ENDOCRINE SYSTEM Part III-PATHOPHYSIOLOGY OF DIABETES MELLITUS

1. ENDOCRINE SYSTEM Part III
PATHOPHYSIOLOGY OF DIABETES MELLITUS
Prepared and presented by:
Marc Imhotep Cray, M.D.
IVMS Endocrine Secretion and
Action
Part I
Part II
WebPath Pathology:
Endocrine Pathology
70 Images
Recommended Reading:
Management of Diabetes
Formative Assessment
Practice question set #1
Clinical:
E-Medicine Article
Diabetes Mellitus, Type 2 –
A Review
1

2. Pathophysiology of
Diabetes Mellitus
2

3. Pancreas
Islets of Langerhans
3

4. Endocrine Pathology
(Next 7 Slides)
Islets of Langerhans
Source: http://library.med.utah.edu/WebPath/ENDOHTML/ENDOIDX.html#6
1. Islets of Langerhans Islet of Langerhans, normal, microscopic
2. Islet of Langerhans, immunoperoxidase staining with antibody to
insulin (on right) and glucagon (on left), microscopic
3. Islet of Langerhans, insulitis in type I diabetes mellitus,
microscopic
4. Islet of Langerhans, amyloid deposition in type II diabetes
mellitus, microscopic
5. Islet of Langerhans, islet cell adenoma, low power microscopic
6. Islet of Langerhans, islet cell adenoma, medium power
microscopic
7. Islet of Langerhans, islet cell adenoma with immunoperoxidase
staining with antibody to insulin, (insulinoma), microscopic
4

5. Islet of Langerhans, normal, microscopic
Here is a normal pancreatic islet of Langerhans
surrounded by normal exocrine pancreatic acinar
tissue. The islets contain alpha cells secreting
glucagon, beta cells secreting insulin, and delta
cells secreting somatostatin.
5

6. Islet of Langerhans, immunoperoxidase staining with
antibody to insulin (on right) and glucagon (on left),
microscopic
Immunoperoxidase staining can help identify the
nature of the cells present in the islets of
Langerhans. On the right, antibody to insulin has
been employed to identify the beta cells. On the left,
antibody to glucagon identifies the alpha cells.
6

7. Islet of Langerhans, insulitis in type I
diabetes mellitus, microscopic
This is an insulitis of an islet of Langerhans in a
patient who will eventually develop type I diabetes
mellitus. The presence of the lymphocytic infiltrates
in this edematous islet suggests an autoimmune
mechanism for this process. The destruction of the
islets leads to an absolute lack of insulin that
7

8. Islet of Langerhans, amyloid deposition in type II
diabetes mellitus, microscopic
This islet of Langerhans demonstrates pink
hyalinization (with deposition of amyloid) in many
of the islet cells. This change is common in the
islets of patients with type II diabetes mellitus.
8

9. Islet of Langerhans, islet cell adenoma, low
power microscopic
An islet cell adenoma is seen here, separated
from the pancreas by a thin collagenous capsule.
A few normal islets are seen in the pancreas at
the right for comparison.
9

10. Islet of Langerhans, islet cell adenoma, medium
power microscopic
The islet cell adenoma at the left contrasts with
the normal pancreas with islets at the right. Some
of these adenomas function. Those that produce
insulin may lead to hypoglycemia. Those that
produce gastrin may lead to multiple gastric and
duodenal ulcerations (Zollinger-Ellison
syndrome). 10

11. Islet of Langerhans, islet cell adenoma with
immunoperoxidase staining with antibody to insulin,
(insulinoma), microscopic
This is an immunohistochemical stain for insulin
in the islet cell adenoma.
Thus, it is an insulinoma.
11

