Regarding type 1 diabetes mellitusRegarding type 1 diabetes mellitus, ,

which one statement is correct:which one statement is correct:

a.a. Most commonly develops in old age Most commonly develops in old age

b.b. Type 1 diabetes is an autoimmune disease with Type 1 diabetes is an autoimmune disease with

pancreatic beta islet cell destruction caused by T-pancreatic beta islet cell destruction caused by T-

lymphocytes lymphocytes

c.c. Usually not associated with genetic susceptibilityUsually not associated with genetic susceptibility

d.d. Type 1 diabetes is an autoimmune disease with Type 1 diabetes is an autoimmune disease with

pancreatic beta islet cell destruction caused by B-pancreatic beta islet cell destruction caused by B-

lymphocytes lymphocytes

Regarding type 1 diabetes mellitusRegarding type 1 diabetes mellitus,, which which

one statement is correct: one statement is correct:

a.a. Most commonly develops in old age Most commonly develops in old age

b.b. Type 1 diabetes is an autoimmune Type 1 diabetes is an autoimmune

disease with pancreatic beta islet cell disease with pancreatic beta islet cell

destruction caused by T-lymphocytesdestruction caused by T-lymphocytes

c.c. Usually not associated with genetic susceptibilityUsually not associated with genetic susceptibility

d.d. Type 1 diabetes is an autoimmune disease with Type 1 diabetes is an autoimmune disease with

pancreatic beta islet cell destruction caused by B-pancreatic beta islet cell destruction caused by B-

lymphocytes lymphocytes

Regarding type-2 diabetes mellitusRegarding type-2 diabetes mellitus

(DM)(DM), which one statement is correct:, which one statement is correct:

a.a. Genetic factors less important than in type 1 Genetic factors less important than in type 1

DMDM

b.b. There is no link between obesity and DMThere is no link between obesity and DM

c.c. Insulin resistance is the primary event, followed Insulin resistance is the primary event, followed

by progressive pancreatic beta cell destruction by progressive pancreatic beta cell destruction

d.d. Regulation of adipokines may lead to insulin Regulation of adipokines may lead to insulin

resistance resistance

Regarding type-2 diabetes mellitusRegarding type-2 diabetes mellitus

(DM)(DM), which one statement is correct:, which one statement is correct:

a.a. Genetic factors less important than in type 1 Genetic factors less important than in type 1

DMDM

b.b. There is no link between obesity and DMThere is no link between obesity and DM

c.c. Insulin resistance is the primary Insulin resistance is the primary

event, followed by progressive event, followed by progressive

pancreatic beta cell destructionpancreatic beta cell destruction

d.d. Regulation of adipokines may lead to insulin Regulation of adipokines may lead to insulin

resistance resistance

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using using

fasting plasma glucosefasting plasma glucose

a.a. 6.0 mmol/L6.0 mmol/L

b.b. 5.0 mmol/L5.0 mmol/L

c.c. 4.0 mmol/L4.0 mmol/L

d.d. 7.0 mmol/L7.0 mmol/L

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using using

fasting plasma glucose levels (FPG):fasting plasma glucose levels (FPG):

a.a. 6.0 mmol/L6.0 mmol/L

b.b. 5.0 mmol/L5.0 mmol/L

c.c. 4.0 mmol/L4.0 mmol/L

d.d. 7.0 mmol/L7.0 mmol/L

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using two using two

hour plasma glucose levelhour plasma glucose level using 75 using 75

gram oral glucose tolerance test gram oral glucose tolerance test

(OGTT):(OGTT):

a.a. 10.1 mmol/L10.1 mmol/L

b.b. 11.1 mmol/L11.1 mmol/L

c.c. 9.1 mmol/L9.1 mmol/L

d.d. 8.1 mmol/L8.1 mmol/L

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using using two two

hour plasma glucosehour plasma glucose level using 75 level using 75

gram oral glucose tolerance test gram oral glucose tolerance test

(OGTT):(OGTT):

a.a. 10.1 mmol/L10.1 mmol/L

b.b. 11.1 mmol/L11.1 mmol/L

c.c. 9.1 mmol/L9.1 mmol/L

d.d. 8.1 mmol/L8.1 mmol/L

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using using

randomrandom plasma glucose levels: plasma glucose levels:

a.a. 10.1 mmol/L10.1 mmol/L

b.b. 9.1 mmol/L9.1 mmol/L

c.c. 11.1 mmol/L11.1 mmol/L

d.d. 8.1 mmol/L8.1 mmol/L

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus criteria for diabetes mellitus using using

randomrandom plasma glucose levels: plasma glucose levels:

