma of plasma oncotic pressureoncotic pressure..b. Fatty liverb. Fatty liver1) Caused by 1) Caused by decreased synthesis of apolipoproteinsdecreased synthesis of apolipoproteins..2) 2) Apolipoprotein B-100Apolipoprotein B-100 is required for assembly and secretion is required for assembly and secretion

of very low density lipoproteins (of very low density lipoproteins (VLDLVLDLs) in the liver.s) in the liver.c. Diarrhea - c. Diarrhea - caused by loss of the brush border enzymes and caused by loss of the brush border enzymes and

parasitic infectionsparasitic infectionsd. Anemia d. Anemia and and defects in cell-mediated immunity defects in cell-mediated immunity (CMI)(CMI)

Page 12: Pathophysiology of carbohydrates and proteins metabolism

Erosions and scaling in kwashiorkor.Erosions and scaling in kwashiorkor.

Page 13: Pathophysiology of carbohydrates and proteins metabolism

1. Pathogenesis1. Pathogenesisa. Dietary a. Dietary deficiency of both protein and deficiency of both protein and caloriescaloriesb. b. Decrease in somatic protein Decrease in somatic protein (muscle (muscle protein)protein)2. Clinical findings:2. Clinical findings:a. a. Extreme muscle wasting ("broomstick Extreme muscle wasting ("broomstick extremities")extremities") 1) Breakdown of muscle protein for 1) Breakdown of muscle protein for energy;energy; 2) Loss of subcutaneous fat;2) Loss of subcutaneous fat;b. b. Growth retardation; anemia; defects in Growth retardation; anemia; defects in cell-mediated immunitycell-mediated immunity (CMI) (CMI)c. Typically occurs in c. Typically occurs in children younger than children younger than 1 y.o., 1 y.o., who are who are deprived of breast-feedingdeprived of breast-feeding and do not have an adequate intake of and do not have an adequate intake of substitute nutrients. substitute nutrients.

Page 14: Pathophysiology of carbohydrates and proteins metabolism
Page 15: Pathophysiology of carbohydrates and proteins metabolism

Feature Feature Kwashiorkor Kwashiorkor MarasmusMarasmus

Definition Definition Protein deficiency with sufficient Protein deficiency with sufficient calorie intake calorie intake

Starvation in infants with overall Starvation in infants with overall lack of calorieslack of calories

Clinical Clinical features features

Occurs in children between 6 months Occurs in children between 6 months and 3 years of ageand 3 years of age

Common in infants under 1 year of Common in infants under 1 year of ageage

Growth failure Growth failure Growth failure Growth failure

Wasting of muscles but preserved Wasting of muscles but preserved adipose tissues adipose tissues

Wasting of all tissues including Wasting of all tissues including muscles and adipose tissuesmuscles and adipose tissues

Oedema, localised or generalised, Oedema, localised or generalised, present present Oedema absentOedema absent

Enlarged fatty liver Enlarged fatty liver No hepatic enlargementNo hepatic enlargement

Serum proteins low Serum proteins low Serum proteins lowSerum proteins lowAnaemia present Anaemia present Anaemia presentAnaemia present‘‘Flag sign’—alternate bands of light Flag sign’—alternate bands of light (depigmented) and dark (pigmented) (depigmented) and dark (pigmented) hairhair

Monkey-like face, protuberant Monkey-like face, protuberant abdomen, thin limbsabdomen, thin limbs

MorphologyMorphology Enlarged fatty liver Enlarged fatty liver No fatty liverNo fatty liverAtrophy of different tissues and Atrophy of different tissues and organs but subcutaneous fat organs but subcutaneous fat preservedpreserved

Atrophy of different tissues and Atrophy of different tissues and organs including subcutaneous fatorgans including subcutaneous fat

Page 16: Pathophysiology of carbohydrates and proteins metabolism
Page 17: Pathophysiology of carbohydrates and proteins metabolism

HolodomorHolodomor

Page 18: Pathophysiology of carbohydrates and proteins metabolism

1. Increased serum uric acid concentration (hyperuricaemiahyperuricaemia).2. Recurrent attacks of characteristic type of acute arthritis in which crystals of crystals of monosodium urate monohydrate monosodium urate monohydrate may be demonstrable in the leucocytes present in the synovial fluid.3. Aggregated deposits of monosodium urate monohydrate (tophitophi) in and around the joints of the extremities.4. Renal disease involving interstitial tissue and blood vessels.5. Uric acid nephrolithiasisnephrolithiasis.6. Other factors include age (rare before 30 years), genetic predisposition (X-linked alteration of enzyme hypoxanthine-guanine X-linked alteration of enzyme hypoxanthine-guanine phosphoribosyltransferase [HGPRT]phosphoribosyltransferase [HGPRT]), excessive alcohol consumption, obesity, certain drugs (especially thiazidesthiazides), and lead toxicity.

Gout is a syndrome caused by an inflammatory response to uric acid production or excretion resulting in high levels of uric acid in the blood (hyperuricemia) and in other body fluids, including synovial fluid.

Manifested by Manifested by the following the following features, occurring singly or in features, occurring singly or in combination:combination:

Page 19: Pathophysiology of carbohydrates and proteins metabolism

When the uric acid reaches a certain concentration in fluids, it crystallizes, forming insoluble precipitates that are deposited in connective tissuesthroughout the body.

Crystallization in synovial fluid causes acute, painful inflammation of the joint, a condition known as gouty arthritis. With time, crystal deposition insubcutaneous tissues causes the formation of small, white nodules, or tophi, that are visible through the skin. Crystal aggregates deposited in the kidneys can form urate renal stones and lead to renal failure.

In classic gouty arthritis, monosodium urate crystals form and cause joint inflammation. Pseudogout is caused by the formationof calcium pyrophosphate dihydrate (CPPD) crystals. The effect of either crystal is the same—the onset of a cytokinemediated acute inflammatory response.

Page 20: Pathophysiology of carbohydrates and proteins metabolism
Page 21: Pathophysiology of carbohydrates and proteins metabolism

Carbohydrates must be broken down into monosaccharides, or single sugars, before they can be absorbed from the small intestine.

