Pathology Ch 24 1130-1146
The Endocrine Pancreas (Diabetes)
Pancreas has 1 million clusters of cells, islets of Langerhans containing 4 major and 2 minor cell
types; main ones are β, α, δ, and PP
-β cells produce insulin, α cells secrete glucagon, δ cells secrete somatostatin (suppresses both
insulin and glucagon release); PP cells contain a unique pancreatic polypeptide that stimulates
secretion of gastric and intestinal enzymes and inhibit intestinal motility
D1 cells secreting vasoactive intestinal polypeptide (VIP) to induce glycogenolysis and
hyperglycemia; stimulates GI gluid secretion and causes diarrhea
Enterochromaffin cells synthesize serotonin and are source of pancreatic tumors causing
carcinoid syndrome
Diabetes Mellitus – group of metabolic disorders with hyperglycemia as underlying feature;
results from defects in insulin secretion, insulin action, or both
-diabetes affects 20 million children/adults and 7% of population in US
-leading cause of end-stage renal disease, adult-onset blindness, and extremity amputations
-54 million adults have pre-diabetes, defined as elevated blood sugar not yet at diabetes
Diagnosis of Diabetes – blood glucose normally at 70-120mg/dL; diagnosis is made on any of
these criteria:
1. Random glucose concentration greater than 200mg/dL with symptoms
2. Fasting glucose concentration greater than 126 mg/dL
3. Abnormal oral glucose tolerance test (OGTT): glucose >200mg/dL after carb load
a. Euglycemia = 100-140mg/dL
b. Pre-diabetes = fasting level of 100-126, or OGTT value >140, <200mg/dL
Classification – Type I diabetes is an autoimmune disease characterized by pancreatic β cell
destruction and absolute deficiency of insulin (5-10% of cases, most common <20 years old)
-Type II diabetes caused by peripheral resistance to insulin action and inadequate secretory
response by β cells (relative insulin deficiency), occurs in 90-95% of cases, many people obese
-long-term complications of both types (kidneys, eyes, nerves, vessels) are the same
Glucose Homeostasis – glucose regulated by 3 processes: production in liver, uptake and
utilization by peripheral tissues, and actions of insulin and counter-regulatory hormones
-insulin/glucagon have opposing regulatory effects on glucose homeostasis
-low insulin/high glucagon induces hepatic gluconeogenesis and glycogenolysis, decreasing
glycogen synthesis to prevent hypoglycemia
-fasting glucose levels determined by hepatic glucose output
-after a meal, insulin rises and glucagon falls in response to glucose load, and insulin
promotes glucose uptake/utilization in tissues, majority in skeletal muscle
Regulation of Insulin Release – preproinsulin synthesized in rER and delivered to golgi, where it
is cleaved to generate mature insulin + C-peptide, which are both stored in granules and
secreted after stimulation
-MOST IMPORTANT stimulus for insulin synthesis and release is glucose itself
-glucose uptake into is facilitated by GLUT-2 (a glucose independent transporter)
-β cells express an ATP-sensitive K channel on membrane comprising inward K+ channel (Kir6.2)
and sulfonylurea receptor (SUR1), the latter being the binding site of sulfonylurea drugs
-glucose metabolism forms ATP, resulting in increase in cytoplasmic ATP/ADP ratios
-this inhibits the activity of ATP sensitive K channel, leading to membrane depolarization and
influx of extracellular Ca through voltage-dependent Ca channels which stimulate insulin
secretion immediately, known as immediate release of insulin, if stimulus persists, delayed
response follows called active synthesis of insulin
-Leucine/arginine stimulate insulin release, but not synthesis
Insulin Action and Insulin Signaling Pathways – principal function is to increase rate of glucose
transport into certain cells in the body, providing an increased source of energy
-striated muscle cells and adipocytes are affected most, and brain uses insulinindependent mechanisms
-in muscles, glucose is stored as glycogen, and in fat glucose turns into lipids
-insulin also inhibits lipid degradation in adipocytes
-insulin promotes AA uptake and protein synthesis/inhibits protein degradation
-anabolic effects of insulin attributable to increased synthesis and reduced degradation of
glycogen lipids and proteins
-insulin has mitogenic functions such as DNA synthesis for growth/differentiation
