DIABETES MELLITUS. What is diabetes mellitus? The majority of intake of food is converted into...

DIABETES DIABETES MELLITUSMELLITUSDIABETES DIABETES MELLITUSMELLITUS

What is diabetes mellitus?

The majority of intake of food is The majority of intake of food is converted into glucose. converted into glucose.

The pancreas produces the insulin The pancreas produces the insulin hormone, which help the organism to hormone, which help the organism to take advantage of glucose. take advantage of glucose.

In persons with diabetes, the insulin does In persons with diabetes, the insulin does not work. Therefore, the sugar and the not work. Therefore, the sugar and the fat increase in the blood.fat increase in the blood.

The World Wide Epidemic:Prevalence of Diabetes

5%

8%14%

4%

3%

The Worldwide Epidemic:Diabetes Trends

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1985 1995 2000 2010 2025 2030

Sources: www.who.intwww.idfZimmet P. et al Nature: 414, 13 Dec 2001

PHYSIOLOGICAL IMPACT 66thth leading cause of death by disease leading cause of death by disease Decreases life expectancy of middle-aged people Decreases life expectancy of middle-aged people

by 5-10 yearsby 5-10 years 2-4 x greater risk of death d/t heart disease2-4 x greater risk of death d/t heart disease

– Compounding factors include: duration of disease, Compounding factors include: duration of disease, glycemic control, HTN, smoking, dyslipidemia, glycemic control, HTN, smoking, dyslipidemia, decreased activity, and obesitydecreased activity, and obesity

Leading cause of blindness in 25-74 year oldsLeading cause of blindness in 25-74 year olds Leading cause of non-traumatic amputationsLeading cause of non-traumatic amputations Responsible for 25-30% of all new dialysis Responsible for 25-30% of all new dialysis

patientspatients

DIABETES MELLITUS

Definition: a metabolic disorder in which Definition: a metabolic disorder in which there is deficiency of insulin there is deficiency of insulin production or resistance of organs to production or resistance of organs to the effect of insulinthe effect of insulin

DIABETES MELLITUS

Diabetes is a disorder of metabolism--the way Diabetes is a disorder of metabolism--the way our bodies use digested food for growth and our bodies use digested food for growth and energy. energy.

Most of the food we eat is broken down into Most of the food we eat is broken down into glucose, the form of sugar in the blood. glucose, the form of sugar in the blood.

Glucose is the main source of fuel for the Glucose is the main source of fuel for the body.body.

<http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what><http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>

DIABETES MELLITUS After digestion, glucose passes into the After digestion, glucose passes into the

bloodstream, where it is used by cells for bloodstream, where it is used by cells for growth and energy. growth and energy.

For glucose to get into cells, insulin must be For glucose to get into cells, insulin must be present. present.

Insulin is a hormone produced by the Insulin is a hormone produced by the pancreas, a large gland behind the stomach.pancreas, a large gland behind the stomach.


Regulation of Blood Sugar

High blood sugarHigh blood sugar Insulin

Pancreas Glycogen Glucose

Decreased

Glycogen synthase

IncreasedIncreased

Hormone

Signal TransductionSignal Transduction

Blood

LiverLiver

Low blood sugar Glucagon

GTP-protein-linked receptor

Tyrosine-kinase-linked receptor

Glycogen phosphorylase

Cori & Cori (1947)

Juang RH (2004) BCbasics

Normal glucose homeostasis is tightly regulated by three interrelated processes:

(1) glucose production in the liver, (1) glucose production in the liver, (2) glucose uptake and utilization by (2) glucose uptake and utilization by

peripheral tissues, chiefly skeletal muscle, peripheral tissues, chiefly skeletal muscle, (3) actions of insulin and counter-(3) actions of insulin and counter-

regulatory hormones (e.g., glucagon). regulatory hormones (e.g., glucagon).

DIABETES MELLITUS NORMAL: When non-diabetic people eat, the NORMAL: When non-diabetic people eat, the

pancreas automatically produces the right pancreas automatically produces the right amount of insulin to move glucose from blood amount of insulin to move glucose from blood into our cells. into our cells.