The average daily intake of carbohydrate in the American diet is approximately 350 to 400 g. StarchStarch makes up approximately 50% of this total, sucrose (i.e., table sugar) approximately 30%, lactose (i.e., milk sugar) approximately 6%, and maltose approximately 1.5%.

Digestion of starch begins in the mouth with the action of amylase. Pancreatic secretions also contain an amylase. Amylase breaks down starch into several disaccharides, including maltose, isomaltose, and α-dextrins. The brush border enzymes convert the disaccharides into monosaccharides that can be absorbed.

Dietary CarbohydratesDietary Carbohydrates EnzymeEnzyme Monosaccharides ProducedMonosaccharides ProducedLactose Lactase Glucose and galactoseSucrose Sucrase Fructose and glucoseStarch Amylase Maltose, maltotriase, and α-dextrinsMaltose and maltotriose Maltase Glucose and glucoseα-Dextrins α-Dextrimase Glucose and glucose

Page 22: Pathophysiology of carbohydrates and proteins metabolism

SucroseSucrose yields yields glucoseglucose and and fructosefructose, , lactoselactose is converted to is converted to glucoseglucose and and galactosegalactose, and , and maltosemaltose is converted to is converted to two two glucose moleculesglucose molecules. When the disaccharides are not broken . When the disaccharides are not broken down to monosaccharides, they cannot be absorbed but down to monosaccharides, they cannot be absorbed but remain as osmotically active particles in the contents of the remain as osmotically active particles in the contents of the digestive system, causing diarrhea. digestive system, causing diarrhea.

Persons who are Persons who are deficient in deficient in lactaselactase, the enzyme that breaks , the enzyme that breaks down lactose, down lactose, experience diarrhea experience diarrhea when they drink milkwhen they drink milk or eat dairy or eat dairy products.products.

Fructose Fructose is transported across is transported across the the intestinal mucosa intestinal mucosa by by facilitated diffusion, which does facilitated diffusion, which does not require energy expenditure. not require energy expenditure. In this case, fructose moves In this case, fructose moves along a concentration gradient.along a concentration gradient.

Page 23: Pathophysiology of carbohydrates and proteins metabolism

GlucoseGlucose and and galactosegalactose are transported by way of a are transported by way of a sodiumdependent carrier systemsodiumdependent carrier system that that uses uses adenosine triphosphate adenosine triphosphate and the and the Na+/K+-ATPase pump Na+/K+-ATPase pump as an energy source.as an energy source.

Water absorption Water absorption from the intestine is linked to from the intestine is linked to absorption of osmotically active particlesabsorption of osmotically active particles, , such as such as glucose and sodiumglucose and sodium. It follows that an important consideration in facilitating the . It follows that an important consideration in facilitating the transport of water across the intestine (and decreasing diarrhea) after temporary transport of water across the intestine (and decreasing diarrhea) after temporary disruption in bowel function is to include sodium and glucose in the fluids that are taken.disruption in bowel function is to include sodium and glucose in the fluids that are taken.

Page 24: Pathophysiology of carbohydrates and proteins metabolism

• 1.  To the liverTo the liver.  Here excess sugar from meals is stored to cover sugar shortages between meals and to make fat from excess sugar. 

• Transport of sugar goes both to and from the liver.  The liver fills the "Sugar Central" between meals.

• 2.  To the brainTo the brain.  The brain is completely dependent upon sugar combustion for its supply of energy, in any case under normal conditions. It uses really huge amounts of sugar.

• 3.  3.  To muscles and fat tissueTo muscles and fat tissue. .  At least 40% of the body is comprised of skeletal muscles. These can use both fats and sugar to supply energy. •The rate of sugar uptake and burning follows physical activity; more work; more sugar burned. • MusclesMuscles do take up and store glucose to cover future activity but they cannot release sugar back to the blood stream or "Sugar Central". •Fat tissue Fat tissue stores surplus sugar as fat.  About half of this comes from the liver, the rest is made by fat itself.

Page 25: Pathophysiology of carbohydrates and proteins metabolism

Regulation of glucose metabolismRegulation of glucose metabolism The glucose concentration in The glucose concentration in

blood describes carbohydrates blood describes carbohydrates metabolism both of healthy metabolism both of healthy man and sick. Illnesses base of man and sick. Illnesses base of which is disorder of which is disorder of carbohydrates metabolism can carbohydrates metabolism can flow with rise of glucose flow with rise of glucose concentration in blood and concentration in blood and with lowering of it. with lowering of it.

Rise of glucoseRise of glucose concentration is named concentration is named hyperglicemiahyperglicemia lowering lowering hypoglicemiahypoglicemia. .

For exampleFor example, , hyperglicemiahyperglicemia is is very typical for very typical for diabetes diabetes mellitusmellitus, , hypoglycemiahypoglycemia – for – for glycogenosisglycogenosis.  . 

Page 26: Pathophysiology of carbohydrates and proteins metabolism

Normal glucose level in the blood 65 -110 mg/% 3.85 - 6.05 mmol/L

(5.5 mmol/L)

Impairments of glucose Impairments of glucose balance balance

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

GLUCOSEGLUCOSE

3.85 6.05NORM HyperglycemiaHyperglycemiaHypoglycemiaHypoglycemia

Page 27: Pathophysiology of carbohydrates and proteins metabolism

Blood Glucose & HormonesBlood Glucose & Hormones HormoneHormone

InsulinInsulin GlucortocoidsGlucortocoids GlucagonGlucagon Growth HormoneGrowth Hormone EpinephrineEpinephrine

ActionAction

GlucoseGlucose GlucoseGlucose GlucoseGlucose GlucoseGlucose GlucoseGlucose

Page 28: Pathophysiology of carbohydrates and proteins metabolism

Counter-insulin hormonesCounter-insulin hormones ACTHACTH, , growth hormone growth hormone,, cortisol cortisol,, thyroid thyroid

hormonehormone,, glucagon glucagon,, adrenalineadrenaline

1. Stimulate absorption of carbohydrates ((cortisol, thyroid hormone)cortisol, thyroid hormone) 2. glycogenolysis in liver and muscles,

glycogenesis ((adrenaline, cortisol, thyroidadrenaline, cortisol, thyroid)) 3. Inhibit hexokinase activity and therefore its

utilization ((cortisol, growth hormonecortisol, growth hormone)) 4. Stimulate gluconeogenesis ((cortisol, thyroid, glucagoncortisol, thyroid, glucagon)) 5. Activate insulinase ((growth hormone, thyroidgrowth hormone, thyroid))

