Endocrine Pancreas Flashcards
What is insulin made by?
Insulin is made by B-cells as proinsulin is proteolytically cleaved in the Golgi complex to generate the mature hormone and a peptide byproduct, C-peptide .
Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation
What is the diagnostic utility of C peptide?
C-peptide can be used to measure B-cell mass because it is not removed by the liver and has a longer half life than insulin.
NOTE: If some one is using exogenous insulin, there is no c-peptide, they love to test this!!
The presence of high glucose in the body leads to glycosylation of essentially all surfaces of the body, but especially _____
basement membranes.
NOTE: Excess intracellular glucose can also go down the sorbitol pathway to produce fructose, an even more potent glycosylator than glucose
Diabetes is the leading cause of:
END-STAGE RENAL DIAEASE,
ADULT-ONSET BLINDNESS, and
NONTRUMATIC LOWER EXTREMITY AMPUTATION
What are the main ways of testing for diabetes?
A1C, fasting glucose glucose (mg/dL), OGTT (mg/dl)
What are some situations in which A1c testing may not be accurate for diagnosing/monitoring diabetes?
If an individual has a hemoglobin variant, such as sickle cell hemoglobin (hemoglobin S), they will have a decreased amount of hemoglobin A. This may limit the usefulness of the A1c test in diagnosing and/or monitoring this person’s diabetes, depending on the method used.
If a person has anemia, hemolysis, or heavy bleeding, A1c test results may be falsely low. If someone is iron-deficient, the A1c level may be increased.
If a person has had a recent blood transfusion, the A1c may be inaccurate and may not accurately reflect glucose control for 2 to 3 months.
What is the main difference between the cause of Type I and Type II diabetes?
Type I diabetes is the result of an autoimmune reaction against B cell antigens that destroy insulin production while Type II diabetes results from a combination of peripheral insulin resistance and inadequate beta cell response in patients with an underlying genetic predisposition
What autoantibodies have been identified to be implicated in Type I diabetes?
anti-insulin, anti-GAD, anti-ICAS12
How does Type I diabetes present?
The onset is typically pediatric and is usually marked by the triad of polyuria, polydipsia, and polyphagia BUT these patients typically maintain normal weight or may even present with weight loss
DKA is more common in which diabetes?
Type I because only small amounts of insulin are required to prevent ketone body formation
What MHC Class II genes have been linked to Type I diabetes?
HLA-DR3 and DR4
also linked to polymorphisms in CTLA4 and PTPN22 that inhibit T-cell response as well as insulin gene VNTRs
How does Type I diabetes present upon pathologic examination?
Insulitis (inflammatory infiltrate of T cells and macrophages), B-cell depletion, and islet atrophy
Type II diabetics are more prone to what complication?
Nonketotic hyperosmolar coma
What genetic variations predispose to Type II diabetes?
No HLA linkage but there are obesity-related genes such as TCFL2, PPARG, and FTO which appear to be upregulated often
How does Type II diabetes present upon pathologic examination?
No insulitis but you do see mild B cell depletion as well as amyloid deposition in islets
The two cardinal metabolic defects that characterize type 2 diabetes are:
- Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin (insulin resistance)
- Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β-cell dysfunction)
Describe insulin’s relationship/function in terms of fat and protein
In adipose glucose is stored as lipids and insulin supports/promotes lipogenesis and prevents lipid breakdown. Insulin promotes proteogenesis as well
How does insulin affect the liver?
Insulin reduces the production of glucose from the liver
How does glucagon work?
Glucagon (made by a-cells) binds to a Gs protein receptor, which activates adenyl cyclase. Cyclic AMP activates protein kinase A, which phosphorylates proteins in many different pathways to promote glucose mobilization and lipolysis, among other things.
Glucagon action is in liver and adipocytes, not muscle.
The chronic complications of diabetes are primarily due to vascular impairment and can manifest in small or large vessels. What primarily mediates small vessel damage?
Non-enzymatic glycosation from glucose overload
How does small vessel disease from diabetes present?
thickened basement membranes: leads to retinopathy, glaucoma, neuropathy, nodular glomerulosclerosis (Kimmelsteil-Wilson nodules), progressive proteinuria and arteriolosclerosis in kidneys. With HTN and chronic renal failure, hyaline ateriolosclerosis
How does diabetic large vessel damage present?
CAD, peripheral occlusive disease, limb loss and death. MI is the most common cause of death.
Osmotic damage: sorbitol accumulation in the organs with aldose reductase and decreased or absent sorbitol dehydrogenase: Neuropathy and cataracts
As mentioned, the main player in the complications of diabetes is the formation of advanced glycation end products (AGES). How do these affect diabetics?