12. Properties of IDDM* and NIDDM**
Characteristic IDDM NIDDM
Genetic locus Chromosome 6 unknown
Usually < 40 years of
Typical age of onset > 40 years of age
age
Plasma insulin Low to absent Normal to high
Plasma glucagon High, suppressible High, resistant
Acute complication Ketoacidosis Hyperosmolar coma
Responsive to
Insulin therapy Responsive
resistant
Response to
Unresponsive Responsive
sulfonylurea drugs
* Insulin-dependent diabetes mellitus
**Non-insulin dependent diabetes mellitus
12

13. Alpha cell stimulation
"Inputs to alpha cells and effects of glucagon, including negative
feedback, which increases plasma glucose levels"
Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute
13

14. Beta cell stimulation
"Inputs to beta cells and effects of insulin, including negative
feedback on glucose and amino-acids levels. "
Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute
14

15. "Effects of Insulin deficiency"
Robert H. Parsons, Ph.D., Rensselaer Polytechnic
Institute
15

16. Diabetes Insipidis vs Diabetes Mellitus
• Diabetes Insipidis
– Due to disease of and/or damage to hypothalamus
– Causes Antidiuretic Hormone (ADH) insufficiency
• Water re-absorption in kidney is impaired
• can lose up to 25 liters water/day
• Diabetes Mellitus
– Due to insufficient production of, or insensitivity to
insulin
eMedicine Articles
– Diabetes Mellitus, Type 1
– Diabetes Mellitus, Type 2
– Diabetic Ketoacidosis
16

17. Ketogenesis
Ketogenesis is the process by which ketone bodies are
produced as a result of fatty acid breakdown.
• ketone bodies are created at moderate levels in everyone's
bodies, such as during sleep and other times when no
carbohydrates are available. However, when ketogenesis is
happening at higher than normal levels, the body is said to
be in a state of ketosis. It is unknown whether ketosis has
negative long-term effects or not.
• Ketoacidosis occurs in IDDM, not NIDDM
17

18. Ketogenesis
(See notes, next slide for RXN explanation)
• Both acetoacetate and beta-
hydroxybutyrate are acidic, and, if
levels of these ketone bodies are
too high, the pH of the blood drops,
resulting in ketoacidosis. This is very
rare, and, in general, happens only
in untreated Type I diabetes (see
diabetic ketoacidosis) and in
alcoholics after binge drinking and
subsequent starvation (see
alcoholic ketoacidosis).
18

19. Ketogenesis
The acetyl-CoA produced by mitochondrial beta-oxidation of fatty acids enters the Kreb's
cycle to produce energy, but that is not the only fate of acetyl-CoA. In liver mitochondria,
some acetyl-CoA is converted to acetoacetate, beta-hydroxybutyrate, and acetone,
collectively called ketone bodies. Ketone bodies are transported to other tissues such as
brain, muscle or heart where they are converted back to acetyl-CoA to serve as an
energy source. The brain normally uses only glucose for energy, but during starvation
ketone bodies can become the main energy source for the brain. In the metabolic
condition called ketosis, ketone bodies are produced faster than they are consumed by
tissues and the smell of acetone can be detected on a person's breath. The smell of
acetone is one indication that a person may have diabetes. The consumption of high-
fat/low carbohydrate diets has been used as a weight loss program by many,
intentionally inducing ketosis to consume fat stores, but these ketogenic diets can cause
unwanted side effects related to increased urea production resulting from protein intake
and risk of heart disease from increased cholesterol and fat intake.
19

20. Pancreas: Endocrine Function
• Endocrine functions
– Produces hormones (insulin and glucagon)
that are released into bloodstream
– Islets of Langerhans = hormone-secreting cells
• Beta () cells secrete insulin
• Alpha () cells secrete glucagon
20

21. Absorptive State
• Ingested nutrients
– move from GI tract to bloodstream
– some provide energy for body needs
– some is stored
• Glucose = major energy source
• Principle hormone = Insulin
– promotes glucose (nutrient) uptake and
storage (as glycogen)
21

