Biochemical Aspects of
Diabetes Mellitus
ENDO 412
Overview
• DM is a heterogeneous group of syndromes characterized by an
elevation of fasting blood glucose caused by absolute or relative
deficiency of insulin
• Two types of DM:
Type 1 (insulin-dependent DM)
Type 2 (noninsulin dependent DM)
• Prevalence of type 2 is increasing as:
Aging (increase in rate of life-age of population)
Increasing prevalence of obesity
Comparison between type 1 & type 2 DM
Type 1 Diabetes Mellitus
Type 1 Diabetes Mellitus
•
about 10% of diabetics (in USA)
•
Onset: usually during childhood
•
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 (that allows b-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 b-cells have been destroyed
•
Commonly complicated by diabetic ketoacidosis (DKA)
•
Treated only by insulin
Onset of type 1 DM
Metabolic changes of type 1 DM
1- Hyperglycemia
2- Diabetic Ketoacidosis (DKA)
3- Hypertriacylglyceridemia & hypercholestrolemia
Metabolic changes of type 1 DM (cont.)
1- Hyperglycemia: increased glucose in blood
Due to:
Decreased glucose uptake by muscles & adipose tissues (by GLUT-4)
& Increased hepatic gluconeogenesis (& glycogenlysis)
2- Diabetic Ketoacidosis (DKA):
Increased ketone bodies in blood (ketonemia) leads to metabolic acidosis
DKA occurs in untreated or uncontrolled cases of DM
- In 25 – 40% of newly diagnosed type 1 DM (untreated & uncontrolled yet)
- In stress states demanding more insulin (as during infection, illness or during surgery
Uncontrolled DM)
- 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.
Metabolic changes of type 1 DM (cont.)
Metabolic & Clinical Abnormalities in DKA
Low Insulin
Carbohydrates Metabolism
In Sk. Ms. & Adipose
Glucose Uptake
Plasma
Osmolality
In Liver
Glycogenlysis
Gluconeogenesis
Lipids Metabolism Protein Metabolism
Fatty Acids
in liver
Hyperglycemia
ketone Bodies
Glycosuria
Thirst
Gluconeogenesis
Prerenal Uremia
Coma
(KETOGENESIS)
Osmotic diuresis
Ketonemia
With Loss of water & Na+
Acetone
& Hypovolemia
Nausea
Polyuria,
&
Dehydration
Proteolysis
Uptake of AA by liver
Lipolysis
in Adipose Tissue
Ketonuria Smelt
&
on Breath
Vomiting
Metabolic
Acidosis
Increased
Respiration
Low
Renal H+
Excretion
Low
Blood
Bicarbonate
Low pCO2
Low GFR
Metabolic changes of type 1 DM (cont.)
Metabolic & Clinical Abnormalities in DKA
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)
Metabolic changes of type 1 DM (cont.)
Metabolic & Clinical Abnormalities in DKA
Biochemical Basis of Treatment of DKA
AIM: (EMERGENCY TREATMENT)
1- Correction of dehydration (Hypovolemia): by IV fluids & Sodium
2- Correction of acidosis: by IV bicarbonate
3- Correction of metabolic abnormality: by insulin IV infusion
4- Potassium 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)
Metabolic changes of type 1 DM (cont.)
3- Hypertriacylglyceridemia & hypercholestrolemia:

Released fatty acids from adipose tissues are converted to triacylglycerol & cholesterol
in the liver.
Triacylglycerol is secreted from the liver in VLDL to blood (with liver cholesterol)

Chylomicrons (from diet fat) accumulates (due to low lipoprotein lipase activity as a
result of low or absent insulin)
Chylomicrons contain Triacyglycerols (mainly) & Cholesterol
Increased VLDL & chylomicrons in blood results in
hypertriacylglyceridemia & hypercholesterolemia
Metabolic changes of type 1 DM
Diagnosis of type 1 DM
• Clinically:
Age: during childhood or puberty (< 20 years of age)
With Abrupt (Sudden) 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 glucose: > or equal 126 mg/dl
100 – 125 mg/dl is called impaired fasting blood glucose
HBA1c: High (more than 6% of normal hemoglobin)
Insulin level in blood: low
Circulating islet-cell antibodies detection
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)
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 225-275 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
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%
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.
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
Type 2 Diabetes Mellitus
Type 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 b-cells
•
Metabolic changes in type 2: are milder than type 1
as insulin secretion, although not adequate, restrains ketoacidosis
•
Diagnosis: blood glucose concentration equal or more than 126 mg/dl
•
Treatment : no requirement for insulin to sustain life
BUT: insulin may be required to control hyperglycemia in some patients
Causes of Type 2 DM
Insulin Resistance & Dysfunctional b-cell
Insulin resistance is the decreased ability of target tissues, such
as liver, adipose tissue & muscle to respond properly to
normal circulating insulin
Obesity is the most common cause of insulin resistance
Obesity causes insulin resistance as:
- substances produced by fat cells as leptin and resistin may contribute to
development of insulin resistance
- Free fatty acids elevated in obesity is involved in insulin resistance
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).
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 levels
________________________________________________
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 levels (hyperglycemia)
Progression of Type 2 DM
Metabolic changes in Type 2 DM
Metabolic abnormalities of type 2 DM are the results of insulin resistance (in liver,
muscle & adipose tissue)
1- Hyperglycemia
2- Hypertriacylglyceridemia
3- Nonketotic hyperglycemic coma
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
leading to very high plasma osmolality (with hypernatremia)
& marked dehydration
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:
Fluid replacement + Insulin IV infusion + follow up (Emergency Case!!)
Metabolic changes in Type 2 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
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
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:
12345-
Weight reduction (to control insulin resistance)
Exercise
Dietary modification
Hypoglycemic agents
Insulin (required in some cases)
Case Study
Parents of a 15 years old boy was reported by his school that he was found drowsy & they have
got to take him to hospital according to the advice of his school doctor.
In the hospital, his mother told the doctor that her son seemed unusually thirsty for the last 3
months & she thought that he had lost weight. She admitted also that on the morning
before leaving for school, he was complaining of abdominal pain & discomfort.
On examination:
 Semiconscious
 Deep & rapid respiration
 Pulse rate 120 beats/minute
 BP: 90/50
 Cold extremities
What investigations were recommended for him??
What is the diagnosis of this case??
What is the treatment ??
Case Study cont.
Clinical Biochemistry Lab Investigations
Blood Chemistry
• Random Blood Glucose: 550 mg/dl
• Urea: 160 mg/dl (N: 20 -40)
• Na+: 127 mmol/L (N: 135 – 145)
• K+: 6.9 mmol/L
(N: 3.5 – 4.5)
• pCO2: 2.9 kPa
(N: 4.4 – 6.1)
• HCO3- : 7 mmol/L (N: 21 – 27.5)
• pO2: 14 kPa
(N: 12 – 17)
Urine Analysis:
• Urine Dipstick Test:
- Glucose +++
- Ketone +++
- Albumin ++