Diabetes Mellitus

Diabetes MellitusDiabetes Mellitus

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OverviewOverview

• DM is a heterogeneous group of syndromes characterized by an DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative elevation of fasting blood glucose caused by absolute or relative deficiency of insulindeficiency of insulin

• Two types of DMTwo types of DM:: Type 1 (insulin-dependent DM)Type 1 (insulin-dependent DM) Type 2 (noninsulin dependent DMType 2 (noninsulin dependent DM)

• Prevalence of type 2 is increasing as:Prevalence of type 2 is increasing as: Aging (increase in rate of life-age of population)Aging (increase in rate of life-age of population) Increasing prevalence of obesityIncreasing prevalence of obesity

Comparison between type 1 & type 2 DMComparison between type 1 & type 2 DM

Type 1 Diabetes MellitusType 1 Diabetes Mellitus

Type 1 Diabetes MellitusType 1 Diabetes Mellitus • about 10% of diabetics (in USA)

• Onset: usually during childhood

• Caused by absolute deficiency of insulin absolute deficiency of insulin : : may be caused by autoimmune attack of -cells of the pancreas, viral infection or toxin Destruction is enhanced by environmental factors as viral infection & a genetic element (that allows -cells to be recognized as nonself) In identical twins if one sibling has type 1 DM, the other twin has only 30- 50% chance of

developing DM

• Rapid symptoms appear when 80-90% of the -cells have been destroyed

• Commonly complicated by diabetic ketoacidosis (DKA)

• Treated onlyonly by insulin

Onset of type 1 DMOnset of type 1 DM

Metabolic changes of type 1 DMMetabolic changes of type 1 DM

1-1- HyperglycemiaHyperglycemia: increased glucose in blood Due to: Decreased glucose uptake by muscles & adipose tissues (by GLUT-4) & Increased hepatic gluconeogenesis

2-2- KetoacidosisKetoacidosis: increased ketone bodies in blood (in untreated or uncontrolled cases)

• in 25 – 40% of newly diagnosed type 1 DM• in stress states demanding more insulin (as during infection, illness or during surgery)• no comply with therapy (intake of meals with no insulin medication) Biochemical causes of diabetic ketoacidosis (DKA)Biochemical causes of diabetic ketoacidosis (DKA) Absence of insulin leads to increased mobilization of FFA from adipose tissues in the liver, FFA are oxidized to yield excess acetyl CoA that will synthesize KETONE BODIES.

Metabolic changes of type 1 DM Metabolic changes of type 1 DM (cont.)(cont.)

3- Hypertriacylglyceridemia: 3- Hypertriacylglyceridemia: increased TAG in blood • Released fatty acids from adipose tissues adipose tissues are converted to triacylglycerol Triacylglycerol is secreted from the liver in VLDL VLDL to blood.

• ChylomicronsChylomicrons (from diet fatdiet fat) accumulates (low lipoprotein lipase in DM)

• Increased VLDL & chylomicrons VLDL & chylomicrons results in hypertriacylglyceridemia

Metabolic changes of type 1 DMMetabolic changes of type 1 DM

Diagnosis of type 1 DMDiagnosis of type 1 DM

• Clinically:

Age: during childhood or puberty (< 20 years of age) Abrupt appearance of : Polyuria (frequent urination) Polydepsia (excessive thirst) Polyphagia (excessive hunger) Fatigue Weight loss Complication as ketoacidosis (common, may be the cause of diagnosis)

• Laboratory diagnosis:

Fasting blood glucoseFasting blood glucose: > or equal 126 mg/dl: > or equal 126 mg/dl 100 – 125 mg/dl is called impaired fasting blood glucose Insulin level in bloodInsulin level in blood: low Circulating islet-cell antibodies detection Circulating islet-cell antibodies detection

Treatment of type 1 DMTreatment of type 1 DM

AIMAIMExogenous insulin by subcutaneous injection to control Exogenous insulin by subcutaneous injection to control hyperglycemia & ketoacidosishyperglycemia & ketoacidosis

Strategies of treatmentStrategies of treatment:

1- Standard treatment1- Standard treatment 2- Intensive treatment (tight control)2- Intensive treatment (tight control)

1- Standard treatment:1- Standard treatment:

by one or two injections of insulin/day AIMAIM: Mean blood glucose levelMean blood glucose level 225-275 mg/dl (normal: 110 mg/dl) HbA1c levelHbA1c level: 8-9 % of total Hb (normal: 6% of total HB) HbA1c: HbA1c: is proportional to average blood concentration over the previous several months So, it provides a measure of how proper treatment normalized blood glucose in diabetic over several months

Treatment of type 1 DM Treatment of type 1 DM (cont.)

