Disorders of carbohydrate metabolism including diabetes mellitus type 1 and 2, glycosuria, glycohemoglobin, hypoglycemia and glycogen storage diseases

1. DISORDERS OF
CARBOHYDRATE
METABOLISM
AFREEN KHAN
SENIOR RESEARCH FELLOW
DEPARTMENT OF
BIOCHEMISTRY
ELMCH, ERA UNIVERSITY

2. DIABETES MELLITUS

3. DIABETES MELLITUS
Diabetes mellitus is a heterogenous group of multifactorial, polygenic syndromes
characterized by an elevated fasting blood glucose (FBG) caused by relative or
absolute deficiency of insulin
It is a state of chronic hyperglycemia which may result from many environmental
and genetic factors, often acting jointly due to:
I. Decreased insulin secretion
II. Decreased insulin action
III. Increased counter hormones

4. TYPES OF DIABETES MELLITUS
Diabetes mellitus
Primary
Insulin dependent diabetes mellitus
Noninsulin dependent diabetes mellitus
Secondary
Provoked by other diseases like pancreatic disease,
hormonal abnormalities, chemical or drug induced
Gestational diabetes mellitus
Malnutrition diabetes mellitus

5. INSULIN DEPENDENT DIABETES MELLITUS
• Also called as Type-1 diabetes/ Juvenile onset diabetes
• Constitute less than 10%
• Characterized by absolute deficiency of insulin caused by autoimmune attack
on β cells of the pancreas
• The islets of Langerhans become infilterated with activated T lymphocytes,
leading to a condition called insulitis
• This autoimmune attack leads to gradual depletion of the β cell population

6. • Symptoms appear when 80%-90% of the β cells have been destroyed
• At this point, pancreas fails to respond adequately to ingestion of glucose
• and insulin therapy is required to restore metabolic control and prevent the life-
threatening ketoacidosis

7. DIAGNOSIS OF TYPE-1 DIABETES
• Onset is typically during childhood or puberty and symptoms develop suddenly
• Abrupt appearance of polyuria (frequent urination), polydipsia (excessive thirst)
and polyphagia (excessive hunger)
• These symptoms are usually accompanied by fatigue and weight loss
• Diagnosis is confirmed by glycosylated hemoglobin concentration ≥ 6.5mg/dl
(normal is less than 5.7) or a FBG ≥ 126mg/dl (normal is 70-100)
• Diagnosis can also be made on the basis of nonfasting (random) blood glucose
level greater than 200mg/dl in an individual with symptoms of hyperglycemia
• Oral glucose tolerance test can also be used but is less convenient (generally used
to identify gestational diabetes)

8. METABOLIC CHANGES IN TYPE-1 DIABETES
• The metabolic abnormalities of type-1 diabetes mellitus result from deficiency of
insulin that profoundly affects metabolism in three tissues: Liver, muscle,
adipose
1. Hyperglycemia and ketoacidosis: Elevated levels of blood glucose and
ketone bodies are the hall marks of untreated T1DM. Hyperglycemia is caused
by increased hepatic production of glucose via gluconeogenesis. Ketosis results
from increased mobilization of fatty acids from adipose tissue and accelerated
fatty acid β oxidation

9. 2. Hypertriacylglycerolemia: Excessive fatty acids are converted to
triacylglycerol (TAG) which is packed and secreted in VLDLs. Chylomicron are
produced by dietary lipids following a meal. The plasma chylomicron and VLDL
levels are elevated, resulting in hypertriacylglycerolemia

10. TREATMENT OF TYPE-1 DIABETES
• Individuals with T1DM must rely on exogenous insulin delivered subcutaneously
either by periodic injection or continuous pump-assisted infusion to control the
hyperglycemia and ketoacidosis
• Two therapeutic regimens currently in use are standard and intensive insulin
treatment

11. NON INSULIN DEPENDENT DIABETES
MELLITUS
• Also called as Type-2 diabetes/ Maturity onset/ prevalence diabetes
• Most common form of diabetes
• constitute more than 90%
• Develops gradually without obvious symptoms
• Often detected by routine screening tests
• Characterized by hyperglycemia, insulin resistance, impaired insulin secretion
and ultimately β cells failure
• Many individuals with T2DM have symptoms of polyuria and polydipsia of
several weeks duration, polyphagia maybe present but less common

12. • Patients have combination of insulin resistance and dysfunctional β cells but do
not require insulin to sustain life, although insulin eventually will be required to
control hyperglycemia and keep HBA1c below 7%in over 90% of patients
• Metabolic alterations observed are milder than those described for T1DM
• Pathogenesis does not involve autoimmune antibodies or viruses and is not
completely understood
• An acute complication of T2DM in the elderly is hyperosmolar hyperglycemic
state characterized by severe hyperglycemia and dehydration and altered mental
status

