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Pancreas

Diabetes mellitus

Author: Deepali Jain, M.D.

Last author update: 1 August 2012

Last staff update: 26 November 2024 (update in progress)

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PubMed Search: Diabetes mellitus pancreas

Table of Contents

Cite this page: Jain D. Diabetes mellitus. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasdmgeneral.html. Accessed December 25th, 2024.

Definition / general

Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response (Wikipedia: Diabetes Mellitus [Accessed 8 December 2017])

Epidemiology

3% of world population, 26 million in U.S. but only 75% are clinically diagnosed
#7 leading cause of death in 2007 (underlying cause on 71,382 death certificates) (American Diabetes Association: Statistics About Diabetes [Accessed 8 December 2017])
Lifetime risk of diabetes: type 1 - 0.5%, type 2 - 5%
Numerous variations, all with hyperglycemia

Etiology

Destruction of islets due to drugs (steroids, thiazides, pentamidine), hemochromatosis ("bronze diabetes" due to hemosiderin deposition in pancreas), hereditary ceruloplasmin deficiency (Hum Pathol 1997;28:499), infections (congenital rubella, CMV, coxsackievirus [Arch Pathol Lab Med 1980;104:438], enteroviruses [Diabetologia 2004;47:225]), pancreatitis, surgery, tumors, endocrinopathies (pituitary, adrenal, pregnancy) or idiopathic

Type 1

Chronic disease of carbohydrate, fat and protein metabolism due to reduction in beta cell mass causing severe, absolute lack of insulin (eMedicine: Type 1 Diabetes Mellitus [Accessed 8 December 2017])
10% of all cases
Without insulin, patients develop diabetic ketoacidosis (DKA), coma and death

Etiology

Presumed autoimmune cause for islet cell destruction but precise etiology unclear (Wikipedia: Diabetes Mellitus Type 1 [Accessed 8 December 2017])
Usually Northern European descent
70% concordance in identical twins, HLA-D linked
Genetic predisposition may affect immune responsiveness to a beta cell autoantigen or method of presentation to T cells

Viruses and IDDM:

Viruses may damage beta cells, exposing antigens which trigger an autoimmune response
May be due to molecular mimicry (immune response develops against shared amino acid sequences): GAD and Coxsackie B4 virus share a six amino acid sequence
Retrovirus may serve as a superantigen

Autoimmune aspects:

Islet cell autoantibodies present in 70%; also CD8+ T cell infiltrate in islets
Antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides
GAD antibodies precede clinical symptoms, present in most newly diagnosed patients and 80% of first degree relatives
GAD antibody also causes stiff man syndrome, whose patients often have a history of IDDM
Many IDDM patients also have antithyroid peroxidase, antiparietal cell and antiadrenocortical antibodies
Some NIDDM patients have autoantibodies but no other features of IDDM
Usually chronic (years)
Clinical disease when 90% of islet cells are destroyed

Clinical features

Onset at age < 20 years, normal weight (unlike most NIDDM)
Characterized by PPP (polyuria, polydipsia, polyphagia) and ketoacidosis (DKA)
Polyphagia combined with weight loss is specific for IDDM; type 2 patients rarely have either
Severe fasting hypoglycemia is due to cessation of glycogen storage in fat and muscle
Glycosemia causes glycosuria with depletion of water and electrolytes
Also: low / absent plasma insulin, high plasma glucagon, unstable glucose tolerance (very sensitive to changes in insulin, diet, exercise, infection, stress), presence of free fatty acids (due to breakdown of adipose stores), which produces ketone bodies (acetoacetic acid and beta hydroxybutyric acid)
May get hyperosmotic nonketotic coma - dehydration due to hyperglycemic diuresis with failure to drink enough fluids to compensate, often in an elderly person with diabetes and stroke / infection
"Dead in bed syndrome": sudden death in young people with type 1 diabetes, cause unknown (Hum Pathol 2010;41:392)

Type 2 (NIDDM)

Also called adult onset, non insulin dependent diabetes mellitus / NIDDM, type 2
80 - 90% of cases of diabetes (Wikipedia: Diabetes Mellitus Type 2 [Accessed 8 December 2017])
Usually > 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity), normal or increased blood insulin, rare diabetic ketoacidosis, no anti-islet antibodies

Pathophysiology
Early:

Normal insulin secretion and plasma levels but loss of pulsatile, oscillating pattern of secretion
Also loss of rapid first phase of insulin secretion triggered by glucose
NO insulinitis is present

Later:

Mild / moderate insulin deficiency, may be due to beta cell damage
Beta cells may be "exhausted" due to chronic hyperglycemia and persistent beta cell stimulation

Amylin:

37 amino acid peptide, normally produced by beta cells, packaged and cosecreted with insulin
In NIDDM patients, tends to accumulate outside beta cells and resembles amyloid