Page 29: Pathophysiology of carbohydrates and proteins metabolism

HypoglycemiaHypoglycemia

ExogenousExogenous

EndogenousEndogenous FunctionalFunctional

Page 30: Pathophysiology of carbohydrates and proteins metabolism

Exogenous Exogenous hypoglycemiahypoglycemia

• Insulin injectionInsulin injection

• Alcohol (develops 6-36 hours Alcohol (develops 6-36 hours

after heavy consumption)after heavy consumption)

• Some drugs (e.g. salicylates)Some drugs (e.g. salicylates)

• Long term physical exerciseLong term physical exercise

Page 31: Pathophysiology of carbohydrates and proteins metabolism

Endogenous Endogenous hypoglycemiahypoglycemia

insulinoma (hyperplasia insulinoma (hyperplasia of of -cells)-cells) glycogenosisglycogenosis hereditary fructose hereditary fructose

intoleranceintolerance insufficiency in insufficiency in

phosphoenolpyruvate phosphoenolpyruvate carboxykinasecarboxykinase

Hepatocellular insufficiencyHepatocellular insufficiency Impaired absorptionImpaired absorption

Islet blood flow during hyperglycemia and hypoglycemia. Islet blood flow during hyperglycemia and hypoglycemia. Images taken at peak fluorescence intensity in the same Images taken at peak fluorescence intensity in the same islet under islet under experimental design 1experimental design 1 during hyperglycemia ( during hyperglycemia (AA) ) and hypoglycemia (and hypoglycemia (BB) or under ) or under experimental design 2experimental design 2 during hypoglycemia (during hypoglycemia (CC) and hyperglycemia () and hyperglycemia (DD).).

Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo Lara R. Nyman , Eric Ford , Alvin C. Powers , David W. Piston / American Journal of Lara R. Nyman , Eric Ford , Alvin C. Powers , David W. Piston / American Journal of Physiology - Endocrinology and MetabolismPublished 1 April 2010Vol. 298no. Physiology - Endocrinology and MetabolismPublished 1 April 2010Vol. 298no. E807-E814DOI: 10.1152/ajpendo.00715.2009E807-E814DOI: 10.1152/ajpendo.00715.2009

Page 32: Pathophysiology of carbohydrates and proteins metabolism

1.1.AlimentaryAlimentary (after gastrectomy, demping (after gastrectomy, demping syndrome)syndrome)

2.2.Spontaneous reactiveSpontaneous reactive (cause is not known (cause is not known diarrhea, tachycardy, tremor, headache, diarrhea, tachycardy, tremor, headache, weakness)weakness)

3.3.Alcohol Alcohol (consumption in hungry state)(consumption in hungry state)4.4.Endocrine insufficiencyEndocrine insufficiency (decrease in counter- (decrease in counter-

insulin hormone insulin hormone ))5.5. Hepatic failureHepatic failure6. Malnutrition 6. Malnutrition 7. Heavy physical load7. Heavy physical load (without carbohydrate (without carbohydrate

uptake)uptake)8.8. Transient functional hypoglycemia of childrenTransient functional hypoglycemia of children• Neonatal (10%)Neonatal (10%)• Maternal diabetesMaternal diabetes• ErythroblastosisErythroblastosis• KetogenicKetogenic

Functional HypoglycemiaFunctional Hypoglycemia

Page 33: Pathophysiology of carbohydrates and proteins metabolism

Manifestations of hyperglycemiaManifestations of hyperglycemia GlucosuriaGlucosuria PolyuriaPolyuria PolydypsiaPolydypsia Hypohydration of the organismHypohydration of the organism Arterial hypotensionArterial hypotension

Manifestations of hypoglycemiaManifestations of hypoglycemia StarvationStarvation TremorTremor Excessive sweatingExcessive sweating TachycardiaTachycardia Headache, dizzinessHeadache, dizziness Impaired visionImpaired vision Anxiety, fearAnxiety, fear Impaired cognitionImpaired cognition

Page 34: Pathophysiology of carbohydrates and proteins metabolism

• Diabetes mellitus Diabetes mellitus is not a single disease but a is not a single disease but a group of clinically group of clinically heterogeneous disorders that heterogeneous disorders that

have glucose intolerance in common. It have glucose intolerance in common. It encompasses many causally unrelated diseases and encompasses many causally unrelated diseases and

includes many different etiologies of disturbed includes many different etiologies of disturbed glucose tolerance. glucose tolerance.

• The term The term diabetes mellitus diabetes mellitus is used to describe a is used to describe a syndrome characterized by syndrome characterized by chronic chronic

hyperglycemiahyperglycemia and other and other disturbances of disturbances of carbohydrate, fat, and protein metabolismcarbohydrate, fat, and protein metabolism..

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ClassificationClassification Primary DMPrimary DM – – (primary - no other (primary - no other

disease)disease) Type I – IDDM / Juvenile – 10%.Type I – IDDM / Juvenile – 10%.

Subtype 1A (immune-mediated) DM characterised by autoimmune destruction of β-cells which usually leads to insulin deficiency.

Subtype 1B (idiopathic) DM characterised by insulin deficiency with tendency to develop ketosis but these patients are negative for autoimmune markers. Type II – NIDDM /Adult onset – 80%.Type II – NIDDM /Adult onset – 80%.

MODY (MODY (Maturity-onset diabetes of the young) – 5% ) – 5% maturity onset - Geneticmaturity onset - Genetic

Gestational DiabetesGestational Diabetes Secondary DMSecondary DM – (secondary to other – (secondary to other

dis.)dis.) Pancreatitis, tumors, hemochromatosis.Pancreatitis, tumors, hemochromatosis. Infectious – congenital rubella, CMV.Infectious – congenital rubella, CMV. Endocrinopathy.Endocrinopathy. Drugs – Corticosteroids.Drugs – Corticosteroids.

