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Path 1130-1146 Endocrine Pancreas Islets of Langerhans – 4 major and 2 minor cell types o Main types are β, α, δ, and PP (pancreatic polypeptide) cells; differentiated by ultrastructural characteristics of their granules and hormone content Insulin-containing intracellular granules of β cells contain rectangular crystalline matrix surrounded by halo Glucagon secreted by α cells; induces hyperglycemia by glycogenolytic activity in liver; granules round with closely applied membranes and dense center Somatostatin secreted by δ cells; suppresses both insulin and glucagon release; large, pale granules with closely applied membranes PP cells contain pancreatic polypeptide that exerts GI effects (stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility) Small, dark granules scattered in exocrine pancreas as well as endocrine pancreas o Rare cell types are D1 cells and enterochromaffin cells D1 cells elaborate VIP that induces glycogenolysis and hyperglycemia; stimulates GI fluid secretion and causes secretory diarrhea Enterochromaffin cells synthesize serotonin and is source of pancreatic tumors that cause carcinoid syndrome Diabetes Mellitus Group of metabolic disorders sharing common underlying feature of hyperglycemia o Can result from defects in insulin secretion, insulin action, or both Chronic hyperglycemia and metabolic dysregulation may be associated with secondary damage to kidneys, eyes, nerves, and blood vessels Diabetes is leading cause of end-stage renal disease, adult-onset blindness, and non-traumatic lower extremity amputations Pre-diabetes – elevated blood sugar that doesn’t reach criterion accepted for outright diagnosis of diabetes; patients at risk for developing frank diabetes Prevalence increasing sharply in developing world as people adopt more sedentary life styles (India and China are largest contributors) Diagnosis of Diabetes Blood glucose values should be 70-120 mg/dL Diagnosis of diabetes is made by any of the following o Random glucose concentration greater than 200 with classical signs and symptoms o Fasting glucose concentration greater than 126 on more than one occasion o Abnormal oral glucose tolerance test (OGTT) in which glucose concentration greater than 200 2 hours after standard carb load Individuals with fasting glucose concentrations less than 100 or less than 140 following OGTT are euglycemic Those with fasting glucose concentrations of 100-126, or OGTT values 140-200 considered to have impaired glucose tolerance (pre-diabetes) o Pre-diabetic individuals at risk for cardiovascular disease as result of abnormal carb metabolism as well as coexistence of other risk factors such as low HDL, hypertriglyceridemia, and increased PAI-1 Classification of Diabetes Vast majority of cases fall into one of 2 broad categories: type 1 and type 2 o Type 1 diabetes – autoimmune disease of pancreatic β-cell destruction and absolute deficiency of insulin; accounts for 5-10% of all cases; most common subtype diagnosed in patients under 20 o Type 2 – caused by combination of peripheral resistance to insulin action and inadequate secretory response by pancreatic β cells (relative insulin deficiency; about 90-95% of diabetic patients have type 2 and vast majority are overweight Variety of monogenic and secondary causes responsible for remaining cases Long-term complications affecting kidneys, eyes, nerves, and blood vessels are same despite the classification Glucose Homeostasis Glucose normally controlled by glucose production in liver, glucose uptake and utilization by peripheral tissues (chiefly skeletal muscle), and actions of insulin and counter-regulatory hormones (including glucagon) on glucose uptake and metabolism Insulin and glucagon have opposing regulatory effects on glucose homeostasis o During fasting states, low insulin and high glucagon facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, preventing hypoglycemia Fasting plasma glucose levels determined primarily by hepatic glucose output o Following meal, insulin levels rise and glucagon levels fall in response to large glucose load; insulin promotes glucose uptake and utilization in tissues Skeletal muscle is major insulin-responsive site for postprandial glucose utilization and is critical for preventing hyperglycemia and maintaining glucose homeostasis Preproinsulin synthesized in rER from insulin mRNA and delivered to Golgi apparatus; series of proteolytic cleavage steps generate mature insulin and cleavage peptide (C-peptide) o Both insulin and C-peptide stored in secretory granules and secreted