Clinical features

90%+ concordance in twins, apparently due to multiple genetic polymorphisms (no HLA association)
Due to insulin resistance (associated with obesity and pregnancy) or derangement in beta cell secretion of insulin
Associated with amyloid deposits in islets (amyloid associated with basement membrane heparan sulfate proteoglycan) (Arch Pathol Lab Med 1992;116:951) and pituitary (Arch Pathol Lab Med 1995;119:1055)

Maturity onset diabetes of the young

1 - 2% of all cases of diabetes (Diabetes Metab Syndr Obes 2012;5:101)
Also called monogenic diabetes (Wikipedia: Maturity Onset Diabetes of the Young [Accessed 8 December 2017])
Type 2 diabetes-like condition which occurs in 2+ generations, with autosomal dominant inheritance (Diabetes Care 2011;34:1878)
Autosomal dominant but not a single entity - mutations in 9 genes identified to date (see Diagrams / tables below)
Common genes affected are hepatic nuclear factor 1 or 4 alpha, glucokinase
Onset before age 25, normal weight, mild hypoglycemia
No GAD antibodies, no insulin resistance, no beta cell loss but impaired beta cell function

Diagrams / tables

Images hosted on other servers:

Single gene mutations
resulting in monogenic
diabetes / MODY

Clinical complications

General

Main complications are microangiopathy, retinopathy, nephropathy, neuropathy - all due to hyperglycemia
Kidneys transplanted into diabetic patients develop nephropathy within 3 - 5 years but kidneys from diabetic patients transplanted into normal patients have remission of nephropathy
Strict control of diabetes delays progression of microvascular complications
Complications are due to nonenzymatic glycosylation and disturbances in polyol pathways

Nonenzymatic glycosylation

Glucose + protein => Schiff base (protein - NH = CH (CHOH)4-CH2OH) => Amadori product
(protein - NH-CH2-C = 0-(CHOH)3-CH2OH) => protein - protein cross linking via N-C-N bonding
Early reactions are reversible and related to HbA1c level
Advanced glycosylation end products (AGE) are not reversible
AGE traps LDL in blood vessels, enhances cholesterol deposition, accelerating atherosclerosis
AGE inhibition antagonizes diabetic complications in experimental models

Vascular complications

Relative risk is 100:1
Accelerated atherosclerosis in aorta and large / medium sized vessels
Myocardial infarction: most common cause of death, no gender preference
Gangrene of lower extremities
Micro description:
- Hyaline arteriolosclerosis, associated with hypertension, more common / severe in diabetes but not specific
- Amorphous hyaline thickening in arteriolar wall
- Related to severity of disease and hypertension
- Microangiopathy: diffuse basement membrane thickening with protein leakage in capillaries of skin, skeletal muscle, retina, renal glomeruli, renal medulla, renal tubules, Bowman capsule, peripheral nerves, placenta

Diabetic renal disease

See Diabetic kidney disease

Ocular

#4 cause of blindness in U.S.
Associated with retinopathy, cataracts, glaucoma
Polyol pathways: important in lens and other tissues (nerves, kidney, blood vessels) that don't require insulin for glucose transport
- High intracellular glucose plus aldose reductase produces sorbitol and later fructose, causing water influx and osmotic cell injury
- In lens, causes swelling and opacity
- Inhibition of sorbitol may reduce formation of cataracts and neuropathy

Neuropathy

Peripheral, symmetric neuropathy of lower extremity most common, sensory more common than motor

Diagnosis

High fasting glucose or impaired glucose tolerance (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period)

Case reports

Adult with acute onset, death within 3 days, T cell pancreatic infiltrate (Arch Pathol Lab Med 1994;118:84)
Islet inflammation with Coxsackie B5 infection (Hum Pathol 1982;13:661)

Treatment

Type 1: immunosuppressive therapy is effective in children with new onset disease
Type 2: diet, exercise and education (eMedicine: Type 2 Diabetes Mellitus [Accessed 8 December 2017])
- Lifestyle intervention and metformin delay onset of diabetes (N Engl J Med 2012;367:1177)

Microscopic (histologic) description

Type 1: inconsistent reduction in number and size of islets, uneven insulinitis (T lymphocytes)
Type 1: early insulinitis with marked islet atrophy and fibrosis and severe beta cell depletion (Islets 2011;3:131)
Type 2: subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in aging nondiabetics); associated with marked fatty replacement
Type 2: amyloid in the islets of Langerhans is the uniform pathologic feature
Gestational diabetes: lower total insulin+ area due to smaller islets (Islets 2011;3:231)
Infants of diabetic mothers: islet cell hypertrophy / hyperplasia

Videos

Histopathology pancreas: type 2 diabetes mellitus

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