Lecture 1.Lecture 1.

Etiology, pathogenesis, classification, Etiology, pathogenesis, classification, early diagnosis, clinical presentation early diagnosis, clinical presentation and differential diagnosis of Diabetes and differential diagnosis of Diabetes

Mellitus. Metabolic syndrome.Mellitus. Metabolic syndrome.

IRYNA KOSTITSKAIRYNA KOSTITSKACandidate of Sciences (Medicine)Candidate of Sciences (Medicine)

Associate professorAssociate professor of endocrinology chair of endocrinology chair

PLAN OF THE LECTUREPLAN OF THE LECTURE1.1. Preface.Preface.2.2. History of Diabetes Mellitus.History of Diabetes Mellitus.3.3. Hormones of pancreas. Mechanisms secretion and the Hormones of pancreas. Mechanisms secretion and the

actions of insulin. actions of insulin. 4.4. Definition of Diabetes Mellitus.Definition of Diabetes Mellitus.5.5. Classifications of Diabetes Mellitus.Classifications of Diabetes Mellitus.6.6. Etiology, pathogenesis of Diabetes Mellitus.Etiology, pathogenesis of Diabetes Mellitus.7.7. Clinical presentation of Diabetes Mellitus.Clinical presentation of Diabetes Mellitus.8.8. Early diagnosis of Diabetes Mellitus. Criteria of Early diagnosis of Diabetes Mellitus. Criteria of

diagnostics of diabetes mellitus and other types of diagnostics of diabetes mellitus and other types of hyperglycemia.hyperglycemia.

9.9. Criteria of compensation of Diabetes Mellitus.Criteria of compensation of Diabetes Mellitus.10.10. Differential diagnosis of Diabetes Mellitus.Differential diagnosis of Diabetes Mellitus.11.11. Metabolic syndrome.Metabolic syndrome.

DM DM will surely be one of our most common and challenging health problems in the 21in the 21stst century. century.

One of the most challenging health problems facing the One of the most challenging health problems facing the world:world:

346 million people 346 million people worldwide diagnosed in 2011201155thth leading cause leading cause of death of death in developed countries

ComplicationsComplications – heart attacks, stroke, kidney failure, – heart attacks, stroke, kidney failure, amputations and blindness amputations and blindness

According to the World Health Organization (WHO), World Health Organization (WHO), the number of global cases of DM is expected to increase in the

next 25 years 25 years nearly 580 million people.nearly 580 million people.

Diabetes Mellitus (DM)Diabetes Mellitus (DM)The name 'diabetes mellitus' 'diabetes mellitus' derives from:GreekGreek: : 'diabetes' 'diabetes' – “siphon” – “siphon” or “to pass “to pass through”through”Latin: Latin: 'mellitus''mellitus' – “honeyed– “honeyed” or “sweet”“sweet”

History of Diabetes MellitusHistory of Diabetes Mellitus

First known reference comes from an First known reference comes from an Egyptian papyrusEgyptian papyrus dating backdating back

to 1550 B.C. to 1550 B.C. Earliest known record of diabetes mentioned on 3rd Dynasty Egyptian

papyrus by physicianphysician Hesy-RaHesy-Ra; mentions polyuria as a symptom.

Diabetes Diabetes was named by the Greek Greek physician physician AretaeusAretaeus between 30 and between 30 and

90 A.D. 90 A.D.

400 B.C400 B.C.-Indian surgeon .-Indian surgeon Susruta Susruta describes ‘honeyed ‘honeyed urines’ urines’ produced by ‘big eaters of rice and sugar’.‘big eaters of rice and sugar’.

AvicennaAvicenna, a famous Arab , a famous Arab physician, described the physician, described the

complications of the disease and complications of the disease and how it progressedhow it progressed

History of Diabetes MellitusHistory of Diabetes Mellitus

250 A.D.- 250 A.D.- Apollinius of Apollinius of MemphisMemphis coins the name coins the name

‘diabetes’‘diabetes’

History of Diabetes MellitusHistory of Diabetes Mellitus1674 1674 - Thomas Willis Thomas Willis publishes ‘The Diabetes or Pissing Evil’. ‘The Diabetes or Pissing Evil’. Writes ‘those laboring with this ‘those laboring with this Disease, piss a great deal more Disease, piss a great deal more than they drink’than they drink’ asserting that all diabetic urine ‘‘was wonderfully was wonderfully sweet as if it were imbued with sweet as if it were imbued with

Honey or Sugar’.Honey or Sugar’.1798 1798 - John Rollo John Rollo documents

excess sugar in blood and urine18131813- Claude Bernard Claude Bernard links

diabetes with glycogen metabolism

History of Diabetes MellitusHistory of Diabetes Mellitus18691869- Paul Langerhans Paul Langerhans (German medical student) finds islets in the pancreas, but is

unable to explain function.