in equimolar quantities after physiologic stimulation o C-peptide levels serve as surrogate for β cell function, decreasing with loss of β-cell mass in type 1 diabetes or increasing with insulin resistance-associated hyperinsulinemia Most important stimulus for insulin synthesis and release is glucose; rise in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by insulin-independent GLUT-2 o β cells express ATP-sensitive K+ channel on membrane, that has 2 subunits inward rectifying K+ channel (Kir6.2) and sulfonylurea receptor (SUR1) SUR1 is binding site for oral hypoglycemic agents (sulfonylureas) used in treatment of diabetes o Metabolism of glucose by glycolysis generates ATP, resulting in increase in β-cell cytoplasmic ATP/ADP ratios, which inhibits activity of ATP-sensitive K+ channel, leading to membrane depolarization and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels Resultant increase in intracellular Ca2+ stimulates secretion of insulin from stored hormone in βcell granules Above is phase of immediate release of insulin o If secretory stimulus persists, delayed, protracted response follows that involves active synthesis of insulin Intestinal hormones, leucine, and arginine can stimulate insulin release, but not synthesis Insulin is most potent anabolic hormone known; principal metabolic function is to increase rate of glucose transport into skeletal muscle cells (majorly) and adipose tissue (minorly) in body, providing increased source of energy; in muscle cells, glucose is either stored as glycogen or oxidized to generate ATP; in adipose tissue, glucose primarily stored as lipid o Insulin inhibits lipid degradation in adipocytes o Insulin promotes amino acid uptake and protein synthesis, while inhibiting protein degradation o Insulin initiates DNA synthesis in certain cells and stimulates their growth and differentiation Insulin receptor is tetrameric protein with 2 α-subunits and 2 β-subunits o β-subunit cytosolic domain possesses tyrosine kinase activity o Insulin binding to α-subunit extracellular domain activates β-subunit tyrosine kinase, resulting in autophosphorylation of receptor and phosphorylation (activation) of several intracellular substrate proteins, such as IRS proteins o Substrate proteins activate multiple downstream signaling cascades, including PI-3K and MAP kinase pathways, which mediate metabolic and mitogenic activities of insulin on cell o Insulin signaling facilitates trafficking and docking of vesicles containing GLUT-4 to PM, which promotes glucose uptake; mediated by AKT (principal effector of PI-3K pathway) Mediated independently by cytoplasmic protein CBL, which is direct phosphorylation target of insulin receptor o Insulin signaling attenuated by inhibitors that act along components of pathway PTPN1B dephosphorylates insulin receptor and inhibits insulin signaling Phosphatase PTEN can attenuate insulin signaling by blocking AKT activation by PI-3K pathway Pathogenesis of Type 1 Diabetes Mellitus Autoimmune disease in which islet destruction caused primarily by immune effector cells reacting against endogenous β-cell antigens Most commonly develops in childhood, becomes manifest at puberty, and progresses with age Insulin dependence not consistent distinguishing feature, but most patients with type 1 DM depend on insulin for survival Rare form of idiopathic type 1 diabetes doesn’t have definitive evidence for autoimmunity There is a genetic basis for type 1 diabetes (as well as type 2 diabetes) Most important locus is HLA locus; contributes as much as 50% of genetic susceptibility to type 1 diabetes; 9095% of Caucasians with type 1 DM have either HLA-DR3 or HLA-DR4 haplotype (only 40% of normal people have these); 40-50% of type 1 diabetics are combined DR3/DR4 heterozygotes (5% of normal people) o Those with either DR3 or DR4 haplotype concurrently with DQ8 demonstrate one of highest inherited risks for type 1 DM o Polymorphisms in HLA molecules located in or adjacent to peptide-binding pockets; code for molecules that have particular features of antigen display Insulin gene with variable number of VNTRs in promoter region associated with disease susceptibility o Polymorphisms influence level of expression of insulin in thymus, altering negative selection of insulinreactive T cells CTLA4 and PTPN22 linked to susceptibility to type 1 DM (as well as autoimmune thyroiditis) o Both inhibit T-cell responses, so polymorphisms that interfere with functional activity set stage for excessive T-cell activation CD25 encodes α-chain of IL-2 receptor; polymorphism reduces activity of this receptor (critical for maintenance of functional regulatory T cells) Environmental factors, especially viral infections may trigger islet cell destruction in type 1 DM o Epidemiologic associations with infections of mumps, rubella, coxsackie B, and CMV o Some viral infections may be protective o No causal association between childhood vaccinations and risk of developing type 1 diabetes Clinical onset often abrupt, but autoimmune process usually starts many years before disease becomes evident with progressive loss of insulin reserves over time o Classic manifestations of hyperglycemia and ketosis occur after more than 90% of β cell destroyed Fundamental immune abnormality in type 1 diabetes is failure of self-tolerance in T-cells o Initial activation of autoreactive cells occurs in peripancreatic lymph nodes in reaction to antigens released from damaged islets o Activated T cells go to pancreas, where they cause β cell injury o TH1 cells injure β cells by secreted cytokines, including IFN-γ and TNF o CD8+ CTLs directly kill β cells Islet autoantigens include insulin itself, β-cell enzyme GAD, and ICA512 (autoantigen on islet surface) Autoantibodies against islet antigens found in vast majority of patients with type 1 DM as well as asymptomatic family members at risk for progression to overt disease Pathogenesis of Type 2 Diabetes Mellitus Heavy genetic factors as well as environmental factors (greater concordance between monozygotic twins than type 1) o Polymorphisms in genes associated with β-cell function and insulin secretion confer some of strongest genetic risk for developing type 2 diabetes o TCF7L2 encodes transcription factor in WNT signaling pathway o Not linked to genes involved in immune tolerance and regulation; no evidence of autoimmune basis Type 2 diabetes characterized by decreased response of peripheral tissues to insulin (insulin resistance) and βcell dysfunction manifested as inadequate insulin secretion in face of insulin resistance and hyperglycemia o Insulin resistance predates development of hyperglycemia and usually accompanied by compensatory βcell hyperfunction and hyperinsulinemia in early stages of disease Insulin resistance leads to decreased uptake of glucose in muscle, reduced glycolysis and fatty acid oxidation in liver, and inability to suppress hepatic gluconeogenesis o Loss of insulin sensitivity in hepatocytes is largest contributor to pathogenesis of insulin resistance Few factors play as important a role in development of insulin resistance as obesity o Visceral obesity observed in greater than 80% of patients o Insulin resistance found in simple obesity unaccompanied by hyperglycemia o Distribution of body fat has effect on insulin sensitivity; central obesity (abdominal fat) more likely to be linked with insulin resistance than peripheral (gluteal/subcutaneous) fat depots o Nonesterified fatty acids (NEFAs) – inverse correlation between fasting plasma NEFAs and insulin sensitivity; level of intracellular triglycerides often markedly increased in muscle and liver tissues of obese individuals because excess circulating NEFAs deposited in these organs Central adipose tissue more lipolytic than peripheral sites Excess intracellular NEFAs overwhelm fatty acid oxidation pathways, leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG) and ceramide Toxic intermediates activate serine/threonine kinases, which cause aberrant serine phosphorylation of insulin receptor and IRS proteins Phosphorylation at serine residues attenuates insulin signaling Insulin normally inhibits hepatic gluconeogenesis by blocking activity of phoephoenolpyruvate carboxykinase (first enzymatic step in gluconeogenesis); attenuated insulin signaling allows this enzyme to ramp up gluconeogenesis Excess NEFAs compete with glucose for substrate oxidation, leading to feedback inhibition of glycolytic enzymes, and thereby further exacerbating existing glucose imbalance o Adipokines – adipose tissue is functional endocrine organ that releases hormones in response to changes in metabolic status Variety of proteins secreted into systemic circulation collectively termed adipokines Pro-hyperglycemic adipokines (e.g., resistin and RBP4) and anti-hyperglycemic adipokines (e.g., leptin, adiponenctin) Leptin and adiponectin improve insulin sensitivity by directly enhancing activity of AMPK (enzyme that promotes fatty acid oxidation) in liver and skeletal muscle Adiponectin levels reduced in obesity, contributing to insulin resistance AMPK is also target for metformin (commonly used oral antidiabetic medication) o Inflammation – adipose tissue secretes variety