Pathology of Diabetes Mellitus

Endocrine Pancreas
- Islets of Langerhans
o β cells - insulin o D1 cells – vasoactive intestinal polypeptide (glycogenolysis,
o α cells – glucagon hyperglycemia; stimulates gastrointestinal fluid secretion,
o δ cells – somatostatin (suppresses both insulin and glucagon causes secretory diarrhea)
release) o Enterochromaffin cells - serotonin (source of pancreatic
o PP cells - pancreatic polypeptide (stimulation of secretion of carcinoid tumors)
gastric and intestinal enzymes and inhibition of intestinal
motility)
Diabetes Mellitus
- Group of metabolic disorders with hyperglycemia from defect in insulin secretion/action
- Leading cause of end-stage renal disease, adult-onset blindness, below knee amputations and peripheral neuropathy
- “Prediabetes” – elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of diabetes
- 1.5 to 2 times ↑ risk in Native Americans, African-Americans, Hispanics
- “Diabesity” epidemic
Diagnosis of Diabetes (ADA, WHO criteria)
- Fasting plasma glucose ≥ 126 mg/dL
- Random plasma glucose ≥ 200 mg/dL (with classic hyperglycemic signs)
- 2-hour plasma glucose ≥ 200 mg/dL following a 75-gm glucose OGTT
- Glycated hemoglobin (HbA1C) level ≥ 6.5%
Impaired glucose tolerance (Prediabetes)
- Fasting plasma glucose: 100 - 125 mg/dL (“impaired fasting glucose”)
- 2-hour plasma glucose: 140 - 199 mg/dL following 75-gm glucose OGTT
- Glycated hemoglobin(HbA1C): 5.7 - 6.4%
Classification
- Type 1 diabetes (5 - 10% cases)
o Autoimmune disease, pancreatic β cell destruction
o Absolute deficiency of insulin
o Most common type in patients <20 years
- Type 2 diabetes (90 - 95% cases)
o Peripheral resistance to insulin + inadequate secretory response by pancreatic β cells
o Relative insulin deficiency
o Mostly adult-onset
Classification
- 1. Type 1 diabetes - 6. Endocrinopathies
- 2. Type 2 diabetes - 7. Infections
- 3. Genetic defects of β-cell function - 8. Drugs
- 4. Genetic defects in insulin processing or action - 9. Genetic syndromes associated with diabetes
- 5. Exocrine pancreatic defects - 10. Gestational diabetes mellitus
Secondary causes
- Pancreatic disease Cystic fibrosis, Chronic pancreatitis
- Drugs Glucocorticoids, Thiazides, α-interferon
- Endocrine disease Pheochromocytoma, Cushing syndrome, Glucagonoma
- Genetic disease Metabolic syndrome, Maturity Onset Diabetes of Young (MODY)
- Insulin-receptor deficiency Acanthosis nigricans is a phenotypic marker
- Infections Mumps, Cytomegalovirus
Metabolic syndrome
- 25% of the U.S. population
- Genetic defect causes insulin resistance that is exacerbated by obesity
- Commonly associated with Polycystic ovary syndrome in women
- May be associated with Acanthosis nigricans
- Increased risk for developing Alzheimer's disease
- Typical acanthosis nigricans of the neck - traditionally characterized by hyperpigmented, velvety plaques in body folds. Hyperinsulinemia, a consequence of insulin
resistance that occurs associated with obesity, stimulates the formation of these characteristic plaques.