(absolute insulin deficiency)

(insulin resistance with an insulin secretory deficit)

(other specific types)

Page 36: Pathophysiology of carbohydrates and proteins metabolism

The criteria for the diagnosis of diabetes include symptoms, elevated fasting plasma glucose (FPG) concentration, and/or abnormal oral

glucose tolerance test (OGTT).

Two conditions associated with a high risk for diabetes, impaired fasting glucose (IFG) and

impaired glucose tolerance (IGT), are considered prediabetes.

Page 37: Pathophysiology of carbohydrates and proteins metabolism

Normal Pancreatic Islet:Normal Pancreatic Islet:

ß cells ß cells (Insulin) αα cells cells (Glucagon)

δδ cells cells (Somatostatin) pp Cells pp Cells (pan prot)

ßß αα

Page 38: Pathophysiology of carbohydrates and proteins metabolism

Type-IType-I Type-Type-IIII

Less common Age < 25 Years Insulin-

Dependent Onset: Weeks Acute Metabolic

complications Autoantibody:

Yes Family History:

No Insulin levels:

very low Islets: Insulitis 50% in twins

More common Adult >25 Years Insulin

Independent * Months to years Chronic Vascular

complications No Yes Normal or high * Normal /

Exhaustion 60-80% in twins

Page 39: Pathophysiology of carbohydrates and proteins metabolism

Insulin-dependent diabetes mellitusInsulin-dependent diabetes mellitus Insulin-dependent diabetes Insulin-dependent diabetes

mellitusmellitus arises as result of arises as result of absolute absolute insulin insufficiencyinsulin insufficiency. .

It is described by It is described by insulinopenia insulinopenia and by inclination to and by inclination to ketoacidosisketoacidosis. .

This diabetes occur more This diabetes occur more frequently is in frequently is in childrenchildren and and young peoples young peoples (till 30 years). (till 30 years).

Insulin is needed for sustentation Insulin is needed for sustentation of patient life. Attached to it’s of patient life. Attached to it’s absence absence ketoacidic comaketoacidic coma develops. develops.

Page 40: Pathophysiology of carbohydrates and proteins metabolism

Carbohydrate metabolism in normal conditions and diabetes mellitus

INSULIN

1. Increase in permeability of myocyte and adipocyte membranes for glucose (Glut-4)2. Increase in activity of glucokinase, glycogen-sythetase, aerobic glycolysis, pentose-phosphate shunt and Krebs cycle enzymes3. Increased rate of glycogen synthesis in liver4. Increase in synthesis of lipids from glucose5. Inhibition of gluconeogenesis

IMPAIRMENTIMPAIRMENT

HYPERGLYCEMIAHYPERGLYCEMIA

Page 41: Pathophysiology of carbohydrates and proteins metabolism

FormsForms of insulin-dependent of insulin-dependent diabetes mellitusdiabetes mellitus

Autoimmune Autoimmune –– DR3DR3 Virus-inducedVirus-induced –– DR4 DR4

Page 42: Pathophysiology of carbohydrates and proteins metabolism

Chr.Chr. – 2 HNF – 2 HNF4a4a (MODY (MODY II )) - Hepatic Nuclear - Hepatic Nuclear factor 4 factor 4 gene gene

Chr.Chr.-7 -7 glucokinaseglucokinase (MODY (MODY II II )) Chr.Chr.-11, 12 HNF-11, 12 HNF1a1a (MODY (MODY I I I I I I )) - Hepatic - Hepatic

Nuclear factor mutationNuclear factor mutation Mitochondrial DNA mutations, other Mitochondrial DNA mutations, other

genetic defectsgenetic defects

Maturity-onset diabetes of the Maturity-onset diabetes of the youngyoung

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Genetic Genetic HLA-DR3/4HLA-DR3/4 EnvironmentEnvironment

Viral infe..?Viral infe..?

Insulin deficiencyInsulin deficiencyType I / IDDMType I / IDDM

Autoimmune InsulitisAutoimmune InsulitisAb to ß cells/insulin Ab to ß cells/insulin

ß cell ß cell DestructionDestruction

1.1. Drugs, chemicals Drugs, chemicals (streptozotocin, alloxane, (streptozotocin, alloxane, pentamidine) pentamidine)

2.2. Dietary (cow milk, high Dietary (cow milk, high nitrosamine levels)nitrosamine levels)

3.3. Viruses (Viruses (Coxsackie, Coxsackie, measles)measles)

((molecular mymicry)molecular mymicry)

Page 44: Pathophysiology of carbohydrates and proteins metabolism

PATHOGENESIS OF DIABETES MELLITUSPATHOGENESIS OF DIABETES MELLITUS

Insulin insufficiencyInsulin insufficiencyFatty acids Fatty acids

Ketone bodies Ketone bodies

-- hydroxybutirate, hydroxybutirate, acetoacetate accumulation in acetoacetate accumulation in

bloodblood

Metabolic Metabolic acidosisacidosis KetonuriaKetonuria

Kussmaul's Kussmaul's respirationrespiration

CNS depressionCNS depression

Blood glucose level Blood glucose level

glucosuriaglucosuria

polyuripolyuriaa

dehydrationdehydration thirst thirst

HypovolemiaHypovolemiaSHOCKSHOCK

Poly-Poly-dipsiadipsia

Page 45: Pathophysiology of carbohydrates and proteins metabolism

Autoimmune insulin-dependent Autoimmune insulin-dependent diabetes arises in persons with diabetes arises in persons with genome genome DR3DR3. It is associated with other . It is associated with other autoimmune endocrinopathies, for autoimmune endocrinopathies, for example, with illnesses of example, with illnesses of thyroid gland thyroid gland ((autoimmune thyroiditis, diffuse toxic autoimmune thyroiditis, diffuse toxic goitergoiter), ), adrenal gland adrenal gland ((Addison’s Addison’s diseasedisease). ).

This diabetes type develops in any age This diabetes type develops in any age more frequent in womenmore frequent in women. .

Autoimmune is diabetes described by Autoimmune is diabetes described by presence in blood of patient presence in blood of patient autoantibodiesautoantibodies against of Langergans against of Langergans islets. islets.