2- Intensive treatment: 2- Intensive treatment: (tight control)

Conducted by more frequent monitoring & subsequent injection of insulin (3 or more times / day). More closely normalize blood glucose to prevent complications of existence of hyperglycemia for a long period AIMAIM: Mean blood glucose levelsMean blood glucose levels of 150 mg/dl HbA1cHbA1c : approximately 7% of total Hb

Advantage: Reduction in chances of occurrence of complications of DM: e.g. retinopathy, nephropathy & neuropathy by about 60%


Complications of treatment by insulin:Complications of treatment by insulin:

HypoglycemiaHypoglycemia is a common complication of insulin treatment (in more than 90% of patients)More Common with intensive treatment regimens

Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia as:as: No glucagon (early in the disease) No epinephrine (with progression of the disease diabetic autonomic neuropathy with inability

to secrete epinephrine in response to hypoglycemia) So, patients with long-standing type 1 DM are particularly vulnerable to hypoglycemia

Hypoglycemia can be caused by strenuous exerciseHypoglycemia can be caused by strenuous exercise. Exercise promotes glucose uptake into muscles & decrease the need for exogenous insulin. So, blood glucose level should be checked before & after exercise to avoid hypoglycemia.


Contraindications of intensive treatment:Contraindications of intensive treatment:

• ChildrenChildren: risk of episodes of hypoglycemia may affect the brain development

• Elderly peopleElderly people: as hypoglycemia can cause strokes & heart attacks in older people


Type 2 Diabetes MellitusType 2 Diabetes Mellitus

Type 2 DMType 2 DM

• 90% of diabetics (in USA)• Develops gradually • may be without obvious symptoms• may be detected by routine screening tests• BUT: many type 2 diabetics have symptoms of polyuria & polydepsia

• In type 2 DM: a combination of insulin resistance & dysfunctional -cells

• Metabolic changes in type Metabolic changes in type 2: are milder than type 1 as insulin secretion restrain ketoacidiosis (although not adequate)• DiagnosisDiagnosis: blood glucose concentration equal or more than 126 mg/dl

• TreatmentTreatment : no requirement for insulin to sustain life BUT: insulin may be required to control hypoglycemia in some patients

Insulin resistance is the decreased ability of target tissues, such Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to as liver, adipose tissue & muscle to respond properly to

normal circulating insulinnormal circulating insulinObesityObesity is the most common cause of insulin resistance

Obesity causes insulin resistance as:Obesity causes insulin resistance as: - substances produced by fat cells as leptin and resistin substances produced by fat cells as leptin and resistin may contribute to

development of insulin resistance - Free fatty acids elevated in obesity Free fatty acids elevated in obesity is involved in insulin resistance

Causes of type 2 DM Causes of type 2 DM (cont.)(cont.)Insulin resistance & dysfunctionalInsulin resistance & dysfunctional-cell -cell

• MostMost people with obesity & insulin resistance do not develop DM ?? In the absence of defect in -cell function, nondiabetic, obese individuals

can compensate for insulin resistance by increasing levels of secretion of insulin from -cell

So, glucose levels in blood remain within normal range

• In late cases -cell dysfunction occurs due to increased amounts of free fatty acids & other factors secreted by fat cells in addition to impaired glucose tolerance may end in development of type 2 DM (hyperglycemia).


In type 2 DMInitially (In early stages)

the pancreas retains -cell capacity

insulin is secreted (may be higher than normal)

normal blood glucose levels________________________________________________

With time (late stages)-cells become dysfunctional -cells become dysfunctional

(fat cells substances , FFA & impaired glucose tolerance)

-cells fail to secrete enough insulin

Increased blood glucose levels (hyperglycemia)


Progression of type 2 DMProgression of type 2 DM

Metabolic changes in type 2 DMMetabolic changes in type 2 DM

metabolic abnormalities of type 2 DM are the results

of insulin resistance (in liver, muscle & adipose tissue)

1- hyperglycemiahyperglycemia ((BUTBUT: diabetic ketoacidosis is minimal or absent): diabetic ketoacidosis is minimal or absent)

2- hypertriacylglyceridemiahypertriacylglyceridemia

Metabolic changes in type 2 DMMetabolic changes in type 2 DM

Chronic effects of DMChronic effects of DM

The long-standing hyperglycemia causes the chronic The long-standing hyperglycemia causes the chronic complications of DMcomplications of DM::

1- AtherosclerosisAtherosclerosis : diabetic retinopathy diabetic nephropathy diabetic neuropathy cardiovascular diseases & stroke 2- Sorbitol accumulation in certain cells Sorbitol accumulation in certain cells with its complicationswith its complications 3- Glycated proteins formationGlycated proteins formation with microvascular complications with microvascular complications

For avoiding these complications, lomg-term control og hyperglycemia is For avoiding these complications, lomg-term control og hyperglycemia is recommernded for all types of DMrecommernded for all types of DM

Chronic effects of DM Chronic effects of DM (cont.)

in cells where entry of glucose is not dependent on insulin (eye lenslens, retinaretina, kidneykidney, neuronesneurones)

intracelluar levels of glucose

SORBITOL accumulation in these cells SORBITOL accumulation in these cells

cataractcataract diabetic retinopathydiabetic retinopathy

diabetic nephropathydiabetic nephropathy diabetic neuropathydiabetic neuropathy

Treatment of type 2 DM Treatment of type 2 DM

• AIMAIM: 1- To maintain blood glucose concentrations within normal limits 2- To prevent the development of long-term complications occurring due to prolonged hyperglycemia

• Lines of treatment:Lines of treatment: 1- Weight reduction Weight reduction (to control insulin resistance) 2- ExerciseExercise 3- Dietary modificationDietary modification 4- Hypoglycemic agents Hypoglycemic agents 5- Insulin (required in somesome cases)

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Diabetes Mellitus