of pro-inflammatory cytokines like TNF, IL-6, and macrophage chemoattractant protein-1 (attracting macrophages to fat deposits) Reducing levels of pro-inflammatory cytokines enhances insulin sensitivity Cytokines induce insulin resistance by increasing cellular stress, which activates multiple signaling cascades that antagonize insulin action on peripheral tissues o PPARγ – nuclear receptor and transcription factor expressed in adipose tissue; plays seminal role in adipocyte differentiation Thiazolidinediones (antidiabetic medication) acts as agonist ligands for PPARγ and improves insulin sensitivity Activation of PPARγ promotes secretion of anti-hyperglycemic adipokines like adiponectin and shifts deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle Rare mutations of PPARγ that cause profound loss of protein function can result in monogenic diabetes β cells exhaust capacity to adapt to long-term demands of peripheral insulin resistance; insulin secretion initially higher; can often maintain normal plasma glucose for years o Eventually, β cell compensation becomes inadequate, and there is progression to hyperglycemia o Intrinsic predisposition to β cell failure must also exist o Excess NEFAs and attenuated insulin signaling (lipotoxicity) predispose to both insulin resistance and β cell failure o Agents like metformin that enhance fatty acid oxidation through AMPK activation also improve β cellfunction; shared pathogenetic mechanisms between insulin resistance and β cell failure o Amyloid replacemtn of islets characteristic finding in individuals with long-standing type 2 diabetes and is present in more than 90% of diabetic islets examined Monogenic Forms of Diabetes Classified separately from type 1 and type 2 DM; result from either primary defect in β cell function or defect in insulin-insulin receptor signaling 1-2% of diabetics harbor primary defect in β cell function that occurs without β cell loss, affecting either β cell mass and/or insulin production o Caused by heterogeneous group of genetic defects o Characterized by autosomal-dominant pattern with high penetrance, early onset (usually before age 25 and occasionally in neonatal period), absence of obesity, and absence of β cell autoantibodies o Largest subgroup of patients in this category is maturity-onset diabetes of the young (MODY) because of its resemblance to type 2 diabetes and occurrence in young people Results from hemizygous loss-of-function mutations in one of 6 genes Glucokinase (GCK) (implicated in MODY2) catalyzes transfer of phosphate from ATP to glucose (rate-limiting step in glucose metabolism) β cell GCK controls entry of glucose into glycolytic cycle, which is coupled to insulin secretion Mutations of GCK gene increase glucose threshold that triggers insulin release, causing mild increases in fasting blood glucose (familial mild fasting hyperglycemia) As many as 50% of carriers of GCK mutations develop gestational diabetes mellitus 2-5% of women with gestational DM and first-degree relative with DM carry mutation in GCK gene Other MODY genes encode transcription factors that control insulin expression in β cells and β cell mass; IPF1 (PDX1) plays central role in development of pancreas o Permanent neonatal diabetes occurs as result of mutations of KCNJ11 (encodes Kir6.2 subunit) and ABCC8 (encodes SUR1 subunit) genes of ATP-sensitive K+ channel; inactivation of this channel required for membrane depolarization and physiologic insulin secretion from β cell cells, so gain-of-function mutations cause constitutive activation of K+ channel, membrane hyperpolarization, and hypoinsulinemic diabetes Presents with severe hyperglycemia and ketoacidosis, and ⅕ of patients also have neurologic symptoms like epilepsy o Maternally inherited diabetes and deafness results from mtDNA mutations; impairment of mitochondrial ATP synthesis in metabolically active islet cells results in decreased insulin secretion Mitochondrial diabetes associated with bilateral sensorineural deafness o Mutations in insulin gene most commonly presents in neonatal period, but also in childhood and adolescence Rare instances of insulin receptor mutations that affect receptor synthesis, insulin binding, or receptor tyrosine kinase activity can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance) o Patients show velvety hyperpigmentation of skin (acanthosis nigricans), hypertriglyceridemia, insulin resistance, and abnormal fat deposition in liver (hepatic steatosis) o Females frequently have polycystic ovaries and elevated androgen levels o Lipoatrophic diabetes is hyperglycemia accompanied