1. Diabetes mellitus is a metabolic disorder characterized by hyperglycemia that affects over 29 million people in the US and 422 million worldwide. 2. There are several types of diabetes including type 1 caused by autoimmune destruction of beta cells, type 2 caused by insulin resistance and relative insulin deficiency, and gestational diabetes during pregnancy. 3. Chronic complications of diabetes include damage to blood vessels leading to heart disease, stroke, and kidney failure as well as nerve damage causing neuropathy. Rare forms include monogenic diabetes and pancreatic tumors such as insulinomas.

1. FRONT E
I R
Lecture 7. Diabetic Mellitus
& Pancreatic Tumour:

2. • Diabetes mellitus is a group of metabolic disorders
characterized by hyperglycemia.
• According to the American Diabetes Association,
diabetes affects over 29 million children and adults,
or 9.3% of the population.
• About 422 million people worldwide have
diabetes, the majority living in low-and middle-
income countries, and 1.6 million deaths are
directly attributed to diabetes each year.

3. • Diagnosis:
• According to the American Diabetes Association (ADA)
and the World Health Organization (WHO), diagnostic
criteria for diabetes include the following:
1. A fasting plasma glucose greater than or equal to
126 mg/dL.
2. A random plasma glucose greater than or equal to
200 mg/dL (in a patient with classic hyperglycemic
signs.
3. A 2-hour plasma glucose greater than or equal to
200 mg/dL during an oral glucose tolerance test
with a loading dose of 75 gm.
4. A glycated hemoglobin (HbA1C) level greater than
or equal to 6.5%.

4. Classification:

5. Normal Insulin Physiology and
Glucose Homeostasis:
• Normal glucose homeostasis is tightly regulated by
three interrelated processes:
(1) glucose production in the liver.
(2) glucose uptake and utilization by peripheral tissues,
chiefly skeletal muscle.
(3) the actions of insulin and counterregulatory
hormones.
• The principal function of insulin is to increase the rate
of glucose transport into certain cells in the body.
• Glucose uptake in the brain, is insulin-independent.
• Insulin reduces the production of glucose from the
liver.

6. • The most important stimulus that triggers insulin
release from pancreatic beta cells is glucose itself.
• Oral intake of food leads to secretion of multiple
hormones, notably the incretins produced by cells
in the intestines. These hormones stimulate insulin
secretion from beta cells.
• In peripheral tissues (skeletal muscle and adipose
tissue), secreted insulin binds to the insulin
receptor, triggering a number of intracellular
responses that promote glucose uptake and
postprandial glucose utilization, thereby
maintaining glucose homeostasis.

9. TYPE1 DIABETICS:
• Type 1 diabetes is an autoimmune disease
characterized by pancreatic β-cell destruction and
an absolute deficiency of insulin.
• It accounts for approximately 5% to 10% of all
cases.
• Patients younger than 20 years of age.
• Most patients with type 1 diabetes depend on
exogenous insulin for survival.
• The classic manifestations of the disease (such as
ketoacidosis) occur late in its course, after more
than 90% of the beta cells have been destroyed.

10. Pathogenesis of TYPE 1 Diabetics:
• The pathogenesis of type 1 diabetes involves:
1. Genetic susceptibility.
2. Environmental factors.
• Genome-wide association studies have identified
over 20 susceptibility loci for type 1 diabetes.
• Genetic susceptibility:
I. Class II MHC (HLA-DR) genes especillay HLA-
DR3, or DR4.
II. Non-HLA:
a) CTLA-4 is an inhibitory receptor of T cells.
b) PTPN-22 is a protein tyrosine phosphatase.
• Both are thought to inhibit T-cell responses.

11. • Environmental factors:
I. Viral infections (mumps, rubella, and coxsackie B
viruses), they have antigens mimic beta cell antigens.
II. Reduction in human microbiome ‘normal flora’.
• The fundamental immune abnormality in type 1
diabetes is a failure of self-tolerance in T cells specific
for beta cell antigens.
• One consequence of loss of self tolerance is the
production of autoantibodies against a variety of beta
cell antigens, including insulin and the beta cell enzyme
glutamic acid decarboxylase, which are detected in the
blood of 70% to 80% of patients.
• Pancreatic examination shows necrosis of beta cells and
lymphocytic infiltration so-called “insulitis”.

13. TYPE 2 DIABETICS:
• Type 2 diabetes is caused by a combination of
peripheral resistance to insulin action and an
inadequate secretory response by the pancreatic β
cells (“relative insulin deficiency”).
• Approximately 90% to 95% of diabetic patients
have type 2 diabetes.
• Many of patients are overweight.
• Adult-onset.

