DIABETES MELLITUS (DM)

OBJECTIVES

Review pancreatic hormones Synthesis, secretion, mechanism of

action and functions of insulin. Review pathophysiology of DM. Review clinical picture of DM. Discuss the diagnosis of DM. Discuss some cases about DM

Alpha cells (A cells) secrete the hormone glucagon.

Beta cells (B cells) produce insulin and are the most abundant of the islet cells.

Delta cells (D cells) secrete somatostatin

Gamma cells (F cells) secrete a pancreatic polypeptide

ISLET CELLS ISLETS of Langerhan

•Source β Cells of Islets of Langerhan•Chemistry Peptide [51 aa]• Molecular Weight 5808•Half Life 5-10 min• Basal Levels 3 ng/ml or < 10 mIU/ml •Fate Endocytosis and Proteolysis (80 % in Liver & Kidneys)•Species Specificity (Bovine & Human)

Chromosome 11

INSULIN

Ribosomes on Rough ER

Packed in Golgi Apparatus(Secretory Vesicles)

Pro InsulinCleaved in

Endoplasmic Reticulum

Pre Pro Insulin

Insulin + C-Peptide

Released by ExocytosisInsulin

C-Peptide

SYNTHESIS OF INSULIN

GGG

G G

ATP

Ca++

Ca++Ca++

Ca++

Ca++Ca++

Ca++ Ca++

K+ K+

K+

Amino acids Fatty acidsAcetylcholine gastrin

Secretin GIPCCK

GL

UT

2

BETA CELL

K+

K+

GL

UT

2

Glycolysis

G

G

IRS-1

TyrosineKinase

TyrosineKinase

PP

ECF

ICF

Phospho Kinase

GLUT-4

GGG

G G

Grb2&SOS

RASRAF

MAP-K

G

Ins Ins

MECHANISM OF ACTION

• Loss of the first phase result in elevation of the postprandial glucose.• Delayed second phase- can result in post-meal hypoglycemia.

NORMAL

TYPE 2 DM

15 300 20 355 25 4010 45 50 55 60

Time (Minutes)

Pla

sm

a I

nsu

lin

(u

U/m

l)%

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HOW INSULIN IS RELEASED?

TYPE 1 DM

Insulin secretion is continuous=BASAL INSULIN SECTRETION Increases after carbohydrate consumption =BIPHASIC

•Insulin affects uptake of Glucose into:

• Muscle cells,

• Adipose tissue,

• Connective tissues,

• White blood cells;

•Insulin DOES NOT affects Glucose uptake into:

• Brain,

• Liver,

• Kidneys

•Insulin counter regulatory hormones oppose actions of Insulin (counter regulatory hormones are):

• Glucagon,

• Epinephrine,

• Glucocorticoids, and

• Growth hormone

InsulinIGF1

Glucagon GH T3 T4Catecholamines Steroids

DIABETES MELLITUSDiabetes is a life-long disease marked by high levels of glucose in the blood

It can be caused by too little insulin, resistance to insulin, or both

There are three major types of diabetes:1. Primary DM: is generally sub-classified into:

•Type I DM: Insulin Dependent Diabetes Mellitus (IDDM);

•Type 2 DM: Non-Insulin Dependent Diabetes Mellitus

2. Secondary DM: may be due to:

•Pancreatic disease,

•Endocrine disease (Cushing’s syndrome),

•Adrenal diabetes,

•Drug therapy,

•Insulin receptor abnormalities,

3. Gestational diabetes

Aetiology of DiabetesAetiology of Diabetes

Type 1 Diabetes (10-15%) results when the body’s immune system destroys its own beta cells in the pancreas. No insulin production is then possible.

