1. Biochemical Aspects of Diabetes Mellitus
ENDO 412

2. Diabetes Mellitus (DM)
DEFINITION
Diabetes Mellitus (DM)
is a group of metabolic diseases
characterized by hyperglycemia
caused by
defects in Insulin secretion
defects in insulin action
Or both
DM is a life-long disease

3. Classification of Diabetes Mellitus
According to WHO, DM can be categorised into the followings major types. 1- Primary DM: subclassified into - Type 1 DM: (Insulin Dependent Diabetes Mellitus, IDDM) due to autoimmune cause (b-cells of the pancreas is destroyed by immunoglobulins) - Type 2 DM: (Non-Insulin Dependent Diabetes Mellitus, NIDDM) due to - insulin resistance (esp. in obese persons) or - inadequate insulin production (in lean people) or - combination of both 2- Secondary DM: due to - Pancreatic disease - Endocrine disease (as in Cushing’s syndrome) - Drug-induced - Insulin receptors abnormalities (genetic) 3- Gestational : Glucose intolerance during pregnancy caused by metabolic & hormonal changes DM is diagnosed during pregnancy Requires insulin injection May disappear after birth BUT with increase risk of developing DM for mother & child

4. Primary DM Type 1 & Type 2 DM

5. Type 1 Diabetes Mellitus (Type 1 DM)
Type 1 DM constitutes about 10% of diabetics
DM usually appears for the first time during childhood (and persists for life)
Caused by absolute deficiency of insulin :
may be caused by autoimmune attack of b-cells of the pancreas, viral infection or toxin
Destruction is enhanced by environmental factors as viral infection & a genetic element
Islet cells antibodies are available in serum of patients
In identical twins if one sibling has type 1 DM, the other twin has only % chance of developing DM
N.B. 80% of type 1 diabetics have nor diabetic relatives. (So, genetic element is not strong in type 1)
Sudden onset of severe symptoms appear when 80-90% of the b-cells have been destroyed
Characterized by rapid weight loss in a relatively short period (muscle wasting)
Commonly complicated by diabetic ketoacidosis (DKA)
DM type 1 is treated only by insulin (insulin injection is essential for life)

6. Onset of
clinical symptoms
of Type 1 DM
When
80-90 % of b-cells
are destroyed

7. Type 2 Diabetes Mellitus (Type 2 DM)
Type 2 DM patients constitutes about 90% of diabetics
Age: common to in middle age (over 35 years)
Symptoms are mild & develops gradually (mainly polyuria & polydepsia)
BUT may be in some cases without obvious symptoms & may be detected by routine
screening tests. Many cases present with complications even before DM is diagnosed
Type 2 DM: is a combination of insulin resistance & dysfunctional b-cells
Most cases produce normal amounts of insulin (in early periods), but it is unable to work
properly due to insulin resistance (hyperinsulinemia may occur in some cases)
DKA is NOT common in type 2 DM as insulin secretion is available & although not adequate yet it still can prevent the occurrence of ketoacidosis
Treatment : NO requirement for insulin to sustain life (not given in all cases)
Diet & weight reduction esp. in obese can control type 2 DM
BUT: insulin may be required to control hyperglycemia in some patients

8. Aetiology of Type 2 DM Insulin Resistance & Dysfunctional b-cell
is the decreased ability of target tissues, such as liver, adipose & muscles to respond properly to normal circulating insulin
Obesity
is the most common cause of insulin resistance
Due to:
- Substances produced by fat cells as Leptin & Resistin may contribute to
development of insulin resistance
- Free Fatty Acids elevated in obesity is involved in insulin resistance

9. Causes of type 2 DM (cont.) Insulin Resistance & Dysfunctional b-cell
Obesity, Insulin Resistance & DM
Obesity is the most common cause for insulin resistance.
HOWEVER, Most people with obesity & insulin resistance do not develop DM !!
How insulin resistance leads to DM??
1- In the absence of defect in b-cell function, nondiabetic, obese individuals can compensate for insulin resistance by secreting high amounts of insulin from b-cell (i.e. Hyperinsulinemia)
So, glucose levels in blood remain within normal range
2- In late cases, b-cell dysfunction with low insulin secretion occurs due to increased amounts of free fatty acids & other factors secreted by fat cells (as leptin & resistin) may end in development of type 2 DM (hyperglycemia).

