Endo Path: Pancreas Dm

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Glucose

Back 1

* major fuel of body
* derived from dietary starch
*during fasting glycogen metab to release glc from liver & musc
* glycogen stores last only a few hours
* glc produced in liver via GNG
* insulin - regulate glc, produced as proinsulin--> insulin & c peptide
* c peptide not in commercial insulin.

Front 2

Hyperglycemia

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* glc = osmotic agent, leads to loss of water & electrolytes
* Glc can attach to prot--> organ injury (alter activity/prevent turnover)

Front 3

Glc lab tests

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* serum: measured by glc oxidase, fasting state
* finger stick glc: measure glc plasma
* urine glc: measured by glc oxidase w/ colorimetric indicators

Front 4

Glycated Proteins

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* glc attaches to prot molec in circ as fxn of plasma glc levels. Attachment reversible intially but rearranges & lasts life of prot
* glycated prot measurements measure avg glc concentration over molec lifespan
* Ex: hemoglobin A1c

Front 5

Hemoglobin A1c

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* major form of glycosylated hemoglobin
* not affected by hemoglobin varient
* can be expensive, difficult to perform

Front 6

DM Type 1

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*PATH: Tcells react w/ beta cells Ag, autoimmune w/ genetic susceptibility & env factor, severe lack of insulin,
*destruction begins years before sx. CD4 Tcels + mphags. CD8 tcells: directly kill beta cell & secrete CK-->+mphags.
* Insulinitis: islets show necrosis & lymphocytic infiltration

Front 7

Insulinitis

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*surviving beta cells express class II MHC molecules
* GAD: glutamic acid decarboxylase & insuliin = autoAb
* Ck: IFN, TNF, IL-1 = beta cell apoptosis
* autoAb against islet cells & insulin
*autoAb reactive w/ beta cell Ag, GAD

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type 1 vs type 2 DM

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*type 1: <20yo, normal weight, dec blood insulin, antiislet cell Ab, ketoacidosis, MHC class II HLA genes, autoimmune destory beta cells, No insulin, insulitis, atrophy, fibrosis, b cell depletion

* type 2: >30yo, obese, inc blood insulin, insulin resistance, b cell dysfxn, focal atrophy, amyloid deposits

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DM morphology

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*macrovascular dz: large & med sized arteries--> inc atherosclerosis, inc MI, inc strokes & gangrene

*microvascular dz: retina, kidney, peripheral nerves

* panc: not dramatic change. Dec in # & size of islets, especially DM1. leukocytic infiltration of T cells.
Beta Cell degranulation w/ depletion of stored insulin. Amyloid replaces islets in DM2 around BV & btwn cells.
Non DM newborns born of DM moms have hyperplasia of islets in response to maternal hyperglycemia


* 3 met pathways: 1. AGE 2. pkc 3. polyol disturbances

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3 Metabolic Pathways of DM: Advanced glycation end products

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Advanced glycation end products (AGE): from rxn btwn intracell glc derived dicarbonyl precursors w/ amino group of intracell & extrall prot.
*Cause abnorm cross linking btwn peptides of ECM. Collagen 1--> dec elastin--> endoth injury.
Collagen 4--> inc fluid filtration.
Prot-->resist degradation-->dec removal & inc deposition.
Matrix components trap nongylcated/interstitial material (LDL)-->atherosclerosis.
Binds albumin-->thick BM --> microangiopathy.
*circ plasma prot modified by added AGE--> prot bind AGR-R on mphag/endoth/mesangial cell--> inc CK, growth factor, proinflam.
*Inc synth ECM, Inc endo permeability, inc procoag

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3 metabolic pathways of DM: Activation of Protein Kinase C

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2. + prot kinase c: intracell hyperglycemia--> synth diacylglycerol & + PKC--> VEGF --> neovasc in DM retinopathy.
* inc vasoconstrictor endothelin 1 & dec NO synthase
*prod profibrogenic molec (GF Beta) --> inc ECM deoposits & thick BM
*prod plasminogen activator inhib-1--> dec fibrinolysis & vasc occlusion
* prod pro inflam CK

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3 metabolic pathways of DM: disturbances in polyol

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3. intracellular hyperglycimia = disturbances in polyol

* inc cell response to oxidative injury
* inc glc in cell-->fructose which uses NADPH which is needied for antioxidant glutathione.

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DM macrovascular dz

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* accelerated atherosclerosis of aorta, large & med arteries
* MI most common cause of death in DM
* gangrene of lower extremities
* hyaline ateriolosclerosis: amorphous hyaline thickening of walls of arterioles-->narrowed lumen

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DM microangiopathy

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* diffuse thickening BM by concentric layers of hyaline composed of type 4 collagen
* leaky plasma membranes
* underlies nephropathy, retinopathy, neuropathy

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DM glomerulosclerosis

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* Adv end stage kidney dz in 40% of DM
*glomeruli affected: non nephrotic range proteinuria, nephrotic syndrome, chronic renal failure.
*arterioles: hyalinizing arteriolar sclerosis
*predisposed to papillary necrosis
* assoc w/ microangiopathy

*CAUSE: insulin defect & hyperglycemia-->collagen 4 & fibronectin deposits with dec heparan sulfate proteoglycan.
* nonenymatic glycation of prot-->adv glycolation end products.
*hemodynamic changes leading to glomerular hypertophy

Front 16

pyelonephritis

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more common in DM and more sever.

Necrotizing papillitis: more common in diabetes.

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retinopathy

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*thick BM of ciliary body & renal mesangium.

* PREPROLIFERATIVE: fxnal & structural abnorm of angiogenesis w/in retina. BM of retinal BV thick. microaneurysms. Macular edema. Hemorrhagic exudates. Retinal microcirculation = hyperpermeable w/ microocclusions. Non perfusion of retina--> up reg of VEGF & angiogenesis

*proliferative retinopathy: new vessels sprout from existing vessels. Form neovascular memb: angiogenic vessels w/ or w/o suppurative stroma. Massive hemorrhage may occur in neovascular memb. memb wrinkles retina--> disturbed vision

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DM neuropathy

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*depends on duration of dz.

*distal sensory neruopathy: axonal neuropathy-->some demyelination
*autonomic neuropathy
*focal or multifocal asymmetric neuropathy from vasc insufficiency to peripheral nerves

Front 19

DM Glomerulosclerosis (cont)

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MORPH: capillary BM & tubular BM thicken.
*Diffuse mesangial sclerosis: inc mesangial matrix
*nodular glomerulosclerosis: kimmelstiel-wilson dz
*oval nodules of matrix in periphery of glomerulus. Nodules: msangiolysis w/ formation of capillary microaneurysms. Not all glomerulus lobules involved but those have diffuse mesangial sclerosis. Nodules compress capillaries --> ischemic kidney --> tubular atrophy, insterstital fibrosis & contraction in size.

CLINIC: inc GFR, microalbuminemia, proteinuria--> nephrotic levels. Progressive loss of GFR. HTN.