Type 2 Diabetes (85-90%)results from either

Insulin resistance (overweight people)Inadequate insulin production (lean people)A combination of both

Gestational Diabetes Diabetes diagnosed during

pregnancy Increased health risk to mother and baby require insulin injections Goes away after birth, but increased risk of developing Type 2 DM for mother and child

Type 1 Diabetes Usually under 30 yrs of age

Autoimmune disorder Sudden onset of severe symptoms Rapid weight loss Total lack of insulin in the body Insulin injections essential for life Ketones produced Genetic predisposition, though 80% have no relatives with the disease

Presence of Islet cell antibodies in Serum may predicts future development of Type 1 DM; Islet-cell antibodies act against Glutamic Acid Decarboxylase (GAD)

•Environmental precipitating factors of DM:

• Viral infections,

• Dietary factors (anti-metabolites in some foodstuffs)

CHARACTERISTICS OF TYPE 1 DM

•Type 1 DM is usually characterized by:

•Deficiency in Insulin and consequent Hyperglycemia,•Hyperglycemia causes blood glucose level to exceed Renal Threshold of 200mg/dl or 11mmol/L, Resulting in Glucosuria,

•Following sequence of events occur:

•Sugar is excreted in urine (Glucosuria), •Water follows the sugar due to osmosis (Osmotic diuresis),•Large volume of urine is passed out (Polyuria),

Patient becomes thirsty, drinks lots of water (Polydipsia),

There is Lack of Insulin:

•Thus, Muscles, Adipose tissue, Connective tissues and White Blood Cells cannot utilize Glucose present in blood

(Starvation in the midst of plenty),

Patient become hungry and eats a lot (Polyphagia),

Due to continuous lack of Insulin, Glucose cannot enter Muscle and other tissues, thus patient may start to loose weight (Wasting),

Patient may develop Ketoacidosis (Why?)

CONSEQUENCES IF TYPE 1 DM IS NOT CONTROLLED?

• Hyperglycemia:

•Partly due to inability of Insulin-dependent tissues to use blood glucose (Starvation in the midst of plenty, (Why?) •Increased Hepatic Gluconeogenesis, •Depressed Glycolysis due low glucose levels in cells;

•Hyper-Lipoproteinemia (Chylomicrons and VLDL):

•Due to low Lipoprotein Lipase activity in Adipose tissue, •Insulin is required for biosynthesis of Lipoprotein Lipase

•Ketoacidosis: Increased production of Ketone bodies:

•Acetone, •Acetoacetic acid, •βHydroxybutyric acid;

WHY CAN INSULIN BE USED TO CONTROL TYPE 1 DM?

Administration of insulin does not cure Type 1 DM, but it alters the clinical course of the disease;

•Insulin promotes Glucose uptake & restoration of normal metabolism,

•When the hyperglycemia is corrected:

•Loss of water and electrolytes ceases,•Formation of Ketone bodies ceases,•Metabolism of Glucose via Glycolysis and TCA Cycle also allows Acid-Base balance to return to normal,

•Changes in plasma Bicarbonate levels during treatment serve as guide to monitor success of treatment

CONSEQUENCES OF DKA? EMERGENCY CASE•Decreased Glucose transport into tissues leads to Hyperglycemia, which gives rise to Glucosuria,•Increased Lipolysis leads to formation of Ketone bodies, Resulting in Ketonemia and Ketonuria. Acetone is exhaled in Lungs and passed out in breath, Acetoacetic acid and β-Hydroxybutyric acid causes acidosis•[HCO3-] in blood falls causing Metabolic acidosis and more Carbonic acid (H2CO3) is formed, Carbonic acid is converted to CO2, which then stimulates respiratory center to remove excess CO2. Increased removal of CO2 causes rapid deep breathing (Hyperventilation) observed in patients with DKA; Hyperventilation (Kussmaul breathing) is a response by the lungs to compensate for Metabolic Acidosis, by removing excess CO2

Glycosuria causes Osmotic Diuresis, which leads to: •Loss of water, •Loss of Electrolytes, •Loss of Calcium, Magnesium, and Phosphate, Dehydration if severe produces Pre-renal Uremia and may lead to Hypovolaemic Shock, Frequent vomiting may be present and increases loss of water and electrolytes, DKA is a series of interlocking vicious circles which must be broken to restore normal Carbohydrate, Lipid and Protein metabolism,•Correction of DKA requires rapid treatment dictated by severity of metabolic abnormalities and associated tissue water and electrolyte imbalance;

LADA"SLOW ONSET TYPE 1" DIABETES OR "TYPE 1.5 DM

Latent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune (type 1 diabetes) which is diagnosed in individuals who are older than the usual age of onset of type 1 diabetes.

