brief introduction of blood glucose homeostasis

1. Blood Sugar Homeostasis
Presented by:
Dipesh Tamrakar
Msc. Clinical Biochemistry

2. Overview
• Introduction
• Hormones of Blood Glucose Homeostasis
• Fasting state
• Postprandial state
• Well feed
• Starvation
• Condition of hypo and hyper glycemia
• Summary

3. Glucose homeostasis
• Homeostasis is the maintenance of a stable internal environment
within an organism, carefully regulate many parameters including
glucose levels in the blood.
• Glucose homeostasis reflects a balance between hepatic glucose
production and peripheral glucose uptake and utilization.
• Insulin is the most important regulator of this metabolic
equilibrium, but neural input, metabolic signals, and other
hormones (e.g., glucagon) result in integrated control of glucose
supply and utilization.

4. Plasma glucose concentration
• Hepatic glycogen stores; sufficient to maintain plasma glucose
levels for approximately 8 hour
• This time period can be shorter if glucose demand is increased
by exercise or if glycogen stores are depleted by illness or
starvation.
Fasting Blood Glucose:
70–110 mg/dL (3.9–6.1 mmol/L)
Random Blood Glucose:
<140 mg/dL (<7.8 mmol/L)
Post-prandial Blood Glucose:
<140 mg/dL (<7.8 mmol/L)

6. Systemic glucose balance
Maintenance of the normal plasma glucose concentration is
accomplished by-
• A network of hormones,
• Neural signals and
• Substrate effects
that regulate endogenous glucose production and glucose
utilization by tissues other than the brain

7. Hormonal regulation of glucose homeostasis
• Insulin
• Glucagon
• Thyroxine
• Epinephrine
• ACTH
• GH

8. Insulin
• Insulin is a polypeptide hormone produced by the β cells of the
islets of Langerhans
• Its metabolic effects are anabolic and favoring synthesis of
glycogen, triacylglycerols, and protein
• Insulin is composed of 51 amino acids arranged in two
polypeptide chains, designated A and B, which are linked
together by two disulfide bridges
• Pig (porcine) and beef (bovine) insulin differ from human insulin
at one and three amino acid positions, respectively.
• Each can be used in humans for the treatment of diabetes;
however, antibodies to these foreign proteins can develop

11. Regulation of insulin secretion
Stimulation of insulin secretion by
• Glucose:
• Ingestion of glucose or a carbohydrate-rich meal leads to a
rise in blood glucose, which is a signal for increased insulin
secretion
• Amino acids:
• Ingestion of protein causes a transient rise in plasma amino
acid levels, which, in turn, induces the immediate secretion of
insulin.
• Gastrointestinal hormones
• intestinal peptides cholecystokinin and gastric-inhibitory
polypeptide increase insulin secretion in response to oral
glucose, and so are referred to as “incretins.”

12. Inhibition of insulin secretion
• The synthesis and release of
insulin are decreased when:
-scarcity of dietary fuels
-during periods of stress
(for example, fever or infection).
• These effects are mediated
primarily by epinephrine

13. Role of insulin
• Glucose is the key regulator of insulin secretion by the
pancreatic beta cells
• Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin
synthesis
• Glucose stimulation of insulin secretion begins with its transport
into the beta cell by the GLUT2 glucose transporter
• Insulin promotes peripheral glucose uptake and utilization, and
inhibits gluconeogenesis as well as glycogenolysis.

