Diabetes mellitus is a group of metabolic diseases characterized by high blood glucose levels due to defects in insulin secretion or insulin action. The two main types are type 1 diabetes, caused by destruction of beta cells resulting in insulin deficiency, and type 2 diabetes, caused by insulin resistance and relative insulin deficiency. Chronic hyperglycemia can lead to damage of various organs, especially the eyes, kidneys, nerves, heart and blood vessels. Treatment involves lifestyle management, oral medications or insulin to maintain blood glucose levels as close to normal as possible.

2. Diabetes Mellitus
 Diabetes Mellitus is a group of multifactorial,
polygenic syndromes
 characterized by an elevation of blood glucose
 caused by a relative or absolute deficiency in
insulin.

3. Insulin
 Insulin is the most important hormone
coordinating the use of fuels by tissues.
 Its metabolic effects are anabolic, favoring, for
example, synthesis of
 glycogen,
 triacylglycerols, and
 protein.

4. Insulin Structure
 Insulin is composed of 51 amino acids
 arranged in two polypeptide chains, designated A
and B.
 Linked together by two disulfide bridges
 and an intramolecular disulfide bridge between
amino acid residues of the A chain.

5. Insulin Synthesis
 Insulin is produced by
the β cells of the islets
of Langerhans, in
pancreas.
 The islets of Langerhans
make up only about 1–
2% of the total cells of
the pancreas

6. Steps of Insulin Synthesis
 Preproinsulin synthesized
in RER Ž
 cleavage of “presignal” Ž
proinsulin
 stored in secretory
granules
 Žcleavage of proinsulin Ž
 Exocytosis of insulin and
C-peptide in equimolar
amounts by beta cells
upon stimulation

8. Regulation of Insulin Secretion
Stimulation of insulin secretion:
1. Glucose
2. Amino acids
3. Beta adrenergic stimulation
4. GI hormones: e.g. GIP (Gastric Inhibitory
Peptide)
CCK (cholecystokinin)

9. Regulation of Insulin Secretion
Inhibition of insulin secretion:
By far, the most important inhibitor of insulin
secretion is Epinephrine.
 In conditions of stress, such as
 exercise,
 infection
 surgery,
 this action of epinephrine is necessary to maintain
adequate blood glucose levels.

14. Metabolic Effects of Insulin
 •Increased glucose transport in
 liver,
 skeletal muscle and
 adipose tissue
 Most cells of the body take up glucose by an
Insulin- independent mechanism.
 Increased glycogen synthesis and storage
 Decreased glycogenolysis and gluconeogenesis

16. Metabolic Effects of Insulin
 Increased triglyceride synthesis
 Decreased triglyceride degradation
•
 Increased Na+ retention (kidneys)
ƒ
 •Increased protein synthesis (muscles, proteins)
ƒ
 •Increased cellular uptake of K+ and amino acids
•
 Decreased glucagon release

17. In the absence of Insulin there is
 Decreased GLUCOSE UPTAKE,
 Decreased GLYOGENESIS
and
 Increased GLYCOGENOLYSIS and
 Increased GLUCONEOGENSIS
This results in HYPERGLYCEMIA.

18. In the absence of Insulin there is
 Decreased LIPOGENESIS,
 Decreased PROTEOGENESIS
and
 Increased LIPOLYSIS,
 Increased PROTEOLYSIS
This results in decreased muscle mass and
increased levels of fatty acids in the body.

19. Diabetes Mellitus
 Diabetes Mellitus is a group of multifactorial,
polygenic syndromes
 characterized by an elevation of blood glucose
 caused by a relative or absolute deficiency in
insulin.

20. OVERVIEW OF DIABETES MELLITUS
 Most cases of diabetes mellitus can be separated
into two Groups,
 type 1 (formerly called insulin-dependent diabetes
mellitus)
 type 2 (formerly called noninsulin-dependent
diabetes).