a.a. 10.1 mmol/L10.1 mmol/L

b.b. 9.1 mmol/L9.1 mmol/L

c.c. 11.1 mmol/L11.1 mmol/L

d.d. 8.1 mmol/L8.1 mmol/L

Which one of these satisfy the Which one of these satisfy the

diagnostic criteria for diabetes diagnostic criteria for diabetes

mellitus using mellitus using blood blood glycosylated glycosylated

haemoglobinhaemoglobin levels in levels in

percentages:percentages:

a.a. HbA1c HbA1c << 5.5 % 5.5 %

b.b. HbA1c HbA1c << 4.5 % 4.5 %

c.c. HbA1c HbA1c >> 6.5 % 6.5 %

d.d. HbA1c HbA1c << 3.5 % 3.5 %

Which one of these satisfy the diagnostic Which one of these satisfy the diagnostic

criteria for diabetes mellitus using criteria for diabetes mellitus using blood blood

glycosylated haemoglobin levelsglycosylated haemoglobin levels in in

percentagespercentages::

a.a. HbA1c HbA1c << 5.5 % 5.5 %

b.b. HbA1c HbA1c << 4.5 % 4.5 %

c.c. HbA1c HbA1c >> 6.5 % 6.5 %

d.d. HbA1c HbA1c << 3.5 % 3.5 %

Patients with each of the following Patients with each of the following

conditions may manifest with conditions may manifest with elevated elevated

blood glucose levelsblood glucose levels except: except:

a.a. Pheochromocytoma Pheochromocytoma

b.b. Cushing’s syndrome Cushing’s syndrome

c.c. Glucagonoma Glucagonoma

d.d. Pancreatic beta cell neoplasms Pancreatic beta cell neoplasms

e.e. Elevated Growth hormone Elevated Growth hormone

Patients with each of the following Patients with each of the following

conditions may manifest with conditions may manifest with elevated elevated

blood glucose levelsblood glucose levels except: except:

a.a. Pheochromocytoma Pheochromocytoma

b.b. Cushing’s syndrome Cushing’s syndrome

c.c. Glucagonoma Glucagonoma

d.d. Pancreatic beta cell neoplasmsPancreatic beta cell neoplasms

e.e. Elevated Growth hormone Elevated Growth hormone

Complication of Complication of diabetes mellitus diabetes mellitus

(D.M)(D.M)

Brig Rizwan HashimBrig Rizwan Hashim

Pathology dept Pathology dept

Army Medical CollegeArmy Medical College

Diabetes Mellitus vs Impaired Fasting Glucose/Impaired Glucose Tolerance

DM – Risk of DM – Risk of macrovascularmacrovascular and and microvascularmicrovascular complications complications

IFG/IGT – Risk of IFG/IGT – Risk of macrovascularmacrovascular complications (But not microvascular)complications (But not microvascular)

D.M ComplicationsD.M Complications

Short termShort term Complications: Complications: (metabolic)(metabolic) HypoglycemiaHypoglycemia Diabetic KetoacidosisDiabetic Ketoacidosis Non Ketotic hyperosmolar diabetic Non Ketotic hyperosmolar diabetic

comacoma Lactic acidosisLactic acidosis

Patho-physiology of DKAPatho-physiology of DKA Relative or absolute insulin

deficiency in the presence of catabolic counter-regulatory stress hormones (particularly glucagon and catecholamines, but also growth hormone and cortisol) leads to hepatic overproduction of glucose and ketones.

Patho-physiology of DKA Lack of insulin combined with Lack of insulin combined with

excess stress hormones excess stress hormones promotes promotes lipolysislipolysis, with the , with the release of non-esterified release of non-esterified fatty fatty acidsacids (NEFA (NEFAss) from adipose tissue ) from adipose tissue into the circulation.into the circulation.

Mechanisms of ketoacidosis. NEFA, non-esterifies fatty acids.

Clinical features of diabetic ketoacidosis.

ComplicationsComplications

Long termLong term complications: complications:(microangiopathy)(microangiopathy) Angiopathy, Angiopathy, Retinopathy, Retinopathy, Nephropathy, Nephropathy, NeuropathyNeuropathy

Long termLong term Complications:Complications:

AngiopathyAngiopathy AtherosclerosisAtherosclerosis Hyaline arteriolosclerosisHyaline arteriolosclerosis Diabetic microangiopathyDiabetic microangiopathy

NephropathyNephropathy Nodular glomerulosclerosisNodular glomerulosclerosis

RetinopathyRetinopathy Non Proliferative & ProliferativeNon Proliferative & Proliferative

NeuropathyNeuropathy Peripheral axonal neuropathyPeripheral axonal neuropathy

PathogenesisPathogenesis of of Microangiopathy:Microangiopathy:

LongLong standing diabetes standing diabetes Combination of glucose with proteins - Combination of glucose with proteins -

Particularly collagen in blood vessels - Particularly collagen in blood vessels - GlycosylationGlycosylation..