19. Role of other hormones
Epinephrine:
• Secreted by adrenal medulla that increases blood glucose level
• Acts both on muscle and liver to bring glycogenolysis by
increasing phosphorylase activity
• Secreted in response to stress, trauma, or extreme exercise.
• Epinephrine has a direct effect on energy metabolism, causing a
rapid mobilization of energy-yielding fuels, including glucose from
the liver (produced by glycogenolysis or gluconeogenesis)
Thyroxine:
• Hormone of thyroid gland
• Elevates blood glucose level by stimulating hepatic glycogenolysis
and gluconeogenesis

20. Glucocorticoids:
• Hormones of adrenal cortex
• Stimulate protein metabolism and increase gluconeogenesis
• Inhibits glucose utilization by extrahepatic tissues
• Increases blood glucose level
Growth Hormone and adrenocorticotropic hormone (ACTH):
• Hormones of anterior pituitary gland causing hyperglycemia
• Glucose uptake by certain tissues decreased by GH
• ACTH decreases glucose utilization

21. Condition of fasting!!!

22. In the early fasting state
• The peripheral cells switch to alternative fuels, such as fatty
acids and ketone bodies.
• Ketone bodies are synthesized by the liver but utilized in the
peripheral cells.
• Glycerol and amino acids released form the adipose tissue and
muscle respectively are used for glucose production.
• Glucose is the main fuel for brain.
• TAG synthesis is decreased in adipose tissues

23. Role of insulin in the fasting state
• low insulin levels increase glucose
production by- Promoting hepatic
gluconeogenesis and
glycogenolysis and Reducing
glucose uptake in insulin-sensitive
tissues (skeletal muscle and fat)
•
• promotes mobilization of stored
precursors such as amino acids
and free fatty acids (lipolysis).
These effects are mediated by
Glucagon.

24. Role of glucagon in the fasting state
• Glucagon, secreted by pancreatic alpha cells when blood
glucose or insulin levels are low, stimulates – Glycogenolysis,
• Gluconeogenesis by the liver and renal medulla and Prevents
glucose uptake by the peripheral cells

26. Condition of well fed!!!

27. Glucose homeostasis in well fed state
• In the well fed state, glucose absorbed from gut is supplied to
all cells
• it acts as a signal for the release of insulin from Beta cells of
pancreas
• it is oxidized completely to provide energy
• the surplus is stored as glycogen in liver and muscle.
• Acetyl co A obtained from pyruvate, can be used for lipogenesis
, the triglycerides are stored in adipose tissue.

29. Postprandial glucose homeostasis
• Postprandially, the glucose load elicits a rise in insulin and fall in
glucagon, leading to a reversal of these processes.
• Insulin, an anabolic hormone, promotes the storage of
carbohydrate and fat and protein synthesis.
• The major portion of postprandial glucose is utilized by skeletal
muscle, an effect of insulin-stimulated glucose uptake.
• Other tissues, most notably the brain, utilize glucose in an
insulin-independent fashion.

31. Glucose metabolism:
1. Increased phosphorylation of glucose
2. Increased glycogen synthesis
3. Increased activity of the hexose monophosphate pathway
4. Increased glycolysis
5. Decreased gluconeogenesis

32. In post absorptive phase
• Glucose utilization is decreased in the liver, muscle and adipose
tissue
• Liver glycogenolysis provides the most glucose (75%)
• gluconeogenesis providing the remainder
• The glucose-alanine cycle becomes active.
• 50-60% of glucose is consumed by the brain

33. In the state of starvation
• Glucose alanine cycle is active.
• Alanine and glutamine released from muscle are used in liver
and kidney respectively for glucose production
• Ketones play a central role in prolonged starvation, replacing
glucose as the primary fuel for the brain and signaling a
reduction in protein catabolism and alanine output from muscle.

35. Role of hormones in glucose homeostasis

36. Variations in blood glucose levels
•A) Hypoglycemia-
• Decrease in blood glucose below the normal (<45 mg/dl) is
called hypoglycemia.
• A decrease in insulin secretion is the first defense against
hypoglycemia.
• As plasma glucose levels decline just below the physiologic
range, glucose counter regulatory (plasma glucose–raising)
hormones are released.
• Among these, pancreatic α cell glucagon, which stimulates
hepatic glycogenolysis, plays a primary role.
• Glucagon is the second defense against hypoglycemia