Page 46: Pathophysiology of carbohydrates and proteins metabolism

• Virus-induced insulin-dependent diabetes mellitus binded with genome DR4 and different from autoimmune on mechanisms of development. In this case there are no autoantibodies against islets of pancreas. Its certainly can appear in blood but rapidly (pending of year) disappear. They do not perform essential role in pathogenesis of illness.

• Development of this diabetes type frequently precede from viral infectious epidemic parotitis, german measles, measles, viral hepatitis.• Pathogenic viruses action is not specific. It consists in development of inflammatory process in Langergans islets. Insulitis arises. Lymphoid infiltration of damaged islets develops at first after then destruction.  

Page 47: Pathophysiology of carbohydrates and proteins metabolism

• Such substances are called β-cytotoxic. They are, for example, alloxane and streptosocine. They create a favourable background for immediate viruses action on membrane of β-cells.

• Virus-induced diabetes arises early before 30 years of life. It is identically widespread and among males, both among women.

• Sometimes the specific (immune) destruction mechanisms of β-cells are linked. The viruses pervert antigen membranes properties of affected β-cells and are followed with attack of autoimmune mechanisms.

• There is one more possibility. Membrane β-cells is lightly damaged by much chemical substances even in insignificant concentrations.

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Page 49: Pathophysiology of carbohydrates and proteins metabolism

Insulin-independent diabetes Insulin-independent diabetes mellitusmellitus

This diabetes type principle differs from the first. This diabetes type principle differs from the first. Patients, as a rule Patients, as a rule don’t need to exogenic insulindon’t need to exogenic insulin.. Metabolic disorders attached to this diabetes are Metabolic disorders attached to this diabetes are

minimal. Diet therapy and per oral glucose minimal. Diet therapy and per oral glucose decreasing medicines are sufficiently for their decreasing medicines are sufficiently for their compensation. compensation.

Only in stress Only in stress (trauma action, sharp infection) (trauma action, sharp infection) conditions conditions patient use insulinpatient use insulin. .

Illness can course for Illness can course for years without hyperglycemiayears without hyperglycemia. . Sometimes it is disclosed in age more 40 years.Sometimes it is disclosed in age more 40 years.

There are three factors group, which play a decisive There are three factors group, which play a decisive role in forming of this diabetes type.  role in forming of this diabetes type.  Here are:Here are:

the genetic factors

functional disturbance of β-cells

insulin resistance

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Genetic factorsGenetic factors determine hereditary liability to disease. Specific genetic marker (special diabetogenic gene) is not found. It is known only, that inclination to insulin-independent diabetes is not coupled with major complex of histocompatibility.

Function of Function of ββ-cells-cells of patient with insulin-independent diabetes is violated. Amount of them is diminished. Attached to loading by glucose they do not multiply insulin secretion in necessary amount. Diabetologist  connects these violations with amyloidosis of Langergans islets.

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IDDMIDDM

Genetic /Genetic / ß cell defectß cell defect

Pathogenesis of Type II DMObesity /Obesity /

Life style ?Life style ?

ß cell ß cell exhaustionexhaustion

Type II NIDDMType II NIDDM

Abnor. SecretionAbnor. SecretionInsulin ResistanceInsulin Resistance

Relative Relative Insulin Def.Insulin Def.

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Insulin-resistance• Insulin-resistance arises or on genetic base or as result of influence

of external factors (risk factors). Biological insulin action is mediated over receptors. They are localized on cells-targets membranes (myocytes, lypocytes). Interaction of insulin and receptor is followed with changes of physical state of cells-targets membrane.

• As result of this transport system is activated, which carries glucose over cellular membrane.

• Transmembrane moving of glucose is provided by proteins-transmitters. • Amount of glucose carried in cell depends on closeness of insulin receptors on membrane and on receptor affinity to insulin. These parameters depend on insulin level in blood. • Hyperinsulinemia diminishes amount of receptors and their affinity to insulin. Hypoinsulinemia on the contrary multiplies amount of receptors and their affinity to insulin.

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•  Chronic resistance of insulin Chronic resistance of insulin receptorsreceptors causes a chronic hyperfunction of β-cells and

surplus production of insulin. This in turn raises receptor

resistance. Thus arises a vicious circle. Protracted loading of β-

cells conduces to exhaustion of their functions.

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Page 55: Pathophysiology of carbohydrates and proteins metabolism

About 4% pregnant women developDM due to metabolic changes during pregnancy. Although they revert back to normal glycaemia after delivery, thesewomen are prone to develop DM later in their life.

Mitochondrial DNA is inherited maternally and encodes several genes in the oxidative phosphorylation pathway, ribosomal RNAs, and 22 transfer RNAs (tRNAs). In rare cases, (<1%), diabetes is associated with point mutations in a mitochondrial tRNA gene, tRNALeu(UUR). Mitochondrial diabetes is caused by a primary defect in β-cell function. Recall that ATP is required for insulin secretion in β cells, and impairment of mitochondrial ATP synthesis results in decreased insulin secretion.

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2. Genetic defects in 2. Genetic defects in insulin processing or insulin processing or insulin action:insulin action:• Defects in proinsulin Defects in proinsulin conversionconversion• Insulin gene mutationsInsulin gene mutations• Insulin receptor mutationsInsulin receptor mutations

3. Exocrine 3. Exocrine pancreatic pancreatic

defectsdefects• Chronic Chronic pancreatitispancreatitis• PancreatectomyPancreatectomy• NeoplasiaNeoplasia• Cystic fibrosisCystic fibrosis• HemachromatosisHemachromatosis• Fibrocalculous Fibrocalculous pancreatopathypancreatopathy

5. 5. EndocrinopathiesEndocrinopathies• AcromegalyAcromegaly• Cushing syndromeCushing syndrome• HyperthyroidismHyperthyroidism• PheochromocytomaPheochromocytoma• GlucagonomaGlucagonoma