French physician Apollinaire BouchardatApollinaire Bouchardat recognized the importance of calorie intake

in the 1870s.in the 1870s.

18891889- Josef Baron von Mering Josef Baron von Mering and Oskar OskarMankowski Mankowski prove that diabetes develops when they remove the pancreas of dogs.

History of Diabetes MellitusHistory of Diabetes Mellitus1901 - Eugene Opie, an American pathologist at Johns Hopkins University, made the association between the degeneration of these cells, which had been named the “islets of Langerhans,” and the onset of diabetes.  1910-1910- English physiologist, Sir Sir Edward Albert Sharpey-SchaferEdward Albert Sharpey-Schafer, suggested that a single chemical component was missing from the pancreas of diabetics and called it “insulininsulin”.

History of Diabetes MellitusHistory of Diabetes Mellitus

19221922- James Bertram Collip James Bertram Collip The first clinical tests on a

human patient were conducted on a severely diabetic 14 year

old boy. 

The Face of IDDM The Face of IDDM in 1920 was in 1920 was

not encouragingnot encouraging

1923 - 1923 - Frederick Banting Frederick Banting and Charles Charles HerbertHerbert Best Best awarded Nobel Prize for

Discovery and use of Insulin in thetreatment of IDDM.

History of Diabetes MellitusHistory of Diabetes MellitusFrederick BantingFrederick Banting John James Rickard John James Rickard

MacleodMacleod

James Bertram James Bertram CollipCollip

Charles Charles Herbert BestHerbert Best

Normal Insulin PhysiologyNormal Insulin PhysiologyProduced within the

pancreas by β cells, islets of Langerhans – identified

by Paul Langerhans in 1869.

Islets of Langerhans – α cells – secrete glucagons,glucagons,

delta cells – somatostatinsomatostatin

PP cells – pancreatic pancreatic polypeptide.polypeptide.

Insulin is an anabolic hormone.

Insulin is a polypeptide (built from 51 amino acids:

Chain A consists of 21, chain B of 30 amino acids. 2

chains linked by disulfide disulfide bondsbonds)

Daily pancreatic production of insulin in the adult

individual to approximately 50 units ( 0.7–1.3 mg).

Mechanisms of insulin secretionMechanisms of insulin secretion

INSULININSULIN

Synthesis of glycogenSynthesis of glycogenGLYCOLYSISGLYCOLYSIS

Glucose uptakeGlucose uptake

Blood glucoseBlood glucose

GLYCOGENOLYSISGLYCOGENOLYSIS

EpinephrineEpinephrine

GlucagonGlucagon

ACTHACTHGrowth hormoneGrowth hormoneGlucocorticoidsGlucocorticoids

--

++

++

++

++--

The actions of insulinThe actions of insulin Insulin Insulin increases utilization of glucose by muscles and adipose

tissue, increases the synthesis of glycogen in the liver and muscles, reduces glycogenolysis and glyconeogenesisglycogenolysis and glyconeogenesis.

In adipose tissue insulininsulin increasesincreases synthesis of the fatty acidsfatty acids, promotes lipogenesis, lipolysis and synthesis of ketones. promotes lipogenesis, lipolysis and synthesis of ketones.

InsulinInsulin facilitates protein metabolism, increases absorption of increases absorption of amino acid, synthesis of the proteinsamino acid, synthesis of the proteins and reduces their catabolism.

Insulin Insulin also increases metabolism of the nucleotidesincreases metabolism of the nucleotides – absorption and synthesis of nucleoid acids, as well as of RNA and DNA

increases. InsulinInsulin takes part in the process of growth and differentiation of all growth and differentiation of all

body tissuesbody tissues. It supports their energy status, provides differentiation, activation of the immunocompetent lymphocites, due

to the synthesis of the proteins and nucleotides the processes of transcription and translation of genetic information are carried out.

Action of Insulin on Various TissuesAction of Insulin on Various Tissues MuscleMuscle AdiposeAdipose

↓↓ Glucose Glucose productionproduction

↑↑ Glucose transportGlucose transport ↑↑ Glucose transportGlucose transport

↑↑ GlycolysisGlycolysis ↑↑ GlycolysisGlycolysis ↑↑ Lipogenesis& Lipogenesis& lipoprotein lipase lipoprotein lipase

activityactivity

↑↑ TG TG synthesissynthesis

↑ ↑ Glycogen Glycogen depositiondeposition

↓↓ Intracellular Intracellular lipolysislipolysis

↑↑ Protein Protein synthesissynthesis

↑↑ Protein synthesisProtein synthesis

Effects of insulin deficiencyEffects of insulin deficiencyMetabolic defects Chemical abnormalities Clinical abnormalities