DIABETES MELLITUS DIABETES: In people with diabetes, when DIABETES: In people with diabetes, when

they eat, the pancreas either produces little they eat, the pancreas either produces little or no insulin, or the cells do not respond or no insulin, or the cells do not respond appropriately to the insulin that is produced appropriately to the insulin that is produced (or both) => glucose builds up in the blood, (or both) => glucose builds up in the blood, overflows into the urine, and passes out of overflows into the urine, and passes out of the body in urine => body loses its main the body in urine => body loses its main source of fuel even though blood contains source of fuel even though blood contains large amounts of glucose.large amounts of glucose.


Diabetes mellitus is not a single disease Diabetes mellitus is not a single disease entity but rather a entity but rather a group of metabolic group of metabolic disorders sharing the common underlying disorders sharing the common underlying feature of hyperglycemia.feature of hyperglycemia.

Hyperglycemia in diabetes results from

defects in insulin secretion,defects in insulin secretion, defects in insulin action, defects in insulin action, most commonly, both. most commonly, both.

The principal metabolic function of insulin The principal metabolic function of insulin is to increase the rate of glucose transport is to increase the rate of glucose transport into certain cells in the bodyinto certain cells in the body

These are the These are the striated muscle cellsstriated muscle cells (including myocardial cells) and, to a lesser (including myocardial cells) and, to a lesser extent, extent, adipocytes,adipocytes, representing collectively representing collectively about two-thirds of the entire body weight.about two-thirds of the entire body weight.

Glucose uptake in other peripheral tissues, Glucose uptake in other peripheral tissues, most notably the brain, is insulin most notably the brain, is insulin independent. independent.

metabolic effects of insulin - anabolic, with metabolic effects of insulin - anabolic, with increased synthesis and reduced increased synthesis and reduced degradation of glycogen, lipid, and protein.degradation of glycogen, lipid, and protein.

In addition - several In addition - several mitogenicmitogenic functions, functions, including initiation of DNA synthesis in including initiation of DNA synthesis in certain cells and stimulation of their growth certain cells and stimulation of their growth and differentiation.and differentiation.

Etiologic Classification of Diabetes Mellitus Type 1 DiabetesType 1 Diabetes - - β-β-cell destruction, leads to absolute insulin cell destruction, leads to absolute insulin

deficiencydeficiency Type 2 DiabetesType 2 Diabetes -Insulin resistance with relative insulin -Insulin resistance with relative insulin

deficiencydeficiency Genetic Defects ofGenetic Defects of ββ--Cell FunctionCell Function Genetic Defects in Insulin Processing or Insulin ActionGenetic Defects in Insulin Processing or Insulin Action Exocrine Pancreatic DefectsExocrine Pancreatic Defects EndocrinopathiesEndocrinopathies InfectionsInfections DrugsDrugs Genetic Syndromes Associated with DiabetesGenetic Syndromes Associated with Diabetes Gestational Diabetes MellitusGestational Diabetes Mellitus

DM TYPE I

Auto-immune diseaseAuto-immune disease

Constitutes 5-10% of DM diagnosed in the USAConstitutes 5-10% of DM diagnosed in the USA

Mostly appears in children and young adultsMostly appears in children and young adults

Develops as a result of auto-immune destruction of Develops as a result of auto-immune destruction of beta-cells in the pancreasbeta-cells in the pancreas

Presents with polyuria, thirst, weight loss, marked Presents with polyuria, thirst, weight loss, marked fatiguefatigue

Can be complicated by coma with ketoacidosisCan be complicated by coma with ketoacidosis• <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what><http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>

DM TYPE II Most common form of diabetesMost common form of diabetes Involves about 90-95% of people with DMInvolves about 90-95% of people with DM Associated with: Associated with:

– older age older age – obesityobesity– family history of DMfamily history of DM– prior history of gestational diabetesprior history of gestational diabetes– physical inactivityphysical inactivity– ethnicityethnicity

• <http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what><http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#what>

