The document discusses the endocrine pancreas. It begins by introducing the pancreas and its endocrine and exocrine functions. It then describes the anatomy of the pancreas and the different cell types in the islets of Langerhans. It discusses the hormones produced by each cell type and their actions. The document also covers the regulation of insulin release and the pathophysiology of diabetes mellitus, including the mechanisms, classification, and complications of both type 1 and type 2 diabetes.

1. ENDOCRINE
PANCREAS
BY
A.NAVEEN

2. INTRODUCTION
Pancreas is a gland that is partly endocrine and partly
exocrine.
Endocrine part secretes hormones
Exocrine part secretes digestive juices.

3. Anatomy

4. Anatomy
J shaped
Located between L1-L2
Weighs about 90g
It is divided into head, neck, body and tail.
Four major cell types : α,β,δ and PP cells.
Two minor cells : D1 cells and enterochromaffin
cells.

5. Histology
Endocrine part of pancreas is made up of microscopic
elements called islet of Langerhans.
Islets have various type of cells.

6. Physiology
 α cells secrete glucagon
 Βeta cells secrete insulin
 Delta cells secrete somatostatin
 Two rare type of cells include D1 cells and
enterochromaffin cells.

7. Actions of insulin

8. Insulin signaling pathway

9. Regulation of insulin
release
Insulin is produced from the beta cell
Prepro insulin pro insulin insulin
Most important stimulus for the insulin
synthesis and release is the glucose itself.

10. GLUT 2
Glucose uptake into pancreatic cell
Release of ATP
Inhibits ATP sensitive k+channel
Membrane depolarisation and influx of Ca
channel
Release of insulin

11. Incretin effect
• Incretins like Glucose dependent insulinotropic
polypeptide(GIP) secreted by K cell and glucagon like
peptide 1(GLP-1) secreted by L cells are responsible for
secretion of insulin. The elevation of incretins after the
food intake is called Incretin effect.
• These incretins are degraded by dipeptidyl transferase
enzyme especially DDP4.
• This effect is blunted in DM2 patients.

12. DIABETES MELLITUS
• Diabetes is a group of metabolic disorder sharing
common features of hyperglycemia.
• Chronic hyperglycemia associated with secondary
damage in multiple organs.

14. Plasma sugar levels in OGTT
NORMAL DIABETES IGT
FASTING <110mg/dl >126mg/dl 110 to 126 mg/dl
2HRS
POSTPRANDIAL
<140mg/dl >200mg/dl 140 to 199 mg/dl

15. AHA Criteria for diagnosis of DM
 FBG ≥126mg/dl
 RBG ≥200mg/dl
 2-hrs PPBG: ≥200mg/dl
 Glycated Hb ≥ 6.5%

16. Prediabetes (Impaired glucose tolerance)
Fasting plasma glucose between 110 to 125mg/dl
2-hrs postprandial between 140 to 199 mg/dl
Glycated Hb level between 5.7% to 6.4%

17. CLASSIFICATION
TYPE 1
 β cell destruction
• Immune mediated
• idiopathic
TYPE 2
 Combination of insulin resistance and β cell
dysfunction
• Genetic defect in β cell function
• Genetic defect in insulin action
• Exocrine pancreatic defect
• Endocrinopathies, infection, drugs, GDM

19. Type 1 vs. Type 2

22. Pathogenesis of Type 1 DM
Type 1 is an autoimmune disease in which islet
destruction is caused primarily by immune effector cells
reacting against endogenous β cell antigens.
Environmental factors: viral infections, molecular
mimicry.(some studies suggest that viral antigen share
epitope with islet antigen, cross reactivity and destruction
of islet tissues occur)

23. Contd…
Genetic susceptibility:
• Multiple gene susceptibility
• 30 susceptibility loci for type 1
• Imp. Locus is HLA gene cluster on chromosome
6p21
• 90-95% of Caucasians have HLA-DR3 or HLA-DR4
involvement

25. Mechanism of β cell destruction
 The fundamental immune abnormality in type 1 diabetes is the
failure of the self-tolerance in T cell specific for islet antigen
 Failure of tolerance may be due to defective clonal deletion of self
reactive T cells in the thymus / defect in the function of regulatory
T cells.
 The T cells are traffic to the pancreas where they cause β cell
injury.
 Several T cell population is involved in this including TH1 cells,
CD8+ CTLs.