Often, patients with LADA are mistakenly thought to have type 2 diabetes , based on their age at the time of diagnosis.

Can be differentiated by presence of GAD antibodies in the blood that mean it is of type one but occurs late.

Type 2 Diabetes

Usually over 40 yrs of age though the age of diagnosis is getting younger Gradual onset with mild symptoms Most produce a normal amount of insulin but it is unable to work properly due to insulin resistance Many have complications at diagnosis

•Type 2 DM: accounts for 85% cases of DM

•Formally called:

•Non-Insulin Dependent Diabetes Mellitus (NIDDM);

•Maturity-onset diabetes mellitus,

•Common in middle-age obese individuals, Can occur in non-obese middle-age individuals, Can occur in any age group;

CAUSES OF TYPE 2 DM

May be due to any of the following:1. Resistance of peripheral tissues to Insulin, despite normal or high Insulin level in blood, 2. Deficiency or defect in Insulin Receptors in target tissues (Relative Insulin deficiency),3. Obesity, (may have clinical features of Type 2 DM),4. Defect in Insulin Receptors is related to increased levels of Tumor Necrosis Factor-α(TNF- α) in Adipocytes,5. Increase adipose tissue mass causes increase TNF-α, which then blocks Insulin Receptors,

Diet can control Type 2 DM in Obese patient,• Obese patients that are motivated to lose weight:

•Insulin receptors will increase in number, •Post-receptor abnormalities will improve, resulting in tissue sensitivity to insulin and Glucose tolerance; • In non-obese individuals: Type 2 DM may be cause not only by Insulin Resistance, but also by Impaired Pancreatic β-cell function resulting in Relative Insulin Deficiency;

VASCULAR COMPLICATIONS OF TYPE 2 DIABETES

Findings from UKPDS show that intensive glycaemic control in the treatment of Type 2 diabetes results in a decrease in diabetes-related microvascular complications

Microvascularnephropathyretinopathyneuropathy

Macrovascularcardiovascular disease peripheral vascular diseasecerebrovascular disease

Ways to reduce risks Control cholesterol, blood pressure No smoking Maintain good blood glucose levels Get regular exercise Aim for healthy body weight Medical checks including electrocardiograph (ECG)

CONSEQUENCES OF UNCONTROLLED TYPE 2 DM:

Uncontrolled Type 2 DM is characterized by: • Hyperglycemia, •Hyper-Triglyceridemia•Hyperglycemia causes accumulation of glucose in:• Eyes (Lens epithelium, Retinal capillaries),• Peripheral Nerve cells (Schwann cells), • Kidneys (Papillae, Glomerulus),

•Aldose Reductase and Sorbitol Dehydrogenase in these tissues converts: Glucose to Fructose, Dulcitol and Sorbitol.

Sorbitol accumulates and crystallizes causing damage to tissues by causing them to swell; Resulting in conditions such as: •Cataract formation in eyes (diabetic cataract), •Diabetic Neuropathy and loss of sensation, •Retinopathy (damage to retina), •Damage to blood vessels (Vascular disease), •Damage to kidneys causing renal failure, •Damage to Cardiac tissue (Ischemic heart disease), Type 2 DM does not cause Ketoacidosis (WHY?)

What is Insulin Resistance?

condition in which the body does not utilise insulin efficiently Insulin resistance is the decreased response of the liver and peripheral tissues (muscle, fat) to insulin

Insulin resistance is a primary defect in the majority of patients with Type 2 diabetes

Type 2 Diabetes Risk Factors

Characteristics of DiabetesType 1 Type 2

Usually over 40 Gradual onset 80% are overweight Most have insulin

resistance Ketosis rare 85% of diagnosed cases Part of metabolic insulin

resistance syndrome Strongly hereditary Diet & exercise,

progressing to tablets, then insulin

Usually under 30 Rapid onset Normal or

underweight Little or no insulin Ketosis common Make up 15% of cases Autoimmune plus

environmental factors Low familial factor Treated with insulin,

diet and exercise

CLINICAL PRESENTATIONS OF DM

SYMPTOMS, SIGNS

DIABETES MELLITUS TYPE 1Clinical Manifestations:

• Polyuria – increased urine• Polydipsia – increased thirst• Polyphagia – increased hunger