DM TYPE II Patient with type II DM usually makes Patient with type II DM usually makes

enough insulin but the body cannot use it enough insulin but the body cannot use it effectively => effectively => insulin resistanceinsulin resistance

Gradually Gradually insulin productioninsulin production decreases over decreases over the following yearsthe following years

Symptoms are similar to type I but develop Symptoms are similar to type I but develop more graduallymore gradually


Genetic defects of β-cell function

Maturity-onset diabetes of the young (MODY), caused by mutations in: Hepatocyte nuclear factor 4α (HNF4A), MODY1 Glucokinase (GCK), MODY2 Hepatocyte nuclear factor 1α (HNF1A), MODY3 Pancreatic and duodenal homeobox 1 (PDX1), MODY4 Hepatocyte nuclear factor 1β (HNF1B), MODY5 Neurogenic differentiation factor 1 (NEUROD1), MODY6 Neonatal diabetes (activating mutations in KCNJ11 and ABCC8,

encoding Kir6.2 and SUR1, respectively) Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A G) Defects in proinsulin conversion Insulin gene ➙mutations

Maturity onset Diabetes of Young {MODY }

Insulin secretory defect without beta cell Insulin secretory defect without beta cell lossloss

Autosomal dominant inheritance with high Autosomal dominant inheritance with high penetrancepenetrance

Early onset before 25Early onset before 25 Impaired Impaired ββ - cell function , normal weight , - cell function , normal weight ,

lack of GAD antibodies ,lack of GAD antibodies , lack of INSULIN resistance syndrome lack of INSULIN resistance syndrome

Genetic defects in insulin action

Type A insulin resistance Lipoatrophic diabetes, including mutations

in PPARG

Exocrine pancreatic defects

Chronic pancreatitis Pancreatectomy/trauma Neoplasia Cystic fibrosis Hemachromatosis Fibrocalculous pancreatopathy

Endocrinopathies

Acromegaly Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma

Infections

Cytomegalovirus Coxsackie B virus Congenital rubella

Drugs

Glucocorticoids Thyroid hormone Interferon-α Protease inhibitors β-adrenergic agonists Thiazides Nicotinic acid Phenytoin (Dilantin) Vacor

Genetic syndromes associated with diabetes

Down syndrome Kleinfelter syndrome Turner syndrome Prader-Willi syndrome

GESTATIONAL DIABETES

Develops only during pregnancyDevelops only during pregnancy More common in:More common in:

– African AmericansAfrican Americans

– American Indians American Indians – Hispanic Americans Hispanic Americans – women with a family history of diabeteswomen with a family history of diabetes

Women with a history of gestational diabetes have a 20-Women with a history of gestational diabetes have a 20-50% chance of getting type II DM within 5-10 years50% chance of getting type II DM within 5-10 years


Gestational Diabetes Mellitus Hyperglycemia diagnosed during pregnancyHyperglycemia diagnosed during pregnancy Occurs in 2-5% of pregnanciesOccurs in 2-5% of pregnancies Occurs due to placental hormone changes that effect insulin Occurs due to placental hormone changes that effect insulin

function (greater resistance)function (greater resistance) Screening usually occurs during the 24Screening usually occurs during the 24 thth-28-28thth week in high risk week in high risk

patientspatients Criteria for diagnosis is different than for Type 1 and Type 2Criteria for diagnosis is different than for Type 1 and Type 2 Dietary changes are initial treatment and insulin is the only BG Dietary changes are initial treatment and insulin is the only BG

lowering agent usedlowering agent used Concern is both for maternal and fetal well-beingConcern is both for maternal and fetal well-being Postpartum BG levels usually return to normalPostpartum BG levels usually return to normal Increased risk for Type 2 diabetes (30-50%)Increased risk for Type 2 diabetes (30-50%)

Pathogenesis of Type 1 Diabetes Mellitus

autoimmune diseaseautoimmune disease in which islet destruction is caused in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly primarily by T lymphocytes reacting against as yet poorly defined defined β-β-cell antigens, resulting in a reduction in cell antigens, resulting in a reduction in β-β-cell masscell mass

genetic susceptibility and environmental influences play genetic susceptibility and environmental influences play important roles in the pathogenesis.important roles in the pathogenesis.

most commonly develops in childhood, becomes manifest at most commonly develops in childhood, becomes manifest at puberty, and is progressive with age. puberty, and is progressive with age.