22. Post-Absorptive State
• Mechanisms initiated to maintain blood glucose
levels even without recent intake of food
– Glycogenolysis
– Gluconeogenesis
– Glucose sparing (fat utilization)
• Main energy source = fats
• Main hormone = glucagon
– promotes conversion of glycogen to glucose
22

23. Insulin
• Produced & secreted as prohormone
– 84 a.a. long
– Beta chain-- connecting peptide-- alpha chain
• After secretion prohormone cleaved to
yield active hormone
– Connecting peptide cut out
– Active hormone formed by the two
remaining chains (alpha and beta),
held together by two -s-s- (disulfide)
bonds
23

24. Insulin Actions
• Lowers blood glucose levels
– Moves glucose from bloodstream into cells
• liver and brain = only cells capable of glucose uptake
independent of insulin
– Promotes muscle and liver conversion of glucose to
glycogen
• Lowers blood levels of free f.a. and a.a.
– Promotes incorporation of free fatty acids into
triglycerides
– Promotes incorporation of amino acids into protein
24

25. Glucagon
• Produced by  cells of Islets of
Langerhans
• Single-chain polypeptide, 29 a.a.
long A microscopic image stained for glucagon
• Glucagon Action
– Raises blood glucose levels
– Promotes gluconeogenesis,
glycogenolysis and triglyceride
utilization, protein catabolism
Rotating stereogram animation of glucagon. (1.70
MB, animated GIF format).
25

26. Diabetes Mellitus
• Impaired carbohydrate (glucose) metabolism
• Type I versus Type II
– Type I (IDDM)
• ‘juvenile onset’
• IDDM = Insulin-dependent diabetes mellitus
– Type II (NIDDM)
• ‘mature onset’
• NIDDM = Non insulin-dependent diabetes mellitus
26

27. Type I Diabetes Mellitus
• Insulin-dependent diabetes Mellitus (IDDM)
– Therapy requires administration of insulin
• Less common form
• Due to insulin insufficiency
– Pancreas secretes little, if any, insulin
– Pancreas secretes higher than normal levels of glucagon
27

28. Possible causes of diabetes
28

29. Insulin Influence on Glucagon
Secretion
• Insulin needed for alpha cells to sense blood
glucose levels properly
• When insulin levels are low, alpha cells cannot
properly detect glucose in blood, respond as if
glucose levels are low, even though glucose
levels are very high in diabetic patient
• Can cause over-secretion of glucagon
29

30. Type I DM (continued)
• Some genetic predisposition
– One twin afflicted; 50% predictive of disease in second
twin
• Environmental factors as important as genetic
factors
– viral infections may play a role
• Most recent studies implicate autoimmune
disease as underlying cause
– Body’s white blood cells attack and destroy pancreas
beta cells
30

31. Type II Diabetes Mellitus
• Non insulin-dependent diabetes mellitus (NIDDM)
• Most common form of DM(90%)
• Pancreas secretes insulin
– Insulin levels normal or high
• Due to insulin insensitivity/insulin resistance
– Altered receptor structure
– Altered cellular responses after hormone activation
31

32. Type II DM (continued)
• Disease mainly seen in overweight adults
– Highly correlated to obesity
– High fat diet may play role in insulin resistance
• Often accompanied by beta cell defect in ability to
secrete insulin in response to rise in plasma
glucose
• High genetic predisposition
– Twin studies; one affected, 100% predictive of
development in other twin
32

33. Type II DM Therapy
• Therapy does not require insulin administration
• Weight loss - eliminate obesity
• Exercise
– endurance exercise often increases insulin
responsiveness
• Dietary modification
– low-fat diet to reduce insulin resistance
• Sulfonylurea drugs can be administered to stimulate
increased beta cell insulin production
33

34. Insulin and Glucagon
Insulin Association of the British Pharmaceutical Industry
• Insulin and glucagon
have opposite effects
on liver and other
tissues for controlling
blood-glucose levels
34

35. Blood Glucose and the Brain
• Brain cannot synthesize, store, or concentrate
glucose
• Brain does not require insulin to take up glucose
from bloodstream
• Amount of glucose taken up in brain is directly
proportional to amount of glucose in bloodstream
35