Carbohydrate MetabolismCarbohydrate Metabolism1.Diminished uptake of glucose by tissues such as muscle, adipose tissue and liver

2. Overproduction of glucose (via glycogenolysis and glyconeogenesis) by the liver

HyperglycemiaPolyuria, polydipsia,

polyphagiaBlurred vision,

Diminished mental alertness

Protein MetabolismProtein Metabolism1.Diminished uptake of amino and diminished synthesis of protein

2. Increased proteolysis

Negative nitrogen balance

Elevated levels of branch chain amino acids

Elevated blood ureanitrogen level

Elevated potassium level

Loss of muscle mass

Weakness

Fat MetabolismFat Metabolism1.Increased lipolysis  2.Decreased lipogenesis3.Increased production of triglycerides

4.Decreased removal of ketones and increased ketone production

Elevated plasma fatty acids level

Elevated plasma glycerol level

Hypertriglyceridemia

Elevated plasma and urine ketones

Loss of adipose tissue

Exudative xanthoma

Lipemia retinalisPancreatitis

(abdominal pain)Hyperventilation

metabolic acidosis

A glossary of A glossary of terms terms will be usedwill be used GlycogenesisGlycogenesis -- the process by which glycogen is formed from

glucose.GluconeogenesisGluconeogenesis –– the formation of glucose, especially by the liver, from noncarbohydrate sources, such as amino acids and the glycerol

portion of fats.Lipogenesis(adipogenesis)-Lipogenesis(adipogenesis)- production of fat, either fatty

degeneration or fatty infiltration. The normal deposition of fat or the conversion of carbohydrate or protein to fat.

LipolysisLipolysis –– the metabolic process of breaking down lipids release free fatty acids, the major oxidative fuel for the body.

EuglycemiaEuglycemia or or NormoglycaemiaNormoglycaemia-- normal blood glucose level (fasting 3.3-5.5 mmol/L and 2 hour after meal less than 7.8 mmol/L).

HHypoglycemia-ypoglycemia- low blood glucose level (<2.75 mmol/L).HHyperglycemia-yperglycemia- high blood glucose level.

HyperinsulinismHyperinsulinism -- high a level of insulin in the blood.Impaired Glucose Tolerance (IGT)Impaired Glucose Tolerance (IGT) -- blood glucose levels higher

than normal but not high enough to be called diabetes (prediabetes).GGlycosuria-lycosuria- high glucose in the urine.KKetonuria-etonuria- ketone bodies in the urine.

PPolyphagiaolyphagia-- excess appetite.PPolyuriaolyuria-- excess urinating.

PPolydypsia-olydypsia- excess drinking.

CLINICAL CASECLINICAL CASE The patient B., 26 years old complainscomplains of weight loss (8 kg during 6 months), moderate dryness in the mouth, gingival hemorrhage, thirst, polyuria (diuresis - 5 L/day), growing the weakness. He feels ill for 5 months. Anamnesis of life: Anamnesis of life: Physical development in childhood was normal. He had history of diabetes mellitus in several family members: mother and grandfather. Allergic reactions were absent. Objectively:Objectively: General conditions of patient is middle heaviness. Body weight - 68 kg. Height -188 cm. BMI – 19,4 kg/m2. His temperature is 36.6 °C. The skin and mucosas are moderately dry, considerable grow thin, especially muscles. Boils on thigh. Tongue is dry. Type of breathing is abdominal. The borders of relative and absolute heart dullness are normal. Pulse – 76 beats/ min, rhythmical, BP- 130/80 mmHg. The loudness of heart tones amplified. Stomach is soft, liver doesn’t increased. Urination – accelerating, mainly in the night. Lab studies:Lab studies: the fasting level of glucose- 14 mmol/L; the level of the HbA1c – 10%; the glucosuria - 22 g/L; reaction of urine to acetone - negative.What is the most likely diagnosis?What is the most likely diagnosis?

Definition Definition DIABETES MELLITUS (DM)DIABETES MELLITUS (DM) (World Health Organization )(World Health Organization )

The term DMDM describes a metabolic disorder of multiple etiology characterized by chronic hyperglycemia with

disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action,

or both.

DMDM is a group of metabolic (endocrine) diseases, resulting from a variable interaction of hereditary and environmental

factors, wich is presented by hyperglycaemia following absolute or relative insulin insufficiency that causes

metabolic manifestations reflected in a tendency toward accelerated non – specific atherosclerosis, macro- and

microangiopathy, neuropathy, increased susceptibility to infection.

