Diabetes mellitus pathophysiol-vnw

Diabetes mellitus

v.nyunt_wai2013

Pathophysiology

ObesityDiabetes mellitus

Hypertension

“Obesity is the mother of metabolic diseases”

The 3 public health scourges of modern times

World-wide estimated number of adults with diabetes by age group and year

Diabetes mellitus is a group of metabolic diseases characterized by

hyperglycemia resulting from• defects in insulin secretion, • defects in insulin action (“insulin resistance”), • or both.

long-term damage, dysfunction, and failure of various organs, especially the eyes kidneynerves heart blood vessels.

“Complications”

Classification of diabetes Type 1 ( was called “insulin- dependent DM”/ juvenile type of DM) ( 5-10%)

Type 2 (was called “non insulin- dependent DM” /adult onset DM ) (90-95%)

The “pre-diabetic stage” (impaired glucose tolerance)

Gestational DM -any degree of glucose intolerance with onset or first recognition during pregnancy [in 2-5% of all pregnancies]

Other specific types (1% - 2%)– genetic syndromes (affecting insulin secretion or action)– endocrinopathies (Acromegaly, Cushing’s syndrome, glucagonoma,

pheochromocytoma, thyrotoxicosis)– diseases of pancreas (chronic pancreatitis, cancer)– drug- or chemical-induced (corticosteroids, beta-blockers, thiazide

diuretics)– infections (viral)

The main focus of this plenary

Type 1 Diabetes“insulin- dependent DM”

“ juvenile-onset DM”

Type 2 Diabetes “Non insulin-

dependent DM”“ adult-onset DM”

Type 1 Diabetes“insulin- dependent DM”

“ juvenile-onset DM”

Type 2 Diabetes “Non insulin-

dependent DM”“ adult-onset DM”

Many require insulini.e. insulin- dependent

May develop when much older

Developing at younger age groups (childhood obesity)

Type 1 Diabetes Type 2 Diabetesdiabetes due to

insulin resistance and inadequate compensatory insulin secretory response

diabetes due to absolute deficiency of

insulin

Positive Family history

Type 1 Diabetes Type 2 Diabetes

(but ”obesity gene” not yet identified)

30 % 10 %

Pathogenesis

Susceptibility genes identifiede.g. HLA haplotypes DR3 & DR4.

cell-mediated autoimmune destruction of the beta-cells of the pancreas by auto-antibodies

genetic predisposition environmental factors

viral infectionsstresstoxins e.g. rat poison

Type 1 Diabetes

absolute insulin deficiency

Sequence of events in the development of

Pathogenesis

Type 1 Diabetes

Pathogenesis

genetic predisposition environmental factors

DietPhysical inactivity

relative insulin deficiency

Obesity

insulin resistance and inadequate compensatory insulin secretory response

Type 2 Diabetes

?Exhaustion?Glucotoxicity? Amyloid deposition

Postreceptor defects(refer to 2nd messenger

systems mediating insulin action)

Impaired insulin action

Insulin

Counter regulatory hormones:

CortisolGrowth hormone

Anti-insulin action

hyperglycaemia

Inadequate secretory response

insulin resistance

Type 2 DiabetesPathogenesis

GlucagonCatecholamines

Target cells

Pancreatic beta-cells:

Hyperglycaemic effectvs

Diabetogenic effect

2nd messenger systems mediating insulin actionWhat and where is the postreceptor defect?

• Multiple, but unified hypothesis yet to be made

Sympathetic nervesa cells

b cells

Glucagon

Insulin

-a receptor (-)

-b receptor (+)

-b receptor (+)

-a receptor (-)Sympathetic nerves

Net effect: incr. glucagon secretion

Net effect: decr. insulin secretion

(-)

(+)

Islets of Langerhans

Insulin-glucagon interaction in normal conditions

Para

crin

e pa

thw

ay

Start here

Sympathetic nerves

Glucagon

Insulin

-a receptor (-)

-b receptor (+)

-b receptor (+)

-a receptor (-)Sympathetic nerves

Net effect: incr. glucagon secretion

Net effect: decr. insulin secretion

Para

crin

e pa

thw

ay

(-)

(+)

Islets of Langerhans

DM: Hyperglucagonaemia is a feature of DM Beta-blockers may further impair insulin secretion

Start here

a cells

b cells

Natural history of Type 2 Diabetes

b cell secretory response to progressive insulin resistance

(Blood glucose normal)

b cells no longer able to compensate

Type 2

Diabetes

Too late?

At the time of diagnosis, 50% of b cell function has already been lost ( A study on patients in the UK)

Type 2 Diabetes

Clinical presentation of DM

• Asymptomatic (particularly type 2 DM)• Features resulting from the effects of insulin

deficiency/resistance (review insulin actions)– The 3 Polys :

• Polyuria / nocturia• Polydipsia• Polyphagia (in the presence of unintentional weight loss)

• Complications– Acute: coma (ketoacidosis) (particularly type 1 DM)– Chronic: macrovascular and microvascular

Pancreas beta cells

Insulin actions

Glucose entry and utilization (oxidation,

storage)

Glucose entry and oxidation

TG synthesis

insulin actions: a review

Pancreas beta cells

Insulin actions

Glucose entry and utilization (oxidation,

storage)

Glucose entry and oxidation

TG synthesis

Metabolic consequences of insulin deficiency/resistance

Clinical Features of DM due to insulin lack

Polyphagia(decr. leptin?)