14. Pathogenesis of TYPE 2Diabetics:
1. Genetics.
2. Environmental risk factors.
3. Inflammation.
• Insulin resistance predates the development of
hyperglycemia and usually is accompanied by
compensatory beta cell hyperfunction and
hyperinsulinemia in the early stages.
• Genetic factors:
o80% to 90% in monozygotic twins.
oDiabetogenic genes.
• Environmental factors:
oSedentary lifestyle.
oDietary habits.

16. • Inflammation factor:
• Is due to excess FFAs within macrophages and
beta cells can activate the inflammasome, a multiprotein
cytoplasmic complex that leads to secretion of the
cytokine interleukin (IL-1β).
• Insulin Resistance:
• The failure of target tissues to respond normally to
insulin.
• Resistance is seen in liver, skeletal muscle, and adipose
tissue
1. Failure to inhibit endogenous glucose production
(gluconeogenesis) in the liver.
2. Abnormally low glucose uptake and glycogen synthesis
in skeletal muscle
3. Failure to inhibit hormone-sensitive lipase in adipose
tissue, leading to excess circulating free fatty acids.

17. • Obesity and Insulin Resistance:
• Visceral obesity being common in a majority of
affected patients.
• Metabolic syndrome from visceral obesity leads to:
1. Insulin resistance.
2. Glucose intolerance.
3. Cardiovascular risk factors such as hypertension
and abnormal lipid profiles.
• Distribution of body fat:
A. Central obesity (abdominal fat).
B. Peripheral obesity (gluteal/subcutaneous).

18. • Obesity can adversely impact insulin sensitivity in
numerous ways:
1. Excess FFAs = potent inhibitors of insulin
signaling.
2. Adipokines (or adipose cytokines) = decreased
level of adiponectin leads to insulin resistance.
3. Inflammation.

20. Beta Cell Dysfunction:
• Beta cells are unable to adapt to the long-term
demands of peripheral insulin resistance, and the
hyperinsulinemic state gives way to a state of relative
insulin deficiency.
• Several mechanisms have been implicated in causing
beta cell dysfunction in type 2 diabetes, including the
following:
1. Excess free fatty acids (lipotoxicity).
2. Chronic hyperglycemia (glucotoxicity).
3. Abnormal incretin effect.
4. Amyloid replacement of islets.
5. Polymorphisms.

21. Insulitis – Type I
Insulinitis

23. Monogenic Forms of Diabetes:
• Are uncommon examples of the diabetes occurring
as a result of loss-of-function mutations within a
single gene.
• Monogenic diabetes can be classified based on
age of onset into:
• Congenital early onset diabetes (manifesting in the
neonatal period).
• Mutations of the insulin gene itself.
• Mutations in mitochondrial DNA.
• Maturity onset diabetes of the young.
• Mutations in genes encoding factors driving beta
cell function.

24. Other Forms of Diabetes:
• Gestational diabetes:
• Approximately 5% of pregnancies occurring in the
United States.
• Have an increased risk for stillbirth and congenital
malformations in the fetus or fetal overgrowth
(macrosomia).
• Gestational diabetes typically resolves following
delivery; however, there is an elevated risk for
developing outright diabetes within the next ten
years.

25. • Pancreatogenic diabetes:
• is defined as hyperglycemia occurring as a result of
a disorder of the exocrine pancreas.
• Is heterogeneous and caused by
• Cystic fibrosis.
• Chronic pancreatitis.
• Pancreatic adenocarcinoma approximately
1% of new-onset diabetes in older adults.

26. • Thyroid diabetes:
• thyroid hormone enhances glucagon secretion. Via
sum of these effects on glucose metabolism by
thyroid hormone, excess thyroid hormone will
deteriorate glucose metabolism and cause glucose
intolerance or diabetes mellitus.
• Cushing diabetes:
• The stimulation of gluconeogenesis and the
development of insulin resistance, in association
with the occurrence of an impairment of insulin
secretion.

27. Acute Metabolic Complications
of Diabetes:
• Initial presentation:
• The onset of diabetes is marked by:
1. Polyuria.
2. Polydipsia.
3. Polyphagia.
• In severe cases, ketoacidosis.
• Diabetic Ketoacidosis and Hyperosmolar Non-ketotic
Coma:
• In patients with type 1 diabetics mellitus:
• Deviations from normal dietary intake, unusual physical
activity, infection, or any other forms of stress.
• The plasma glucose usually is in the range of 500 to 700
mg/dL.