Cardinal symptoms are the 3 ‘Ps”

• Weight loss• Fatigue • Nausea, vomiting

Ketoacidosis may be the first presenting sign

DIABETES MELLITUS TYPE 2

Clinical Manifestations:• Polydipsia – increased thirst• Polyuria – increased urine• Polyphagia – increased hunger• Fatigue• Blurred vision• Slow healing infections• Impotence in men

MODYMATURITY ONSET DIABETES OF THE YOUNG

MODY is a monogenic form of diabetes with an autosomal dominant mode of inheritance:◦ Mutations in any one of several transcription factors or in the enzyme glucokinase lead to insufficient insulin release from pancreatic ß-cells, causing MODY. ◦ Originally, diagnosis of MODY was based on presence of non-ketotic hyperglycemia in adolescents or young adults in conjunction with a family history of diabetes.

• Divided into 2 distinct groups: glucokinase MODY and transcription factor MODY, distinguished by characteristic phenotypic features and pattern on oral glucose tolerance testing.• Glucokinase MODY requires no treatment, while transcription factor MODY (i.e. Hepatocyte nuclear factor -1alpha) requires low-dose sulfonylurea therapy.

INVESTIGATIONS OF DM

DIAGNOSIS

DIAGNOSIS OF DIABETES MELLITUS

Is diagnosis of DM the same as monitoring of DM?

Diagnosis of DM is not the same as monitoring of DM,

•Diagnosis: To clinically establish a condition in a patient,

•Monitoring: To follow progress on a condition already diagnosed,

Specific Biochemical tests and Guidelines are used for diagnosis of DM, Specific Biochemical tests and Guidelines are used for monitoring DM,

BIOCHEMICAL TESTS FOR DIAGNOSIS OF DM

1-Glucosuria (Glycosuria):

Good first-line screening test for DM,

Glucose appears in urine when plasma glucose level rises above renal threshold (11mmol/L or 200mg/dL);

Glucosuria may occur in patients with low renal threshold for glucose; Individuals are said to have Glucosuria without DM,

Renal threshold increases with age, thus some patients may have DM without Glucosuria,

Glucosuria indicates Hyperglycemia over the period of formation of the urine, it does not reflect the exact level of blood glucose at the time of testing;

2- Fasting Blood Glucose (FBG):

•FBG is measured after overnight fast (8 to 10hrs),

•FBG is better than RBG for diagnostic purposes,

•FBG above 8.0mmol/L on two different occasions may be diagnostic of DM,

•FBG between 6.0 to 8.0mmol/L is borderline,

•(Note: to convert mmol/L to mg/dl multiply by 18.0)

•Measurement of FBG on Whole blood, Plasma or Capillary blood have different cut-off points (Table 1)

3- Random Blood Glucose (RBG):

•RBG: one of major tests required in emergency,

•RBG less than 8.0mmol/L is usually expected in non-diabetics,

•RBG higher than 11.0mmol/Lin more than one occasionindicates that the individual be investigated more thoroughly for DM;

•Table 1: WHO guideline for diagnosis

4-Two Hours Post-Prandial blood glucose:

•Measure blood glucose level 2-hours after consumption of a meal,

•It is a better indicator that FBG and RBG,

•Individuals with blood glucose above 11.0mmol/L should be investigated more thoroughly for DM;

•WHO published guidelines for diagnosis of DM on the basis of blood glucose results and the response to an Oral Glucose Load;

•Ketones in Urine (Ketonuria)

•Ketones in Blood plasma (Ketonemia)

•Ketone bodies (Acetone, Acetoacetate, Beta-Hydroxybutyrate) may accumulate in plasma and appear in urine in Type 1 DM,

•Ketonuria, Ketonemia is not automatic diagnosis of Ketoacidosis, which is a serious condition;

•Ketonuria, Ketonemia may occur in prolonged fasting,

5- ORAL GLUCOSE TOLERANCE TEST (OGTT) PERFORMED IN A PATIENT, WHEN REQUESTED

•OGTT is recommended only if RBG and FBG tests cannot be interpreted clearly to justify DM;

•OGTT must be carried out under proper clinical supervision;

•Patient should be sitting comfortably throughout test, should not smoke or exercise and should be on normal diet for at least 3 days prior to the test;

•Brief the patient before starting the procedure;

•Measure FBG and Urine Glucose of patient after an overnight fast;

•Record both results;

•Prepare solution containing 75 g of Glucose in 300ml water;

•Patient should drink all the solution within 5 min,

•Measure blood glucose level every 30 min for 2 hrs,

•Measure glucose in urine after 2 hrs,

•Record all the results;

How do you interpret the OGTT result?