10. Causes of type 2 DM (cont.) Insulin resistance & dysfunctional b-cell
In Type 2 DM
Initially (In early stages : with Insulin resistance)
the pancreas retains b-cell capacity
Insulin is secreted (may be higher than normal i.e. hyperinsulinemia)
Normal Blood Glucose
________________________________________________
With time (late stages)
b-cells become dysfunctional (low function)
(due to harmful effects of FFAs & substances released by increased fat cells)
b-cells fail to secrete enough insulin (low insulin)
Increased Blood Glucose (Hyperglycemia)

11. Progression of Type 2 DM

12. Biochemical Basis of Clinical Manifestations of DM
HYPERGLYCEMIA CAUSES GLUCOSURIA (if above 200 mg/dl)
DUE TO GLUCOSURIA, OSMOTIC DIURESIS OCCURS WITH PASSNG OF LARGE AMOUNTS OF URINE (POLYURIA)
ACCORDINGLY, PATIENT DRINKS BIG AMOUNTS OF WATER (POLYDEPSIA)
MUSCLES & ADIPOSE TISSUE CANNOT UTILIZE GLUCOSE .
ACCORDINGLY, PATIENT LOOSES WEIGHT WITH MUSCLE WASTING & FATIGUE
& HE FEELS HUNGER MOST OF THE TIME WITH EXCESSIVE EATING (POLYPHAGIA)
INCREASED GLUCOSE IN BRAIN & RETINA & EYE CAUSES CONFUSION & BLURRING OF VISION
SUMMARY OF COMMON CLINICAL MANIFESTATIONS of DM
Age: usually below 20 years in type 1 DM & over 35 years in type 2 DM
ONSET: rapid development of marked symptoms in type 1 DM & gradually in type 2 DM (milder)
Cardinal 3 Ps: Polyuria (frequent urination) Polydepsia (excessive thirst) Polyphagia (excessive eating)
Fatigue & Confusion & Blurring of vision
Weight loss & muscle wasting (esp. in type 1 )
Patient may present for the first time with complications of DM as:
Ketoacidosis (common in type 1), Nonketotic hyperglycemic coma (common in type 2 or other systemic complications (chronic cases)

13. Laboratory Diagnosis of DM
1- Screening test by urine analysis for glucose in urine (glucosuria):
Glucose appears in urine if blood glucose level rises above glucose renal threshold (200 mg/dl)
Glucosuria does not reflect the exact level of blood glucose at time of testing BUT indicates hyperglycemia over the period of
formation of urine
VERY IMPORTANT !!
PRESENCE OF GLUCOSURIA IS NOT CONCLUSIVE FOR THE OCCURRENCE OF DM
& ABSENCE OF GLUCOSURIA DOES NOT EXCLUDE THE OCCURRENCE OF DM
2- Standard Criteria of Diagnosis of DM (according to ADA) :
1- Symptoms of DM + Random blood glucose equal or more 200 mg/dl (11.1 mmol/L)
2- Fasting equal or more 126 mg/dl (7 mmol/L)
3- Two-hours postprandial glucose more than or equal 200 mg/dl (11.1 mmol/L)
3- Oral glucose tolerance test
4- Glycosylated hemoglobin HBA1c: esp for follow up of treatment
5- Immunological investigations (Islet cells antibodies for diagnosis of type 1 DM)
6- Insulin C peptide in blood : to detect the endogenous secretion of insulin

14. Laboratory Diagnosis of DM (cont.)
Pre-diabetics (with increased risk of developing DM)
1- Impaired Fasting Blood Glucose
in cases of fasting blood glucose mg/dl
2- Impaired Glucose Tolerance
in cases of two-hours postprandial mg/dl
Patients with pre-diabetics should be monitored
for the early diagnosis of DM

