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, andNONTRUMATIC 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 ahemoglobin 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 hasanemia,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 DR4also linked to polymorphisms in CTLA4 and PTPN22 that inhibit T-cell response as well as insulin gene VNTRs
How doesType 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 doesType 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 collagenand induce inflammatory cells on endothelium and smooth muscleThis 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