Most individuals with type 1 diabetes depend on exogenous Most individuals with type 1 diabetes depend on exogenous insulin supplementation for survival, and without insulin, they insulin supplementation for survival, and without insulin, they develop serious metabolic complications such as acute develop serious metabolic complications such as acute ketoacidosis and coma.ketoacidosis and coma.

The classic manifestations of the disease The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its (hyperglycemia and ketosis) occur late in its course, after more than 90% of the course, after more than 90% of the β β cells have cells have been destroyed. been destroyed.

Several mechanisms contribute toSeveral mechanisms contribute to ββ--cell cell destruction, and it is likely that many of these destruction, and it is likely that many of these immune mechanisms work together to produce immune mechanisms work together to produce progressive loss ofprogressive loss of β β cells,cells, resulting in clinical resulting in clinical diabetes:diabetes:

Type 1 diabetes complex pattern of genetic associationcomplex pattern of genetic association the principal susceptibility locus for type 1 diabetes the principal susceptibility locus for type 1 diabetes

resides in the region that encodes the class II MHC resides in the region that encodes the class II MHC molecules on chromosome 6p21 (HLA-D)molecules on chromosome 6p21 (HLA-D). .

Between 90% and 95% - Between 90% and 95% - HLA-DR3HLA-DR3, or , or DR4DR4, or both, , or both, also evidence to suggest that also evidence to suggest that environmental factorsenvironmental factors, ,

especially infections, - viruses may be an initiating trigger, especially infections, - viruses may be an initiating trigger, -molecular minicry-molecular minicry

Pathogenesis of Type 2 Diabetes Mellitus

pathogenesis of type 2 diabetes remains enigmatic. pathogenesis of type 2 diabetes remains enigmatic. Environmental influences, such as a sedentary life Environmental influences, such as a sedentary life style and dietary habits, clearly have a role,style and dietary habits, clearly have a role,

Nevertheless, Nevertheless, genetic factors are even more genetic factors are even more important than in type 1 diabetes,important than in type 1 diabetes,

Among identical twins, the concordance rate is Among identical twins, the concordance rate is 50% to 90%, while among first-degree relatives 50% to 90%, while among first-degree relatives with type 2 diabetes (including fraternal twins) the with type 2 diabetes (including fraternal twins) the risk of developing the disease is 20% to 40%risk of developing the disease is 20% to 40%

Insulin Resistance Insulin resistance is defined as the failure of

target tissues to respond normally to insulin. leads to decreased uptake of glucose in

muscle, reduced glycolysis and fatty acid oxidation in the liver, and an inability to suppress hepatic gluconeogenesis.

Few factors play as important a role in the development of insulin resistance as obesity.

Obesity and Insulin Resistance. epidemiologic association of obesity with type 2

diabetes - observed in greater than 80% of patients.

Insulin resistance is present even in simple obesity unaccompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fatty excess (see metabolic syndrome, below).

The risk for diabetes increases as the body mass index (a measure of body fat content) increases. It is not only the absolute amount but also the distribution of body fat that has an effect on insulin sensitivity:

central obesity (abdominal fat) is more likely to be linked with insulin resistance than are peripheral (gluteal/subcutaneous) fat depots.

Obesity can adversely impact insulin sensitivity in numerous ways Nonesterified fatty acids (NEFAs): Adipokines:Leptin and adiponectin improve insulin sensitivity by

directly enhancing the activity of the AMP-activated protein kinase (AMPK), an enzyme that promotes fatty acid oxidation, in liver and skeletal muscle. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance.

Inflammation: Adipose tissue also secretes a variety of pro-inflammatory cytokines like tumor necrosis factor, interleukin-6, and macrophage chemoattractant protein-1, the last attracting macrophages to fat deposits. These cytokines induce insulin resistance by increasing cellular “stress,” which in turn, activates multiple signaling cascades that antagonize insulin action on peripheral tissues.