Etiologic Classifications of Diabetes MellitusTYPE 1

DIABETES MELLITUS

β-cell destruction, usually leading to absolute insulin deficiency.

idiopathic type 1 - refers to rare forms of the disease with no known

cause.immune-mediated diabetes - an autoimmune disorder in which the

body's immune system destroys, or attempts to destroy, the cells in the

pancreas that produce insulin. TYPE 2

DIABETES MELLITUS

predominantly insulin resistanceinsulin resistance with relative insulin deficiency or

predominantly an insulin secretory defect with/without insulin resistance.

GESTATIONAL DIABETES

is carbohydrate intolerance resulting in hyperglycaemia of variable severity with

onset or first recognition during pregnancy.

20

Insulinindependent Insulinindependent ((adult-onset diabetesadult-onset diabetes))

HeredityHeredityInactivityInactivityObesityObesity

Insulin resistanceInsulin resistanceMore common in adults More common in adults

after 35 yearsafter 35 years Treatment: diet, sugar Treatment: diet, sugar

lowering drugslowering drugs

Insulindependent Insulindependent ((or or ““juvenile-onset juvenile-onset diabetesdiabetes”,”, "juvenile "juvenile

diabetes," and diabetes," and "ketosis-prone "ketosis-prone

diabetes")diabetes")

AutoimmuneAutoimmune GeneticsGenetics

(HLA-B8, B15(HLA-B8, B15 )) More common More common in younger than in younger than

35 years or children35 years or children

Treatment: diet, Treatment: diet, insulininsulin

Pathogenesis of Type 1 Diabetes MellitusPathogenesis of Type 1 Diabetes MellitusViruses

Infection of Infection of ββ cells cells Systemic infection Systemic infection

Direct Direct cytolyticcytolytic effectseffects

ββ cells necrosis cells necrosis Autoimmune Autoimmune ββ cells damage cells damage

Type 1 Type 1 Diabetes MellitusDiabetes Mellitus

Indirect immune effectsIndirect immune effects• Viral antigens expressedViral antigens expressed

•ββ cell antigens altered cell antigens altered•Expression of cytokines Expression of cytokines

or HLA antigensor HLA antigens

•Activation of immune Activation of immune responseresponse

•Breakdown of immune Breakdown of immune tolerancetolerance

•Immune response cross Immune response cross reacts withreacts with

ββ cell autoantigens cell autoantigens(molecular mimicry)(molecular mimicry)

Insulin Resistance: Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Hyperglycemia /Hyperglycemia /Type 2 DMType 2 DM

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Pathogenesis of Type 2 Diabetes MellitusPathogenesis of Type 2 Diabetes Mellitus

GeneticsGeneticsEnvironmentEnvironment

obesity; obesity; hypodynamia;hypodynamia;polyphagiapolyphagia

CRITERIA FOR DIAGNOSISCRITERIA FOR DIAGNOSIS

POLYDIPSIAPOLYDIPSIA

RAPID WEIGHT LOSSRAPID WEIGHT LOSSPOLYURIAPOLYURIA

HYPERGLYCEMIAHYPERGLYCEMIA> 11.1 mmol/L> 11.1 mmol/L

DIABETES

DIABETES

SYMPTOMS

SYMPTOMS

Diagnose Diagnose DDiabetes iabetes MMellitus ellitus ifif one of the one of the

following is presentfollowing is present

Casual plasma glucoseCasual plasma glucose (is (is defined as any time of the defined as any time of the day, without regard to the day, without regard to the

interval since the last meal)interval since the last meal)

> 11.1 mmol/L> 11.1 mmol/L

Fasting plasma glucoseFasting plasma glucose > 7.0 mmol/L> 7.0 mmol/L2-hour plasma glucose 2-hour plasma glucose during an oral glucoseduring an oral glucose

tolerance testtolerance test>11.1 mmol/L>11.1 mmol/L

Symptoms of diabetesSymptoms of diabetes mellitus mellitus plus plus

Manifestation of Manifestation of diabetes mellitusdiabetes mellitus

Considerable Considerable general general

weaknessweakness

ThirstThirst (polydipsia)(polydipsia) GlucosuriaGlucosuria

IItch of skintch of skin and and

genitalsgenitals

PolyphagiaPolyphagia

Weight lossWeight loss

PoliuriyaPoliuriya

HyperglycemiaHyperglycemia

THE ORAL GLUCOSE TOLERANCE TESTTHE ORAL GLUCOSE TOLERANCE TEST (GTT) (GTT) The The Testing for Diabetes in Asymptomatic Patients;Testing for Diabetes in Asymptomatic Patients;

GTT should be considered in all adults who are overweight (BMI ≥25 kg/m2) and have additional risk factors: • Physical inactivity•First-degree relative with diabetes•High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)•Women who delivered a baby weighing >5 kg or were diagnosed with GDM•Hypertension (≥140/90 mmHg or on therapy for hypertension)•Women with polycystic ovarian syndrome (PCOS)•A1C ≥5.7%, IGT, or IFG on previous testing•Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)•History of CVD

Preparation of the patient:Preparation of the patient:Three days unrestricted, carbohydrate rich diet and activity.Three days unrestricted, carbohydrate rich diet and activity.

