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169 Cards in this Set

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DIABETES MELLITUS - MURPHY - WEDNESDAY JAN 31
PANCREAS ANATOMY AND PHYSIOLOGY
how are cells organizd in the exocrine pancreas?
into numerous small glands called acini, all of which communicate with a series of tiny ducts
what do these ducts eventually anastamose to form, and where does it lead?
they anastamose to the pancreatic duct, which leads into the duodenum
what are main diseases of the exocrine pancreas (2)?
1) pancreatisis; 2) pancreatic cancer
what is the endocrine pancreas composed of, histologically?
microscopic clusterlets of cells called islets of Langerhans
where are these in the pancreas?
studded throughout pancreas
what imporcant cell types from the islets must we know (3) and what hormone does each produce?
1) beta - insulin; 2) alpha - glucagon; 3) delta - somatostatin
what is the function of somatostatin?
suppresses release of both insulin and glucagon
INSULIN PHYSIOLOGY
what does insulin regulate (4)?
metabolism of: 1) fat; 2) protein; 3) nucleic acid; 4) carbohydrate
is it anabolic or catabolic?
anabolic
what are five specific functions of insulin?
1) transport of glucose and amino acids across cell membranes; 2) synthesis of glycogen (from glucose) within liver; 3) conversion of glucose into triglycerides; 4) nucleic acid synthesis; 5) protein synthesis
what is its main role, and the most important function?
regulation of normal glucose homeostasis - most importantly it will increase glucose uptake into most cells in the body
what results when insulin binds to an insulin receptor (most important biochemical response)?
variety of biochemical responses, including translocation of GLUTs from golgi to plasma membrane - glucose can then bind to GLUTs and ender cell
DIABETES MELLITUS
what is diabetes mellitus (what two things can it be characterized by)?
characterized by either: 1) a deficiency of insulin secretion by the islets of Langerhans; 2) a lack of response of target cells to insulin
what is the single most characteristic biochemical feature of DM?
persistent hyperglycemia
what is secondary DM?
due to diseases that physically destroy pancreatic islets (pancreatitis, extensive pancreatic cancer, certain drugs)
what are the three types of primary DM (much more common) and what is the incidence as a % of primary cases of each?
1) type 1 diabetes (10%); 2) type 2 diabetes (80-90%); 3) maturity-onset diabetes of the young (<5%)
what are differences between type 2 and maturity onset diabetes of the young (MODY)?
onset of MODY is at a much younger age and person is not obese
how many americans have primary DM, and how high does it rank as far as leading causes of death?
16 million Americnas (7th leading cause of death)
in what ages does it occur most?
overall, more common in older population - 50% over 55 years
TYPE 1 DIABETES MELLITUS
what is the age of onset?
childhood - typically less than 20 years
are patients usually obese?
no
what is the pathogenesis?
lack/absence of insulin in bloodstream, caused by destruction of pancreatic islets
what are the three mechanisms responsible for this?
1) genetic susceptibility; 2) autoimmunity; 3) environmental factors
in what race does T1DM most commonly occur?
Caucasians of northern European descent
what is the concordance amongst identical twins?
33-70%
what other genes is T1DM associated with?
certain HLA-D genes
what HLA genes are susceptible, and what % of Caucasians with T1DM have these genes (2)?
1) HLA-DR3; 2) HLA-DR4 - 95% of caucasians have one or both of these
what do these gnees probably promote?
autoimmune destruction of islets
what is chronic autoimmune attack directed against, and what does this lead to?
pancreatic beta cells - this leads to depletion of beta cells and ultimately to atrophy and fibrosis of islets
what are three pieces of evidence for this autoimmunity?
1) insulitis; 2) anti-islet cell antibodies; 3) 10% of type 1 patients also have other autoimmune disease
what is insulitis and when does it occur?
early type 1 disease is characterized by lymphocyte-rich inflammatory infiltrate within islets
what % of type 1 patients have anti-islet cell autoantibodies, and what are they directed against?