Peroxisome proliferator-activated receptor γ (PPAR γ): PPARγ is a nuclear receptor and transcription factor expressed in adipose tissue, and plays a seminal role in adipocyte differentiation. Activation of PPARγ promotes secretion of anti-hyperglycemic adipokines like adiponectin, and shifts the deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle. AS DISCUSSED BELOW, RARE MUTATIONS OF PPARG THAT CAUSE PROFOUND LOSS OF PROTEIN FUNCTION CAN RESULT IN MONOGENIC DIABETES.

β-Cell Dysfunction In type 2 diabetes, β cells seemingly exhaust their

capacity to adapt to the long-term demands of peripheral insulin resistance.

In states of insulin resistance like obesity, insulin secretion is initially higher for each level of glucose than in controls. This hyperinsulinemic state is a compensation for peripheral resistance and can often maintain normal plasma glucose for years. Eventually, however, β-cell compensation becomes inadequate, and there is progression to hyperglycemia.

The two metabolic defects that characterize type 2 The two metabolic defects that characterize type 2 diabetes are diabetes are

(1) a decreased ability of peripheral tissues to respond (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and to insulin (insulin resistance) and

(2)(2) ββ--cell dysfunction that is manifested as inadequate cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and insulin secretion in the face of insulin resistance and hyperglycemiahyperglycemia. In most cases, INSULIN . In most cases, INSULIN RESISTANCE IS THE PRIMARY EVENT AND IS RESISTANCE IS THE PRIMARY EVENT AND IS FOLLOWED BY INCREASING DEGREES OF FOLLOWED BY INCREASING DEGREES OF Β-Β-CELL DYSFUNCTION.CELL DYSFUNCTION.

T2DM is a disorder characterized by a Combination of reduced tissue sensitivity to insulin and inadequate secretion of insulin from the pancreas.

Hyperglycemia in T2DM is a failure of theÎ² cells to meet an increased demand for insulin in the body

MORPHOLOGY - PANCREAS

TYPE - 1TYPE - 1

- reduction in number & size of islets- reduction in number & size of islets

- leukocytic infilteration of islets- leukocytic infilteration of islets TYPE - 2TYPE - 2

- subtle reduction in islet cell mass- subtle reduction in islet cell mass

- amyloid replacement of islets - amyloid replacement of islets

Diabetes Mellitus Absence (or ineffectiveness of ) insulinAbsence (or ineffectiveness of ) insulin Cellular resistanceCellular resistance Cells can’t use glucose for energyCells can’t use glucose for energy

– Starvation modeStarvation mode• Compensatory breakdown of body fat/proteinCompensatory breakdown of body fat/protein

• Ketone bodies from faulty fat breakdownKetone bodies from faulty fat breakdown• Metabolic acidosis, compensatory breathing Metabolic acidosis, compensatory breathing

(Kussmal’s breathing)(Kussmal’s breathing)

DM TYPE II Symptoms of type II DM include:Symptoms of type II DM include:

– FatigueFatigue– NauseaNausea– Frequent urination/polyuriaFrequent urination/polyuria– Thirst Thirst – Unusual weight lossUnusual weight loss– Blurred visionBlurred vision– Frequent infections Frequent infections – Slow healing of wounds or soresSlow healing of wounds or sores– Sometimes no specific symptomsSometimes no specific symptoms


Diabetes Mellitus HYPERGLYCEMIAHYPERGLYCEMIA: fluid/electrolyte : fluid/electrolyte

imbalance.imbalance.– PolyuriaPolyuria

• Sodium, chloride, potassium excretedSodium, chloride, potassium excreted

– Polydipsia Polydipsia from dehydrationfrom dehydration– PolyphagiaPolyphagia: cells are starving, so person feels : cells are starving, so person feels

hungry despite eating huge amounts of food. hungry despite eating huge amounts of food. Starvation state remains until insulin is available.Starvation state remains until insulin is available.