21. Type 1 Diabetes Type 2 Diabetes
Age of Onset Usually during childhood
or puberty;
symptoms develop
rapidly
Frequently after age 35;
symptoms develop
gradually
NUTRITIONAL STATUS
AT TIME
OF DISEASE ONSET
Frequently
undernourished
Obesity usually
present
PREVALENCE 10 % of diagnosed
diabetics
90 % of diagnosed
diabetics
Genetic
Predisposition
Moderate Very strong
DEFECT OR
DEFICIENCY
β Cells are destroyed,
eliminating
production of insulin
Insulin resistance
combined with inability
of β cells to produce
appropriate quantities

22. Type 1 Diabetes Type 2 Diabetes
FREQUENCY OF KETOSIS Common Rare
PLASMA INSULIN Low to absent High early in disease;
low in disease of long
duration
ACUTE COMPLICATIONS Ketoacidosis Hyperosmolar Coma
RESPONSE TO ORAL
HYPOGLYCEMIC DRUGS
Unresponsive Usually responsive
TREATMENT Insulin is always
necessary
Diet, exercise, oral
hypoglycemic drugs; insulin
may
or may not be necessary.

23. Type 1 DM
 Formerly called Insulin- Dependent DM
 Characterized by an absolute deficiency of insulin
 Caused by destruction of β cells of the pancreas
(most commonly an auto-immune attack)
 Over a period of years, this autoimmune attack on
the β cells leads to gradual depletion of the β-cell
population.

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

25. Clinical Symptoms:
 The onset of type 1 diabetes is typically during
childhood or
 puberty, and symptoms develop suddenly:
 polyuria (frequent urination),
 polydipsia (excessive thirst), and
 polyphagia (excessive hunger),
 often triggered by stress or an illness.
 These symptoms are usually accompanied by fatigue,
 weight loss, and weakness

26. Metabolic changes in type 1 diabetes
 The metabolic abnormalities of type 1 diabetes
mellitus result from a deficiency of insulin which
profoundly affects metabolism in three tissues:
 liver,
 muscle,
 adipose tissue.

27. Hyperglycemia
 Elevated levels of blood glucose and ketones are
the hallmarks of untreated type 1 diabetes
mellitus.
 Hyperglycemia is caused by increased hepatic
production of glucose, combined with diminished
peripheral utilization muscle and adipose have the
insulin-sensitive Glucose transporters.

28. Ketoacidosis
 Ketosis results from increased mobilization of
fatty acids from adipose tissue, combined with
accelerated hepatic fatty acid β-oxidation and
synthesis of 3-hydroxybutyrate and aceto -
acetate.
 Diabetic ketoacidosis (DKA, a type of metabolic
acidosis) occurs in 25–40% of those newly
diagnosed with type 1 diabetes, and may recur if
the patient becomes ill (most commonly with an
infection) or does not comply with therapy.

30. Ketoacidosis
 DKA is treated by replacing fluid and electrolytes,
and administering short-acting insulin to
gradually correct hyperglycemia without
precipitating hypoglycemia.

31. Signs & Symptoms of DKA
 Acidotic breathing (rapid/deep breathing),
 Headache
 nausea/vomiting,
 abdominal pain,
 dehydration.
 Fruity breath odor (due to exhaled acetone).

32. LAB Findings in DKA
 Hyperglycemia, •
 Increased [H+], •
 Decreased [HCO3–] ( metabolic acidosis), •
 Increased blood ketone levels,
 Hyperkalemia, but depleted intracellular K+.
 Glucosuria and Ketonuria

34. Type 2 DM
 Type 2 diabetes is the most common form of the
disease.
 Typically, type 2 diabetes develops gradually
without obvious symptoms
 Often detected during routine screening tests.
 The classical signs and symptoms of polyuria,
polydipsia and polyphagia may also be present.

35. Type 2 DM
 Patients with type 2 diabetes have a combination
of insulin resistance and dysfunctional β cells
 The metabolic alterations observed in type 2
diabetes are milder than those described for type 1,
 This is because insulin secretion in type 2
diabetes—although not adequate—does restrain
ketogenesis and blunts the development of DKA.

