Diabetes is a leading cause of morbidity and mortality worldwide. This document highlights the brief updates in Diabetes especially the etiological classification. The key points comprises of Normal structure of Pancreas, Definition & epidemiology of Diabetes, Etiological classification of Diabetes, Normal insulin Metabolism, Clinical features of Diabetes, Complications of Diabetes, Pathogenesis of Complications & Diagnosis of Diabetes.

1. DIABETES
MELLITUS
BY: DR. HELEN MORISH MONIKA TUDU
(SENIOR RESIDENT)
DEPARTMENT OF PATHOLOGY
MGM, MCH JAMSHEDPUR

2. CONTENTS:
 Normal structure of Pancreas
 Definition and Epidemiology
of Diabetes
 Etiological classification of
Diabetes
 Normal Insulin metabolism
 Clinical features of Diabetes
 Pathogenesis of Complications
 Complications of Diabetes
 Diagnosis of Diabetes

3. WHAT MUST WE KNOWN IN DM?
 Classification
epidemiology
Etiology
Pathogenesis
Pathology
Clinical laboratory features
Complications & Progression of DM

4. Normal
Structure of
Pancreas:
PANCREAS
EXOCRINE ENDOCRINE

5. ENDOCRINE PANCREAS:
• It consists of about 1 million clusters of microscopic collections of cells
called islets of Langerhans found scattered within the pancreatic lobules,
as well as individual endocrine cells found in duct epithelium and among
the acini.
• 4 major and 2 minor types of islet cells, ultrastructurally and
immunohistochemically.

11. Islet of
Langerhans
1.Beta /B cells (70%):Secrete Insulin; the deficiency or
resistance causes DM
2.Alpha Cells:Comprise 20% of islet cells & secrete
glucagon which induces hyperglycemia
Major cell types
Minor cell types
3.Delta or D cells: Comprises 5-10% of islet cells &
secrete somatostatin suppresses both insulin and
glucagon release
4.Pancreatic polypeptide (PP) cells or F cells: Comprise
1-2% of islet cells and secrete Pancreatic polypeptide
having some gastrointestinal effects
1.D1 cells: elaborate vasoactive intestinal peptide
(VIP) which induces glycogenolysis & hyperglycemia
2.Enterochromaffin cells: Synthesize serotonin in
which pancreatic tumors may induce carcinoid
syndrome.

12. Definition of DM :
DM is defined as a heterogenous metabolic disorder characterized by
common feature of chronic hyperglycemia with disturbance of
carbohydrate, fat, and protein metabolism.

13. Classification

14. EPIDEMIOLOGY OF DM
• DM is a leading cause of morbidity and mortality world over.
• It is expected to continue as a major health problem leading to its serious
complications (End stage renal disease, IHD, gangrene of the lower
extremities, and blindness in the adults etc).
• China, India, Pakistan and the US top the countries with highest number of
diabetic population, largely due to genetic susceptibility combined with
changing life style of low activity and high calorie diet in the growing indian
middle class.
•In India, incidence of DM in adults has increased from 7% in 2009 to 9% in
2019.

15. • The rise in prevalence is more for type 2 Diabetes than for type 1.
• As per International Diabetes Federation (IDF) estimates, there are 535
million adults with diabetes worldwide in 2021 and this figure is
expected to increase to 650 million by the year 2030.

16. ETIOLOGY
 TYPE 1 DM:
• 10% cases of DM
• Previous called as Juvenile-onset diabetes (JOD)/Insulin-dependent
DM.
• 2 Subtypes:1)Subtype 1A (Immune mediated) DM
2)Subtype 1B (Idiopathic) DM
Subtype 1A DM: characterized by autoimmune destruction of beta cells
which leads to insulin deficiency.
Subtype 1B DM: characterized by insulin deficiency with tendency to
develop ketosis, negative for autoimmune markers.

17.  Type 2 DM
• 80% of cases of DM.
• Previously called as maturity onset Diabetes (MOD)/Noninsulin
dependent diabetes mellitus (NIIDM) of obese & non-obese type.
• Occurs due to progressive loss of beta-cell insulin secretion (caused
by Insulin resistance)
 Gestational DM
• 4% pregnant women due to metabolic changes during pregnancy.
• It is defined as diabetes diagnosed in the 2nd
or 3rd
trimester of
pregnancy in a women who did not have overt diabetes earlier.
• These women revert back to normal glycemia after delivery, they are
prone to develop DM later in their life.