CLINICAL

Onset: usually childhood and adolescence Onset: usually adult; increasing incidence in childhood and adolescence

Normal weight or weight loss preceding diagnosis Vast majority are obese (80%)

Progressive decrease in insulin levels Increased blood insulin (early); normal or moderate decrease in insulin (late)

Circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512)

No islet auto-antibodies

Diabetic ketoacidosis in absence of insulin therapy

Nonketotic hyperosmolar coma more common

GENETICS

Major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs

No HLA linkage; linkage to candidate diabetogenic and obesity-related genes (TCF7L2, PPARG, FTO, etc.)

PATHOGENESIS

Dysfunction in regulatory T cells (Tregs) leading to breakdown in self-tolerance to islet auto-antigens

Insulin resistance in peripheral tissues, failure of compensation by β-cells

Multiple obesity-associated factors (circulating nonesterified fatty acids, inflammatory mediators, adipocytokines) linked to pathogenesis of insulin resistance

PATHOLOGY

Insulitis (inflammatory infiltrate of T cells and macrophages)

No insulitis; amyloid deposition in islets

β-cell depletion, islet atrophy Mild β-cell depletion

Type II Diabetes

Diagnostic testing - when to do it:Diagnostic testing - when to do it:

People People 45 years old 45 years old => if normal then => if normal then every 3 yearsevery 3 years

MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004.MKSAP13 Endocrinology and Metabolism. American College of Physicians 2004.

Type II Diabetes: diagnostic testingYounger than 45 yr or more often than every 3 years if:Younger than 45 yr or more often than every 3 years if:

overweightoverweight

first degree relative with diabetesfirst degree relative with diabetes

member of high risk ethnic group (Afro-American, Hispanic American, member of high risk ethnic group (Afro-American, Hispanic American, Native American, Asian American, Pacific Islander)Native American, Asian American, Pacific Islander)

delivered a baby delivered a baby 9 lbs. 9 lbs.

gestational diabetesgestational diabetes

hypertensive (BP hypertensive (BP 140/90mmHg) 140/90mmHg)

High Density Lipoprotein cholesterol 35mg/dl or lessHigh Density Lipoprotein cholesterol 35mg/dl or less

TriGlyceride level 250mg/dl or moreTriGlyceride level 250mg/dl or more

pre-diabetespre-diabetes


Who’s at risk of Type Who’s at risk of Type II?II?

Diabetes Mellitus

The good news:The good news:– Blood glucose control reduces complications of Blood glucose control reduces complications of

Diabetes!Diabetes!

Diabetes Mellitus Complications of chronic hyperglycemiaComplications of chronic hyperglycemia

– MacrovascularMacrovascular complications complications• Cardiovascular disease (heart attack)Cardiovascular disease (heart attack)

• Cerebrovascular disease (strokes)Cerebrovascular disease (strokes)

– MicrovascularMicrovascular• Blindness (retinal proliferation, macular degeneration)Blindness (retinal proliferation, macular degeneration)

• AmputationsAmputations

• Diabetic neuropathy (diffuse, generalized, or focal)Diabetic neuropathy (diffuse, generalized, or focal)

• Erectile dysfunctionErectile dysfunction

The Laboratory Examination

Laboratory plays an important Laboratory plays an important part in the diagnosis and care of part in the diagnosis and care of diabetic patientsdiabetic patients

Diagnosis Blood glucose levels - 70 to 120 mg/dL. Blood glucose levels - 70 to 120 mg/dL. Diagnosis - By Elevation Of Blood Glucose By Diagnosis - By Elevation Of Blood Glucose By

Any One Of Three Criteria: Any One Of Three Criteria: A random blood glucose concentration of 200 A random blood glucose concentration of 200

mg/dL or higher, with classical signs and symptoms mg/dL or higher, with classical signs and symptoms

A fasting glucose concentration of 126 mg/dL or A fasting glucose concentration of 126 mg/dL or higher on more than one occasion, higher on more than one occasion,

An abnormal oral glucose tolerance test (OGTT), in An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load higher 2 hours after a standard carbohydrate load (75 gm of glucose). (75 gm of glucose).