Starvation in the midst of plenty

Hyperosmolar hyperglycemic syndrome (HHS)

Lactic acidosis

Lactic acidosis

Muscle protein breakdown

Acetoacetate,0H-butyrate, acetone

• Ketoacidosis - Life threatening – medical emergency!

Stressful situation

Positive feedback cycleStart here

Stressful situation

Positive feedback cycleStart here

• Treatment: Fluids(normal saline), I.V. insulin. Monitor plasma glucose (and K+ as insulin promotes uptake of glucose and K+ by muscles and adipose tissue)

Insulin pump

Rehydration -fluids

• hyperglycaemia• Excess glucose attaches nonenymatically to

amino acids of proteins [“glycosylation”]• Glycosylation of haemoglobin HbA1C refects

glycaemic control for the past 2 months (half life for RBCs)

• Glycosylation of plasma proteins fructosamine levels refects glycaemic control for the past 6 weeks(shorter half life)

Complications: pathogenesis

Complications: pathogenesis

• Hyperglycaemia • Excess entry of glucose into non-insulin dependent

tissues– Nerves– Lens– Kidneys– Blood vessels

• Increased intracellular glucose metabolized to sorbitol fructose increased osmotic load influx of water osmotic cell injury

• E.g. lens cataract

Vascular complications: pathogenesis

• “glyocosylation”of collagen and other long-lived proteins in tissues

• Irreversible formation of advanced glycosylation end products (AGEs) accumulation of AGEs over the lifetime of blood vessel walls – Protein cross-linking and trapping of plasma lipoproteins

in blood vessel walls– Reduction in protein breakdown– AGE binding to cell receptors/ endothelial dysfunction

• vasculopathy

Microvascular complications

• Retinopathy

• Nephropathy

• Neuropathy

• Impaired skin healing foot ulcers

Microvascular complications

• Diabetic Retinopathy:– Capillary microanuerysms– Macular oedema– neovascularization

– partial or total vision loss

Microvascular complications

• Diabetic nephropathy:– Thickening of glomerular basement membrane– Mesangial cell expansion– glomerulosclerosis

Glomerular hypertensionProgressive decline in glomerular filtration rate nephrotic syndrome (leakage of albumin)/ renal

failure

Microvascular complications

• Diabetic neuropathy– also due to direct effects of hyperglycaemia and

intracellular metabolic changes• impaired nerve function (sensory, motor)

– Symmetric polyneuropathy (distal feet and hands)– Autonomic neuropathy– Cranial neuropathy– Mononeuropathy (median neerve, peroneal nerve)– “diabetic foot”

Macrovascular complications

• Large vessel atherosclerosis (due to hyperinsulinaemia, dyslipidaemia, hyperglycaemia)

• Coronary arteries myocardial ischaemia /infarction

• Cerebral arteries transient ischaemic attacks; cerebrovascular events stroke

• Peripheral artery disease ischaemia intermittent claudication

(1) Symptoms (thirst, increased urination, unexplained weight loss) + a random plasma glucose concentration >200 mg/dL (11.1 mmol/L).(2) Fasting plasma glucose (FPG) >126 mg/dL (7.0 mmol/L) after an overnight (at least 8-hour) fast(3) Two-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) during a standard 75-g oral glucose tolerance test (OGTT)

[ should be confirmed on a later day with one of the three methods listed]

Oral Glucose Tolerance Test (OGTT)(how much one can tolerate a glucose load without undue rise in plasma glucose levels; reflects how efficiently insulin can handle the glucose load))

Procedure

Overnight fast

75 g glucose in 300 ml water given orally over 5 minutes

Basal plasma glucose & every 30 minutes for 2 hours

Urine tested for sugar

Indications

Borderline fasting (FPG) or postprandial PG

Persistent glycosuria

Glycosuria of pregnancy

Pregnant women with family history of DM or had large babies

Pla

sma

gluc

ose

(mm

ol/l)

Symptoms of HYPOGLYCAEMIA

AUTONOMIC• Sweating • Trembling • Pounding heart • Hunger • Anxiety

NUEROGLYCOPENIC• Confusion • Drowsiness • Speech difficulty • Inability to concentrate • In-coordination

NON-SPECIFIC: Nausea, tiredness, headache

Diabetics on Insulin therapy

“Hypoglycaemia awareness”

The end

American diabetic association. Diagnosis and classification of diabetes mellitus. Diabetic care, 2004, 27 (Suppl. 1); 55-60.

Robbins Pathologic basis of disease. Pocket companion. Saunders.

Holt RIG and Hanley N. Essential Endocrinology and Diabetes. 5th ed. 2007, Blackwell.

Merck Manual. iPhone app. Agile Parters. www.Merck Manuals.com.

Diabetes power point file. Prof. Hla-Yee-Yee, IMU.

References