18. PATHOGENESIS:
Depending upon etiology of DM, hyperglycemia may result from the
following:
1) Reduced insulin secretion
2)Decreased glucose use by the body
3) Increased glucose production

19. NORMAL INSULIN METABOLISM

24. PATHOGENESIS OF TYPE 1DM
• Destruction of Beta cell mass, usually leading to absolute insulin
deficiency.
• It is Idiopathic .
• Pathogenesis is immune-mediated and has been extensively studied.
• Pathogenesis based on 3 mutually-interlinked mechanisms:
Genetic susceptibility,
Autoimmunity &
Certain Environmental factors

25. PATHOGENESIS OF TYPE 1 DM

27. PATHOGENESIS OF TYPE 2 DM
• Basic metabolic defect in type 2 DM is either a delayed insulin secretion
relative to glucose load (Impaired insulin secretion), or the peripheral
tissues are unable to respond to insulin (Insulin resistance).
• It is a heterogenous disorder with a more complex etiology.
• It is more common than type 1 but less known about its pathogenesis.
• There are no. of factors implicated. 1.Genetic factors
2.Constitutional factors
3.Insulin resistance
4.Impaired Insulin secretion
5.Increased hepatic glucose synthesis

28. 1.Genetic Factors:
Concordance in identical twins 80%.
Both parents diabetic 50% risk to the child, 1 parent diabetic also a risk to child.
2.Constitutional Factors:
Obesity, HTN, Low physical activity
3.Insulin Resistance: Mechanism of hyperglycemia in these cases is due to
i)Resistance to action of insulin impairs glucose utilization Hyperglycemia
ii)Increased Hepatic synthesis of glucose.
iii) Hyperglycemia in obesity is related to high levels of free fatty acids and
cytokines (e.g TNF-alpha & adiponectin) affect peripheral tissue sensitivity to
respond to insulin.

29. Currently Proposed Molecular defect responsible for Insulin resistance
may be possibly due to :
Polymorphism in various post-receptor intracellular signal pathways
molecules.
Elevated free fatty acids seen in obesity may contribute e.g
by impaired glucose utilization in the skeletal muscle,
by increased hepatic synthesis of glucose, and
by impaired beta cell function.
 Insulin resistance syndrome : A complex of clinical features occurring
from insulin resistance and its resultant metabolic derangements
(hyperglycemia & compensatory hyperinsulinaemia).
C/f: In the form of accelerated cardiovascular disease (both obese & non-obese type 2 DM)
Features include Mild HTN & Dyslipidemia

30. 4.Impaired Insulin Secretion:
In type 2 DM, Insulin resistance & Insulin secretion are interlinked.
i) Hyperinsulinaemia: Compensatory increased secretion of insulin in early
course of ds.
ii) Failure of beta cell function: Adequate insulin secretion later, but some
secretion of insulin is present (Mild to moderate deficiency of Insulin in
T2DM, < T1DM).
Proposed Genetic mechanism :
 Amylin/ Islet amyloid polypeptide: forms fibrillar protein deposits in
pancreatic islets.
 Glucose toxicity: Metabolic environment of chronic hyperglycemia
surrounding the islets impair Insulin cell function.
 Lipotoxicity: Elevated free fatty acids levels worsens islet cell function.

31. 5.Increased Hepatic glucose synthesis:
In T2DM, as a part of insulin resistance by peripheral tissues, the liver also
shows insulin resistance i.e in spite of hyperinsulinemia in the early stage of
disease, gluconeogenesis in the liver is not suppressed. (Resulting
Hyperglycemia)

37. PATHOLOGY

39. Clinical lab features
1) Hyperglycemia
2) Glucosuria
3) Proteinuria
4) Ketonuria
5) Dyslipidemia
6) HbA1c elevation

40. Lab Investigations
1.Urine tests for the presence of glucose, proteins & Ketones for diabetic
nephropathy & nephrotic syndrome :
i) Glucosuria:
Benedict’s Qualitative test detects presence of any reducing substances.
Not specific for glucose.
Urine Dipstick method more sensitive and specific for glucose.
based on enzymatic reaction (strips coated with glucose oxidase)
Turns purple when dipped in urine containing glucose.
Disadvantage of Urinary glucose test
a)It alone is not reliable as individual renal threshold varies.
b) DM is not the only cause of glycosuria (Renal glycosuria, Alimentary (lag storage)
glucosuria, many metabolic disorder like hyperthyroidism, starvation, Intracranial lesions
like cerebral tumor, haemorrhage and head injury).