36. Primary Symptoms of Diabetes Mellitus
• Glucosuria
• Polyuria
• Polydipsia
• Polyphagia
36

37. Glucosuria
• Glucosuria = glucose in the urine
– glucose filtered blood in kidney
– normally, all that is filtered in kidney is reabsorbed
• high glucose levels in DM patients exceed
kidneys capacity for reabsorption, so some
glucose is lost in urine
37

38. Polyuria
• Polyuria = production of large amounts of
urine
• Kidney is unable to reabsorb all the glucose,
so some is lost in urine
– large amounts of water eliminated (urine formed)
as glucose is removed from blood
38

39. Polydipsia
• Polydipsia = increased intake of liquids
• Large amount of water lost in urine causes
profound thirst
– DM patient ingests large amounts of water to
quench thirst
39

40. Polyphagia
• Polyphagia = excessive food intake
• Body’s inability to utilize glucose results in
inadequate nutrient/energy for body
tissues
• Increased ingestion of foods to
compensate, not accompanied by weigh
gain
40

41. Weight Loss
• Although food intake is increased, it is not
accompanied by weight gain
– body is unable to use carbohydrates ingested
• Body breaks down fats and proteins to use as
fuel/nutrient supplies
– fatty acids and amino acids used in Kreb’s cycle to
generate energy
– glycerol and some amino acids can be converted to
glucose
41

42. Ketosis
• Ketones = fatty acid metabolites
– made principally in liver, from acetyl CoA
– acetone, acetoacetate, b-hydroxybutyrate
– brain and other tissues can metabolize them via Kreb’s cycle as
energy source
• Ketones accumulate in blood, build up faster than they’re
used or eliminated
• Ketones volatile, in liquid phase, rapidly move to gaseous
phase
– give diabetic’s breath a fruity odor
42

43. Ketosis (continued)
• Ketones increase hydrogen-ion
concentration in blood; cause acidosis =
ketosis, ketoacidosis
• Ketoacidosis occurs in IDDM, not NIDDM
• Can result in diabetic coma and death
43

44. Diabetic Coma
• Results from untreated/ out-of-control diabetes
• Blood glucose and ketone levels very high
• Fruity breath
• Symptoms: difficulty breathing, nausea, vomitting,
flushing of skin, dehydration, electrolyte imbalance
• Treatment:
– insulin administration to reduce blood glucose
– fluid and electrolyte administration
44

45. High blood Glucose in Diabetes
• The high blood
glucose in diabetes
produces glucose in
the urine and frequent
urination through
effects on the kidneys
45

46. Lack of insulin or insulin resistance
• The lack of insulin or
insulin resistance acts
on many organs to
produce a variety of
effects.
46

47. Complications of DM
47

48. Complications of DM
• Cardiovascular
– atherosclerosis &/or damage to small vessels
• heart attack
• stroke
• poor perfusion of extremities; poor wound healing
– gangrene causes need for limb amputations
• Renal complications
– renal damage leads to kidney failure
48

49. Complications (continued)
• Nervous system complications
– nerve damage
• peripheral neuropathy; loss of sensation in
extremeties
• evident in genitals; impotence in men, loss of
sensation in women
• Vision complications
– damage to retina as small vessels rupture
– produces blindness
49

50. Complications (continued)
• Many, if not all, complications related to high
blood glucose levels
– accumulation of high concentrations of glucose
metabolites (sorbitol) in cells associated with cell
damage
• May be related to high glucagon levels and
altered metabolic activity
• Diabetics die most often from complications,
rather than from diabetes itself (i.e. insulin shock
or diabetic coma)
50

51. Insulin Shock
• Caused by too much insulin for the amount of
glucose present in bloodstream
– administer too much
– body’s demand for glucose not matched to insulin
levels
– body’s dietary intake not matched to insulin levels
• Symptoms: confusion, personality changes,
profuse sweating, unconciousness
• Treatment: raise blood glucose levels
51