1. Genetic defects of b-1. Genetic defects of b-cell functioncell function

Maturity-onset diabetes of Maturity-onset diabetes of the young (MODY), caused by the young (MODY), caused by mutations in:mutations in:• Hepatocyte nuclear factor Hepatocyte nuclear factor 4a [HNF-4a] (MODY1)4a [HNF-4a] (MODY1)• Glucokinase (MODY2)Glucokinase (MODY2)• Hepatocyte nuclear factor Hepatocyte nuclear factor 1a [HNF-1a] (MODY3)1a [HNF-1a] (MODY3)• Insulin promoter factor Insulin promoter factor [IPF-1] (MODY4)[IPF-1] (MODY4)• Hepatocyte nuclear factor Hepatocyte nuclear factor 1b [HNF-1b] (MODY5)1b [HNF-1b] (MODY5)• Neurogenic differentiation Neurogenic differentiation factor 1 [Neuro D1] (MODY6)factor 1 [Neuro D1] (MODY6)• Mitochondrial DNA Mitochondrial DNA mutationsmutations 7. Infections7. Infections

• CytomegalovirusCytomegalovirus• Coxsackie virus BCoxsackie virus B

4. Drugs4. Drugs• GlucocorticoidsGlucocorticoids• Thyroid hormoneThyroid hormone• αα-interferon-interferon• Protease inhibitorsProtease inhibitors• ββ-adrenergic -adrenergic agonistsagonists• ThiazidesThiazides• Nicotinic acidNicotinic acid• PhenytoinPhenytoin

6. Genetic 6. Genetic syndromes syndromes

associated with associated with diabetesdiabetes

• Down syndromeDown syndrome• Kleinfelter Kleinfelter syndromesyndrome• Turner syndromeTurner syndrome

8. Gestational Diabetes 8. Gestational Diabetes MellitusMellitus

• Diabetes associated with Diabetes associated with pregnancypregnancy

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IMPAIRMENT OF LIPID METABOLISM IN DIABETES MELLITUS

Decreased glucose utilization

Decreased lipogenesis

Mobilization of fats to depoes

Hyperlipidemia

Metabolic acidosis Increased ketogenesis and cholesterol productoin

Ketonemia and hypercholesterolem

ia

Ketonuria

Loss of Na+

Keto-acidotic coma

Insulin deficiency

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Decreased glucose utilizationDecreased glucose utilization

Increase in proteolysisIncrease in proteolysis

Aminacidemia, increased uptake of aminoacids by Aminacidemia, increased uptake of aminoacids by the liverthe liver

1. Activation of gluconeogenesis1. Activation of gluconeogenesis

2. Increased removal of nitrogen via urea2. Increased removal of nitrogen via urea

Loss of potassium and other ions by the cellsLoss of potassium and other ions by the cells

Dehydration of Dehydration of the cellsthe cells Potassium loss by Potassium loss by

the organismthe organism

Insulin deficiencyInsulin deficiency

IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES MELLITUSMELLITUS

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Symptoms of diabetes mellitusMajor symptoms are:• hyperglycemia, • glucosuria and • polyuria.

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Pathogenesis of diabetes mellitus symptoms

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GlucosuriaGlucosuria In healthy man practically has not In healthy man practically has not

glucose in urine. It is excreated in glucose in urine. It is excreated in amount amount not more 1 gnot more 1 g. Attached to . Attached to sugar diabetes amount of excreted sugar diabetes amount of excreted glucose increases repeatedly. glucose increases repeatedly.

If glucose concentration in blood and If glucose concentration in blood and primary urine does primary urine does not exceed 9 not exceed 9 mmol/lmmol/l, epithelium of canaliculi , epithelium of canaliculi reabsorbed it. This maximum reabsorbed it. This maximum concentration is called concentration is called nephritic nephritic threshold. threshold.

If a glucose concentration exceeds a If a glucose concentration exceeds a nephritic threshold (9 mmol/l), part of nephritic threshold (9 mmol/l), part of glucose goes in secondary urine glucose goes in secondary urine (glucosuria).(glucosuria).

10 mmol/L

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Glomerular damage• Loss of negative charge• Glomerulosclerosis• Thickening of basement membrane• Mesangial expansion

Chronic hyperglycemia

Increased RBF (hyperperfusion)

Hypertension

Increased intraglomerular

capillary pressure

Renal vasodilation

Protein glycation

Increased protein excretion

Increased GFR

MicroalbuminuriaMacroalbuminuria

Decreased GFR and renal failure

RBF - Renal blood flowGFR - Glomerular filtration rate

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Polyuria• Glucose is osmotic active substance. • Increasing of it’s concentration in

primary urine raises osmotic pressure. • Water is exuded from organism together

with glucose (osmotic diuresis). • Patient excretes 3-4 L of urine per day,

sometimes till 10 L.

Page 64: Pathophysiology of carbohydrates and proteins metabolism

Decreased glucose utilization

Increased glucose production

Hyperglycemia

Glucosuria

Osmotic diuresis

Hyperosmolarity and dehydration

PATHOGENESIS OF HYPERGLYCEMIC PATHOGENESIS OF HYPERGLYCEMIC COMACOMA

C O M A SHOCKDEATH

DIC syndrome

Insulin deficiency

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 Complication of diabetes mellitus

The very frequent diabetes complications are following: ketoacidosis, macroangiopathy, microangiopathy, neuropathy.

angiopathy

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Page 67: Pathophysiology of carbohydrates and proteins metabolism

Ketoacidosis.Ketoacidosis. In healthy peoples synthesis of In healthy peoples synthesis of ketone ketone bodies bodies in liver is strictly controled. Main regulatory in liver is strictly controled. Main regulatory mechanism is access limitation of fat acids in mechanism is access limitation of fat acids in mytochondries of hepatocytes. Over head permissible mytochondries of hepatocytes. Over head permissible concentration limit of ketone bodies in blood is concentration limit of ketone bodies in blood is approximately approximately 0,1 mmol/L0,1 mmol/L. .

In case of exceedingIn case of exceeding this level regulatory mechanisms this level regulatory mechanisms are stated. Foremost are stated. Foremost ketone bodies ketone bodies put specific put specific receptors back up on membrane β-cells of Langergan’s receptors back up on membrane β-cells of Langergan’s islets. Insulin excretion in blood increases. islets. Insulin excretion in blood increases. Insulin Insulin stimulates resynthesis of fat acidsstimulates resynthesis of fat acids. First stage of . First stage of resynthesis is derivation of malonil-CоА. Surplus amount resynthesis is derivation of malonil-CоА. Surplus amount of malonil-CоА oppresses penetration of fat acids in of malonil-CоА oppresses penetration of fat acids in mytochondries. Synthesis of mytochondries. Synthesis of ketone bodies slowsketone bodies slows..