37. • Adreno- medullary epinephrine, which stimulates hepatic
glycogenolysis and gluconeogenesis (and renal
gluconeogenesis), is not normally critical, however, it becomes
critical when glucagon is deficient.
• Epinephrine is the third defense against hypoglycemia.
• When hypoglycemia is prolonged, cortisol and growth hormone
also support glucose production and limit glucose utilization.
• Hypoglycemia is a laboratory ‘diagnosis’ which is usually
considered a blood glucose level below 60 mg/dL.
• Symptoms begin at plasma glucose levels in the range of 60
mg/dL and Impairment of brain function at approximately 50
mg/dL.

38. Types of hypoglycemia
• Spontaneous hypoglycemia in adults is of two principal types:
1) Fasting hypoglycemia:
Observed in patients with pancreatic beta cell tumor and hepatocellular
damage
it is often sub acute or chronic and usually presents with neuroglycopenia
as its principal manifestation.
2) Postprandial hypoglycemia:
Reactive hypoglycemia with an elevated insulin secretion following a meal
it is relatively acute and is often heralded by symptoms of neurogenic
autonomic discharge (sweating, palpitations, anxiety, and tremulousness).
3) Insulin-induced hypoglycemia: Hypoglycemia occurs frequently in
patients with diabetes who are receiving insulin treatment

39. 4) Hypoglycemia and alcohol intoxication:
• Alcohol is metabolized in the liver by two oxidation reactions
• Ethanol is first converted to acetaldehyde by alcohol
dehydrogenase. Acetaldehyde is subsequently oxidized to acetate
by aldehyde dehydrogenase.
• In each reaction, electrons are transferred to NAD+, resulting in a
massive increase in the concentration of cytosolic NADH.
• The abundance of NADH favors the reduction of pyruvate to
lactate, and of oxaloacetate to malate.
• Thus, the ethanol-mediated increase in NADH causes the
intermediates of gluconeogenesis to be diverted into alternate
reaction pathways, resulting in the decreased synthesis of glucose.
This can precipitate hypoglycemia, particularly in individuals who
have depleted their stores of liver glycogen.

40. A. Normal gluconeogenesis in the absence of ethanol
consumption.
B. B. Inhibition of gluconeogenesis resulting from hepatic
metabolism of ethanol

41. Common causes of hypoglycemia
A) Physiological- Pronged fasting or starvation.
B) Pathological
1. Fasting hypoglycemia
• Drug induced- Insulin, oral hypoglycemic drugs, alcohol,
sulfonamides etc.
• Critical illnesses - Hepatic, renal, or cardiac failure, and sepsis.
• Hormone deficiencies- Cortisol, growth hormone, or both,
Glucagon and epinephrine (in insulin-deficient diabetes)

42. • Endogenous hyperinsulinism
• Insulinoma
• Autoimmune (autoantibodies to insulin or the insulin receptor)
• Ectopic insulin secretion
• Congenital hyperinsulinism and
• Inherited enzyme deficiencies
2. Postprandial (reactive) hypoglycemia
• Alimentary (Post-gastrectomy)
• Hereditary fructose intolerance,
• Galactosemia
• Idiopathic.

43. Hyperglycemia
• Increase in blood glucose level above the normal physiological
limit is called as Hyperglycemia
• Causes of hyperglycemia
1. Diabetes mellitus
2. Diseases of pancreas(pancreatitis, hemochromatosis,
carcinoma head of pancreas, Cystic fibrosis)
3. Infections and sepsis
4. Anesthesia
5. Asphyxia

44. 6. Hormonal tumors- Acromegaly, Cushing's syndrome,
Glucagonoma and Pheochromocytoma
7. Pharmacologic agents (corticosteroids, sympatho mimetic
drugs, thiazide diuretics and niacin)
8. Liver disease (cirrhosis, hemochromatosis)
9. Muscle disorders (myotonic dystrophy)
10. Adipose tissue disorders (Lipodystrophy and truncal obesity)