70-80% of type 1 patients have anti-islet cell autoantibodies, which are directed against intracellular islet cell antigens, including insulin
what other autoimmune diseases were type 1 patients said to have (3)?
1) Graves disease; 2) thyroiditis; 3) Addison's disease
what type of envioronmental factors have been implicated, and what were they thought to induce?
viral infection of beta cells is thought to induce autoimmune reaction
what are three viruses thought to be implicated?
1) cocksackie B; 2) CMV; 3) EBV
TYPE 2 DIABETES MELLITUS
what is the age of onset?
over 30
what is true about 80% of type 2 diabetics?
obese
what is the link between obesity and T2DM?
insulin resistance, which can be present in obesity, and particularly central obseity, even in the absence of hyperglycemia
what is the importance of genetic factors in type 2 disease, compared to type 1?
even more important than in type 1 disease
what is concordance rate amongst identical twins?
up to 90%
what % of those with a first degree relative who has T2DM will develop this disease (range)?
20 to 40% - much higher than type 1
what type of genes is this linked to?
non-HLA genes - multipele genetic defects
what is insulin secretion by beta cells like?
deranged - islets are able to produce insulin, but not enough in relation to the degree of hyperglycemia
so, what is insulin deficiency like, and what are insulin levels like?
there is a relative insulin deficiency, although in reality serum insulin levels may be normal or even increased
can an absolute insulin deficiency develop?
yes, in the late stages, although never to the degree seen in T1DM
what may this type of deficiency be due to?
1) beta cell damage caused by genetic predisposition to injury; 2) metabolic toxicity resulting from prolonged hyperglycemia
what are the two molecular mechanisms of insulin resistance?
1) decrease in number of insulin receptors; 2) impairment of post-receptor signaling by insulin, e.g. GLUTs do not translocate to cell membrane
what accumulates in the islets in T2DM, what is it, and where does it come from?
amylin, a 37 amino acid peptide normally produced by beta cells, which has the staining characteristics of amyloid
what may happen in late stage T2DM related to amylin?
in late stage disease, islets may be replaced by amyloid
what is the role of amylin in pathogenesis of T2DM?
unknown
LATE (CHRONIC) COMPLICATIONS OF DIABETES
what are late complications of DM usually a consequence of, and what is the primary culprit?
derangements in metabolism (carbohydrate, fat, and protein) with the primary culprit being very prolonged hyperglycemia
what do long-lasting elevations in serum glucose lead to (3 nonspecific problems that lead to other damage)?
1) formation of advanced glycation end products; 2) intracellular hyperglycemia; 3) activation of protein kinase C (PKC)
what is glycation?
the process by which excess glucose non-enzymatically attaches to amino groups of vacrious proteins within serum and tissues
how are advanced glycation end products (AGEs) formed?
glycated proteins can cross-link with one another
in what tissues is there intracellular hypoglycemia?
only in tissues that do NOT require insulin for glucose uptake into cells
what are two examples given of such tissues?
1) lens of eye; 2) Schwann cells of peripheral nerves
what happens to these cells after lots of glucose accumulates?
the glucose converts to sorbitol via the polyol pathway, and the cell accumulates sorbitol
what are two consequences of sorbitol accumulation?
1) osmotic cell injury (water influx); 2) impairment of ion pumps
why does activation of PKC occur (2)?
1) DAG synthesis; 2) increase in calcium ions within a cell
why is DAG (diacylglycerol) synthesis increased?
by glycolytic intermediates generated by excess intracellular glucose
why is there an increase in calcium ions within a cell?
due to ischemia brought about by diabetic vascular disease
what is the msot common, and second most common, cause of death in diabetics?
1) MI; 2) renal failure
SPECIFIC COMPLICATIONS OF DIABETES - VASCULAR
what are the main vascular problems caused by DM (3)?
1) accelerated atherosclerosis; 2) hyaline arteriosclerosis; 3) microangiopathy
where does the accelerated atherosclerosis occur, and when?
occurs in large and medium size arteries, earlier than the general population
what do diabetics have an increased incidence of, that is a major risk factor for atherosclerosis?
hypertension
what other causes of increased atherosclerosis are there in diabetics (3)?
