Pathophysiology of

Endocrine Pancreas
Frank Vuitch, MD

Endocrine Pancreas
Learning Objectives
Understand normal insulin physiology
Understand classification of diabetes mellitus
Differentiate between Type 1 and Type 2 diabetes
mellitus with respect to clinical features,
genetics, pathogenesis, and islet pathology
Describe acute metabolic complications of diabetes,
Ketoacidosis and Hyperosmolar coma
Discuss pathogenesis of chronic complications of
diabetes, especially vascular complications, and
describe morphologic changes, especially those
involving pancreas, blood vessels, kidney, retina
Clinical syndromes associated with pancreatic
endocrine tumors (insulinoma and gastrinoma)

Islets of Langerhans
Insulin Physiology
1 million islets, total 1.5 grams, 2/3 beta-cells,
preproinsulin, cleaved to insulin & C-peptide
Glucose homeostasis is regulated by:
Glucose production in the liver
Uptake and utilization by peripheral tissues
Insulin secretion, triggered by hyperglycemia
Persistent hyperglycemia (detected by islet
cell via GLUT-2) active insulin synthesis
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Pancreatic Beta Cells

Insulin Physiology
Major Anabolic
Hormone
Insulin
binds to target cell membrane receptor, initiates
cascade of intracellular responses, including
GLUT-4 (glucose transport protein in striated
muscle & fat) translocation to membrane
Insulin needed for anabolic activities, inhibits catabolic:
Transmembrane transport of glucose (via GLUT-4) and
amino acids into target cells
Glycogen formation in liver and skeletal muscle
Glucose conversion to triglycerides
Protein synthesis, Nucleic acid synthesis

Diabetes Mellitus
Classification
Diabetes mellitus represents a heterogeneous group
of disorders with common features
hyperglycemia, impaired glucose tolerance
Diabetes may occur secondary to extensive
destruction of pancreatic islets (pancreatitis, drugs,
neoplasms, iron overload, etc), but most cases are
due to primary disorders of the islet cell - insulin
signaling system
Most important are type 1 (IDDM, juvenile, 510%)
and type 2 (NIDDM, adult-onset, 90-95%)

Diabetes Mellitus
Unifying Features
While major types of diabetes have different
pathogenetic mechanisms, the long-term
complications in kidneys, eyes, nerves,
and blood vessels are the same, as are the
major causes of morbidity and death.
In USA, about 20 million people are affected,
about 2/3 are clinically diagnosed, with 54
million in pre-diabetes. 5-10% per year
progression to DM of those with IGT.
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Diabetes Mellitus
Type 1 vs Type 2

Clinical
Onset < 20 years old Adult onset usually
Features
Normal weight
Obese (80%)
Low blood insulin Normal to high insulin
Anti-islet cell antibodies No anti-islet cell Abs
Ketoacidosis common
Ketoacidosis rare
Genetics
50% twin concordance
80% concordance
HLA-D linked
No HLA association
Pathogenesis Autoimmunity Insulin resistance
Severe insulin deficit
Relative insulin deficit
Islet cells
Insulitis early No insulitis
Atrophy
Atrophy and amyloid
Marked B-cell depletion Mild B-cell depletion

Type 1 Diabetes
Pathogenesis
The hallmark of Type 1 diabetes is
islet cell destruction severe
and absolute lack of insulin.
Three inter-locking
mechanisms are
responsible for islet
cell destruction

Environmental
Insult

Genetic
Susceptibility

Autoimmunity

Type 1 Diabetes
Genetic Susceptibility
Type 1 diabetes occurs most frequently in those
of Northern European descent
90-95% of white patients with type 1 diabetes
have either HLA-DR3 or HLA-DR4 alleles or
both, which encode cell surface
glycoproteins, and may alter recognition by
T-cell receptors