36. Insulin Resistance
 Insulin resistance is the decreased ability of target
tissues, such as liver, adipose, and muscle, to
respond properly to normal (or elevated)
circulating concentrations of insulin.
 For example, insulin resistance is characterized by
uncontrolled hepatic glucose production, and
decreased glucose uptake by muscle and adipose
tissue.

37. Dysfunctional β cells
 In type 2 diabetes, 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

39. Metabolic changes in type 2
diabetes
 The metabolic abnormalities of type 2 diabetes
mellitus are the result of insulin resistance
expressed primarily in
 liver,
 muscle, and
 adipose tissue

40. Hyperglycemia
 Hyperglycemia is caused by increased hepatic
production of glucose,
 combined with diminished peripheral use.
 Ketosis is usually minimal or absent in type 2
patients because the presence of insulin—even in
the presence of insulin resistance—diminishes
hepatic ketogenesis

41. Dyslipidemia
 VLDL and Chylomicrons are responsible for
transporting hepatic and dietary lipids to the
peripheral tissues by the help of Lipoprotein
Lipase in adipose and muscle tissues.
 Lipoprotein lipase is low in diabetics, the plasma
chylomicron and VLDL levels are elevated,
resulting in hypertriacylglycerolemia
 Low HDL levels are also associated with type 2
diabetes.

42. Hyperglycemic Hyperosmolar non-
ketotic coma (HONK)
 HONK usually presents in older patients with type 2
DM and carries a higher mortality than DKA
 In a preexisting lack of or resistance to insulin, a
physiologic stress such as an acute illness can cause
further net reduction in circulating insulin and
increase in glucagon, epinephrine and other stress
hormones.
 This can lead to severe hyperglycemia.

43. HONK
 HONK is characterized by hyperglycemia and
hyperosmolarity, and osmotic diuresis without
significant ketoacidosis.
 Most patients present with severe dehydration
most notably cerebral dehydration and can lead to
focal or global neurologic deficits, such as
Drowsiness and lethargy
Delirium
Coma
Focal or generalized seizures
Visual changes or disturbances

44. Laboratory Findings in HONK
These include:
 Plasma glucose level of 600 mg/dL or greater
 Effective serum osmolality of 320 mOsm/kg or
greater
 Profound dehydration, up to an average of 9 L
 Serum pH greater than 7.30
Normal Range =285 - 295 mOsm/kg

45. DKA and HONK at a glance

47. CHRONIC EFFECTS OF DIABETES
 Available therapies moderate the hyperglycemia
of diabetes, but fail to completely normalize
metabolism.
 The long-standing elevation of blood glucose is
associated with the chronic complications of
diabetes.

48. HbA1C
 HbA1C is a measure of Haemoglobin
Glycosylation.
 It occurs non-enzymatically
 Proportional to blood glucose concentration
 As average lifespan of RBCs is 3 months, HbA1C
can be used as a measure of blood glucose conc.
control over three months.

49. HbA1C
 The better the control, lesser is the HbA1C
 It is expressed as a percentage, not mmol/l
 Normal HbA1C is < 5.7%

50. Hyperglycemia Can Cause Serious
Long-Term Problems

51. How hyperglycemia causes the
chronic complications of diabetes?
Two main mechanisms:
 1. In cells where entry of glucose is not dependent
on insulin, elevated blood glucose leads to
increased intracellular glucose and its metabolites.
For example, increased intracellular sorbitol
contributes to the formation of cataracts.
 2. Hyperglycemia promotes the non-enzymic
condensation of glucose with cellular proteins and
proteins of the basement membrane in a manner
analogus to that of formation of HbA1C

52. Vascular Complications of
Type 2 Diabetes
 Vascular complications are the major cause of
morbidity and mortality in Type 2 diabetes
Microvascular
nephropathy
retinopathy
neuropathy
Macrovascular
cardiovascular disease
peripheral vascular
disease
cerebrovascular disease