26. Pathogenesis of Type 2 DM
Type 2 diabetes is a complex disease that
involves an interplay of genetic and
environmental factors and a proinflammatory
state.
Genetic factors:
First degree relatives
genome wise assoc. studies-30 loci

27. Contd…
Environmental factors:
• Central or visceral obesity leads to cardinal abnormalities
or insulin resistance
• Wt. loss and exercise

28. Metabolic defects in diabetes
Insulin resistance(decreased response of the
peripheral tissues to insulin)
β-cell dysfunction(inadequate insulin secretion)

29. Insulin resistance
Insulin resistance results in:
Failure to inhibit endogenous glucose production
(gluconeogenesis) in the liver, which contributes to high
fasting blood glucose levels
 Failure of glucose uptake and glycogen synthesis to
occur in skeletal muscle following a meal, which
contributes to high post-prandial blood glucose level
Failure to inhibit lipoprotein lipase in adipose tissue,
leading to excess circulating free fatty acids (FFAs),
which in turn, amplify the state of insulin resistance

30. Contd..
1. Insulin resistance reduced tyrosine
phosphorylation of insulin receptor , IRS
protein compromises insulin signalling
pathway and reduces the level of GLUT-4 on
cell surface .
1

31. Obesity and insulin resistance
 Major factor contribute to insulin resistance.
 One of the skin problems associated with obesity is acanthosis
nigricans, manifested by darkening and thickening of the skinfolds
on the neck, elbows, and dorsal interphalangeal spaces. Acanthosis
reflects the severity of underlying insulin resistance
 Excess FFA overwhelm the fatty acid pathway and leads to
accumulation of DAG.
 These toxic substances attenuate the insulin signalling pathway.
 In liver cells, insulin normally inhibits gluconeogenesis, but
attenuated insulin pathway ramp up the gluconeogenesis.

32. Contd..
Adipokines: some of the adipokines promote
hyperglycemia, others like leptin, adiponectin decreases
blood glucose. In obesity adiponectin levels get decreased
thus contribute to insulin resistance.
Inflammation: proinflammatory cytokines secreted in
response to excess nutrients such as FFA and glucose
results in insulin resistance and β cell dysfunction.
Excess FFA inflammasome IL-1β other
cytokines acts on major site of insulin action resist

33. β cell dysfunction
β cell dysfunction is virtually a requirement for
diabetes.
Initially β cell function increases as to
compensate insulin sensitivity, eventually β cell
exhaust their capacity to adapt to the long term
demands.

34. Contd..
 Several mechanisms have been implicated in promoting
β-cell dysfunction in type 2 diabetes, including:
o Lipotoxicity
o Glucotoxicity
o Abnormal Incretin effect (dec. GIP and
GLP-1 hormones, that promote insulin
release)
o Amyloid deposition

35. Diabetes and Pregnancy
DM IN PREGNANCY
PREGESTATIONAL GESTATIONAL DM
Pregestational diabetes-still birth, congenital
malformation
Gestational diabetes- excessive birth weight,
obesity and diabetes later in life

36. Screening test(GCT)
Diagnostic test Weeks of pregnancy
1st Diagnostic test Ideally 12 to 16 weeks or at
the first visit for AN check
up
2nd Diagnostic test 24 to 28 week
3rd Diagnostic test 32 to 34 week

37. Complications seen in diabetes
complicating pregnancy
Maternal : pregnancy induced HT, infections
Pregnancy complication : abortion, preterm labour,
hydraminos
Fetal: neural tube defects, cardiac anomaly, VSD, ASD,
fetal death.

38. Complications

39. Clinical features
 classic triad, when severe diabetic
ketoacidosis all result in metabolic
derangement.
Insulin deficiency
Triad
polyuria
polydipsiapolyphagia

40. Insulin deficiency
Catabolic state(gluc, fat, protein
metabolism)
Secr. of counter regulatory hormone
Assimilation of glucose decreased
Glycogenolysis
Hyperglycemia
Exceeds renal threshold
Glycosuria
polyuria
Renal water loss insulin
deficiency
hyperosmalarity catabolism
Inc. glucose in blood proteolysis
Deplete intracellular water level release of aa
Osmoreceptor in thirst center -ve energy balance
Polydipsia ↑ appetite
polyphagia

41. Complications
complications
acute
Hyperosmolar
hyperosmotic syndrome.
hypoglycemia
Diabetic ketoacidosis
chronic
microvascular
neuropathy
nephropathy
retinopathy
macrovascular
CAD
Peripheral vascular disease
Cerebro vascular disease

42. Complications

43. Acute metabolic
complications

44. Complications contd..
Failure to
take insulin
Illness, infection
Trauma
drugs
KETOACIDOTIC
STATE
• Diabetic ketoacidosis is the severe acute
metabolic complication of DM mainly type1
• Second major effect of insulin deficiency is
activation of ketogenic machinery

45. Contd…
 Clinical manifestation of DKA is fatigue,
nausea, vomiting, severe abdominal pain,
fruity odour, kussmaul breathing.
 Persistance of ketotic state leads to
diabetic coma.
 Most common acute metabolic
complication in either type is
hypoglycaemia.
 Hyperosmolar hyperosmotic syndrome.
Insulin deficiency
Lipoprotein lipase
↑ free fatty acid
liver
Fatty acyl Co-A
Ketone bodies
synthesis
Ketonemia, ketonuria
Diabetic ketoacidosis

46. Chronic complications
Microvasular complications (retinopathy, neuropathy,
nephropathy)
Macrovascular complications (atherosclerosis, MI,
stroke)

47. Chronic
complications

48. Pathogenesis of chronic complications
Persistant hyperglycemia seems to be the reason for the
chronic complications.
4 distinct mechanism (formation of AGEs, activation of
protein kinase C, oxidative stress and disturbance in
polyol pathway, hexosamine pathway) is the reason.
Increased glucose flux affect the above mentioned
pathways and release harmful substance and causes end
organ damage.