-insulin receptor – tetrameric protein containing two α and two β subunits, with the β subunit
cytosolic domain having tyrosine kinase activity
-insulin binds α subunit, to activate the tyrosine kinase on β subunit, resulting in
autophosphorylation of receptor and activation of several intracellular substrate proteins
including IRS1-IRS4 and GAB1, which activate PI-3K and MAP kinase which mediate metabolic
and mitogenic activities of insulin on cell
-insulin facilitates trafficking and docking of vesicles containing glucose transporter protein
GLUT-4 to plasma membrane, which promotes glucose uptake: mediated by AKT and protein
CBL, direct phosphorylation target of insulin receptor
-Protein tyrosine phosphatase 1B (PTPN1B) dephosphorylates insulin receptor and inhibits
insulin signaling
-PTEN can inhibit insulin signaling by blocking AKT activation by PI-3K pathway
Pathogenesis of Diabetes Mellitus Type 1 – autoimmune disease in which islet destruction is
caused by immune effector cells reacting against endogenous β cell antigens
-develops in childhood, and patients depend on insulin for survival
Genetic Susceptibility – most important is HLA locus on chromosome 6p21, and 95% of
Caucasians with type 1 diabetes have HLA-DR3 or HLA-DR4 haplotype
-people with DR3 or DR4 concurrently with DQ8 have highest inherited risk
-the insulin GENE with variable number of tandem repeats (VNTR) in promoter region increase
disease susceptibility
-CTLA-4 and PTPN-22 inhibit T cell responses, and mutations in these will activate T cells, which
may contribute to type 1 diabetes
-another polymorphism is in CD25, encoding alpha chain of IL-2 receptor, where mutation
reduces activity of receptor, critical for maintenance of regulatory T cells
Environmental Factors – viral infections and other factors may be involved in pathogenesis;
associations are reported between mumps, rubella, coxsackie B, cytomegalovirus; 3 different
mechanisms have been proposed to explain role of viruses in autoimmunity
1. bystander damage where viral infections induce islet injury and inflammation leading to
release of sequestered β cell antigens and activation of autoreactive T cells
2. viruses produce proteins that mimic β cell antigens, and immune response to viral
protein cross-reacts with self-tissue
3. viral infections early in life might persist in tissue of interest, and reinfection with
related virus leads to immune response against the infected islet cells, called viral déjà
vu
Mechanisms of β-Cell Destruction in Type 1 Diabetes – classic manifestations of type 1 diabetes
occurs late in course, once 90% of β cells have been destroyed
-Fundamental immune abnormality in type 1 diabetes is failure of self-tolerance in T cells
-failure of tolerance results from defective clonal deletion of self-reactive T cells in thymus as
well as defects in functions of regulatory T cells or resistance of effector T cells to suppression by
regulatory T cells
-thus, autoreactive T cells survive and are posed to respond to self-antigens to cause B cell injury
-auto-antigens that are targets of immune attack may include insulin, β-cell enzyme glutamic
acid decarboxylase (GAD), and islet cell autoantigen 512
-antibodies have a role because autoantibodies against islet antigens have been found
Pathogenesis of Type 2 Diabetes – includes both genetic and environmental factors
-GWAS studies identified over a dozen susceptibility loci; polymorphisms associated with β cell
function and insulin secretion confer strongest genetic risk to type 2 diabetes
-most reproducible association is transcription factor 7-like-2 (TCF7L2), encoding transcription
factor in WNT signaling pathway
-Type 2 diabetes not linked to genes involved in immune tolerance and regulation
-two metabolic defects that characterize type 2 diabetes are:
(1) decreased response of peripheral tissues to insulin (insulin resistance)
(2) β cell dysfunction manifested as inadequate insulin secretion in the face of insulin
resistance and hyperglycemia
-insulin resistance predates hyperglycemia and accompanied compensatory β
cell hyperfunction and hyperinsulinemia in early stages of evolution of diabetes
Insulin Resistance – defined as failure of target tissues to respond normally to insulin leading to
decreased uptake of glucose in muscle, reduced glycolysis and fatty acid oxidation in liver, and