1) glycation of serum lipoproteins; 2) glycated collagen within blood vessel walls form AGE complexes which trap LDL; 3) AGE-modified plasma proteins bind to receptors on endothelial cells, causing generation of pro-atherogenic cytokines and growth factors
in diabetics, what are blood lipid levels like (HDL and LDL)?
HDL is low, LDL is high - both favor atherogenesis
what are AGE products?
advanced glycation end products (AGEs) are formed when excess glucose non-enzymatically attaches to amino groups of proteins within serum/tissues
what is the most common cause of death in diabetics?
MI
besides MI, what does increased atherosclerosis lead to increased incidence of (2)?
1) stroke; 2) gangrene of lower extremities
how common is gangrene of lower extremities, and what does it lead to?
extremely common - leads to amputation
what is hyaline arteriosclerosis typically associated with, and how is it different in diabetes?
typically associated with hypertension, but more prevalent and severe in diabetics vs. non-diabetics)
what changes occur in arterioles (2)?
1) arteriolar walls are thickened; 2) lumens are narrowed
what does this lead to directly, and what is an indirect consequence (one example)?
leads to ischemia, which leads to problems such as poor wound healing
what is microangiopathy?
diffuse thickening of basement membranes that surround capillaries
in what locations is this a big problem (2)?
1) retina; 2) kidneys
what is the possible mechanism?
thickening due to plasma proteins binding to glycated proteins within basement membrane
how leaky are diabetic capillaries to plasma proteins than normal capillaries?
they are more leaky to plasma proteins than normal, possibly due to AGE binding to endothelial cells, which increases endothelial permeability
NEPHROPATHY
what three lesions is diabetic nephropathy represented by?
1) nephrosclerosis; 2) glomerulosclerosis; 3) pyelonephritis
what is the nephrosclerosis lesion, specifically, and where does it occur?
hyaline arteriosclerosis of renal arterioles, both the afferent and efferent arterioles of the glomeruli
what do these thickened, narrowed vessels cause?
focal ischemia of renal parenchyma
under what conditions is the process more extensive and severe?
if patient has co-existent hypertension
what types of glomerulosclerosis occur (2)?
1) diffuse; 2) nodular
in diffuse glomerulosclerosis, what are glomeruli characterized by (3)?
1) diffuse increase in mesangial matrix; 2) mild proliferation of mesangial cells; 3) thickening of basement membranes of glomerular capillaries (i.e. microangiopathy)
what is nodular glomerulosclerosis known as, and what is it characterized by?
Kimmelstiel-Wilson disease - discrete, spherical, PAS-positive massses are located at the periphery of the glomerulus
how large may nodules grow to?
nodules may become so large as to compress/obliterate glomerular capillaries
what is the result if these nodules grow large?
1) renal ischemia; 2) interstitial fibrosis
what other conditions besides diabetes have K-W disease?
K-W disease is virtually pathognomonic for diabetes
what are the clinical consequences of diabetic glomerulosclerosis (3)?
1) increasing proteinuria, progressing to nephrotic syndrome; 2) progressive loss of GFR, resulting in CRF; 3) exacerbation of hypertension
is acute or chronic form of pyelonephritis common in diabetics?
both acute and chronic forms are common
what is a form of acute pyelonephritis that is more common in diabetics, and what happens in it?
papillary necrosis (necrotizing papillitis) - tips of medullary pyramids undergo necrosis
EYE COMPLICATIONS
does diabetes often cause blindness in the US?
yes, it is common
what types of retinopathy are caused by diabetes (2)?
1) background retinopathy; 2) proliferative retinopathy
what does background retinopathy reflect?
retinal capillary alterations, e.g. microangiopathy
what do complications of retinopathy include (4)?