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Type 1 Diabetes
Autoimmunity
Clinical onset of Type I diabetes is often abrupt, with
sudden onset of hyperglycemia and ketoacidosis,
but disease results from chronic autoimmune
attack destroying more than 90% of beta-cells.
Lymphocyte-rich inflammatory infiltrate (insulitis) is
seen in early stages (CD4 & CD8 T lymphocytes)
Abnormal expression of MHC molecules
Most patients have autoantibodies against insulin
and intracellular islet cell antigens (e.g. glutamic
acid decarboxylase GAD)
Unclear if autoantibodies cause injury or result from
islet injury

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Type 1 Diabetes
Environmental Factors
Epidemiologic implication of viruses as trigger Coxsackievirus Group B, and others
Direct virus-induced beta-cell injury is thought
not to be severe enough to cause diabetes
Proposed mechanisms for viral injury
1. Viral-induced mild beta-cell injury followed
by autoimmune reaction (bystander)
2. Immune response develops against a viral
protein that shares amino acid sequences with
beta-cells (molecular mimicry)
3. Early predisposing viral infection persists,
subsequent infection with precipitating virus

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Type 2 Diabetes
Pathogenesis
Genetic Factors are more important than in Type 1:
Identical Twins: Concordance 35-60%
1st degree relatives: increased risk, 20-40%
(vs. 5-7% in general population)
Not linked to HLA genes, instead it is polymorphic
(multiple genetic defects); no autoimmune basis
Two metabolic defects identified:
Insulin Resistance - decreased response of target
tissues to uptake, metabolize, and store glucose
Beta-cell dysfunction - inadequate insulin
secretion in setting of insulin resistance and
hyperglycemia

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Insulin Resistance
Mechanisms complex and under research
Insulin Resistance results in:
Inability of circulating insulin to direct
disposition of glucose
Persistence of hyperglycemia
Prolonged stimulation of beta-cells.
Obesity contributes to disease onset
(free fatty acids and adipokines - eg leptin),
and weight loss may help control disease.
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Beta-cell Dysfunction
Preclinical: Chronic hyperinsulinemia develops
due to beta-cell physiologic response to
insulin resistance
Early, qualitative dysfunction: Loss of
normal pulsatile, oscillating pattern of insulin
secretion, and attenuated rapid first phase of
insulin secretion triggered by glucose
Late, quantitative dysfunction: Decreased
beta-cell mass, islet degeneration, deposition
in islets of amyloid (? injurious) - No evidence
that beta-cell damage is immune-mediated
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Monogenic forms of
diabetes
2 to 5% of diabetic patients do not fall clearly
into the Type 1 or 2 categories.
Autosomal dominant inheritance
Early onset < 25 years
Impaired beta-cell function, with normal
weight, lack of islet cell antibodies, and lack
of insulin resistance syndrome
Maturity Onset Diabetes of the Young (MODY) heterogeneous group of genetic defects in
beta-cell function: 6 variants are known

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Pathogenesis of
Complications
Morbidity of long-standing diabetes results from
complications, including macro- and micro-vascular:
Accelerated atherosclerosis (MI, stroke, PAD)
Retinopathy, Nephropathy, Neuropathy
Predictive utility of microalbuminuria (30-300 mg/d)
Metabolic derangements due to hyperglycemia:
Formation of advanced glycation end products
(AGEs, nonenzymatic glycosylation, HbA1c)
Activation of protein kinase C
Intracellular hyperglycemia with disturbances in
polyol pathways

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Advanced Glycation
End Products (AGEs)
Glucose-derived compounds chemically attach to amino groups
of proteins without the aid of enzymes
Degree of AGE formation is related to blood glucose level monitor glycosylated Hemoglobin A1C in blood, target < 7%
Glycosylated collagen and protein in connective tissues and
blood vessel walls slowly undergo chemical rearrangement
to form irreversible Advanced Glycosylation End-products
(AGE) which accumulate, resist proteolysis, and cause
pathology:
AGE cross-links with collagen and traps plasma or interstitial
proteins, e.g. LDL in large vessels Atherosclerosis
AGE binds to receptors of many cell types, inducing biologic
activities which contribute to diabetic complications:
Monocyte migration, release of cytokines, increased
endothelial permeability, increased production of
extracellular matrix by fibroblasts and smooth muscle