No medication on the day of the test.No medication on the day of the test. 12-h fast.12-h fast.

No smoking.No smoking.Glucose load: Adults 75 g in 300 – 400 mL of water.

Children: 1,75 g/Kg up to 75 g glucoseSolutions containing glucose and oligosaccharides are commercially available.

For interpretation of results, refer to Table: For interpretation of results, refer to Table:

Criteria of diagnostics of diabetes mellitus Criteria of diagnostics of diabetes mellitus and other types of hyperglycemia (WHO, 1999)and other types of hyperglycemia (WHO, 1999)

DiagnosisConcentration of glucose, mmol/L

Whole blood PlasmaVenous Capillary Venous Capillary

Diabetes mellitus: Diabetes mellitus: Fasting level

In 2 hours after glucose load

6.1

10.0

6.1

11.1

7.0

11.1

7.0

12.2

Impaired tolerance Impaired tolerance to glucose:to glucose:

Fasting level

In 2 hours after glucose load

6.1

6.7-10.0

6.1

7.8-11.1

7.0

7.8-11.1

7.0

8.9-12.2

Impaired glycemia in Impaired glycemia in the fasted statethe fasted state

5.6-6.1 5.6-6.1 6.1-7.0 6.1-7.0

Laboratory TestsLaboratory TestsFasting plasma glucose (FPG)Fasting plasma glucose (FPG)

GGlycosylated lycosylated HHemoglobin emoglobin TTestest ( (HbA1c, glycohemoglobinHbA1c, glycohemoglobin)) - It is produced by nonenzymatic condensation of glucose

molecules with free amino groups on the globin component of hemoglobin. Level of HbA1c shows an average blood

concentration during the previous 2 – 3 month. Normal Normal level of level of HbA1cHbA1c is 4-6%. is 4-6%.

C-peptideC-peptide is a connective peptide between A and B by the is a connective peptide between A and B by the chainlets of insulin.chainlets of insulin. The level of C – peptide is 1- of 2,8 1- of 2,8

mmol/mlmmol/ml, it is determined by radioimmune test kits. The level of c-peptide in type 1 diabetus mellitus is reduced.

FructosamineFructosamine is a product of glycosilation of the plasma is a product of glycosilation of the plasma proteins, particilarly of the albumen which has a period of proteins, particilarly of the albumen which has a period of

semilife of 14 days.semilife of 14 days. Normal level is less then 0,285 mmol/LNormal level is less then 0,285 mmol/L.

Immunoreactive insulin -Immunoreactive insulin - the secretion of the endogenous e secretion of the endogenous insulin in a healthy man is on average insulin in a healthy man is on average 5- 20 5- 20 мкЕмкЕ /mL /mL in the in the

fasted state.fasted state.

Laboratory TestsLaboratory Tests

Insulin autoantibody Insulin autoantibody (IAA), glutamic acid decarboxylase glutamic acid decarboxylase (GADA), islet cell antibodies islet cell antibodies ( ICA) ,-now replaced by tyrosine tyrosine

phosphatase autoantibodies phosphatase autoantibodies (IA-2,IA2-b) are the most commonly used tests .

Self-monitoring of blood glucoseSelf-monitoring of blood glucose by people with diabetes (Diabetes Control and Complications TrialDiabetes Control and Complications Trial):blood glucose

monitors / glucometers (Accu-Chek Sensor, Van Touch Ultra and other ) and ccontinuous glucose monitoring systemontinuous glucose monitoring system ..

Fasting lipid profileFasting lipid profile (14 hours): total cholesterol, HDL cholesterol, triglycerides, and LDL cholesterol.

Renal and liver function tests:Renal and liver function tests: serum creatinine and blood

urea nitrogen (BUN) levels, and a glomerular filtration rate (GFR); albumin, bilirubin, AST, ALT.

Lima Blood Sugar AnalyserLima Blood Sugar Analyserthe technological base of lima is the non-invasive measurementthe technological base of lima is the non-invasive measurement

via infrared radiationvia infrared radiation

Freedom Meditech promises glucose-Freedom Meditech promises glucose-monitoring eye scannermonitoring eye scanner

Laboratory TestsLaboratory TestsURINE TESTSURINE TESTS::

GlucosuriaGlucosuria appears in the urine of a healthy man when glycemia rises above kidney threshold that corresponds the

level of glycemia ofglycemia of 8.8- 9.0 mmol/L. 8.8- 9.0 mmol/L.

