Term
| what is not found in commercial insulin preparations? |
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Definition
| C-peptide, which is cleaved from endogenous proinsulin. therefore the presence of C-peptide can distinguish between exogenous and endogenous insulin. |
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Term
| what is some of the pathogenesis associated with hyperglycemia? |
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Definition
| glucose can act as an osmotic agent, leading to loss of water and electrolytes. glucose can attach to proteins - leading to organ injury. attachment of glucose to a protein may alter its activity or prevent turnover. |
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Term
| how are glucose levels tested? |
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Definition
| serum glucose: measures glucose oxidase (best done in fasting state). finger stick glucose: measures glucose in plasma. urine glucose: measured by glucose oxidase w/colorimetric indicators (dipstick). |
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Term
| what characterizes glycated proteins? what is HbA1c? |
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Definition
| glucose attaches to protein molecules in circulation as a function of plasma glucose levels. initially this attachment is reversible - but eventually undergoes a rearrangement that lasts the life of the protein molecule. *glycated protein measurements measure the avg glucose concentration over the lifespan of the molecule. HbA1c is the major form of glycosylated Hb and is not affected by Hb variants - testing for this is difficult, but it appears to becoming standard. |
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Term
| what characterizes type I DM? |
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Definition
| this involves immune-mediated destruction of beta cells (T cells attack beta cell antigen), resulting in a severe lack of insulin. pts w/this who are untreated may develop ketoacidosis and coma. |
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Term
| what characterizes the beta cell destruction seen in type I DM? |
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Definition
| CD4 T cells activate macrophages and CD 8 T cells directly kill beta cells as well as secrete cytokines which activate more macrophages. once clinically evident, only 10% of of beta cells usually remain as autoimmune destruction begins years before development of clinical symptoms. ultimately, this leads to *insulitis which consists of necrosis and lymphocytic infiltration of the islets. |
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Term
| what characterizes insulitis as seen in type I DM pts? |
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Definition
| autoantibodies are produced against insulin and are reactive w/beta cell antigen (including GAD = glutamic acid decarboxylase). cytokines such as IFN, TNF, and IL-1 damage the beta cells and induce apoptosis. surviving beta cells may express class II MHC molecules. amyloid deposition is also common in the islets secondary to these changes. |
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Term
| what are the three metabolic pathways leading to both microvascular and macrovascular disease in DM pts? |
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Definition
| formation of AGEs, activation of protein kinase C, and disturbance in polyol pathways |
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Term
| what is involved in macrovascular disease due to DM? |
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Definition
| large and medium sized arteries are affected - leading to increased atherosclerosis, increased MIs, increased strokes, and increased gangrene. |
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Term
| what is involved in microvascular disease due to DM? |
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Definition
| the retina, kidney and peripheral nerves are most affected by DM |
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Term
| what characterizes formation of AGEs in DM pts? |
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Definition
| advanced glycation end products are formed from the reaction between intracellular glucose-derived dicarbonyl precursors and the amino groups of intracellular and extracellular proteins. thus, the peptides of extracellular matrix components (ECM) are crosslinked w/AGEs leading to abnormal matrix-matrix and matrix-cell interactions. |
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Term
| what are some specific examples of pathology due to AGEs? |
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Definition
| crosslinked collagen I molecules have decreased elastin = *endothelial injury. crosslinked collagen IV in the basement membrane = *increased fluid filtration. proteins crosslinked w/AGEs are *resistant to proteolytic degradation, decreasing protein removal and increasing deposition. crosslinked ECM components trap nonglycated/interstitial material such as *LDL = atherosclerosis. albumin may bind to the glycated basement membrane = *thickening of the basement membrane as seen in microangiopathy. circulating plasma proteins are modified by addition of AGE residues, which can then *bind to the AGE receptor of macrophages/endothelial cells/mesangial cells = generation of cytokines, growth factors, and pro inflammatory molecules. ultimately these events lead to increased ECM synthesis, increased endothelial permeability, and increased procoagulant activity on endothelial cells/macrophages. |
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Term
| what characterizes pathology due to activation of protein kinase C in DM pts? |
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Definition
| intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC, which then leads to *VEGF production (= neovascularization as seen in diabetic retinopathy) and *increased activity of vasoconstrictor endothelin 1 and *decreased activity of the vasodilator endothelin NO synthase. PKC activation also leads to production of profibrogenic molecules such as *TGF beta (increased ECM deposition/thickening of basement membrane) and *plasminogen activator inhibitor-1 (PAI-1 = decreased fibrinolysis/vascular occlusion). PKC also increases *proinflammatory cytokine production. |
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Term
| how does intracellular hyperglycemia cause disturbances in polyol pathways? how does this cause pathology in DM pts? |
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Definition