by loss of adipose tissue over subcutaneous fat Multiple subtypes, each ascribed to different causal mutation Dominant-negative mutations in DNA-binding domain of PPARG found in subset of patients, which interfere with function of wild-type PPARγ in nucleus, leading to severe insulin resistance Pathogenesis of Complications of Diabetes Morbidity associated with long-standing diabetes results from several serious complications, caused mainly by lesions involving both large and medium-sized muscular arteries (macrovascular disease) and capillary dysfunction in target organs (microvascular disease) o Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of MI, stroke, and lower extremity gangrene o Effects of microvascular disease most profound in retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy Persistent hyperglycemia (glucotoxicity) is key mediator of long-term complications Percentage of glycosylated hemoglobin (Hgb A1C) formed by nonenzymatic covalent addition of glucose moieties to hemoglobin in RBCs o HbA1C provides measure of glycemic control over lifespan of RBC (120 days) and is little affected by dayto-day variations o Recommended that HbA1C be kept below 7% in diabetic patients Advanced glycation end products (AGEs) formed as result of non-enzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) with amino groups of both intracellular and extracellular proteins o Natural rate of AGE formation greatly accelerated in presence of hyperglycemia o AGEs bind to RAGE, which is expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle o Detrimental effects of AGE-RAGE signaling axis within vascular compartment include Release of pro-inflammatory cytokines and growth factors from intimal macrophages Generation of reactive oxygen species in endothelial cells Increased procoagulant activity on endothelial cells and macrophages Enhanced proliferation of vascular smooth muscle cells and synthesis of ECM o Endothelial-specific overexpression of RAGE accelerates large vessel injury and microangiopathy o AGEs can directly cross-link ECM proteins; cross-linking of collagen type I molecules in large vessels decreases their elasticity, which may predispose vessels to shear stress and endothelial injury o AGE-induced cross-linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid o Proteins cross-linked by AGEs resistant to proteolytic digestion, so cross-linking decreases protein removal while enhancing protein deposition AGE-modified matrix components trap nonglycated plasma or interstitial proteins In large vessels, trapping of LDL retards efflux from vessel wall and enhances deposition of cholesterol in intima, accelerating atherogenesis In capillaries (including renal glomeruli) plasma proteins such as albumin bind to glycated basement membrane, accounting for part of basement membrane thickening characteristic of diabetic microangiopathy Activation of intracellular PKC by Ca2+ and second messenger DAG important in many cellular systems o Intracellular hyperglycemia stimulates de novo synthesis of DAG from glycolytic intermediates, and hence causes activation of PKC o Downstream effects of PKC activation include Production of proangiogenic VEGF, implicated in neovascularization characterizing diabetic retinopathy Elevated levels of vasoconstrictor endothelin-1 and decreased levels of NO due to decreased expression of endothelial NO synthase Production of profibrogenic factors like TGF- β, leading to increased deposition of ECM and basement membrane material Production of PAI-1, leading to reduced fibrinolysis and possible vascular occlusive episodes Production of pro-inflammatory cytokines by vascular endothelium In some tissues that don’t require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia in extracellular space leads to increase in intracellular glucose o Excess glucose metablized by enzyme aldose reductase to sorbitol and eventurally to fructose in reaction that uses NADPH as cofactor o NADPH also required by enzyme glutathione reductase in reaction that regenerates reduced glutathione (GSH; one of important antioxidant mechanisms in cell) o Any reduction in GSH increases cellular susceptibility to oxidative stress o With sustained hyperglycemia, progressive depletion of intracellular NADPH by aldol reductase compromises GSH regeneration, increasing cellular susceptibility to oxidative stress o In neurons, persistent hyperglycemia is major underlying cuase of diabetic neuropathy (glucose neurotoxicity) Morphology of Diabetes and its Late Complications In individuals with tight control of diabetes, onset of complications