•Use results obtained to draw a graph of “Time vs. Blood Glucose level”

•In Asymptomatic patients, OGTT should be interpreted as diagnostic of DM only when:

•There is an increased 2-hrs Glucose level, and Blood Glucose is equal to or greater than 11.0mmol/L (200.0 mg/dL) at some other point during the test;

•If patient has normal FBG, but the 2hrs value is in the diabetic range, test should be repeated after 6wks;

•IGT is considered abnormal; it is an intermediate stage between normality and DM; an increased risk of developing DM;

6- HOW CAN A PATIENT WITH DM BE MONITORED?(LONG-TERM INDICES OF DIABETIC CONTROL)

WHAT IS GLYCOSYLATED HEMOGLOBIN (HBA1C)?

•About 98% of Hb in RBC is HbA1. HbA1is made up of HbA1a, HbA1b,HbA1c

•HbA1c is highest in amount, and is the component that strongly undergoes Glycosylation with Glucose; HbA1combines with blood glucose in a non-enzymatic reaction to form Glycosylated Hb (HbA1c),

•Amount of HbA1c formed is dependent on amount of Glucose in blood over 120-days life span of RBC;

•HbA1c level reflects the average blood sugar level for the 100-to 120-day period before the test; Elevation of HbA1c occurs about 3 weeks after sustained elevation in blood glucose; It takes about 4 weeks for HbA1c to decrease after a sustained reduction in blood glucose,

•Measurement of HbA1c is a good Clinical indicator of Glycemic control in a patient on DM medication,

1. HbA1c is a good index of diabetic control, it is used to complement results from single blood glucose level, or as patient’s log of own blood glucose measurements;

2. Used to evaluate DM treatment and compliance;3. Use to compare past and new diabetic therapy,4. Used to estimate duration of hyperglycemia in patients with

newly diagnosed DM,

•In healthy person HbA1c is 4% to 6% of total HbA, •In prolonged Hyperglycemia the level of HbA1c may rise to as much 12% of Total HbA or more according to DM severity

uses of Test for HbA1c

7- INVESTIGATION OF COMPLICATIONS:

Micro albuminuria (MAU)•MAU is increase in urinary albumin that cannot be detected during urinalysis with Albustick, Clinistick, Dipstick or Multistick

•MAU is urinary albumin level between 25 to 250mg/day,

•MAU is may lead to progressive increase in proteinuria resulting in clinical Albuminuria (Macro albuminuria) and declining Glomerular Filtration Rate, •For a diabetic patient MAU indicates early (Sub-clinical), reversible renal damage;

•Macro albuminuria may be associated with renal damage leading to end stage renal failure and increased coronary mortality among diabetic and hypertensive patients;

WHAT IS HYPOGLYCEMIA?•Hypoglycemia is a laboratory “diagnosis” that means blood glucose level below 2.2mmol/L (40.0 mg/dl);

•Hypoglycemia may be due to:

• •Endocrine disorders, • •Liver disease, • •Inborn errors of metabolism, • •Gastrointestinal surgery,

•Imbalance between glucose intake, endogenous glucose production and glucose utilization

Low blood glucose level leads to Catecholamine secretion and correction of the hypoglycemia via stimulation of Glucagon, Cortisol and Growth Hormone secretion;•Catecholamine surge accounts for the signs and symptoms most commonly seen in Hypoglycemia, i.e., Sweating, Shaking, Tachycardia, Nausea and Weakness;

•Prolonged hypoglycemia reduces glucose supply to the brain; it may lead to brain damage particularly in infants;

8- Plasma C-peptide: •Insulin secretion in Insulin-treated diabetics cannot be assessed by measuring plasma insulin, because insulin given therapeutically will also be measured in the assay;

•Insulin and its associated Connecting-peptide (or C-peptide) are secreted by the Islet cells in equimolar amounts,