Method: Glucose Oxidase

GLU+2HGLU+2H22O+OO+O2 2 GODGOD Gluconic acid Gluconic acid

+2H+2H22OO22

2H2O22H2O2 +4-aminoantipyrine +1,7-dihy-+4-aminoantipyrine +1,7-dihy-

droxynaphthalene droxynaphthalene POD POD red dyered dye

Reference IntervalFasting glucose : 3.9 - 6.11mmol/lFasting glucose : 3.9 - 6.11mmol/l

(fasting is defined as no calorie intake for at least 8 hours)

Urine Tests URINE "GLUCOSEURINE "GLUCOSE""

– lacks sensitivity = positivity in diseaselacks sensitivity = positivity in disease

– poor specificity = negativity in poor specificity = negativity in healthhealth ProblemsProblems

– renal threshold variable 6 to 15 mmol/Lrenal threshold variable 6 to 15 mmol/L

– interferences : Clinitest / Glucose oxidase stripsinterferences : Clinitest / Glucose oxidase strips

IF URINE TEST POSITIVE IF URINE TEST POSITIVE

A CONFIRMATORY BLOOD TESTA CONFIRMATORY BLOOD TEST IS NEEDED IS NEEDED

Blood TestsGlucoseGlucose

– whole blood 10-15% lower than plasmawhole blood 10-15% lower than plasma

– venous 10% lower than capillaryvenous 10% lower than capillary

– Venous blood - loss of 0.33 mmol/L per Venous blood - loss of 0.33 mmol/L per hourhour

– There is no decrease within 24 h in the There is no decrease within 24 h in the presence of sodium fluoridepresence of sodium fluoride

Oral Glucose Tolerance Test (OGTT) A venous blood sample will be collected for A venous blood sample will be collected for

the determination of fasting glucosethe determination of fasting glucose Load of 75g of glucose is ingested within 5 Load of 75g of glucose is ingested within 5

minmin Blood samples will be collected at timed Blood samples will be collected at timed

intervals (30min, 60min, 120min) for the intervals (30min, 60min, 120min) for the determination of glucosedetermination of glucose

OGTT Criteria

Plasma glucose (mmol/L)Plasma glucose (mmol/L)

0 min 120 min 0 min 120 min

Non diabeticNon diabetic < 6.1 < 6.1 < 7.8 < 7.8

Impaired glucose tolerance 6.1 - 6.9Impaired glucose tolerance 6.1 - 6.9 >7.8 - 11.1>7.8 - 11.1

DiabeticDiabetic > 7.0 > 7.0 > 11.1 > 11.1

Glycosylated proteinsCaused by non-enzymatic glycosylationCaused by non-enzymatic glycosylation

– Glycosylated hemoglobinGlycosylated hemoglobin• HbAHbA1c - 1c - LGI ref range 4.6-6.5 %LGI ref range 4.6-6.5 %• indicates previous 2-3 months glycaemic exposureindicates previous 2-3 months glycaemic exposure• n.b. affetced by altered red cell survivaln.b. affetced by altered red cell survival

– FructosamineFructosamine• mirrors glycosylation of all serum proteinsmirrors glycosylation of all serum proteins• indicates previous 2-3 weeks glycaemic exposureindicates previous 2-3 weeks glycaemic exposure• used pregnancy/children in some sitesused pregnancy/children in some sites

– Glycosylated albuminGlycosylated albumin• indicates previous several days glycaemic exposureindicates previous several days glycaemic exposure• not commonly usednot commonly used

Hemoglobin A1c

HbA1c is stable glycosylated HbA1c is stable glycosylated hemoglobinhemoglobin

Its percentage concentration indicates Its percentage concentration indicates cumulative glucose exposurecumulative glucose exposure

Hemoglobin A1c

A good indicator of blood glucose control.A good indicator of blood glucose control. Gives a % that indicates control over the Gives a % that indicates control over the

preceding 2-3 months.preceding 2-3 months. Performed 2 times a year.Performed 2 times a year. A hemoglobin of 6% indicates good control A hemoglobin of 6% indicates good control

and level >8% indicates action is needed.and level >8% indicates action is needed.