52. REMEMBER
Glycosylated Hemoglobin
• Formed by addition of glucose to nml Hgb molecules
• Formed in larger amounts in diabetics under poor
glycemic control because they have high levels of
glucose in bloodstream
• Molecule is very stable so once formed does not readily
break down (RBC lifespan is 120 days)
– This makes it a good indicator of long term glycemic control
– Measuring normal blood glucose is a better indicator of
immediate glucose control
52

53. Animations and Tutorials
• Glucose Homeostasis Gerard Scholte & Ineke
Marree
• Glucose Metabolism for the Endocrine System
Wisconsin Online
• Insulin Association of the British
Pharmaceutical Industry
53

54. Q&A
• Q#: I : The features characteristic of non-insulin
dependent diabetes mellitus include which of the
following?
• A. Age of onset is below forty years
• B. Insulin level is often decreased
• C. Responds to an oral hypoglycernic agent
(sulfonylurea)
• D. Genetic locus is present in chromosome 6
• E. Prone to develop diabetes ketoacidosis
54

55. Q&A
• Q#: 2 : Diabetes mellitus is divided into three categories based
on etiology. Which disease occurs most commonly in those
individuals who are less than 40 years of age and what is the
cause?
• A. Gestational diabetes and high serum insulin
• B. Insulin-dependent and high blood glucose
• C. Gestational diabetes and low serum insulin
• D. Non-insulin dependent and low blood glucose
55

56. Q&A
• Q#: 3 : The main cause of acidosis in the untreated
diabetic patient is
• A. Elevated blood levels of ketone bodies
• B. Consumption of a high protein diet
• C. Excess production of bicarbonate
• D. Elevated levels of insulin are present
• E. Decreased blood levels of ketone bodies
56

57. Q&A
• Q#: 4 : In which of the following childhood diseases
does ketone bodies reach dangerous levels in
untreated cases?
• A. Diabetes mellitus
• B. OTCD
• C. Phenylketonuria
• D. Von Gierke's disease
• E. Medium chain acyl-CoA dehydrogenase deficiency
57

58. Q&A
• Q#: 5 : For which of the following diseases would you
perform the urine test, Glucose?
• A. Cushing syndrome
• B. 11 -hydroxylase deficiency
• C. Diabetes mellitus
• D. Pheochromocytorna
• E. Diabetes insipidus
58

59. Q&A
• Q#: 6 : Which of the following statements about the
epidemiology of diabetes is true?
• A. Women are at higher risk of developing insulin dependent
diabetes mellitus than men
• B. Almost half of all diabetics develop nephropathy during the
course of their illness
• C. Of diabetics in the U.S., approximately 75% have insulin
dependent diabetes mellitus
• D. The majority of people with non-insulin dependent
diabetes mellitus are obese
• E. Blacks have a higher incidence rate of insulin dependent
diabetes mellitus than whites
59

60. Q&A
• Q#: 7 : In individuals with untreated diabetes
mellitus, there is a shift in fuel usage from
• A. Fats to carbohydrates
• B. Fats to ketone bodies
• C. No change occurs
• D. Ketone bodies to carbohydrates
• E. Carbohydrates to fats
60

61. Q&A
• Q#: 8 : Elevated levels of hemoglobin A1c in
the blood could be an indication of
• A. Gout
• B. Sickle cell anemia
• C. Thalassemia
• D. Hypertension
• E. Diabetes mellitus
61

62. Q&A
• Q#: 9 : Which one of the following is a characteristic
of Type II diabetes mellitus?
• A. Rare occurrence
• B. Increased insulin resistance caused by decrease in
the number of cell receptor sites
• C. Strong association with HLA-DR3 and HLA-DR4
• D. Usual occurrence in underweight or normal adults
• E. Peak onset at age 11 to 13
62

63. End of Session
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