inability to suppress hepatic gluconeogenesis
-loss of insulin sensitivity in hepatocytes is likely LARGEST CONTRIBUTOR to pathogenesis of
insulin resistance
-reduced tyrosine phorphosylation and increased serine phosphorylation of insulin
receptor are functional defects
-few factors play as important a role in development of insulin resistance as obesity
Obesity and Insulin Resistance – obesity occurs in >80% of diabetes type 2 patients; insulin
resistance is present even in simple obesity unaccompanied by hyperglycemia, indicating
fundamental abnormality of insulin signaling in states of fatty excess
-risk of diabetes increases as BMI increases
-Obesity can adversely impact insulin sensitivity in numerous ways:
1. Nonesterified fatty acids (NEFAs) – inverse correlation between fasting plasma NEFAs
and insulin sensitivity
a. Level of intracellular triglycerides is often markedly increased in muscle and liver
tissues of obese people because excess NEFAs are deposited in these organs
b. Central adipose is more lipolytic than peripheral sites to explain particularly
deleterious consequences of pattern of fat distribution
c. Excess intracellular NEFAs overwhelm fatty acid oxidation pathways, leading to
accumulation of cytoplasmic intermediates like DAG and ceramide
i. These toxic intermediates activate serine/threonine kinases, which
cause aberrant serine phosphorylation of insulin receptor and IRS
proteins
d. Phosphorylation of serines inhibits insulin signaling; insulin normally inhibits
hepatic gluconeogenesis by blocking activity of phosphoenopyruvate
carboxykinase, first enzymatic step in process
i. Attenuated insulin signaling allows this enzyme to ramp up
gluconeogenesis, and excess NEFAs also compete with glucose for
substrate oxidation, leading to feedback inhibition of glycolytic enzymes
to further exacerbate existing glucose imbalance
2. Adipokines – adipose is not just a storage organ, but is also endocrine and releases
hormones in response to changes in metabolic status, called adipokines
a. Both pro-hyperglycemic adipokines (resistin, RBP4) and anti-hyperglycemic
adipokines (leptin, adiponectin) have been identified
b. Leptin/adiponectin – improve insulin sensitivity by enhancing AMP-activated
protein kinase (AMPK) to promote fatty acid oxidation in muscle and liver
i. Adiponectin levels are reduced in obesity = insulin resistance
ii. AMPK is target for metformin, an oral antidiabetic medication
3. Inflammation – adipose secretes pro-inflammatory cytokines like TNF, IL-6, and
macrophage chemoattractant protein-1 (attract macrophages to fat)
a. Induce insulin resistance by increasing cellular stress to activate cascades that
antagonize insulin action on peripheral tissues
4. Peroxisome proliferator-activated receptor γ (PPARγ) – PPARγ is a nuclear receptor and
transcription factor expressed in adipose and is involved in adipocyte differentiation
a. Thiazolidinediones are PPARγ agonists to improve insulin sensitivity
b. activation of PPARγ promotes anti-hyperglycemic adipokines like adiponectin
and shifts deposition of NEFAs toward adipose tissue and away from
liver/muscle
β-cell Dysfunction – in type II diabetes, β-cells exhaust capacity to adapt to demands of
peripheral insulin resistance, and initially in states of insulin resistance, like obesity, insulin
secretion is higher
-hyperinsulinemic state is compensation for peripheral resistance and can maintain for years
-eventually, compensation becomes inadequate, and hyperglycemia ensues
-not all obese people with insulin resistance develop diabetes, and so a predisposition exists
-HIGHEST RISK FOR TYPE II DIABETES are variants gene TCF7L2 which are associated with
reduced insulin secretion from islets, indicating propensity toward β-cell failure
-excess NEFAs and attenuated (inhibited) insulin signaling (lipotoxicity) predispose both to
insulin resistance and β-cell failure
-amyloid replacement of findings is a characteristic in people with type 2 diabetes and is present
in more than 90% of islets
Monogenic Forms of Diabetes – forms of diabetes with defined genetic causes, and are distinct
from type 1 or 2 diabetes; result in either a primary defect in β-cell function or a defect in
insulin-insulin receptor signaling
Genetic Defects in β-cell Function – 1-2% of diabetics have primary defect in β-cell function that