Lowering HbA1C Reduces Risk of Complications

Secondary Diabetes Mellitus DM occurs as a result of another problem (primary)DM occurs as a result of another problem (primary)

– DiseasesDiseases– ConditionsConditions– MedicationsMedications

• ThiazidesThiazides• DiureticsDiuretics• Beta blockersBeta blockers• SteroidsSteroids

Hyperglycemia is diagnostic for DMHyperglycemia is diagnostic for DM Treatment of the primary cause may resolve the DM but Treatment of the primary cause may resolve the DM but

lifestyle modifications and medications may be needed lifestyle modifications and medications may be needed as wellas well

Pre-Diabetes

Pre-diabetes refers to a state between “normal” Pre-diabetes refers to a state between “normal” and “diabetes” = fasting plasma glucose 100-and “diabetes” = fasting plasma glucose 100-125mg/dL (higher than normal but not high 125mg/dL (higher than normal but not high enough for diagnosis of diabetes)enough for diagnosis of diabetes)Affects about 41 million people in USAAffects about 41 million people in USA(previously referred to as either impaired fasting glucose or impaired glucose tolerance)(previously referred to as either impaired fasting glucose or impaired glucose tolerance)

http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#typeshttp://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm#types


Impaired Fasting Glucose

Defined as a fasting plasma blood glucose Defined as a fasting plasma blood glucose of >/= to 110 but < 126 of >/= to 110 but < 126

Increased risk for DMIncreased risk for DM Must educate regarding risks and need for Must educate regarding risks and need for

lifestyle modificationslifestyle modifications

Impaired Glucose Tolerance Defined as a plasma blood glucose of >/= to 140 but < 200 after Defined as a plasma blood glucose of >/= to 140 but < 200 after a 2 hour 75 gram glucose tolerance testa 2 hour 75 gram glucose tolerance test

8-10% of US population have this problem with a 25 % risk of 8-10% of US population have this problem with a 25 % risk of developing DM 2developing DM 2

Compounding risk factors effect risk of developing Type 2 DMCompounding risk factors effect risk of developing Type 2 DM– AgeAge– ActivityActivity– ComorbiditiesComorbidities– WeightWeight

Increased risk for macrovascular diseasesIncreased risk for macrovascular diseases Must educate regarding risks and need for lifestyle modificationsMust educate regarding risks and need for lifestyle modifications

Diabetes is preventable by life style modification

Maintain a healthy body weightMaintain a healthy body weight Half an hour of exercise dailyHalf an hour of exercise daily Eat a healthy dietEat a healthy diet

(fruits, vegetables, bread, milk)

Triad of Treatment

DietDiet

MedicationMedication– Oral hypoglycemicsOral hypoglycemics

– InsulinsInsulins

ExerciseExercise

Diabetes Mellitus Prevention of effects: combination approachPrevention of effects: combination approach

– Increased exerciseIncreased exercise• Decreases need for insulinDecreases need for insulin

– Reduce calorie intakeReduce calorie intake• Improves insulin sensitivityImproves insulin sensitivity

– Weight reductionWeight reduction• Improves insulin actionImproves insulin action

Classification of DiabetesType I DMType I DM Type II DMType II DM

Aetiology Autoimmune

(- cell destruction)

Insulin resistance and -cell dysfunction

Peak age 12 years 60 years

Prevalence 0.3% 6% (>10% above 60 years)

Presentation Osmotic symptoms, weight loss (days to weeks), DKA

Patient usually slim

Osmotic symptoms, diabetic complications (months to years).

Patient usually obese

Treatment Diet and insulin Diet, exercise (weight loss), oral hypoglycemics, Insulin later

Diabetes is a very complicated disease. It is Diabetes is a very complicated disease. It is easy to diagnosis and it is difficult to treat easy to diagnosis and it is difficult to treat

Laboratory plays an important part in the Laboratory plays an important part in the diagnosis and care of diabetic patientsdiagnosis and care of diabetic patients

In Conclusion :

DIABETES MELLITUS. What is diabetes mellitus? The majority of intake of food is converted into...

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