15. Metabolic Changes of DM
1- Hyperglycemia
2- Hypertriacylglyceridemia & Hypercholesterolemia
3- Diabetic Ketoacidosis (DKA) esp. in type 1 DM
4- Nonketototic Hyperglycemia esp. in type 2 DM

16. Metabolic Changes of DM (cont.)
1- Hyperglycemia:
Due to:
Absence or inefficient action of insulin (or both) that lead to:
Decreased glucose uptake by muscles & adipose tissues (by GLUT-4)
Increased hepatic glucose synthesis (gluconeogenesis) & glycogenolysis

17. Metabolic Changes of DM (cont.)
2- Hypertriacylglyceridemia & Hypercholesterolemia:
High hormone sensitive lipase activity (by absence of insulin)
TAG of adipose tissues are hydrolysed to fatty acids
Fatty acids are transported to liver in high amounts
In the liver, these fatty acids are converted to TAG
Triacylglycerol (TAG) (with cholesterol) are secreted from the liver in VLDL to blood
So, VLDL are increased in blood (with increased TAG & Cholesterol)
low lipoprotein lipase activity (by absence of insulin)
Chylomicrons are accumulated in blood (TAG is not hydrolysed by lipoprotein lipase)
Chylomicrons contain Triacyglycerols (mainly) & cholesterol
Increased VLDL & Chylomicrons in blood results in
Hypertriacylglyceridemia & Hypercholesterolemia

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

19. Metabolic Changes DM (cont.)
3- Diabetic Ketoacidosis (DKA): Common in TYPE 1 DM
Increased ketone bodies in blood (ketonemia) that may lead to metabolic acidosis
DKA occurs in untreated or uncontrolled cases of DM
1- In 25 – 40% of newly diagnosed type 1 DM (Untreated & Uncontrolled DM)
2- In stress states demanding more insulin (as during infection, illness or during surgery Uncontrolled DM)
3- No comply with therapy (intake of meals with no insulin medication i.e. Uncontrolled DM)
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.

20. Metabolic Changes & Clinical Manifestations in DKA
Low Insulin
Carbohydrates Metabolism
In Sk. Ms. & Adipose In Liver
Glucose Uptake Glycogenlysis
Gluconeogenesis
Lipids Metabolism
Lipolysis
in Adipose Tissue
Fatty Acids
in liver
ketone Bodies
(KETOGENESIS)
Protein Metabolism
Proteolysis
Uptake of AA by liver
Gluconeogenesis
Hyperglycemia
Plasma
Osmolality
Coma
Prerenal Uremia
Glycosuria
Metabolic
Acidosis
Low
Renal H+
Excretion
Osmotic diuresis
Ketonemia
With Loss of water & Na+
& Hypovolemia
Low
Blood
Bicarbonate
Low pCO2
Nausea
&
Vomiting
Acetone
Smelt
on Breath
Increased
Respiration
Ketonuria
Polyuria,
&
Dehydration
Thirst
Low GFR

21. Diagnosis of DKA 1- History (for a cause of DKA)
2- Clinical Examination
3- Lab Investigations: (to confirm the diagnosis & follow up of treatment)
- Urine by dipstick: Glucose & Ketones +++ (RAPID TEST)
- Blood Chemistry Analysis:
* Blood Glucose: High
* Blood Urea: High (due to dehydration)
* Electrolytes: Low (or normal) sodium
High (or normal) potassium
* Assessment of acid-base status: (metabolic acidosis)
- Blood Bicarbonate: Low (usually below 5 mmol/L)
- pCO2: Low (compensatory)

22. Biochemical Basis of Treatment of DKA
EMERGENCY TREATMENT
1- Correction of DEHYDRATION : by IV fluids & Sodium (isotonic saline)
2- Correction of ACIDOSIS: by IV bicarbonate
3- Correction of METABOLIC ABNORMALITY : by insulin IV infusion
4- POTTASIUM is given with insulin treatment as insulin induces K+ entry into cells
5- IV GLUCOSE SHOULD BE STARTED IN CASE GLUCOSE IN BLOOD FALLS BELOW 10 mmol/L (AVOID HYPOGLYCEMIA INDUCED BY INSULIN)
6- FOLLOW UP is QUITE IMPORTANT to monitor
Blood glucose level
Electrolytes (Na+ & K+)
Acid-base status (blood bicarbonate level)