13. INSULIN RESISTANCE
• Insulin resistance is the decreased ability of target tissues, such as liver, adipose
and muscle, to respond properly to normal circulating concentrations of insulin
• Insulin resistance is characterized by increased hepatic glucose production,
decreased glucose uptake by muscle and adipose tissue and increased adipose
lipolysis with production of free fatty acids

14. DYSFUNCTION OF β CELLS
• In T2DM, the pancreas initially retains β-cell capacity, resulting in insulin levels
that vary from above normal to below normal
• However with time, the β-cell becomes increasingly dysfunctional and fails to
secrete enough insulin to correct the prevailing hyperglycemia

16. METABOLIC CHANGES IN TYPE-2 DIABETES
• The metabolic abnormalities of type-1 diabetes mellitus result of insulin resistance
expressed primarily in Liver, muscle and adipose tissue
1. Hyperglycemia: Hyperglycemia is caused by increased hepatic production of glucose
combined with diminished peripheral use. Ketosis is usually minimal or absent
2. Dyslipidemia: Excessive fatty acids are converted to triacylglycerol (TAG) which is
packed and secreted in VLDLs. Chylomicron are produced by dietary lipids following
a meal. The plasma chylomicron and VLDL levels are elevated, resulting in
hypertriacylglycerolemia (Same as T1DM)

17. TREATMENT OF TYPE-1 DIABETES
• The goal in treating T2D is to maintain blood glucose concentration within
normal limits and to prevent the development of long-term complications
• Weight reduction, exercise and medical nutrition therapy often correct the
hyperglycemia of newly diagnosed T2D
• Hypoglycemic agents ( metformin), sulfonylureas, α-glucosidase inhibitor or
insulin therapy may be required to achieve satisfactory plasma glucose levels

19. GLYCOHEMOGLOBINS

20. GLYCOHEMOGLOBINS
• Glycated hemoglobin (HBA1c) is a glucose-derived product of normal adult
hemoglobin
• Glycation is a type is nonenzymatic post-translational modification of protein
(Hb) occurs when there is hyperglycemia
• NOTE: enzymatic addition of any sugar to proteins is called “glycosylation”
While nonenzymatic process is termed as “glycation”

21. CLINICAL SIGNIFICANCE
• The rate of synthesis of Glycated hemoglobin is directly
related to the exposure of RBC to glucose
• Here the glucose molecule is attached to N-terminal valine of
each β-chain of HbA and it is an irreversible attachment, i.e
once glucose is attached to Hb, it cannot be removed.
Therefore it remains inside the erythrocyte, throughout the
lifespan of RBCs (120 days)

22. • Hence the measurement of Glycated hemoglobin (HBA1c) reveals the mean
blood glucose concentration over the previous 8-10 weeks (120 days)
• The determination of Glycated hemoglobin is not for diagnosis of diabetes
mellitus but only for monitoring the response of treatment
• Normal level of HBA1c 3-5%
• In diabetic patients HBA1c level varies between 6-15 %

23. GLYCOSURIA

24. GLYCOSURIA
DEFINITION:
• Normally urine contains negligible amounts of glucose, which is too insignificant
to be detected by Benedict’s test
• But when sugar is present in urine in sufficient concentration so as to respond
to give positive result with benedict’s test, the condition is known as
Glycosuria or glucosuria

25. MECHANISM:
• Normally the blood glucose passes through renal system and glucose is
completely reabsorbed
• This mechanism functions only when the glucose level is within normal limits of
the renal tubules (renal threshold for glucose)
• But when the blood glucose level is increased beyond the capacity of tubular
mechanism them it starts appearing in urine, causing glycosuria

26. • Normal renal threshold value (on average) is 160-180 mg/dl.
• Usually glycosuria can occur in two conditions: in hyperglycemia and in
normoglycemia
1. Hyperglycemia: glycosuria maybe due to either decreased insulin secretion
(Diabetes mellitus) or due to hyperactivity of hormones of anterior pituitary,
adrenal medulla, adrenal cortex and thyroid
2. Normoglycemia: It may have a physiological or a hereditary cause

27. TYPES OF GLYCOSURIA
• Two types: Physiological and hereditary glycosuria
1. Physiological glycosuria:
• Alimentary glycosuria
• Emotional glycosuria
• Glycosuria in pregnancy and lactation
• Diabetes mellitus