53. Microvascular Complications--
Retinopathy
 Diabetic retinopathy-leading cause of blindness in
those 20-75 and above.
 Blood vessel changes—worst case scenario,
proliferative retinopathy. Also an increased
incidence of cataracts and glaucoma in diabetics.
 Need regular eye exams
 Control BP, control BS and cessation of smoking
can help

54. Microvascular complications-
Nephropathy
 Accounts for 50% of patients with ESRD
 Earliest clinical sign of nephropathy is
microalbuminuria.
 Warrants frequent periodic monitoring for
microalbuminuria—if exceeds 30mg/24h on two
consecutive random urines, need 24h urine sample

55. Nephropathy
 Diabetes causes hypertension in renal vessels
which cause leaking glomeruli, deposits in narrow
vessels, scarring and vascular damage

56. Microvascular disease-Nephropathy
 Medical management: control BP (ACE or ARB)
 Tx of UTIs
 Avoid nephrotoxic agents, contrast dyes
 Low sodium diet
 Low protein diet
 Tight glycemic control

57. Nephropathy
 May require dialysis
 May have co-existent retinopathy
 Kidney transplantation—success now 75-80% for
5 years
 Pancreas transplantation may also be performed at
time of kidney transplantation

58. Neuropathies
 Group of diseases that affect all types of nerves.
 Includes peripheral, autonomic and spinal nerves.
 Prevalence increases with duration of the disease
and degree of glycemic control

59.  Capillary basement membrane thickening and
capillary closure may be present.
 May be demyelination of the nerves, nerve
conduction is disrupted.
 Two most common types of neuropathies are:
sensorimotor polyneuropathy and autonomic
neuropathy.
Neuropathies

60. Macrovascular Complications
 Coronary artery disease
 Cerebrovascular disease
 Peripheral arterial disease

61. Macrovascular Complications
 Macrovascular complications are due to
atherosclerosis, if it is in
 Coronary blood vessels: angina and MI
 Cerebral blood vessels: Stroke
 Peripheral blood vessels: gangrene.

62. Criteria for the Diagnosis of Diabetes
A1C ≥6.5%
OR
Fasting plasma glucose (FPG)
≥126 mg/dL (7.0 mmol/L)
OR
2-h plasma glucose ≥200 mg/dL
(11.1 mmol/L) during an OGTT
OR
A random plasma glucose ≥200 mg/dL
(11.1 mmol/L)
ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2

63. EXTRA SLIDES

64. Websites
 http://www.cdc.gov/diabetes/consumer/index.ht
m
 http://www.emedicinehealth.com/diabetes/articl
e_em.htm#Diabetes%20Overview
 http://www.diabetes.org/

66. Criteria for the Diagnosis of Diabetes
A1C ≥6.5%
The test should be performed in a
laboratory using a method that is
NGSP certified and standardized
to the DCCT assay*
Diabetes Control and Complications Trial (DCCT) “
National Glycohemoglobin Standardization
Program(NGSP)
*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.
ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2

67. Criteria for the Diagnosis of Diabetes
Fasting plasma glucose (FPG)
≥126 mg/dL (7.0 mmol/L)
Fasting is defined as no caloric intake
for at least 8 h*
*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.
ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2

68. Criteria for the Diagnosis of Diabetes
2-h plasma glucose ≥200 mg/dL
(11.1 mmol/L) during an OGTT
The test should be performed as
described by the WHO, using a
glucose load containing the equivalent
of 75 g anhydrous glucose
dissolved in water*
*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.
ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2

69. Criteria for the Diagnosis of Diabetes
In a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis,
a random plasma glucose ≥200 mg/dL
(11.1 mmol/L)
ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2

70. 70
Diagnostic Criteria
• Any one test should be confirmed with a second test,
most often fasting plasma glucose (FPG).
• This criteria for diagnosis should be confirmed by
repeating the test on a different day.

71. 71