Glucose LevelsGlucose Levels and Fractional Urine and Fractional Urine ("block urine")-("block urine")- urine that a person collects for a certain period of time during

24 hours.

KetonuriaKetonuria when decompensation of diabetes mellitus occurs, ”ketone” bodies present in urine. Determination of ketonuria is conducted by the test strips ( «Ketostiks», «Keto- Diastiks»).

Microalbuminuria and proteinuria:Microalbuminuria and proteinuria: the early stage of albuminuria is clinically defined as an albumin excretion rate of 30-

300 mg/24 hours (20-200 g/min).

IndividualIndividualglucometersglucometers

Ketostiks (Bayer)

Glucose + Glucose + Keton bodiesKeton bodies

Clinical classification of diabetes mellitus (A.S. Efimov, 1998)Clinical classification of diabetes mellitus (A.S. Efimov, 1998)I. Type of Diabetes mellitus:I. Type of Diabetes mellitus:Type 1 diabetes mellitus Type 2 diabetes mellitusGestational diabetes mellitus

II.II. Forms (degree) of severity: Forms (degree) of severity: MildMildMediumMediumSevereSevere III.III. State of compensationState of compensation:: Good Good SatisfactorySatisfactoryBad or DecompensationBad or Decompensation

IV. Presence of chronic diabetic complications:IV. Presence of chronic diabetic complications:MikroangiopatMikroangiopathyhy - retinopathy, nephropthy, diabetic food.MakrooangiopathyMakrooangiopathy - with the overwhelming defeat of large vessels

(heart, brain, feet).Universal Universal mikro-mikro- and and makroangiopamakroangiopathy.thy.Polineuropathy Polineuropathy (peripheral, autonomous, visteral).Encephalopathy.Encephalopathy.

V.V. Afection of other organs and systemsAfection of other organs and systems: : steatohsteatohepatoepatosis, cataract, sis, cataract,

dermatopadermatopathy, othy, osteoartropasteoartropathy and thy and other.other.

VI.VI. AcuteAcute complications of diabetes complications of diabetes mellitus:mellitus:

diabetic ketosis, ketoacidosis (DKA, diabetic ketosis, ketoacidosis (DKA, ketoacidotic coma), hyperosmolar ketoacidotic coma), hyperosmolar

(nonketotic) coma, lactacidotic coma, (nonketotic) coma, lactacidotic coma, hypoglycemic coma.hypoglycemic coma.

In UkraineIn Ukraine there are three degrees (forms)three degrees (forms) of severity of manifest diabetes mellitus. Abroad this classification is not used.

The major criteria at the estimation of the severity degree are susceptibility to ketoacidosis, hypoglycemic comas, the dosage and the character of

oral hypoglycemic preparations, which are necessary for achievement and permanent keeping of the state of compensation of disease.

MILD DEGREE:MILD DEGREE:the absence of comas in anamnesis, only diet therapy

(patients with type 2 diabetes mellitus).MEDIUM DEGREE: MEDIUM DEGREE:

diet, oral hypoglycemic preparations or insulin in daily doses is 60 IU (at most), chronic complications (diabetic angioneuropathy of various

intensity and localization).SEVERE DEGREE: SEVERE DEGREE:

diet, insulin therapy more than 60 IU a day, presence of comas in anamnesis and serious form of chronic complications (angioneuropathy,

nephropathy, retinopathy and others).

Criteria of compensation of type 1 diabetes mellitusCriteria of compensation of type 1 diabetes mellitus(European Group on the Type 1 Diabetes, 1998)(European Group on the Type 1 Diabetes, 1998)

Criteria Healthy Adequate control

Inadequate control

Glucose (mmol/L)Glucose (mmol/L)

Fasted stateFasted state 4.0-5.0 5.1-6.5 >6.5

After the mealAfter the meal 4.0-7.5 7.6-9.0 >9.0

Before sleepBefore sleep 4.0-5.0 6.0-7.5 >7.5

Glycosilated Glycosilated haemoglobin (%)haemoglobin (%)

<6.1 6.2-7.5 >7.5

Criteria of compensation of type 2 diabetes mellitusCriteria of compensation of type 2 diabetes mellitus(International group, 1999)(International group, 1999)

Indices Compensation Good Good SatisfactorySatisfactory BadBad

Glycemia mmol/L:Fasting

Postprandial 4.4-6.15.5-8.0

6.2-7.88.1-10.0

>7.8>10.0

Glycosilated haemoglobin (%) <6.5 6.5-7.5 >7.5

Total cholesterol, mmol/L <4.8 4.8-6.0 >6.0Triglicerides, mmol/L <1.7 1.7-2.2 >2.2

