learning objectives 1.discuss the pathophysiology and pathogenesis of diabetes mellitus 2.describe...

Learning objectives1. Discuss the pathophysiology and pathogenesis of diabetes

mellitus2. Describe the symptoms and clinical presentation of diabetes

mellitus3. Enumerate the investigations to diagnose diabetes mellitus and

the complications of diabetes mellitus.

In simple words, Diabetes mellitus is a disease in which the body either doesn't produce enough insulin or doesn’t properly use insulin or both.

This causes glucose levels to rise too high in the blood (hyperglycemia) and also leads to abnormalities in lipid and protein metabolism.

INTRODUCTION

Defining diabetes ?

• Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

Epidemiology of DM(International Diabetes federation 2012)

• Global Prevalence: 371 million people (8.3 % of world population)

• Middle East and North Africa: 34 million (10.9 % of the people in this region)

• Saudi Arabia: 3.4 million (Out of a total of about 26.5 million)

History of Diabetes Mellitus

• An Egyptian manuscript from 1500 BC described a disease mentioning “too great emptying of the urine.

• The term "diabetes" or "to pass through" was first used in 230 BCE by the Greek Appollonius Of Memphis

• The first complete description of diabetes was given by the Ancient Greek physician Aretaeus of Cappadocia (1st century AD), who gave the disease the name “diabetes” because he noted the excessive amount of urine which is passed through the kidneys


In Arabia, Ibn Sīnā (980–1037) provided a detailed account on diabetes mellitus


• The term "mellitus" or "from honey" was added by the Britain John Rolle in the late 1700s to separate the condition from other causes of increased urination

• In 1776 the English physician Matthew Dobson confirmed that the sweet taste comes from an excess of a kind of sugar in the urine and blood

History of Diabetes MellitusJoseph von Mering and Oskar Minkowski in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes

Sir Edward Albert Sharpey-Schafer in 1910 suggested that people with diabetes were deficient in a single chemical produced by the pancreas. He named this insulin, ( Latin: insula meaning island), because of the islets of Langerhans which produce insulin

In 1921, Frederick Grant Banting and Charles Herbert Best confirmed the existence of and discovered Insulin at Toronto, Canada

BantingBest

Marjorie

Insulin is the main hormone that regulates uptake of glucose from the blood into cells (mainly muscle and fat cells).

PATHOGENESIS OF DIABETES

• Insulin is secreted into the blood by beta cells (β-cells) of the Islets of Langerhans in the pancreas.

• This occurs in response to rising levels of blood glucose, such as after a meal.

• Insulin is used by the body's cells to take up glucose from the blood for use as fuel.


Insulin Secretion In Response To Elevations In Blood Glucose Levels After Meals

Insulin is also the main hormone that signals the conversion of glucose to glycogen (Glycogenesis) for storage in the liver and muscle cells.

On the other hand, lowered glucose levels lead to reduced release of insulin from the beta cells and to the conversion of glycogen to glucose (glycogenolysis) when glucose levels fall.


3Muscle

Fat

2Liver

Glycogenolysis

1Pancreas

4GIT

Plasma glucose

INSULIN DEFICIENCY

ABSORPTION

• What would happen if the amount of insulin available is insufficient ?

• Insulin will not have its usual effect and glucose will not be absorbed properly by body cells.

• What would happen if the body’s cells respond poorly to the effects of insulin ?(insulin resistance)

• Once again, Insulin will not have its usual effect and glucose will not be absorbed properly by body cells.

• The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic abnormalities.


INSULIN RESISTANCE

PANCREAS

Pancreas trying hard to increase insulin production to meet the demands

DIABETES MELLITUS

PRE CLINICALDM

• HOMEOSTASIS• CLINICAL

• MOLECULAR• ENVIRONMENT

GENE TISSUE

PANCREATIC OVERLOAD

INSULIN FAILURE

• HOMEOSTASIS• CLINICAL

• MOLECULAR• ENVIRONMENT

GENE TISSUE

PANCREATIC OVERLOAD

INSULIN FAILURE

Usual Time of diagnosis of DM

The common types of Diabetes mellitus are:

• Type 1 DM: which results from the failure of beta cells to produce insulin. This form was previously called insulin-dependent diabetes mellitus (IDDM) but this term SHOULD NOT BE USED.

