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