occurs WITHOUT β-cell loss, affecting either β-cell mass or insulin production, characterized by:
1. autosomal-dominant inheritance with high penetrance
2. early onset, before 25 and even in neonatal period
3. absence of obesity and absence of β-cell autoantibodies
-largest subgroup of patients categorized as having maturity-onset diabetes of the young
(MODY) because of resemblance of type II diabetes in younger patients. MODY results from
mutations in 1 of 6 genes:
1. glucokinase phosphorylates glucose to G6P (rate-limiting step in glycolysis). Mutations
in β-cell glucokinase (GCK) increase glucose threshold that triggers insulin release,
causing mild increases in fasting blood glucose
a. 50% of carriers of GCK mutations develop gestational diabetes mellitus
2. IPF1 (also known as PDX1) plays a central role in development of the pancreas, and is a
transcription factor controlling insulin expression in β-cells and β-cell mass
a. other 4 genes are also transcription factors
Permanent neonatal diabetes occurs as a result of mutations in KCNJ11 and ABCC8 genes
encoding Kir6.2 and SUR1 components of ATP-sensitive K channel required for membrane
depolarization and physiologic insulin secretion from β-cells
-gain of function mutations in KCNJ1 and ABCC8 cause constitutive activation of K
channel, membrane depolarization and hypoinsulinemic diabetes
-permanent neonatal diabetes presents with severe hyperglycemia and ketoacidosis,
and a fifth develop epilepsy
Maternally inherited diabetes and deafness – results from mitochondrial DNA mutations;
impairment of mitochondrial ATP synthesis in active islets decreases insulin synthesis
-mutations within the insulin gene itself is a form of monogenic diabetes
Genetic Defects in Insulin Action – mutations in the insulin receptor that affect receptor
synthesis, insulin binding, or tyrosine kinase activity can cause severe insulin resistance
accompanied by hyperinsulinemia and diabetes (TYPE A INSULIN RESISTANCE)
-hyperpigmentation of skin (acanthosis nigricans)
-females usually have polycystic ovaries and increased androgen levels
-lipoatrophic diabetes is hyperglycemia with loss of adipose tissue (subcutaneous fat)
-insulin resistance, diabetes, hypertriglyceridemia, acanthosis nigricans, liver steatosis
-dominant-negative mutations in DNA binding domain of PPARG are found in patients
which interfere with function of wildtype PPARγ in nucleus, leading to insulin resistance
-PPARG mutations are associated with type 2 diabetes
Pathogenesis of Complications of Diabetes – morbidity stems from complications such as:
lesions involving medium and large arteries (macrovascular disease), and capillary dysfunction
in target organs (microvascular disease)
-MACROvascular disease cause accelerated atherosclerosis in diabetics  increased risk
MI, stroke, and lower extremity gangrene
-MICROvascular disease presents as diabetic retinopathy, nephropathy, and neuropathy
-pathogenesis of long-term complications of diabetes is multifactorial, although persistent
hyperglycemia (glucotoxicity) is a key mediator
-assessment of glycemic control in hyperglycemia is based on percentage of glycosylated
hemoglobin (HbA1C) which is formed by nonenzymatic ,covalent addition of glucose to
hemoglobin
-HbA1C provides a measure of glycemic control over lifespan of red blood cells (120 days) and
isn’t affected by day-day interactions (recommended level is <7% HbA1C)
-persistent hyperglycemia affects the body through 3 different pathways:
1. Formation of Advanced Glycation End Products (AGEs) – AGEs are formed as a result of
non-enzymatic reactions between glucose dicarbonyl precursors with amino groups of
extracellular proteins; natural rate of AGE formation accelerated during hyperglycemia
a. AGEs bind to a receptor (RAGE) expressed on inflammatory cells, endothelium, and
vascular smooth muscle; detrimental effects of AGE-RAGE signaling include:
i. Release of pro-inflammatory cytokines/growth factors from macrophages
ii. Generation of reactive oxygen species in endothelial cells
iii. Increased procoagulant activity on macrophages/endothelial cells
iv. Proliferation of vascular smooth muscle cells and synthesis of extracellular
matrix
b. Overexpression of RAGE accelerates vessel injury and microangiopathy
c. AGEs can directly cross-link extrcellular matrix proteins such as collagen type I in