• Type 2 DM: results from insulin resistance, in which cells fail to use insulin properly, sometimes combined with a relative insulin deficiency. This form was previously called non insulin-dependent diabetes mellitus (NIDDM) but this term SHOULD NOT BE USED.

• Gestational diabetes: occurs in pregnant women, who have never had diabetes before, develop high blood glucose levels during pregnancy. This condition may precede development of type 2 DM.

TYPES OF DIABETES

Other forms of diabetes mellitus include

1) DM due to genetic defects of beta cell function affecting insulin production ( also called monogenic diabetes or MODY (Maturity onset Diabetes of the Young))

2) Diseases of the Pancreas (eg Cystic fibrosis-related diabetes, Pancreatitis, Viral infections)

3) Steroid induced diabetes induced by high doses of glucocorticoids (Secondary DM)

TYPES OF DIABETES

THE CLASSIFICATION OF DM

Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, Volume 36, Supplement 1, January 2013 : S70

Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Types of Diabetes MellitusTypes of Diabetes Mellitus

• Type 1: pancreatic beta cell destruction predominantly by an autoimmune process

• Type 2: a combination of beta cell dysfunction and insulin resistance

• Other– Genetic defects in insulin production– Genetic defects in insulin action– Diabetes secondary to other diseases– Drug interactions

• Gestational diabetes mellitus

DM classification at diagnosis

T1 DMMajority

T2DMOthers

• Type 2 diabetes is the most common form.

• This condition usually appears in middle-aged adults; but nowadays adolescents and young adults are developing type 2 diabetes at an increasing rate.

• It develops when the body cells are unable to efficiently use the insulin (insulin resistance) usually due to problems with insulin receptors, post receptor mechanisms, elevated plasma levels of free fatty acids and proinflammatory cytokines.

• The pancreas initially tries to make more insulin (hyperinsulinemia) in order to overcome insulin resistance, but eventually there is beta cell exhaustion and failure and then the beta cells don’t make enough insulin leading to relative or absolute insulin deficiency (especially if Type 2 DM has been present for a long time)

FEATURES OF TYPE 2 DM


• Type 2 DM is characterized by a combination of insulin resistance and inadequate insulin secretion by pancreatic beta cells

• Insulin resistance, leads to decreased glucose transport into muscle cells, elevated hepatic glucose production, and increased breakdown of fat.

• Also there is evidence that the reciprocal relationship between the glucagon-secreting alpha cell and the insulin-secreting beta cell is lost, leading to hyperglucagonemia which may worsen hyperglycemia.

• Susceptibility to type 2 diabetes is also be affected by genetic variants and a number of genetic variants are associated with beta-cell dysfunction and insulin resistance

• As T2DM progresses postprandial blood glucose levels increase first.

• Eventually, fasting hyperglycemia develops as suppression of hepatic gluconeogenesis fails.

Type 2 DM

Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes

Beta cell level

Peripheral tissue level

• There is a well established preclinical asymptomatic period for diabetes

• The duration varies from 6 to 12 years but the exact course is unknown

• Cardiovascular damage in this period is equal to established diabetes

• Diagnosis in this period is crucial for macrovascular and microvascular risk reduction

A

B

C

D

E

F

Am Fam Physician. 2004 Aug 1;70(3):489-500.

Type 2 DM

+ +Insulin resistance Insulin resistance

Abnormal beta cell function

Normal Beta cell function

Compensatory hyperinsulinemia

Euglycemia

Relative Insulin deficiency

Hyperglycemia

T2DM

•Genes •Lifestyle•Gluco-toxicity•Lipotoxicity•Others

GenesLifestyle

Genesis of T2DM

Insulin resistance Beta cell failure

CMacro-vascular disease

1. Heart2. Brain3. Limbs

BMicro-vascular disease

1. Eyes2. Kidney3. Nerves

AHYPERGLYCEMIA

T2DM at a glance

+

• Obesity• Smoking

• Hypertension• Dyslipidemia• Other factors

Pathogenesis of Type2 DM

• Genetic factors• Acquired (environmental) factors.

– Obesity– Inactivity

• Obesity: central obesity, decrease adiponectin release

Insulin Resistance and the Metabolic Syndrome.