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Disturbances in
Polyol Pathways
In some tissues which do not require insulin for
glucose transport (nerve, lens, kidney, blood
vessel) hyperglycemia increased intracellular
glucose metabolized by aldose reductase
sorbitol (a polyol) and to fructose - depletes
NADPH, increased cellular susceptibility to
oxidative stress
? Role of osmotic cell injury
Opacification of lens (cataracts)
Neuron damage with peripheral neuropathy
Pericytes of retinal capillaries, microaneurysms
(diabetic retinopathy, role of protein kinase C)

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Diabetic Ketoacidosis
Shift in hormonal balance in favor of the counter-regulatory hormones glucagon, growth hormone, and epinephrine - over insulin, typically
triggered by major stress; catabolic state.
Severe hyperglycemia (500-700 mg/dL) results from decreased glucose
uptake by tissues, increased gluconeogenesis, and glycogenolysis.
Hyperglycemia induces osmotic diuresis - fluid and electrolyte loss.
Increased lipolysis triggered by counter-regulatory hormones releases
free fatty acids, which can be converted to ketone bodies in liver.
Increased ketone bodies result in metabolic ketoacidosis, manifested as
low pH and low bicarbonate (consumed in buffering keto acids).
Metabolic acidosis stimulates respiratory center to try to reduce pCO2 to
correct acid-base disturbance; resulting increased respiration,
classically deep, sighing Kussmaul respiration, reduces pCO2.

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Hyperosmolar
Nonketotic Coma
Type 2 diabetics typically do not develop
high ketone body serum levels and
acidosis.
With extreme hyperglycemia, they may
have hyperosmolar osmotic diuresis with
severe dehydration (may be exacerbated
by inadequate fluid intake due to
infirmity, such as stroke or infection).
Coma may ensue.
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Renal Pathology:
Low Power
Thickened vessel due to
hyalinization
Hyalinized glomerulus
Tubular destruction with
interstitial fibrosis
Nodular
glomerulosclerosis

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Renal Pathology:
High Power
Nodular deposits in
mesangium of
glomeruli
What is the
pathogenesis of
these changes ?
What is the clinical
consequence ?
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Pancreatic Pathology
Pancreatic acini
Islet of Langerhans
What is the pink
homogeneous
material within the
islets ?
Is this change seen in
Type 1 diabetes ?

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Other Pathologic
Lesions
In large blood vessels, severe
extensive atherosclerosis
occurs earlier in diabetics
than in nondiabetics.
Kidneys are often severely
affected from vascular
disease affecting both the
large blood vessels and
glomerular capillaries, and
increased predisposition to
infections. Kidneys with
diabetic glomerulosclerosis
show diffuse granularity of
cortical surface resulting
from the destruction and
scarring of the glomeruli.

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Pancreatic Endocrine
Neoplasms Insulinoma
Beta-cell
tumor, most common
Whipple Triad:
Hypoglycemia < 50 mg/dL
CNS symptoms of
hypoglycemia
Precipitated by exercise or fast,
and respond to glucose Rx
90% are solitary, benign
Often < 2 cm diameter
Micro- looks like giant islet
Therapy is excision

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Zollinger-Ellison
Syndrome Gastrinoma
Arise in pancreatic islets, duodenum, soft tissue
Associated with hypersecretion of gastric acid,
peptic ulceration (duodenum : stomach, 6 : 1)
Ulcers in 90-95% of patients, intractable to Rx
Diarrhea in 50% (presenting complaint in 30%)
Morphology similar to insulinoma, yet > 50%
are malignant - however, 10 year survival
possible, even with known liver metastases
Therapy - block acid secretion with histamine
(H2) receptor blockers, excise neoplasm

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