Excess Excess depositiondeposition of glycosylated type of glycosylated type IV collagen in the basement membraneIV collagen in the basement membrane

ThickThick and and LeakyLeaky blood vessels. blood vessels. Chronic Chronic IschemiaIschemia & & proteinprotein loss into loss into

tissues.tissues. Organ damage...Organ damage...

Microvascular complicationsMicrovascular complications Proposed mechanismsProposed mechanisms

HyperglycaemiaHyperglycaemia- stimulates aldol - stimulates aldol reductase enzymes – metabolise reductase enzymes – metabolise glucose to glucose to sorbitolsorbitol (polyol sugar) - (polyol sugar) - tissue accumulationtissue accumulation

Non-enzymatic glycationNon-enzymatic glycation of of proteins (Amadori products, ‘ proteins (Amadori products, ‘ advanced glycation endproducts’)advanced glycation endproducts’)

C

(CHOH)4

| CH2OH

NH||CH|(CHOH)4

|CH2OH

Glucose Protein

Schiff base

H 0

NH|CH2

|C=O|(CHOH)3

|(CH2OH)

N

N

Protein cross-link in

advanced glycosylation

end products

Amadori product

NH2

ReversibleK1

K-1(hours)

K2 K-2 Reversible (days)

KN

Irreversible (Weeks)

A

Ischemic Stage of Diabetic Retinopathy(low magnification)

The microphotograph shows multiple capillary aneurysms

Pathogenesis of RetinopathyPathogenesis of Retinopathy

Diabetic Eye DiseaseDiabetic Eye Disease

Diabetic RetinopathyDiabetic Retinopathy

Cotton wool spots

New vessels on the iris (rubeosis iridis). There is also vitreous haemorrhage.

Diabetic cataract

Diabetic Diabetic NephropathNephropath

yy

Evolution of diabetic nephropathy

Diabetic GlomerulosclerosisDiabetic Glomerulosclerosis

End-Stage Lesion of Diabetic Nephropathy

The glomerulus in the center of the microphotograph is completely sclerotic. The most common cause of chronic renal failure in the United States is diabetic nephropathy.

Renal Tubules(high magnification)

The basement membrane of the tubules are markedly thickened leading to tubular atrophy and dysfunction

Renal Necrotizing Papillitis

Necrotizing papillitis is can occur in diabetics as a renal complication. The papilla extending into the minor calyces become necrotic as demonstrated in the microphotograph (arrows). Necrotizing papillitis can also be caused by sickle cell disease (vaso-occlusive) and indomethicin (toxicity).

Diabetic Diabetic NeuropathyNeuropathy

Generalized wasting of the interossei (and hypothenar eminence) caused by bilateral ulnar nerve palsies in a diabetic patient.

Neuropathic foot, showing clawed toes, dry skin and prominent veins.

Typical neuropathy ulcer.

Note the surrounding callus.

Distended veins on the dorsum of the foot of a diabetic patient with painful peripheral neuropathy.

Neuroischaemic damage caused by tightly fitting shoes.

MacroMacrovascular Diseases vascular Diseases in Diabetesin Diabetes

Diabetic Macrovascular DiseasePathophysiologyPathophysiology Multiple metabolic changesMultiple metabolic changes Lipid changes in DMLipid changes in DM

- - RaisedRaised total cholesterol, LDL and triglycerides total cholesterol, LDL and triglycerides - - LowLow HDL HDL

LDL subfraction profile (small dense LDL)LDL subfraction profile (small dense LDL) Glycation and peroxidation of:Glycation and peroxidation of:

- Lipoproteins- Lipoproteins - - Thrombotic/thrombolytic factorsThrombotic/thrombolytic factors

Lipid disorder in DMLipid disorder in DM

Motility disorders associated with diabetes at various levels of the gastrointestinal tract.

Candidiasis

Other investigations:

•Serum Urea.

•Serum Creatinine

•Serum Lipid profile: cholesterol; triglyceride; LDL-C; HDL-C.

•Serum sodium, potassium,

•24 hour urine for: protein; creatinine clearance; microalbumin;

•Spot urine for microalbumin

•Spot urine for albumin creatinine ratio- ACR

Other investigations and evaluations:

Blood complete picture

•Urine routine examination: glucose; protein/, albumin, WBC, sp gravity.

•Urine for ketone bodies

•Arterial blood gases-ABG’s

•Ultra sound liver- Fatty liver

•Fundoscopy- for diabetic retinopathy;

•Routine eye exam: diabetic cataract

•Blood pressure measurement

•Examination of feet- ulcer; poor sensations/neuropathy

Insulin pens

Management

Monitoring Monitoring

Metabolic abnormalities leading to Microvascular Metabolic abnormalities leading to Microvascular complications in DMcomplications in DM

Figure 18.4Figure 18.4

Flowchart for the investigation of diabetic ketoacidosis

The stages and

determinants of diabetic

nephropathy.(AER, albumin

excretion rate.)

Diabetic nephropathy