49. Formation of AGEs
 Advanced glycated end products are formed as a result of
nonenzymatic reaction between intracellular glucose
derived dicarbonyl precursors with both intra/ extra
cellular proteins.
 AGEs bind to specific receptors RAGE which is
expressed on inflammatory cells, endothelium, and
vascular smooth muscle.

50. Contd…
The effects are
 Release of cytokines, growth factors ,TGFβ leads to
deposition of excess basement membrane material, VEGF
implicated in diabetic retinopathy
 Generation of ROS in endothelial cells
 Inc. procoagulant activity
 Enhanced proliferation of vascular smooth muscle cells

51. Contd…
 Cross linking of AGE with collagen type 1 in large
vessels dec. the elasticity, so that predispose these vessels
to stress and endothelial injury.
 Cross linking with type 4 collagen decreases endothelial
cell adhesion and inc. extravasation of fluid
 Cross linking with protein resist proteolytic digestion
leads to protein deposition
 Trapping of LDL enhance the deposition of cholesterol
thus accelerating atherogenesis .

52. Activation of protein kinase C:
Ca2+ dependent activation of intracellular protein kinase c
and diacyl glycerol(DAG) leads to production of VEGF,
TGF- β and procoagulant protein plasminogen activator
protein 1(PAI-1)
Oxidative stress and polyol pathway:
 Excess glucose aldose reductase sorbitol(polyol) fructose
NADPH
NADPH is also required for GSH, an antioxiadnt
Formation
Depletion of NADPH leads to GSH depletion provoke to
oxidative stress.
Sorbitol accumulation in lens cause cataract

53. Morphology
Reduction in number and size of islets in type 1
Leukocytic infiltrates in the islets
Reduction in islet cell mass
Amyloid deposition in the islets in type 2
Increase in the number and size of the islets in non
diabetic new-born of diabetic woman

54. Diabetic macrovascular disease
Endothelial dysfunction & damage
Accelerated atherosclerosis involving aorta, large and
medium sized arteries
MI caused by atherosclerosis of coronary arteries is the
most common cause of death in diabetics
Gangrene of lower extremities(due to vascular disease)
Hyaline arteriosclerosis(hyaline thickening of arteriole
wall cause narrowing of lumen)

55. Diabetic microangiopathy
Diffuse thickening of basement membrane(both vascular
and non vascular structures)
Diabetic capillaries are more leaky than normal to plasma
proteins
Diabetic neuropathy: prevalence of neuropathy depends
on duration of disease

56.  Diabetic ocular complications: diabetes induced
hyperglycemia leads to cataract, glaucoma and optic nerve
damage. Preproliferative and proliferative retinopathy occurs.
 Diabetic nephropathy:
1) Glomerular lesion
2) Renal arteriosclerosis
3) pyelonephritis

57. Diabetic
nephropathy
Glomerular lesions
Capillary basement
membrane
thickening
Diffuse mesangial
sclerosis
Nodular
glomerulosclerosis
Renal
arteriosclerosis
pyelonephritis

58. Clinical manifestations
MACROVASCULAR COMPLICATIONS like MI, CAD,
atherosclerosis, HT, dyslipidemia,.
DIABETIC NEUROPATHY is leading cause of end stage
renal disease. microalbuminuria.
VISUAL IMPAIRMENT: diabetic retinopathy, cataract
formation, glaucoma, total blindness
DIABETIC NEUROPATHY: distal symmetric neuropathy,
motor neuropathy, sensory neuropathy, autonomic neuropathy.
INFECTION: skin infection, TB, pneumonia, pyelonephritis

60. Management

61. Insulinoma
 Beta cell tumors (insulinomas) are the most common type of
Pancreatic endocrine neoplasm and may produce sufficient insulin
to induce clinically significant hypoglycemia.
 The characteristic clinical picture is dominated by attacks of
hypoglycemia, which occur when plasma blood glucose levels fall
below 50 mg/dL.
 The attacks consist principally of such central nervous system
manifestations as confusion, stupor, and loss of consciousness.
 They are precipitated by fasting or exercise and are promptly
relieved by feeding or parenteral administration of glucose.

62. Whipple’s triad

63. Nesidioblastosis
 The abnormal histologic aspects of the tissue included
the presence of islet cell enlargement, islet cell dysplasia,
beta cells budding from ductal epithelium, and islets in
apposition to ducts.
 Nesidioblastosis is a medical term for hyperinsulinemic
hypoglycemia attributed to excessive function of
pancreatic beta cells with abnormal microscopic
appearance.

64. Thank you..