may be delayed In most patients, morphologic changes likely to be found in arteries (macrovascular disease), basement membranes of small vessels (micrangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues Pancreas – lesions inconstant and rarely of diagnostic value; distinctive changes more commonly associated with type 1 than type 2 diabetes o Reduction in number and size of islets – most often seen in rapidly advancing type 1; most islets small and inconspicuous o Leukocytic infiltrates in islets (insulitis) principally composed of T lymphocytes Lymphocytic infiltrates may be present in type 1 diabetics at time of clinical presentation Distribution of insulitis may be uneven Eosinophilic infiltrates may also be found, particularly in diabetic infants who fail to survive immediate postnatal period o In type 2 diabetes, there may be subtle reduction in islet cell mass o Amyloid deposition in islets in type 2 diabetes; begins in and around capillaries and between cells At advanced stages, islets may be virtually obliterated Fibrosis may be observed Similar lesions may be found in elderly non-diabetics as part of aging Diabetic macrovascular disease – endothelial dysfunction predisposes to atherosclerosis and other cardiovascular morbidities; consequence of deleterious effects of persistent hyperglycemia and insulin resistance on vascular compartment o Hallmark is accelerated atherosclerosis involving aorta and large and medium-sized arteries o MI caused by atherosclerosis of coronary arteries is most common cause of death in diabetics o Elevated risk for CVD observed in pre-diabetics o MI almost as common in diabetic women as men; MI usually uncommon in women of reproductive age o Gangrene of lower extremities as result of advanced vascular disease is 100x more common in diabetics than general population o Larger renal arteries subject to severe atherosclerosis, but most damaging effect on kidneys exerted on glomeruli and microcirculation o Hyaline arteriolosclerosis – vascular lesion associated with hypertension; more prevalent and more severe in diabetics, but not specific for either diabetes or hypertension Amorphous hyaline thickening of wall of arterioles, which causes narrowing of lumen Diabetic microangiopathy – one of most consistent morphologic features of diabetes is diffuse thickening of basement membranes; thickening most evident in capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla (may also be seen in renal tubules, Bowman capsule, peripheral nerves, and placenta) o Despite increase in thickness of basement membranes, diabetic capillaries more leaky than normal to plasma proteins o Microangiopathy underlies development of diabetic nephropathy, retinopathy, and some forms of neuropathy Diabetic nephropathy – renal failure second only to MI as cause of death from diabetes o Can be glomerular lesions, renal vascular lesions (principally arteriolosclerosis), or pyelonephritis (including necrotizing papillitis) o Capillary basement membrane thickening – widespread thickening of glomerular capillary basement membrane (GBM) occurs in virtually all cases of diabetic nephropathy and is part of diabetic microangiopathy Thickening begins as early as 2 years after onset of type 1 diabetes and by 5 years amounts to 30% increase; continues progressively and usually concurrently with mesangial widening Simultaneously thickening of tubular basement membranes o Diffuse mesangial sclerosis – diffuse increase in mesangial matrix; can be mild proliferation of mesangial cells early in disease process, but cell proliferation not prominent part of this Mesangial increase typically associated with overall thickening of GBM As disease progresses, expansion of mesangial areas can extend to nodular configurations Progressive expansion of mesangium correlates with measures of deteriorating renal function such as increasing proteinuria o Nodular glomerulosclerosis – also called intercapillary glomerulosclerosis or Kimmelsteil-Wilson disease Glomerular lesions ovoid or spherical, often laminated, nodules of matrix situated in periphery of glomerulus; lie within mesangial core of glomerular lobular and can be surrounded by patent peripheral capillary loops or loops that are markedly dilated Nodules often show features of mesangiolysis with fraying of mesangial/capillary lumen interface, disruption of sites at which capillaries are anchored into mesangial stalks, and resultant capillary microaneurysm formation as untethered capillaries distend outward as result of intracapillary pressures and flows Not all lobules in individual glomerulus involved