Attached to diabetes mellitus disturb mechanism of both Attached to diabetes mellitus disturb mechanism of both synthesis regulation of synthesis regulation of ketone bodies ketone bodies – both on level of – both on level of β-cells, and on level of hepatocytes. Receptor β-cells, and on level of hepatocytes. Receptor stimulation of β-cells by ketone bodies does not cause stimulation of β-cells by ketone bodies does not cause increased excretion insulin in blood. increased excretion insulin in blood.

In conditions of insulinopenia fat acids penetrate in In conditions of insulinopenia fat acids penetrate in hepatocytes in unrestricted amount. Liver synthesizes hepatocytes in unrestricted amount. Liver synthesizes many ketone bodies. Extrahepatic tissues can not utilize many ketone bodies. Extrahepatic tissues can not utilize them. Amount of ketone bodies in blood increases. them. Amount of ketone bodies in blood increases. Metabolic acidosis occurMetabolic acidosis occur. It can complete by . It can complete by ketoacid ketoacid comacoma..

Seldom attached to Seldom attached to diabetes mellitus lactoacidosis diabetes mellitus lactoacidosis occur. occur. It is attached to insulin-independent diabetes mellitus, It is attached to insulin-independent diabetes mellitus, attached to combination of diabetes with hypoxia, sepsis, attached to combination of diabetes with hypoxia, sepsis, shock. shock.

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MacroangiopathyMacroangiopathy MacroangiopathyMacroangiopathy is vessels atherosclerosis  is vessels atherosclerosis

of cerebrum, heart, kidneys, legs. Diabetes of cerebrum, heart, kidneys, legs. Diabetes lead to atherosclerosis development.  lead to atherosclerosis development. 

There are three There are three acceleration way of acceleration way of atherogenesis atherogenesis in patients with diabetes. In in patients with diabetes. In conditions of insulin insufficiency growth conditions of insulin insufficiency growth hormone synthesis increases. Here upon hormone synthesis increases. Here upon proliferation of proliferation of smooth myocites accelerates smooth myocites accelerates key stage of atherogenesiskey stage of atherogenesis. Attached to . Attached to diabetes vessels endothelium damages.  diabetes vessels endothelium damages. 

Synthesis of Synthesis of thromboxane increasethromboxane increase, and this , and this helps to adhesion of thrombocytes. helps to adhesion of thrombocytes. Thrombocytes excret mitogene thrombocytic Thrombocytes excret mitogene thrombocytic growth factor (growth factor (TGFTGF). It also stimulates ). It also stimulates proliferation of smooth myocytes. proliferation of smooth myocytes.

Attached to diabetes concentration of Attached to diabetes concentration of  lipoproteids low density, increase  lipoproteids low density, increase concentration of lipoproteids of high density.concentration of lipoproteids of high density.

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Page 70: Pathophysiology of carbohydrates and proteins metabolism
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Page 72: Pathophysiology of carbohydrates and proteins metabolism

• Microangiopathy develop in shallow vessels – arterials, venues, capillaries. Two process form their pathogenic base – thickining of basal membrane and reproduction endothelium.

• Direct cause of microangiopathy is hyperglycemia and synthesis of glycoproteids in basal membrane.

• There are two main clinical forms microangiopathy: diabetic retinopathy

diabetic nephropathy

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Page 74: Pathophysiology of carbohydrates and proteins metabolism

A composite photograph showing a pretreatment fundus photograph (A), and a photograph demonstrating radiation retinopathy at 24 months (B). A fluorescein angiogram demonstrates intraretinal microangiopathy next to the tumour (C), and regression to chorioretinal scar after laser photocoagulation (D).

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Neuropathy• Neuropathy manifest

by violation of nerves function sensible, motor, vegetative. Essence of these decreases is demyelinisation of nervous fibres, decrease of axoplasmatic flow.

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• This is hereditary illness. In it’s base lies an blockade of galactose metabolism. In organism intermediate metabolits accumulate.

• There are two the main forms of galactosemia on base of:

transferase insufficiency and

galactokinase insufficiency.

Page 77: Pathophysiology of carbohydrates and proteins metabolism

Deficit of glucose-1-phosphat uridyltransferase.

• This enzyme converts galactose-1-phosphate in glucose-1-phosphate. Attached to it’s insufficiency galactose-1-phosphate and sugar alcohol of galactose (galactit) accumulates in tissues lens of the eye, liver, brain, kidneys. Mammal and cow milk contains lactose.

• Therefore the illness symptoms appear with first days of child life.  • Diarrhea, vomiting, dehydrotation occur. • Liver increases (splenomegalia). Hepatocytes lose ability to conjugate

bilirubine. Children become yellowish. • Affection of kidneys displays in proteinuria, aminoaciduria and

acidosis. • For galactosemia cataract is very typical. Their beginnings related to

accumulation of osmotic active galactite in vitreous bodies of eyes. Galactite absorb in water, and water breaks tissues.

• Dangerous consequences arise in the brain. This foremost is delay of mental development.

• Mortal end is possible. • Cure method is diet without galactose.

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Deficit of galactokinase.Deficit of galactokinase. Attached to this illness Attached to this illness

variant a process of variant a process of phosphorilation of galactose phosphorilation of galactose is blocked,  that is is blocked,  that is transformation of galactose in transformation of galactose in galactose-1-phosphat. Illness galactose-1-phosphat. Illness displays in cataracts. displays in cataracts.

Other symptoms are absent Other symptoms are absent or minor. Cure is  diet without or minor. Cure is  diet without galactose.galactose.