41. Renal Glucosuria
It is a benign condition unrelated to diabetes and runs in families and
may occur temporarily in pregnancy without symptoms of diabetes
where the blood glucose level is below 180 mg/dl i.e below normal
renal threshold for glucose but glucose still appears regularly and
consistently in the urine due to lowered renal threshold.

42. Alimentary (Lag storage) Glucosuria
A rapid and transitory rise in blood glucose level above the normal
renal threshold may occur in some individuals after a meal. During
this period, glucosuria is present. This type of response to meal is
called ‘lag storage curve’ or more appropriately ‘alimentary
glucosuria’.
A characteristic feature is that unusually high blood glucose level
returns to normal 2 hours after meal.

44. ii) Test for Proteinuria:
Diabetic nephropathy is one of the common systemic causes of nephrotic
syndrome.
MicroalbuminuriaFrank albuminuria & Nephrotic syndrome.
Method:Heat acetic acid test, Heller nitric acid test, strip test.
iii) Test for Ketone bodies:
Required for assessing severity of DM, not for diagnosis.
Both glucosuria & Ketonuria presentDiagnosis of DM is certain.
Method:Rothera test (nitroprusside reaction), Strip test.

45. DIAGNOSIS OF DIABETES

47. 2
2) Single blood sugar estimation
• It is the absolute necessary test.
• Methods are O-toluidine, Somogyi-Nelson & Glucose oxidase methods.
• Sample: Whole blood or plasma (WB values <15% plasma values)
• A grossly elevated single determination of plasma volume may be sufficient
to make the diagnosis of diabetes.
Fasting Glucose test
Screening test for T2DM.
Fasting: No calorie intake for at least 8 hr. prior to test.
Recommended to all age above 45 years (Screening f.glucose test every 3
yr, & relatively earlier if the person is overweight.

48. 3) 2 hour plasma glucose test/ Oral Glucose tolerance test:
Indication: Not for routine diagnosis of either T1DM or T2DM.
In patients where fasting plasma glucose is in the range of impaired fasting glucose (100-
125 mg/dl).
 Diagnosis of Gestational DM.
Uncertainty about the diagnosis of DM.
Preparation of the patient:
 The patient should be taking an unrestricted carbohydrate diet for at least 3 days or more
before the test (As carbohydrate-restricted diet reduces glucose tolerance).
 The patient should be with normal physical activity.
 Test is performed in the morning after overnight fasting/at least 8 hr fast.
 The patient should rest for at least half an hour before starting the test,
 Refrain from smoking, tea/coffee, or exercise during the test

49. TEST:
 A fasting venous sample of blood is drawn to estimate the glucose level.
 The patients are given 75g of anhydrous glucose dissolved in 250-300ml of water
orally over 5 minutes.
 The dose in children is 1.75g of glucose per kg body weight upto a maximum of 75g.
 The time of starting glucose is taken as zero/0 hours.
 A single venous sample of blood is drawn 2 hrs. after the glucose administration and
glucose level estimated.

50. 4) Postparandial Plasma Glucose:
• No standardized role in the diagnosis of DM
• Useful in patients treatment.
• Determination of Plasma glucose level 2 hours after food.

51. 5) Glycosylated haemoglobin (HBA1C):
• It is a minor hemoglobin component present in normal persons.
• Non-enzymatic glycosylation of hemoglobin takes place over 90-120 days, lifespan of
red cells; hence
• HbA1C determination provides control of blood glucose in the previous 3-4 months.
• Measurements of plasma glucose level may alter due to dietary intake of the previous
day.
• Normal value: <5.7%,
• Borderline range (prediabetics): 5.7-6.4%
• Diabetics: More than or equal to 6.5% + f.plasma glucose value + 2 hr plasma glucose
level + OGTT.