These are formed from glucose precursors and proteins and bind to endothelial cells and cross link antigens like type IV collagen and induce inflammatory cells on endothelium and smooth muscle
This creates a proinflammatory state, ROS, procoagulant activity, crosslinks other proteins and “traps” other proteins in vessel walls (LDL, albumin) that leads to thickened basement membranes that mediate complications such as retinopathy, glaucoma, and renal complications
What is this showing?
The image on the left shows normal pancreatic morphology while the image on the right shows characteristic changes seen in Type I diabetes. You can see the Leukocytic infiltrates in the islets (insulitis) that is a common early manifestation. These infiltrates are principally composed of T lymphocytes. Also of note (cant see well here), later is disease progression there is significant reduction in the number and size of islets.
NOTE: A pancreatic biopsy is not the norm and doesnt have much diangostic practicality
What type of diabetes is this showing? How do you know?
This is type II diabetes. In type 2 diabetes there may be a subtle reduction in islet cell mass but the key here is the amyloid deposition (middle, pink).
What is this showing?
Diabetes exacts a heavy toll on the vascular system. Hyaline arteriolosclerosis, the vascular lesion associated with HTN, is both more prevalent and more severe in diabetics than in nondiabetics.
It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen.
Diffuse thickening of basement membranes is a hallmark of diabetes, especially in the capillaries. Where is this most evident?
capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla. This is called diabetic microangiopathy and this underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
What is this?
Electron micrograph of a renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic (left) compared to normal on the right
What is seen on the left compared to the normal glomeruli on the right?
This lesion consists of diffuse increase in mesangial matrix.
As the disease progresses, the expansion of mesangial areas can extend to nodular configurations.
The progression correlates with measures of deteriorating renal function such as increasing proteinuria.
What is this?
Nodular Glomerulosclerosis (aka Kimmelstiel-Wilson disease) seen in diabetes in a PAS stain (left) and H&E (right). Nodules of pink hyaline material form in regions of glomerular capillary loops in the glomerulus. This is due to a marked increase in mesangial matrix from damage as a result of non-enzymatic glycosylation of proteins.
Approximately 15% to 30% develop nodular glomerulosclerosis, and in most instances it is associated with renal failure.
What is this showing?
This is a PAS stain of nodular glomerulosclerosis (Kimmelstiel-Wilson disease) in a patient with long-standing diabetes mellitus. Note also the markedly thickened arteriole at the lower right which is typical for the hyaline arteriolosclerosis that is seen in diabetic kidneys as well.
What is this image showing?
Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the cortical tissue (right) . Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far right).
What is this showing?
Thickening of the renal arteriolar wall. This arteriole has an “onion skin” appearance to the media. The thickening has left a tiny lumen.
What are some pathologic manifestations of end stage kdiney disease (as seen in diabetes and other pathologies)?
- severe arteriosclerosis
- a fibrotic cortex commonly
- sclerotic glomeruli that lack normal appearance
- scattered chronic inflammatory infiltrates
- thyroidization of the tubules due to dilation and filling with pink casts
What are some non-proliferative retinal manifestations of diabetes?
microaneurysms, Hemorrhages (circled at the bottom of the left image), cotton-wools spots (circled at the top of the left image)
What is this image showing?
Diabetic retinopathy seen via funduscopy showing neovascularization with diabetic proliferative retinopathy.
Note the proliferation (arrow) of small vessels near the optic disc. They are prone to bleed, producing vitreal hemorrhages that obscure vision.
What is this image showing?
Funduscopy showing microangiopathy that occurs with diabetes mellitus associated with edema and retinal exudates that are “soft” microinfarcts or “hard” yellowish waxy exudates, which are deposits of plasma proteins and lipids.
Note the extensive hard exudates (arrow), typical of the “background retinopathy” of diabetes mellitus.
What is this?
Charcot joint (neuropathic arthropathy): progressive (slow or rapid), destructive variant with large amounts of dead bone and cartilage particles embedded in synovium; severe subluxation or dislocation of joint with extreme deformity; also fibroblastic proliferation, reactive new bone formation
Additional diabetic manifestation
Note that AN can be a paraneoplastic syndrome as well
What is the earliest histological change seen in diabetic neuropathy?
segmental demyelination
This image uses a Luxol Fast Blue stain- which stains myelin blue. This nerve has lost about 75% of its myelin.
What is this?
Normal nerve as seen with a Luxol Fast blue stain