Body mass index, kg/m2

men women

<25 <24

25-27 24-25

>27 >25

Blood pressure, mm Hg systolic

diastolic <120<80

120-140 80-90

>140 >90

Correlation of A1C with Estimated Correlation of A1C with Estimated Average Glucose (eAG)Average Glucose (eAG)

HbA1C (%)HbA1C (%) Mean plasma glucoseMean plasma glucose(mmol/L)(mmol/L)

66 7.07.077 8.68.688 10.210.299 11.811.8

1010 13.413.41111 14.914.91212 16.516.5

Contains the correlation between A1C levels and mean plasma glucose (PG) Contains the correlation between A1C levels and mean plasma glucose (PG) levels based on data from the international A1C-Derived Average Glucose levels based on data from the international A1C-Derived Average Glucose

(ADAG) with type 1 and type 2 diabetes (ADAG) with type 1 and type 2 diabetes

Differential diagnosis of Diabetes MellitusDifferential diagnosis of Diabetes Mellitus

Symptomatic Hyperglycemia Symptomatic Hyperglycemia in patient in patient

with Hyperthyroidismwith Hyperthyroidism

Symptomatic HyperglycemiaSymptomatic Hyperglycemia in patient with in patient with

PheochromocytomaPheochromocytoma

Symptomatic HyperglycemiaSymptomatic Hyperglycemia in patient within patient with

Cushing’s DiseaseCushing’s Disease

Renal (Nondiabetic) Glucosuria

Symptomatic HyperglycemiaSymptomatic Hyperglycemia in patient with in patient with

Cushing’s syndromeCushing’s syndrome

Symptomatic HyperglycemiaSymptomatic Hyperglycemia in patient that use in patient that use Medications such as Medications such as

diuretics , phenytoin , and high-dose diuretics , phenytoin , and high-dose glucocorticoidsglucocorticoids ect ect

Diabetes InsipidusDiabetes Insipidus

CLINICAL CASECLINICAL CASEThe patient G., a 45 year old is concerned she may have

diabetes mellitus. She had diabetes during her last pregnancy managed with diet. Lately she has been feeling tired but

otherwise has no complaints. Her mother and one of her two sisters already have diabetes treated with tablets. She has been overweight since her last pregnancy and has taken a tablet for blood pressure for the last 2 years. She is obese, body mass

index 34.5 kg/m2. Blood pressure is 140/90 mmHg, but otherwise her examination is normal. She undergoes a testing and her fasting glucose is 9.4 mmol/L. Obese, strong family

history, aged in 40s, previous history of diabetes in pregnancy all point to type 2 diabetes mellitus.

METABOLIC SYNDROMEMETABOLIC SYNDROMEAlso known as Also known as Cardiovascular Dysmetabolic Syndrome, Cardiovascular Dysmetabolic Syndrome, Insulin Resistance Syndrome, Syndrome X, The Deadly Insulin Resistance Syndrome, Syndrome X, The Deadly

quartet, Cardiometabolic Syndrome, Beer Belly Syndrome, quartet, Cardiometabolic Syndrome, Beer Belly Syndrome, Reaven’s SyndromeReaven’s Syndrome

a cluster of symptomsa cluster of symptoms including centralincluding central adiposity, adiposity, hypertriglyceridemia, hypertension,low levels of high-hypertriglyceridemia, hypertension,low levels of high-

density lipoprotein (HDL) cholesterol,density lipoprotein (HDL) cholesterol, and elevated fasting and elevated fasting plasma glucose levels, isplasma glucose levels, is associated withassociated with increased risk increased risk

for heart disease, type 2 diabetes mellitus,for heart disease, type 2 diabetes mellitus, and and cardiovascular and all-cause mortalitycardiovascular and all-cause mortality..

SHORT HISTORY OF SEARCH FOR SHORT HISTORY OF SEARCH FOR METABOLIC SYNDROMEMETABOLIC SYNDROME

1923:1923: Kylin describes clustering of hypertension, gout, and Kylin describes clustering of hypertension, gout, and hyperglycemiahyperglycemia

1988:1988: Reaven describes “Syndrome X” – hypertension, Reaven describes “Syndrome X” – hypertension, hyperglycemia, glucose intolerance, elevated triglycerides, and hyperglycemia, glucose intolerance, elevated triglycerides, and

low HDL cholesterollow HDL cholesterol

1998:1998: WHO defines “metabolic syndrome” as clustering of WHO defines “metabolic syndrome” as clustering of hypertension, low HDL, hypertriglyceridemia, insulin resistance, hypertension, low HDL, hypertriglyceridemia, insulin resistance, glucose intolerance or type 2 diabetes, high waist-to-hip ratio, glucose intolerance or type 2 diabetes, high waist-to-hip ratio,

and microalbuminuriaand microalbuminuria

2001:2001: NCEP ATP III provides clinical definition of “metabolic NCEP ATP III provides clinical definition of “metabolic syndrome”syndrome”