by nodular lesions, but even uninvolved lobules and glomeruli show striking diffuse mesangial sclerosis As disease advances, individual nodules enlarge and may eventually compress and engulf capillaries, obliterating glomerular tuft Frequently accompanied by prominent accumulations of hyaline material in capillary loops (fibrin caps) or adherent to Bowman’s capsules (capsular drops) Both afferent and efferent glomerular hilar arterioles show hyalinosis As consequence of glomerular and arteriolar lesions, kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes overall contraction in size 15-30% of individuals with long-term diabetes develop nodular glomerulosclerosis, and in most instances associated with renal failure Renal atherosclerosis and arteriolosclerosis constitute part of macrovascular disease in diabetics o Hyaline arteriolosclerosis affects afferent and efferent arterioles (efferent arteriolosclerosis rarely, if ever, encountered in individuals without diabetes) Pyelonephritis – acute or chronic inflammation of kidneys that usually begins in interstitial tissue and spreads to affect the tubules; both acute and chronic forms occur in non-diabetics as well but more common in diabetics o Once affected, diabetics tend to have more severe involvement o Necrotizing papillitis (papillary necrosis) much more prevalent in diabetics than non-diabetics Diabetic ocular complications – ocular involvement may be retinopathy, cataract formation, or glaucoma Diabetic neuropathy – central and peripheral nervous systems both affected Clinical Features of Diabetes In initial 1-2 years following onset of overt type 1 diabetes, exogenous insulin requirements may be minimal because of ongoing endogenous insulin secretion (honeymoon period); thereafter, any residual β-cell reserve exhausted and insulin requirements increase dramatically o Transition from impaired glucose tolerance to overt diabetes may be abrupt and often brought on by an event, such as infection, associated with increased insulin requirements o Onset marked by polyuria, polydipsia (excessive thirst), polyphagia, and when severe, ketoacidosis; all result from metabolic derangements Deficiency of insulin results in catabolic state that affects glucose, fat, and protein metabolism Unopposed secretion of glucagon, GH, and epinephrine plays role in metabolic derangements Assimilation of glucose into muscle and adipose tissue sharply diminished or abolished Storage of glycogen in liver and muscle ceases, and reserves of glycogen depleted by glycogenolysis Resultant hyperglycemia exceeds renal threshold for reabsorption, and glycosuria ensues o Glycosuria induces osmotic diuresis and thus polyuria, causing profound loss of water and electrolytes o Obligatory renal water loss combined with hyperosmolarity resulting from increased levels of glucose in blood tends to deplete intracellular water, triggering osmoreceptors of thirst centers in brain, causing polydipsia With deficiency of insulin, catabolism of proteins and fats becomes prominent; causes proteolysis and gluconeogenic amino acids removed by liver and used as building blocks for glucose o Catabolism of proteins and fats tends to induce negative energy balance, which leads to polyphagia o Despite increased appetite, catabolic effects prevail and cause muscle weakness and weight loss Classic triad of diagnosing diabetes is polyphagia, polydipsia, and polyuria o Combination of polyphagia and weight loss should always raise suspicion of diabetes Diabetic ketoacidosis – not as bad in type 2 diabetes as type 1; marked insulin deficiency and release of epinephrine blocks any residual insulin action and stimulates secretion of glucagon o Insulin deficiency coupled with glucagon excess decreases peripheral utilization of glucose while increasing gluconeogenesis, severely exacerbating hyperglycemia o Hyperglycemia causes osmotic diuresis and dehydration characteristic of ketoacidotic state o Insulin deficiency stimulates LPL with resultant breakdown of adipose stores, and increase in levels of free fatty acids; when free fatty acids reach liver, they are esterified to fatty acyl-CoA Oxidation of fatty acyl-CoA in hepatic mitochondria produces ketone bodies (acetoacetic acid and β-hydroxybutyric acid); rate at which keton bodies formed may exceed rate at which they can be utilized by peripheral tissues, leading to ketonemia and ketonuria If urinary excretion of ketones compromised by dehydration, systemic metabolic ketoacidosis results Release of ketogenic amino acids by protein catabolism aggravates ketotic state Type 2 DM may present