1) retinal edema; 2) exudates; 3) microaneurysms; 4) hemorrhages
what is proliferative retinopathy characterized by?
neovascularization
what is the neovascularization caused by?
retinal ischemia
what does this lead to?
activation of PKC
what does this induce?
production of VEGF
what are complications of proliferative retinopathy (3)?
1) hemorrhage; 2) retinal detachment; 3) glaucoma (occlusion of aqueous humor outflow)
what other problem can be caused in the eye?
cataracts
what type of cataracts can be caused (2)?
1) senile cataracts (higher frequency in diabetics); 2) snowflake cataracts
what are snowflake cataracts caused by?
the sorbitol crystallizes and results in opacity
PERIPHERAL NEUROPATHY
what part of the body is particularly affected?
lower extremities
what is a frequent consequence of sensory neuropathy?
diabetic foot ulcers - person is unaware of original injury, and it progresses unbeknownst
why si healing poor in diabetic foot ulcers?
due to chronic ischemia of foot brought (arteriosclerosis/atherosclerosis)
what problems can be caused by autonomic neuropathy (four examples)?
1) hypotension; 2) gastroparesis; 3) impotence; 4) bladder paralysis
what is a possible mechanism for neuropathy?
accumulation of sorbitol within Schwann cells causes injury and loss of myelin production
what does this lead to in peripheral nerves?
segmental demyelination
INFECTIONS
what was mentioned to be a severe infection in diabetes, where death is not uncommon?
mucormycosis of nasal sinuses - severe infection - can quickly lead to necrosis of nasal sinuses
what other organisms, and infection sites, were mentioned to occur more in diabetics (3 examples - incomplete)?
1) skin (Staph); 2) lungs (bacterial pneumonias); 3) GU tract (pyelonephritis)
what are possible mechanisms for increased infection (2 examples)?
1) impaired leukocyte function (AGE binding to leukocytes); 2) atherosclerosis/arteriosclerosis causes ischemia (decreased delivery of inflammatory mediators)
EARLY (ACUTE) COMPLICATIONS
what are two early (acute) complications that are seen in both type 1 and type 1 diabetes mellitus?
1) polyuria; 2) polydipsia (excess drinking)
what is polyuria due to?
hyperglycemia-induced osmotic diuresis
what acute complications (2) are prominent in type 1 disease?
1) polyphagia; 2) diabetic ketoacidosis (almost exclusively type 1)
why is there polyphagia?
lack of insulin leads to catabolism (breakdown) of proteins and fats - causes negative energy balance, leading to increased appetite
hwo does diabetic ketoacidosis arise?
insulin deficiency causes catabolism of lipids into free fatty acids, and liver converts these FFAs into ketone bodies, which are organic acids
what acute complication is seen mainly in type two disease?
hyperosmolar coma
what does this refer to, and why does it occur?
extreme hypoerosmolarity of serum due to superhigh glucose levels
what can follow from hyperosmolar coma, and what can it lead to?
dehydration (due to osmotic diuresis) can lead to CNS signs
how serious is this?
medical emergency - death is not uncommon
LABORATORY TESTING OF DIABETES MELLITUS
if the patient is symptomatic for diabetes (e.g. polyuria, polydipsia, etc), what is the diagnostic test and result?
>200mg/dL random plasma glucose is diagnostic
if this result is obtained, what should be done?
confirm with fasting plasma glucose
if patient is asymptomatic, what is the diagnostic test, and result ?
>126 mg/dL fasting plasma glucose on two separate days
what two tests are useful in monitoring therapy?
1) self-measurement of capillary blood sugar by finger stick - instrument provides glucose value; 2) glycated hemoglobin, specifically hemoglobin A1c
what is finger sticking useful for?
determining insulin dose, and thus maintaining lower mean glucose levels
what will testing HbA1c level reflect, and over what time?
mean blood glucose concentration over preceding 6-8 weeks (long-term control)
in non-diabetics, what is HbA1c level?
does not exceed 6% of all hemoglobin
in a diabetic, what level is considered under control, and what level demands that action be taken?
ADA recommends that action be taken when HbA1c is over 8%, and that diabetes is under control when result is 7% or less