45. Clinical implication of disturbed glucose homeostasis-
glycosuria
• Although normal urine contains virtually no sugar but under
certain circumstances, glucose or other sugars may be excreted
in urine.
• This condition is called ‘Melituria’. The term Glucosuria,
Fructosuria, Galactosuria, Lactosuria and Pentosuria are
applied specifically for urinary excretion of glucose, fructose,
galactose, lactose and pentose respectively.
• Glycosuria (Glucosuria) can be classified in to two main groups
A) Hyperglycemic glycosuria
B) Renal glycosuria

46. A. Hyperglycemia glycosuria
• Alimentary Glycosuria(Excessive ingestion of carbohydrates)
• Emotional Glycosuria(Excessive catecholamine release)-
Stress, anxiety etc.
• Glycosuria due to endocrinal disorders e.g.
o Diabetes Mellitus
o Hyperthyroidism
o Epinephrine hyper secretion
o Hyperactivity of anterior pituitary(Acromegaly)
o Hyperactivity of Adrenal cortex (Cushing’s syndrome/disease)
o Increased secretion of glucagon

47. B. Renal glycosuria
• Renal Tubular disease
• Fanconi's Syndrome
• Toxic renal tubular disease
• Lead Toxicity
• Mercury Toxicity
• Inflammatory renal disease: acute glomerulonephritis, nephrosis
• Increased GFR without tubular damage
• Hereditary renal glycosuria (Carrier protein deficiency)
• Lowering of renal threshold (pregnancy)

48. Diabetes mellitus
• Diabetes mellitus is a syndrome with disordered metabolism and
inappropriate hyperglycemia due to either a deficiency of insulin
secretion or to a combination of insulin resistance and inadequate
insulin secretion to compensate.
• Type 1 diabetes is due to pancreatic islet B cell destruction
predominantly by an autoimmune process, and these patients are
prone to ketoacidosis.
• Type 2 diabetes is the more prevalent form and results from insulin
resistance with a defect in compensatory insulin secretion

49. Dawn Phenomenon
• The dawn phenomenon and the Somogyi effect cause high blood
sugar levels, especially in the morning before breakfast, in people
who have diabetes.
• In the early morning hours, hormones (growth hormone, cortisol,
and catecholamines) cause the liver to release large amounts of
sugar into the bloodstream.
• For most people, the body produces insulin to control the rise in
blood sugar.
• If the body doesn't produce enough insulin, blood sugar levels can
rise. This may cause high blood sugar in the morning (before
eating).

50. Somogyi Effect
• If the blood sugar level drops too low in the early morning hours,
hormones (such as growth hormone, cortisol, and catecholamines)
are released.
• These help reverse the low blood sugar level but may lead to
blood sugar levels that are higher than normal in the morning.
• An example of the Somogyi effect is:
A person who takes insulin doesn't eat a regular bedtime snack,
and the person's blood sugar level drops during the night.
The person's body responds to the low blood sugar by releasing
hormones that raise the blood sugar level. This may cause a high
blood sugar level in the early morning.

51. DRUGS USED IN DIABETES MELLITUS

52. Summary
• Glucose homeostasis reflects a balance between hepatic glucose
production and peripheral glucose uptake and utilization.
• Insulin is the most important regulator of this metabolic
equilibrium.
• In the fasting state, low insulin levels increase glucose production
by promoting hepatic Gluconeogenesis and glycogenolysis and
reduce glucose uptake in insulin-sensitive tissues.
• Glucagon, secreted by pancreatic alpha cells when blood glucose
or insulin levels are low, stimulates glycogenolysis and
gluconeogenesis by the liver and renal medulla.
• Postprandially, the glucose load elicits a rise in insulin and fall in
glucagon, leading to a reversal of these processes. Other tissues,
most notably the brain, utilize glucose in an insulin-independent
fashion.

53. Thank-you
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