large vessels which decreases their elasticity and predisposes them to shear stress
i. AGE-induced cross-linking of type IV collagen in basement membrane
decreases endothelial cell adhesion and increases extravasation of fluid
ii. Proteins cross-linked by AGEs are resistant to proteolytic digestion
iii. AGE modified matrix components can trap proteins like LDL to enhance
atherogenesis; in renal glomeruli, albumin may bind glycated basement
membrane to thicken it resulting in diabetic microangiopathy
2. Activation of Protein Kinase C – activation of PKC by Ca ions and second messenger
diacylglycerol (DAG) is important signaling pathway; hyperglycemia stimulates de novo
synthesis of DAG from glycolytic intermediates and activates PKC, resulting in:
a. Production of pro-angiogenic VEGF = neovascularization in diabetic retinopathy
b. High levels of vasoconstrictor endothelin-1 and decreased levels of vasodilator NO
due to increased expression of endothelial nitric oxide synthase
c. Production of profibrogenic factors like TGF-B = increased deposition of ECM
d. Production of PAI-1, leading to reduced fibrinolysis and vascular occlusive episodes
e. Production of pro-inflammatory cytokines by vascular endothelium
3. Intracellular Hyperglycemia and Disturbances in Polyol Pathways – in tissues not requiring
insulin (nerves, lenses, kidneys, vessels), persistent hyperglycemia in extracellular milieu can
cause increase in intracellular glucose, which is metabolized by aldolase reductase to
sorbitol, a polyol  fructose, using NADPH
a. NADPH is also required by glutathione reductase which regenerates reduced
glutathione (GSH)
b. GSH is important antioxidant, and a reduction in GSH increases cellular susceptibility
to oxidative stress; depletion of NADPH by aldol reductase compromises GSH
regeneration, increasing cellular susceptibility to oxidative stress; in neurons it is
called glucose neurotoxicity
Morphology of Diabetes and its Late Complications – most changes are likely to be found in
macrovascular disease, basement membranes of small vessels (microangiopathy), kidneys
(diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues
Morphology in Pancreas – lesions in pancreas are inconstant and more associated with type 1
diabetes, and may present as:
-reduction in number and size of islets – type 1, rapid advancing disease
-leukocytic infiltrates in islets (insulitis) – composed of T cells, in type 1 diabetes
-subtle reduction in islet cell mass – happens in type 2 diabetes
-amyloid deposition in islets – happens in type 2 diabetes, beginning in capillaries and
between cells; at advances stages the islets can be obliterated with fibrosis seen
-increase in number and size of islets – nondiabetic newborns in diabetic mothers (fetal
islets undergo hyperplasia in response to maternal hyperglycemia)
Diabetic Macrovascular Disease – endothelial dysfunction predisposes to atherosclerosis is
widespread in diabetes and is a consequence of persistent hyperglycemia and insulin resistance
-HALLMARK of diabetic MACROVASCULAR DISEASE is accelerated atherosclerosis of aorta and
large/medium arteries
-MYOCARDIAL INFARCTION, caused by atherosclerosis of coronary arteries, is most common
cause of death in diabetics; MI is uncommon in nondiabetic women of reproductive age
-Gangrene of Lower Extremities – resulting from advanced vascular disease is 100x more
common in diabetics than in general population
-Renal arteries area also at risk for atherosclerosis and can cause glomerular damaged
Hyaline Arteriosclerosis – vascular lesion associated with hypertension is more prevalent, but
not specific to diabetes and may be seen in elderly nondiabetics without hypertension
-takes form of amorphous, hyaline thickening of wall of arterioles to narrow the lumen
Diabetic Microangiopathy – most consistent morphologic feature in diabetes is diffuse
thickening of basement membranes in skin, skeletal muscle, retina, renal glomeruli, and renal
medulla
-despite thickening, diabetic capillaries are MORE LEAKY than normal to plasma proteins
-microangiopathy underlies diabetic nephropathy, retinopathy, and neuropathy
Diabetic Nephropathy - kidneys are targets in diabetes; renal failure is #2 cause of diabetic
death, and three lesions are encountered: (1) glomerular lesions, (2) renal vascular lesions