28. • Alimentary glycosuria: this occurs upon ingestion of carbohydrate rich meal
and results in hyperglycemia above the renal threshold and leads to glycosuria. It
is purely physiological, temporary and harmless.
• Emotional glycosuria: following emotional factors like fear, anger, anxiety,
where there is release of adrenaline, cause hyperglycemia by prompting
glycogenolysis. This transient hyperglycemia produces glycosuria

29. • Pregnancy and lactating glycosuria: this is due to decreased renal threshold for
glucose and increased rate of glomerular filteration. This ceases upon termination
of pregnancy
• Diabetes mellitus: Glycosuria occurs in untreated diabetes mellitus

30. 2. Heriditary glycosuria (Renal glycosuria):
• This condition is also known as renal glycosuria due to defective renal tubular
mechanism of glucose reabsorption
• Because of this glycosuria is present even the blood glucose concentration is
within normal limits.

31. • Experimentally, glycosuria is can be produced in animals by following
mechanisms:
I. Administration of epinephrine leads to glycogenolysis, hyperglycemia
resulting in glycosuria
II. Administration of phlorrhizin cause inhibition of glucose reabsorption in renal
tubules and leads to glycosuria without prevalence of hyperglycemia
III. Administration of growth hormones (diabetogenic) inhibits the peripheral
utilization of glucose leading to hyperglycemia followed by glycosuria
IV. Administration of alloxan inhibits the secretion of insulin from pancreas
leading to hyperglycemia and glycosuria

32. HYPOGLYCEMIA

33. HYPOGLYCEMIA
• When blood glucose level falls below 50 mg/dl the condition is known as
hypoglycemia
CAUSES:
1. Increased insulin production may be due to proliferation of islets of Langerhans
tissue as in tumors of β cells of pancreas
2. Decreased secretion of diabetogenic hormones like anterior pituitary, thyroid,
adrenal cortical hormones
3. Liver failure by poisons
4. Hyperactivity of pancreas of newborn infants born to diabetic mothers

34. SYMPTOMS OR MANIFESTATIONS
• Feeling of hunger, headache, lack of consciousness, sweating, tachycardia,
convulsions, nausea, vomiting, restlessness, palpitation, anxiety coma and may
lead to death
TREATMENT:
• Promptly corrected by ingesting glucose

35. GLYCOGEN STORAGE
DISEASES

36. GLYCOGEN STORAGE DISEASES
• These are group of genetic/inherited diseases that result from a defect in enzyme
required for either glycogen synthesis or degradation
• They result in the formation of glycogen that has an abnormal structure or the
accumulation of excessive amounts of normal glycogen in specific tissue
• These are classifies into different types depending on the deficient enzyme

42. GALACTOCEMIA

43. GALACTOCEMIA
CLASSICAL GALACTOSEMIA:
• Galactosemia (incidence 1 : 30000)
• It is due to the deficiency of the enzyme galactose 1- phosphate uridyltrans-
ferase.
• It is a rare congenital disease in infants
• Inherited as an autosomal recessive disorder.

44. SALIENT FEATURES:
• Galactose metabolism is impaired leading to increased galactose levels in
circulation (galactosemia) and urine (galactosuria)
• The accumulated galactose is diverted for production of galactitol (dulcitol) by
the enzyme aldose reductase. Aldose reductase is present in lens, nervous tissue,
seminal vesicles etc. Increased levels of galactose, has been implicated in the
development of cataract
• The accumulation of galactose 1-phosphate and galactitol in various tissues like
liver, nervous tissue, lens and kidney leads to impairment in their function.

45. • High levels of galactose 1-phosphate in liver results in the depletion of inorganic
phosphate (sequestering of phosphate) for other metabolic functions.
• Galactose 1-phosphate inhibits glycogen phosphorylase resulting in
hypoglycemia.
Clinical symptoms:
• Loss of weight (in infants) hepatosplenomegaly, jaundice, mental retardation etc.
• In severe cases, cataract, amino aciduria and albuminuria are also observed.

46. Diagnosis :
Early detection of galactosemia is possible (biochemical diagnosis) by
measuring the activity of galactose 1-phosphate uridyltransferase in
erythrocytes.
Treatment :
The therapy includes the supply of diet deprived of galactose and lactose.

48. BIBLIOGRAPHY
• Lippincott’s Illustrated reviews Biochemistry 6th Edition
• Harper’s Illustrated Biochemistry 30th Edition
• Biochemistry Instant notes for Medical Students: Seetheramaiah Chittiprol
• U Satyanarayan Biochemistry, 4th Edition

49. THANK YOU