Page 79: Pathophysiology of carbohydrates and proteins metabolism

GLYCOGENOSISGLYCOGENOSIS TypeType І – І –Girke diseaseGirke disease. . Deficit ofDeficit of glucosoglucoso-6--6-phosphatasephosphatase TypeType ІІ – ІІ –Pompe diseasePompe disease.. Deficit ofDeficit of acidic maltaseacidic maltase

(α-1,4- (α-1,4-glucosidaseglucosidase)) TypeType ІІІ – ІІІ –Cori diseaseCori disease, , ForbsForbs diseasedisease.. Deficit ofDeficit of

amyloamylo-1,6- -1,6- glucosidaseglucosidase TypeType ІV – ІV –Anderson diseaseAnderson disease.. Deficit ofDeficit of amyloamylo- 1,4,1,6-- 1,4,1,6-

transglucosidasetransglucosidase TypeType V – V –McArdel diseaseMcArdel disease Deficit ofDeficit of phosphorilase of phosphorilase of

myocytesmyocytes ТТypeype VІ – VІ –Hers diseaseHers disease.. Deficit ofDeficit of phosphorilasic phosphorilasic

complex in livercomplex in liver ТТypeype VІІ. VІІ. Deficit ofDeficit of musclemuscle phosphofructokinasephosphofructokinase

Page 80: Pathophysiology of carbohydrates and proteins metabolism

• Simple carbohydrates deposit in organism as polysaccharides. • In muscles and liver accumulates glycogen. It consist of 4 % of liver

weight and 2 % of  muscles  weight. • Muscles glycogen is used as of ready fuel source for immediate

guaranteeing by energy. Liver – without interruption provides cerebrum and erythrocytes with glucose .

• Synthesis and splitting of glycogen are exactly adjusted and coordinated processes. Attached to immediate need in glucose α–cells of pancreas secret glucagone. It activates adenylatcyclase of hepatic cells.

• Adenilatcyclase stimulates derivation of cAMP. Under action of cAMP takes place activation of proteinkinase and this enzyme raises activity glycogenphosphorilase and oppresses activity of glucogensynthase. Here upon starts intensive glycogenolysis. Supplementary amount of glucose is secreted in blood.

• In other situation after consuming of carbohydrates in blood accumulates surplus of glucose. β-cells of pancreas multiply insulin synthesis.  Insulin raises activity of glycogensyntase. Active glucogenesis starts too. Surplus of glucose reserves in appearance of glucogen in liver and muscles.

• There are illnesses in base of which is accumulation of glycogen in organs. They are called glycogenosesglycogenoses. All of them are hereditary enzymopathy. There are seven main types of glycogenoses.

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Page 82: Pathophysiology of carbohydrates and proteins metabolism

Glycogenosis type I – Girke’s disease.• Girke’s disease cause deficit of

glucose-6-phosphatase. This enzyme provides 90 % of glucose which disengages in liver from glycogen. It play central role in normal glucose homeostasis. Glucose which disengages attached to disintegration of glycogen or is derivated in process of gluconeogenesis obligatory goes over stage of glucose-6-phosphate.

• Enzyme glucose-6-phosphatase tears away a phosphate group from glucose. There free glucose is formed it  goes out in blood. Attached to Girke’s disease stage of tearing phosphate group is blocked. There are no free glucose hypoglycemia occur. Hypoglycemia arises. Attached to Girke’s disease glycogen is deposed in liver and kidneys.

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Glycogen Storage Disorders:• Type 1= Von Gierke’s:

– Shortly after birth: Severe lifethreatening Hypoglycemia– Lactic acidosis –due to isolated glycolysis of G6Po– Hyper-uricemia, hyper lipidemiaHyper-uricemia, hyper lipidemia– Increased association with epistaxis – *HepatomegalyHepatomegaly– **Adverse response to Glucagon with worsening Lactic acidosisAdverse response to Glucagon with worsening Lactic acidosis

• Management requires IV glucose, and then as outpt, close NG corn-starch or glucose solution administration to achieve close to nl glucose homeostasis.

• Frequent snacks and meals. Continuous nighttime glucose infusions up to the age of 2.

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Type ІІ glycogenosis – Pompe’s disease.• Illness is related to

deficit of lysosomal enzyme – sour maltase, or α-1,4-glucosidase.

• This enzyme slits glycogene to glucose in digestive vacuoles. Attached to it’s deficit glycogen accumulates at first in lysosomes and then in cytosole of hepatocytes and myocytes.

Page 85: Pathophysiology of carbohydrates and proteins metabolism

Type 2- Pompe’s disease:• Normal Glucose• Do to an accumulation of

glycogen in lysosomes. • **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD**

• Manifested by massive Cardiomegaly, Hepatomegaly, Macroglossia.

• Fatal If results in CHF. • Limited therapies in Neonatal

Variant.– Attempts at enzyme replacement

ongoing.

Page 86: Pathophysiology of carbohydrates and proteins metabolism

Glycogen in the Liver (left stained to show glycogen, right normal)

Glycogen in Muscle Cells

Type ІІІ glycogenosis – Cori’s disease, Forbs’ disease

This illness is named limited ecstrinosis. In it’s base lies a deficit of amylo-1,6-glucosidase.

Degradation of glycogen pauses in sites of branching.

Glycogen accumulates in liver and muscles. Cure is diet with big proteins maintenance.

Page 87: Pathophysiology of carbohydrates and proteins metabolism

Type ІV glycogenosis – Anderson’s disease.

• It is called by deficit of amilo-1,4,1,6-transglucosidase (branching enzyme).

• As result of this there is derivated anomalous glycogen with very long branches and rare points of branching. It is not exposed to degradation and accumulates in liver, heart, kidneys, spleen, lymphatic nods, skeletal muscles.

Page 88: Pathophysiology of carbohydrates and proteins metabolism

• It’s cause is deficit of phosphorilase of myocytes. Typical pain displays in muscles after physical loading.

• Glycogene does not slit only in muscles. Here it accumulates. In liver mobilization of glycogen comes normal.

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• Illness arises as result of insufficiency of hepatic phosphorilase complex.

• Glycogen accumulates in liver. • Typical sign is hepatomegalia.

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• Type VІІ glycogenosis.Type VІІ glycogenosis. Illness Illness essence is in oppression of muscle essence is in oppression of muscle phosphofrutkinase. Symptoms are phosphofrutkinase. Symptoms are similar to McArdles diseasesimilar to McArdles disease.

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