| intracellular hyperglycemia leads to increased glucose in the cell, which is converted to fructose. this conversion requires NADPH as a co-factor, however NADPH is also a cofactor in the production of glutathione, an antioxidant. therefore, increased glucose conversion leads to an increased oxidative injury to the cell. |
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Term
| what is the morphology of a DM-affected pancreas? |
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Definition
| grossly: nothing dramatic. histologically: a decrease in the number and size of islets (esp in DM type 1). leukocytic infiltration of T cells. beta cell degranulation w/depletion of stored insulin. amyloid replacements of islets around blood vessels/between cells (in type 2 DM). also, non-DM newborns of DM mothers have islet hyperplasia in response to maternal hyperglycemia. |
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Term
| what characterizes macrovascular disease due to DM? |
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Definition
| atherosclerosis is accelerated in the aorta as well as large/medium sized arteries (MI from atherosclerosis is the *most common DM pt cause of death). gangrene may occur in the lower extremities (lack of bloodflow). *hyaline arteriosclerosis also occurs in the vasculature, which consists of amorphous hyaline thickening of the arteriolar walls = narrowing of lumen. |
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Term
| what is diabetic microangiopathy? |
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Definition
| diffuse thickening of the basement membrane by concentric layers of hyaline material - composed mostly of type IV collagen. this causes plasma membranes to leak and underlies nephropathy, retinopathy, and neuropathy. |
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Term
| what are some common complications of DM? |
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Definition
| cataracts, glaucoma, CV infarcts, narrowing of vasculature (unable to vasodilate/HTN), glomerulosclerosis, arteriosclerosis throughout the aorta, nephrosclerosis, stiff "DM bladder" (pyelonephritis), islet cell loss (insulitis: DM1/amyloid: DM2), and peripheral vascular atherosclerosis. |
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Term
| what organ is hit consistently hard in DM pts? how? |
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Definition
| the kidney - advanced end stage kidney disease occurs in up to 40% of all diabetics. the glomeruli are commonly affected leading to non nephrotic range proteinuria, nephrotic syndrome, and chronic renal failure. the arterioles are also affected by hyalinizing arteriolar sclerosis. kidneys affected by DM are also predisposed to papillary necrosis. these changes are associated w/microangiopathy due to collagen IV/fibronectin deposition and decreased heparin sulfate proteoglycans. non-enzymatic glycation of proteins also leads to AGEs. the *resultant hemodynamic changes then lead to compensatory glomerular hypertrophy. |
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Term
| what is the microscopic morphology of a kidney affected by DM? |
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Definition
| the capillary/tubular basement membranes become thickened, diffuse mesangial sclerosis increases (due to increased matrix deposition) and *nodular glomerulosclerosis (kimmelstiel-wilson disease)* occurs, consisting of oval nodules of matrix in parts of the glomerular periphery. these nodules may exhibit mesangiolysis w/the formation of capillary microaneurysms or compress the capillaries = ischemia, tubular atrophy, interstitial fibrosis, and contraction in size. not all lobules of the glomerulus are necessarily affected by nodular glomerulosclerosis - however most are affected by mesangial sclerosis. ~15-30% of long term DM pts develop nodular glomerulosclerosis. |
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Term
| what is the clinical course seen in DM pts? what will help? |
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Definition
| initially increased GFR, microalbuminemia, proteinuria (may progress to nephrotic levels), progressive loss of GFR, and HTN contributing to renal disease. precise control of blood glucose levels will delay or prevent progression to glomerulopathy. |
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Term
| what characterizes the incidence of pyelonephritis in DM pts? |
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Definition
| pyelonephritis occurs more commonly in diabetics, who will also have more severe involvement such as necrotizing papillitis. |
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Term
| what characterizes the incidence of retinopathy in DM pts? |
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Definition
| the ciliary body basement membrane becomes thickened (similar to effect on renal mesangium) along with preproliferative retinopathy and proliferative retinopathy. |
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Term
| what does preproliferative retinopathy consist of? |
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Definition
| *functional and structural abnormalities of angiogenesis which occur in the retina - such as microaneurysms of new blood vessels (which occur even though the basement membrane is thickening due to poor formation). *macular edema occurs due to leaky microcirculation. *hemorrhagic exudates accumulate. *retinal microcirculation becomes hyperpermeable and may have microocclusion: *non-perfusion of the retina leads to VEGF upregulation and angiogenesis. |
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Term
| what does proliferative retinopathy consist of? |
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Definition
| new vessels sprout from existing vessels in the form of neovascular membranes which *may or may not have supportive stroma. lack of stromal support can then lead to *massive hemorrhage or *wrinkling of the membrane (distorts vision). |
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Term
| what characterizes diabetic neuropathy? |
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Definition
| this is most commonly seen in the periphery, but may be seen in the stomach or bladder and extent depends on duration of the disease. *distal axonal/sensory neuropathy results in some demyelination, *autonomic neuropathy may occur, and *focal/multifocal asymmetric neuropathy often results from vascular insufficiency to peripheral nerves. |
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