•Measurement of C-peptide levels together with Insulin can differentiate between hypoglycemia due to Insulinoma (high C-peptide) and therapeutically administered Insulin (low C-peptide);

GLYCAEMIC INDEXRates carbohydrate containing foods according to their effect on blood glucose levels i.e how long the food takes to get from the stomach to the blood

• High GI quickly raises BGL’s to high level (70-100)• Moderate GI is in between (55-70)• Low GI gradually raises BGL’s and not as high (<55)

There is evidence that low GI foods can improve glycaemic control, insulin resistance, lipids and fibrinolysis

Best to include one low GI food at each meal – this helps to stabilize BGL’s by allowing BGL to increase gradually after the meal “The ranking of foods based on their immediate effect on blood sugar levels”

Examples of low GI- wholegrain bread

Refined CHO white bread, rice, regular pasta, soft drinks rapidly digested therefore stimulates pancreas to produce lots of Insulin rapidly. ? Repeated surges contribute to organ failure

WHO SHOULD HAVE INSULIN THERAPY?

1. Newly Diagnosed Type 1

2. The Type 2 diabetic on maximum tablets

3. The Type 2 diabetic with contraindications to OHA e.g renal failure

4. Pregnancy

5. Post acute MI

6. Acute illness/ infection

Control of BGL essential to minimise long term complications

Case StudyCase StudyParents of a 15 years old boy was reported by his school that he was found drowsy & they have got to take him to hospital according to the advice of his school doctor.

In the hospital, his mother told the doctor that her son seemed unusually thirsty for the last 3 months & she thought that he had lost weight. She admitted also that on the morning before leaving for school, he was complaining of abdominal pain & discomfort.

On examination:On examination: Semiconscious Deep & rapid respiration Pulse rate 120 beats/minute BP: 90/50 Cold extremities

What What investigationsinvestigations were recommended for him?? were recommended for him??What is the What is the diagnosisdiagnosis of this case?? of this case??What is the What is the treatmenttreatment ?? ??

Clinical Biochemistry Lab InvestigationsClinical Biochemistry Lab Investigations

Blood ChemistryBlood Chemistry• Random Blood Glucose: 550 mg/dl • Urea: 160 mg/dl (N: 20 -40)• Na+: 127 mmol/L (N: 135 – 145)• K+: 6.9 mmol/L (N: 3.5 – 4.5)• pCO2: 2.9 kPa (N: 4.4 – 6.1)• HCO3- : 7 mmol/L (N: 21 – 27.5)• pO2: 14 kPa (N: 12 – 17)Urine Analysis:Urine Analysis:• Urine Dipstick Test: - Glucose +++ - Ketone +++ - Albumin ++

Case Study Case Study cont.cont.

Case StudyCase StudyA- Personal history:1- Name: X 2-Age: 42 y 3-Gender: MaleB- Clinical examination:

1- General: B.P 140/85 2- Anthropometric measures:1- weight: 99 Kg 2-hight 1.75m3 -BMI: 99/(1.75)² = 32 = Grade II obesity 3-Past medical history: No Past medical history4- Family history: No Family history5- Lab investigation:

1-fasting blood glucose: 1822- Total cholesterol 1853- HDL 40 (< 50 more liable CHD)4- Triglyceride 1445- creatinine: 1.3 6. Urinary microalbuminuria +

48-year old Hispanic woman comes to her doctor for recommendations about her weight.

She is married, has 2 children in school and works full time as a bookkeeper.

She eats breakfast and dinner at home, and buys lunch at various locations.

Age: 48 Weight: 178 lbs. Height: 5' 3" BMI: 31.5

Glucose Monitoring Last A1C: 8.2% Fasting: 158 mg/dL Random: 219 mg/dL

Lipid Profile Total: 230 mg/dL LDL: 145 mg/dL HDL: 45 mg/dL Triglycerides: 200 mg/dL

Kidney Profile Creatinine: 1.0 mg/dL Microalbuminuria: negative

Liver Function ALT: normal AST: normal Blood Pressure Normal: 130/82 mmHg Cardiovascular condition normal

Eye Exam Normal Foot Exam Normal pulses and sensation

Case StudyCase Study