(arteriosclerosis) and (3) pyelonephritis, including necrotizing papillitis
-(1) most important glomerular lesions are capillary basement membrane thickening, diffuse
mesangial sclerosis, and nodular glomerulosclerosis
1. Capillary Basement Membrane Thickening – widespread thickening of glomerular
capillary basement membrane (GBM) occurs in all cases of diabetic nephropathy and
part of diabetic microangiopathy
2. Diffuse Mesangial Sclerosis – lesion consists of diffuse increase in mesangial matrix
with mild proliferation of mesangial cells early in disease; mesangial increase is
associated with overall thickening of GBM
3. Nodular Glomerulosclerosis – also known as intercapillary glomerulosclerosis or
Kimmelstiel-Wilson Disease, where lesions take form of ovoid/spherical, laminated
nodules of matrix situated in periphery of glomerulus and are PAS-positive
a. Nodules lie within mesangial core of glomerular lobules and can be surrounded
by patent peripheral capillary loops
b. Frequently accompanied by accumulations of hyaline material in capillary loops
(fibrin caps or adherent to bowman’s capsules (capsular drops)
c. As a consequence, kidney suffers from ischemia, develops tubular atrophy and
interstitial fibrosis, and can undergo contraction in size
d. 10-15% of patients develop nodular glomerulosclerosis with renal failure
Renal Atherosclerosis and Arteriosclerosis - hyaline arteriosclerosis affects both afferent and
efferent arterioles, and EFFERENT arteriosclerosis is rarely encountered in non-diabetics;
frequently affected by this part of macrovascular disease
Pyelonephritis – acute/chronic inflammation of kidneys beginning in interstitial tissue and
spreading to tubules, more common in diabetics than non-diabetics
-special pattern of acute pyelonephritis is called necrotizing papillitis (papillary
necrosis)
Diabetic Ocular Complications – retinopathy, cataract formation, glaucoma may occur
Diabetic Neuropathy – diabetes can affect CNS and PNS
Clinical Features of Diabetes –
Type 1 Diabetes – can occur at any age; after 1-2 years, exogenous insulin requirements are
minimal due to ongoing endogenous insulin secretion (honeymoon period); any residual β-cell
reserve is exhausted and insulin requirements increase dramatically
-transition from impaired glucose tolerance to diabetes may be abrupt and triggered by
an event such as an infection
-onset of type 1 diabetes marked by polyuria, polydipsia, polyphagia, and ketoacidosis;
-deficiency of insulin results in catabolic state affecting fat and protein metabolism
-assimilation of glucose into muscle/adipose is diminished
-storage of glycogen in liver/muscle ceases, and reserves depleted by glycogenolysis, resulting in
hyperglycemia exceeding renal threshold for reabsorption and glycosuria ensues, which induces
osmotic diuresis and causes polyuria
-loss of water triggers osmoreceptors and increases thirst (polydipsia)
-proteolysis follows insulin deficient catabolism, and gluconeogenic amino acids are removed by
liver and used for glucose
-catabolism of proteins/fats induces negative energy balance leading to increased appetite,
completing diabetic triad: polyuria, polydipsia, and polyphagia
-combination of polyphagia and weight loss is paradoxical and should raise diabetic suspicion
-diabetic ketoacidosis – complication of type 1 diabetes but can also occur in type 2 diabetes;
parients are insulin deficient and release of epinephrine blocks residual insulin action and
stimulates glucagon
-insulin deficiency + excess gluacgon decrease peripheral utilization of glucose while
increasing gluconeogenesis to exacerbate hyperglycemia, which causes osmotic diuresis
and dehydration characteristic of ketoacidotic state
-insulin deficiency stimulates lipoprotein lipase to breakdown adipose stores and
increase levels of free fatty acids, which are esterified to fatty acyl-CoA in liver to
produce ketone bodies (acetoacetic acid and β-hydroxybutyric acid)
-rate of ketone body production surpasses rate of peripheral tissue use, leading
to ketonemia and ketonuria
-if urinary excretion of ketones is compromised by dehydration, systemic
metabolic ketoacidosis occurs
Clinical Features of Type 2 Diabetes – also presents with polyuria and polydipsia, but patients
are often older and obese, but now is seen in younger children with childhood obesity on the
rise.