23. Metabolic Changes in DM (cont.)
4- Nonketotic Hyperglycemic Coma (common in TYPE 2 DM)
In cases with severe hyperglycemia especially in older age diabetics type 2
Hyperglycemia induces osmotic diuresis with loss of ECF
The osmotic diuresis causes loss of water in excess of sodium (more water loss)
leading to very high plasma osmolality (with hypernatremia)
& marked dehydration (esp. in elderly who commonly have some renal impairment & infrequent water drinking)
No ketgenesis due to presence of sufficient insulin to prevent DKA
(or sometimes there is minimal ketogenesis with minimal metabolic
acidosis i.e. Bicarbonate is not much lowered as in DKA)
Treatment: Emergency Case!!
Fluid replacement (hypotonic saline) + Insulin IV infusion + follow up

24. The long-standing hyperglycemia causes the chronic complications of DM
Chronic Effects of DM
The long-standing hyperglycemia causes the chronic complications of DM
1- Atherosclerosis :Diabetic Retinopathy
Diabetic Nephropathy: glomerular proteinuria
Diabetic Neuropathy: peripheral neuritis
Cardiovascular Diseases (as MI) & strokes (as cereb. hge)
2- Sorbitol accumulation in certain cells with its complications
3- Glycated proteins formation with microvascular complications
For avoiding these complications, long-term control of hyperglycemia is recommended for all types of DM

25. Chronic Effects of DM (cont.)
In cells where entry of glucose is not dependent on insulin
(eye lens, retina, kidney, neurones)
Intracellular Levels of Glucose
SORBITOL accumulation in these cells
Cataract
Diabetic Retinopathy
Diabetic Nephropathy
Diabetic Neuropathy

26. Biochemical Aspects for Treatment & Control of Type 1 DM
AIM
Exogenous insulin by subcutaneous injection is given to:
1- Control Hyperglycemia (long run complications)
&
2- Prevent occurrence of Ketoacidosis (emergency case!!)
Strategies of Treatment
1- Standard Treatment
2- Intensive Treatment (Tight Control)

27. Biochemical Aspects for Treatment & Control of Type 1 DM (cont.)
1- Standard Treatment:
By one or two injections of insulin/day
AIM: Mean blood glucose level mg/dl (normal: 110 mg/dl)
HbA1c level: 8-9 % of total Hb (normal: 6% of total hemoglobin)
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

28. Treatment of type 1 DM (cont.)
2- Intensive Treatment: (Tight control)
By more frequent monitoring & subsequent injection of insulin
(i.e. 3 or more times / day)
It will more closely normalize blood glucose to prevent chronic complications of existence of hyperglycemia for a long period.
AIM: Mean blood glucose levels of 150 mg/dl
HbA1c : approximately 7% of total hemoglobin
Advantage: Reduction in chances of occurrence of chronic complications of DM:
e.g. retinopathy, nephropathy & neuropathy by about 60%

29. Biochemical Aspects for Treatment & Control of Type 1 DM (cont.)
Complications of Treatment by Insulin
Hypoglycemia is a common complication of insulin treatment
(in more than 90% of patients on insulin medication)
More Common with intensive treatment strategy
Causes of hypoglycemia due to insulin treatment
Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia 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 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.

30. Contraindications of Intensive Treatment
Biochemical Aspects for Treatment & Control of Type 1 DM (cont.)
Contraindications of Intensive Treatment
Children: risk of episodes of hypoglycemia may affect the
brain development
Elderly people: as hypoglycemia can cause strokes & heart
attacks in older people

31. Biochemical Aspects of Treatment of Type 2 DM
AIM:
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:
1- Weight reduction (to control insulin resistance)
2- Exercise
3- Dietary modification
4- Hypoglycemic agents
5- Insulin (required in some cases)