• Hyperglycemia • Intra-abdominal obesity, • high levels of plasma triglycerides and low levels of high

density lipoproteins (HDLs),• hypertension,• systemic inflammation (as detected by C-reactive

protein[CRP] and other mediators), • abnormal Fibrinolysis, • abnormal function of the vascular endothelium, and• Macro-vascular disease (coronary artery, cerebrovascular,

andperipheral arterial disease).

Metabolic Syndrome

Syndrome X

TYPE 1 DM

• Type 1 diabetes usually occurs in children and young adults.

• This condition results from autoimmune destruction of insulin-producing beta cells of the pancreas

• In Type 1 DM, the beta cells of the pancreas produce little or no insulin and this leads to absolute insulin deficiency

• Also, in Type 1 DM the C-peptide levels, which reflect endogenous insulin production, are low


Type 1 Diabetes Mellitus

• Type 1A immune mediated Diabetes – Against β cell (GAD)– Against insulin (IAAs)

Honeymoon Period: short period of β cell regeneration• Idiopathic type 1B

• Autoimmunity is the major factor in the pathophysiology of type 1 DM.

• Approximately 85% of type 1 DM patients have circulating islet cell antibodies.

• The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD) which is an enzyme found within pancreatic beta cells

• Moreover, in a genetically susceptible individual, a viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules.

• There is lymphocytic infiltration and destruction of pancreatic beta cells.


• As the number of beta-cells (beta cell mass) decreases, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels.

• Once about 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes manifests.

• Therefore these patients need exogenous insulin to prevent the consequences of Insulin deficiency (such as ketosis) and to normalize lipid and protein metabolism.


TYPE 1 DM PATIENTS MUST BE TREATED WITH EXOGENOUS INSULIN

http://www.youtube.com/watch?list=UUXFFcYoTl244oguj2NAisiw&feature=player_detailpage&v=jHRfDTqPzj4

VIDEO ANIMATION OF PATHOGENESIS AND TYPES OF DIABETES MELLITUS





THE DIAGNOSIS OF

DIABETES MELLITUS

What is diabetes ?

• Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

62

WHEN IS DMSUSPECTED

Non classic presentations

Infection

Skin (carbuncles)Urinary tract

infectionEar infection

(fungal)

No Infection

PruritusFatigue

Visual symptomsSensory symptoms

Delayed healing

Classic presentation

PolyuriaPolydipsiaPolyphagiaWeight loss

Hyperglycemic crisis

Clinical clues to DM

Diagnosis of DM

Classification Proving hyperglycemia

1 2

NORMAL ABNORMAL

PRE DIABETES DIABETES

Copyright Aftab SA

RANGE OF GLYCEMIA

DIAGNOSTIC CRITERIA FOR DM

DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013

66

Pre diabetes: diagnostic criteria

Prediabetes

FPG 100 - 125 mg/dL (5.5 - 6.9 mmol/L)

2hPP 140 - 199 mg/dL ( 7.8 - 11 mmol/L)

HbA1c 5.7 - 6.4 %

Diagnosis of Gestational Diabetes Mellitus (GDM)

Clinical Features, Complications and Investigations in a Diabetes patient

The main symptoms of undiagnosed diabetes may include:

1) Polyuria: Passing urine more often than usual, especially at night (Nocturia)2) Polydipsia : Increased thirst 3) Polyphagia : Excess eating because of feeling hungry all the time4) Extreme tiredness 5) Unexplained weight loss 6) Generalized or genital itching 7) Recurrent fungal infections 8) Slow healing of cuts and wounds 9) Blurred vision

In Type 1 diabetes the signs and symptoms are usually very obvious and develop rapidly very quickly (over few weeks). The symptoms are quickly relieved once the diabetes is treated and under control.

In Type 2 diabetes the signs and symptoms may not be so obvious.The condition develops over a period of years and may only be picked up on routine check up.

Clinical Features in Diabetes mellitus

INITIAL PRESENTATION

Of DM

NON CLASSIC

INFECTION

SKINUTI

FUNGAL (ear)

NON INFECTION

PRURITUSFATIGUEVISION

SENSORYHEALING

CLASSIC

POLYURIAPOLYDIPSIA

POLYPHAGIAWEIGHT LOSSHyperglycemic emergencies

learning objectives 1.discuss the pathophysiology and pathogenesis of diabetes mellitus 2.describe...

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