-MOST OFTEN, type 2 diabetes is diagnosed after routine blood or urine testing in
asymptomatic person
-infrequency of ketoacidosis and milder presentation in type 2 diabetes is because of higher
portal vein insulin levels to prevent unrestricted fatty acid oxidation to prevent ketone body
formation
-patients may develop hyperosmolar nonketotic coma due to severe dehydration resulting from
osmotic diuresis
-absence of ketoacidosis and symptoms of nausea/vomiting and respiratory difficulties delays
seeking medical attention
-in BOTH TYPES OF DIABETES – long term effects are more responsible for morbidity and
mortality than are short term affects, 15-20 years after onset of hyperglycemia
-macrovascular complications like MI, renal vascular insufficiency, cerebrovascular accidents
MOST COMMON cause of mortality in long-standing diabetes
-increased risk of coronary artery disease, hypertension, dyslipidemia (increased
triglycerides and LDL levels, and decreased HDL levels)
-insulin resistance favors hepatic production of atherogenic lipoproteins
-diabetics have elevated levels of PAI-1, inhibitor of fibrinolysis and acts as
procoagulant in formation of atherosclerotic plaques
-Diabetic nephropathy is leading cause of end-stage renal disease, small number of patients
with type 2 diabetes progress to end-stage disease
-native americans/Hispanics/African americans have a greater risk of developing endstage renal disease than do non-hispanics with type 2 diabetes
-***earliest manifestation of diabetic nephropathy is presence of albumin in urine,
called microalbuninuria, which is also a marker of cardiovascular morbidity and
mortality in diabetic patients of any type
-80% of type 1 and 30% of type 2 diabetics will develop overt nephropathy with
macroalbuminuria over 10-15 years, accompanied by hypertension
-Visual Impairement – sometimes total blindness is a consequence of long-standing diabetes;
60-80% of patients develop diabetic retinopathy 15-20 years after diagnosis, attributable to
hypoxia-induced overexpression of VEGF in retina
-treatment is intravitreous injection of antiangiogenic agents
-diabetics have increased propensity for glaucoma and cataract formation which
contribute to visual impairment in diabetes
Diabetic Neuropathy – can affect CNS, PNS, and autonomic nervous system; most frequent
involvement is a distal symmetric polyneuropathy of lower extremities affecting motor and
sensory function
-other forms include autonomic neuropathy producing disturbances in bowel and
bladder function and sexual impotence
-diabetic mononeuropathy – sudden footdrop, wristdrop, or cranial nerve palsies
-diabetics have increased susceptibility to infections of SKIN and tuberculosis, pneumonia, and
pyelonephritis due to decreased neutrophil functions (chemotaxis, adherence to endothelium,
phagocytosis, microbicidal activity) and impaired cytokine production by macrophages
Metabolic Syndrome – abdominal obesity and insulin resistance are accompanied by risk factors
for cardiovascular disease like abnormal lipid profiles