INSULIN RESISTANCE IS LINKED TO A RANGE OF INSULIN RESISTANCE IS LINKED TO A RANGE OF CARDIOVASCULAR RISK FACTORSCARDIOVASCULAR RISK FACTORS

Atherosclerosis

HyperglycemiaHyperglycemia

DyslipidemiaDyslipidemia

HypertensionHypertension

Damage to blood Damage to blood vesselsvessels

Clotting Clotting abnormalitiesabnormalities

InflammationInflammation

InsulinInsulinresistanceresistance

IR

Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

Obesity, Metabolic Syndrome, Type 2 Diabetes Obesity, Metabolic Syndrome, Type 2 Diabetes Mellitus and Cardiovascular DiseaseMellitus and Cardiovascular Disease

ObesityObesity

Cardiovascular disease

Metabolic syndromeMetabolic syndrome

Insulin resistanceInsulin resistance

4 Risk

DiabetesDiabetes

DIETDIET

-- ++

++

++

++

Vessels Vessels HeartHeart KidneysKidneys

Vasoconstriction Cardiac output Cardiac output Na+ Na+ reabsorption reabsorption

BLOOD PRESSUREBLOOD PRESSURE

++ ++ ++

Risk factor Risk factor Defining level Defining level Abdominal obesity

(waist measurement)

BMI > 30 kg/mBMI > 30 kg/m22

Men: Greater than 102 cm102 cmWomen: Greater than 88 cm88 cm

Triglycerides 2.2 mmol/L or higher2.2 mmol/L or higher, or taking medicine for high

triglyceridesTotal cholesterol 5.2 mmol/L or higher 5.2 mmol/L or higher

Blood pressure 130/85 mm Hg or higher130/85 mm Hg or higher, or taking medicine for high blood

pressureFasting blood glucose 6.1 mmol/L or higher6.1 mmol/L or higher, or

taking medicine for high blood sugar

Criteria for Criteria for MMetabolic etabolic SSyndromeyndromeMetabolic syndrome ICD-9-CM code: 277.7Metabolic syndrome ICD-9-CM code: 277.7

CComponentsomponents of the Metabolic Syndrome of the Metabolic Syndrome

ComponentsComponentsNCEP ATP III, NCEP ATP III,

≥3≥3

20012001

IDF, WC + ≥2IDF, WC + ≥2

2005 2005

AHA/NHLBI, AHA/NHLBI, ≥3≥3

20052005

Waist Waist circumference circumference

(WC), cm(WC), cm>102 (m) >88 (f)>102 (m) >88 (f)

Europid ≥94 (m) ≥80 (f) Europid ≥94 (m) ≥80 (f) S. Asian ≥90 (m) ≥80 (f)S. Asian ≥90 (m) ≥80 (f)

Japanese ≥85 (m) ≥90 (f) Japanese ≥85 (m) ≥90 (f) >102 (m) >88 (f)>102 (m) >88 (f)

TG, mmol/LTG, mmol/L 1.71.7 1.71.7 1.71.7

HDL-C, HDL-C, mmol/Lmmol/L <<1.031.03 (m) <1.29 (f) (m) <1.29 (f) <1.03 (m) <1.29 (f)<1.03 (m) <1.29 (f) <1.03 (m) <1.29(f)<1.03 (m) <1.29(f)

BP, mm HgBP, mm Hg 130/130/8585 130 OR 130 OR 8585 130 OR 130 OR 8585

FPG, mmol/LFPG, mmol/L 6,16,1 5.65.6 5.65.6

Examples of the diagnosis of diabetes mellitusExamples of the diagnosis of diabetes mellitus

► Type 1 Type 1 Diabetes mellitusDiabetes mellitus first diagnostic first diagnostic with with ketoacidosisketoacidosis ( (datedate – 15.09.12.) – 15.09.12.) in decompensation.in decompensation.► Type 1 Type 1 Diabetes mellitusDiabetes mellitus medium degree medium degree in in

satisfactory compensation. satisfactory compensation. ► Type 1 Type 1 Diabetes mellitusDiabetes mellitus severe degree severe degree in satisfactory in satisfactory

compensation. compensation.

► Type 2 Diabetes mellitus mild degree in good Type 2 Diabetes mellitus mild degree in good compensation. Metabolic syndrome. Obesity class I. compensation. Metabolic syndrome. Obesity class I.

Hypertension. Hypertension. ► Type 2 Type 2 Diabetes mellitusDiabetes mellitus medium degree medium degree in bad in bad

compensation.compensation.