with polyuria and polydipsia, but patients often older and frequently obese o In some cases medical attention sought because of unexplained weakness or weight loss o Most frequently, diagnosis made after routine blood or urine testing in asymptomatic patients o Milder presentation because of higher portal vein insulin levels than in type 1 diabetics, which prevents unrestricted hepatic fatty acid oxidation and keeps formation of ketone bodies in check o In decompensated state, they may develop hyperosmolar non-ketotic coma due to severe dehydration resulting from sustained osmotic diuresis (particularly in patients who don’t drink enough water to compensate for urinary losses from chronic hyperglycemia) o Absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays seeking medical attention until severe dehydration and coma occur In both types, long-term effects are more responsible for overwhelming majority of morbidity and mortality, not acute metabolic complications; in most instances complications appear 15-20 years after onset of hyperglycemia o Macrovascular complications such as MI, renal vascular insufficiency, and cerebrovascular accidents are most common causes of mortality in long-standing diabetes Hypertension found in 75% of individuals with type 2 diabetes and potentiates effects of hyperglycemia and insulin resistance on endothelial dysfunction and atherosclerosis Dyslipidemia – includes increased triglycerides and LDL levels and decreased HDL; insulin resistance contributes to dyslipidemia by favoring hepatic production of atherogenic lipoproteins and suppressing uptake of circulating lipids in peripheral tissues Diabetics have elevated levels of PAI-1, which inhibits fibrinolysis and therefore acts as procoagulant in formation of atherosclerotic plaques o Diabetic nephropathy is leading cause of end-stage renal disease in U.S. 30-40% of diabetics develop clinical evidence of nephropathy; considerably smaller fraction of type 2 diabetes progress to end-stage renal disease, but they may constitute slightly over half of diabetic patients starting dialysis each year Frequency of diabetic nephropathy greatly influenced by ethnicity Earliest manifestation of diabetic nephropathy is appearance of low amounts of albumin in urine (microalbuminuria); also marker for greatly increased cardiovascular morbidity and mortality All patients with microalbuminuria should be screened for macrovascular disease, and aggressive intervention should be undertaken to reduce cardiovascular risk factors Without specific interventions, 80% of type 1 diabetics and 20-40% of type 2 diabetics will develop overt nephropathy with macroalbuminuria over 10-15 years, usually accompanied by appearance of hypertension o Visual impairment, sometimes total blindness; 60-80% of patients develop some form of diabetic retinopathy 15-20 years after diagnosis Fundamental lesion is neovascularization caused by hypoxia-induced overexpression of VEGF in retina; current treatment includes intravitreous injection of anti-angiogenic agents Consists of constellation of changes that together are considered to be virtually diagnostic of diabetes Increased propensity for glaucoma and cataract formation o Diabetic neuropathy can elicit variety of clinical syndromes, afflicting CNS, peripheral sensorimotor nerves, and ANS Most frequent pattern is distal symmetric polyneuropathy of lower extremities that affects both motor and sensory function, but particularly sensory Over time, upper extremities may be involved as well (glove and stocking pattern of polyneuropathy) Autonomic neuropathy produces distubances in bowel and bladder function and sometimes sexual impotence Diabetic mononeuropathy may manifest as sudden footdrop, wristdrop, or isolated cranial nerve palsies o Diabetics plagued by enhanced susceptibility to infections of skin, TB, pneumonia, and pyelonephritis Basis of enhanced susceptibility includes decreased neutrophil functions (chemotaxis, adherence to endothelium, phagocytosis, and microbicidal activity), and impaired cytokine production by macrophages Vascular compromise reduces delivery of circulating cells and molecules required for defense Metabolic syndrome (previously syndrome X) applies to increasingly common condition wherein abdominal obesity and insulin resistance accompanied by constellation of risk factors for CVD like abnormal lipids o Patients benefit greatly from changes in lifestyle, including dietary modifications and weight reduction Benefits can be seen in lifestyle changes in patients with type 2 diabetes Diabetes is one of top 10 killers in U.S.