52. 6) Other tests:
• C-peptide assay
• Islet autoantibodies
• Screening for diabetes-associated complications

53. PATHOGENESIS OF COMPLICATIONS
Biochemical mechanisms Proposed to explain the development of complications
1.Non-enzymatic Protein glycosylation/ Formation of advanced
glycation end products.
2.Polyol pathway mechanism.
3.Excessive reactive oxygen species.
4.Activation of Protein kinase C.

55. COMPLICATIONS OF DIABETES
ACUTE METABOLIC
COMPLICATION
LATE SYSTEMIC
COMPLICATION

56. ACUTE METABOLIC COMPLICATIONS
1.Diabetic Ketoacidosis (DKA)
2.Hyperosmolar Hyperglycaemic non-ketotic coma
3.Hypoglycemia

57. CLINICAL FEATURES
OF DKA
1.Anorexia
2.Nausea
3.Vomitings
4.Deep & Fast breathing
5.Mental confusion
6.Coma

59. LATE SYSTEMIC COMPLICATIONS
1.Atherosclerosis
2.Diabetic microangiopathy
3.Diabetic Nephropathy
4.Diabetic neuropathy
5.Diabetic Ocular complications
6.Infection

60. 1.ATHEROSCLEROSIS
• Both type 1& 2 DM
• Early & more extensive than general population
• Associated with complicated plaques: Ulceration, Calcification &
Thrombosis
• Contributory factors for severity: Hyperlipidemia, Reduced HDL levels,
Non-enzymatic glycosylation, increased platelet adhesiveness, obesity &
HTN.
• Presentation: Early onset of coronary artery disease.
Silent MI (most common cause of death in diabetes)
Cerebral stroke
Gangrene of toes & feet
Hyaline arteriosclerosis

61. 2.Diabetic microangiopathy
• Most consistent morphologic feature: Diffuse thickening of basement
membrane (Capillaries of skin, skeletal muscle, Retina, Renal glomeruli, &
renal medulla, also in bowman capsule, peripheral nerves, placenta).
• Capillaries are leakier than normal capillaries to plasma proteins.
• Microangiopathy underlies the development of diabetic nephropathy,
retinopathy, & some forms of neuropathy.
• Cause & mechanism: Recurrent hyperglycemia causing increased
glycosylation of Hb & Protein (Collagen, & basement membrane
material)Thickening of BM.

62. 3. Diabetic Nephropathy
• Second mc cause of death from this ds.
• 4 types of lesions are encountered:
Glomerular lesions
Renal vascular arteriosclerosis
Pyelonephritis (including necrotizing papillitis).
Tubular lesions or Armanni-Ebstein lesion
• Most important glomerular lesions:
Capillary basement membrane thickening
Diffuse mesangial sclerosis
Nodular glomerularsclerosis/Intercapillary glomerulosclerosis/Kimmelsteil-Wilson ds.
(Glomerular lesions take the form of ovoid or spherical, often laminated, PAS positive nodules of matrix situated in the periphery of the glomerulus)

64. KW Lesion

65. 4.DIABETIC NEUROPATHY
• Affect all parts of the nervous system.
• Characteristic: Symmetric pheripheral neuropathy.
• Pathological changes: Segmental demyelination, Schwann cell injury&
axonal damage.
• Pathogenesis: Diffuse microangiopathy, Accumulation of Sorbitol &
FructoseDeficiency of Myoinositol.

66. 5.DIABETIC OCULAR COMPLICATIONS
• Diabetes-induced hyperglycemia leads to acquired opacification of
lensCataract.
• Increased intraocular pressureGlaucoma, damage optic nerve.
• Most profound changes seen in RETINA
Retinal vasculopathy of diabetes:
1)Background /Preproliferative &
2)Proliferative diabetic retinopathy.

69. 14 NOVEMBER
Theme for year 2025: Diabetes in workplace
WORLD DIABETES DAY

70. References:
1) Robbins & Cotran, Pathologic basis of disease, 10th
edition. Volume II.
2) Harsh Mohan, Textbook of Pathology, 9th
edition.
3) Ramdas Nayak & Rakshatha Nayak, Exam prepatory manual for undergraduates, Pathology.

71. THANK YOU ALL !