28. • The marked hyperglycemia causes an osmotic diuresis and
dehydration characteristic of the ketoacidotic state.
• The second major effect is activation of the ketogenic
machinery.
• In patients with type 2 diabetic mellitus:
• Polyuria and polydipsia. In some cases, medical attention is
sought because of unexplained weakness or weight loss.
• Patients with type 2 diabetes may develop hyperosmolar
nonketotic coma.
• Severe dehydration resulting from sustained osmotic
diuresis and urinary fluid loss due to chronic hyperglycemia.
• The absence of ketoacidosis and its symptoms (nausea,
vomiting, respiratory difficulties) delays recognition of the
seriousness of the situation until the onset of severe
dehydration and coma.

33. Chronic Complications of
Diabetes:
• Damage to both:
1. large- and medium-sized muscular arteries
(diabetic macrovascular disease).
2. Small-vessels (diabetic microvascular disease).
• Macrovascular disease:
• Accelerated atherosclerosis increases:
1. Myocardial infarction.
2. Stroke.
3. Lower-extremity ischemia and claudication.

34. • Microvascular disease:
1. Diabetic retinopathy.
• Cataract.
• Loss of vision.
2. Nephropathy.
• Renal failure.
3. Neuropathy.
• Peripheral neuropathy:
a) Sensory loss.
b) Pain and tingling.
c) Motor loss.
d) Foot ulceration.
e) Arthropathy.
• Autonomic neuropathy:
a) Gastropathies and altered bowel habit.
b) Postural hypotension.

37. • In individuals with tight control of their diabetes, the
onset may be delayed (hence the need for tight control
of hyperglycemia).
Pathogenesis of Chronic Complications of Diabetes:
1. Formation of advanced glycation end products (AGEs).
2. Activation of protein kinase C.
3. Disturbances in polyol pathways.
All of these increases deposition of extracellular
matrix and basement membrane material.

38. • Macrovascular complications, such as myocardial
infarction, renal vascular insufficiency, and
cerebrovascular accidents, are the most common
causes of mortality in long-standing diabetes.
• Diabetic nephropathy is a leading cause of end-
stage renal disease in the United States.
• Visual impairment, sometimes even total blindness,
is one of the more feared consequences of long-
standing diabetes.
• Diabetic patients are plagued by an increased
susceptibility to infections of the skin, tuberculosis,
pneumonia, and pyelonephritis.

39. • Diagnosis:
• Urine testing.
• Screening by fasting glucose test.
• Oral glucose tolerance test.
• Other tests.
1. Glycosylated haemoglobin (HbA1C).
2. Glycated albumin.
3. Insulin assay.
4. C-peptide assay.
5. Islet autoantibodies.

40. • Dietary/lifestyle modification,
• Oral anti-diabetic drugs
• Injected therapies.

43. • Islet cell tumours are rare as compared with tumours
of the
exocrine pancreas.
• Islet cell tumours are generally small and may be
hormonally inactive or may produce hyperfunction.
• They may be benign or malignant, single or multiple.
• They are named according to their histogenesis such
as:
• β-cell tumour (insulinoma), G-cell tumour (gastrinoma),
A-cell tumour (glucagonoma) D-cell tumour
(somatostatinoma), VIpoma (diarrhoeagenic tumour
from D1 cells which elaborate VIP), pancreatic
polypeptide (PP)-secreting tumour, and
carcinoid tumour.
• However, except insulinoma and gastrinoma, all others
are extremely rare and require no further comments.

44. • Most common.
• Highest incidence is b/w 40 – 60 year old.
• The neoplastic β-cells secrete insulin into the blood
stream.
• Hypolgycaemia with blood glucose level falling to
50 mg/ dl or below.
• High plasma insulin level (hyperinsulinism).
• The central nervous manifestations are relieved by
intake of glucose.

45. • Clinical feature:
1. Confusion.
2. Sweating.
3. Weakness.
4. Rapid heartbeat.
5. Anxiety.
6. Weight gain.
7. Clouded vision.
8. Headache.
• Diagnosis:
oLevel of blood glucose, insulin, C peptide.
oCT scan or MRI.

47. • Differential diagnosis:
• Starvation.
• Partial gastrectomy.
• Diffuse liver disease.
• Hypopituitarism.
• Hypofunction of adrenal cortex.
• Treatment:
• Surgery.

48. • Zollinger and Ellison described diagnostic triad
consisting of the following:
• Fulminant peptic ulcer disease.
• Gastric acid hypersecretion.
• Presence of non-β pancreatic islet cell tumour.
• Clinical feature:
1. Pain.
2. Bleeding.
3. Obstruction.
4. Perforation.

49. 5. Diarrhea.
6. Malabsorption.
• Diagnosis:
• Gastrin level.
• CT scan.
• Secretin stimulating test.
• Test for gastric hyper-secretion.
• Treatment:
• Pancreatic tumour resection.