- Hyperinsulinemia : ↑ VLDL, hypertension, CAD; ↓HDL
o Serum triglyceride ≥ 150 mg/dL
o Hypertension (≥130/85 mm Hg) - ↑insulin ↑ sodium retention by renal tubules
o Serum HDL cholesterol < 40 mg/dL in men and <50 mg/dL in women
- Obesity in metabolic syndrome
o Abdominal waistline girth in men > 40 inches (102 cm), women > 35 inches (88 cm)
o Insulin resistance - ↑ adipose tissue down regulates insulin receptor synthesis
- Fasting serum glucose ≥ 110 mg/dL
- Treatment
o Statin drugs to lower lipids
o ACE inhibitors or diuretics to treat hypertension
o Correct insulin resistance with weight loss or drugs
Regulation of Insulin Release
- The most important stimulus for insulin synthesis and release is glucose
- Glucose uptake into pancreatic β cells, facilitated by GLUT-2
- Incretins
o Glucose-dependent Insulinotropic Polypeptide (GIP) - secreted by enteroendocrine “K cells” in the proximal small bowel
o Glucagon-Like Peptide-1 (GLP-1), secreted by “L cells” in distal ileum and colon
- ↑ insulin secretion from β cells, ↓glucagon secretion and delay gastric emptying
- “Incretin effect “ blunted in Type 2 Diabetes
- Degraded by dipeptidyl peptidase (DPPs), especially DPP-4
Insulin Action and Insulin Signaling Pathways
- Most potent anabolic hormone
- ↑rate of glucose transport into striated muscle cells and adipocytes
- ↑synthesis and ↓degradation of glycogen, lipids, and proteins
- Insulin receptor - tetrameric protein (2 α- and 2 β-subunits)
Pathogenesis of Type 1 Diabetes Mellitus
- Autoimmune disease
- Islet destruction caused by immune cells against endogenous β-cell antigens
- Common in childhood, manifest at puberty, and progresses with age
- Most patients require insulin for survival
- HLA gene cluster on chromosome 6p21 (50% of genetic susceptibility)
- HLA-DR3 or HLA-DR4 haplotype (90 to 95% of Caucasians)
- DQA1*0301-DQB1*0302 alleles (highest inherited risks)
- Environmental factors - ? Viral infections
b cell destruction
- T lymphocytes
o CD4+ T cells (TH1) activate macrophages
o CD8+ directly kill b cells
- Local cytokines
o IFN-g , TNF, IL-1
- Auto-antibodies
- The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T-cells
Pathogenesis of Type 2 Diabetes Mellitus
- Genetic Factors
o Concordance rate > 90% in monozygotic twins
o First-degree relatives have 5- to 10-fold higher risk
- Environmental Factors
o 2Obesity
o Sedentary lifestyle (lack of exercise)
Metabolic Defects in Diabetes
- Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin (insulin resistance)
- Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β-cell dysfunction)
Monogenic Forms of Diabetes
- Genetic Defects in β-Cell Function
o “Maturity onset diabetes of the young” (MODY)
o Germline loss of-function mutations including glucokinase (GCK)
- Genetic Defects that Impair Tissue Response to Insulin
o Insulin receptor mutations - insulin resistance with hyperinsulinemia and diabetes (type A insulin resistance)
o Acanthosis nigricans
o Females have polycystic ovaries and elevated androgen levels
o Lipoatrophic diabetes – hyperglycemia + loss of adipose tissue
Maturity onset diabetes of the young (MODY)
- Autosomal dominant (AD) inheritance
- Mutations of transcription factor genes (glucokinase gene)
- Patients <25 years old and are not obese
- Mild to severe hyperglycemia (impaired glucose-induced secretion of insulin release)
- Resistance to ketosis
- May progress into type 2 DM
Diabetes and Pregnancy
- Pre-gestational (overt) diabetes
o Women with preexisting diabetes become pregnant
o Increased risk of stillbirth and congenital malformations in the fetus
o Excessive birth weight in the newborn (macrosomia)
- Gestational diabetes
o Previously euglycemic women develop impaired glucose tolerance and diabetes for the first time during pregnancy
o Anti-insulin effect of human placental lactogen (HPL), cortisol, and progesterone
o Typically resolves following delivery
o Majority of women develop overt diabetes over the next 10 to 20 years
o All pregnant women are screened between 24 and 28 weeks' gestation (50-g glucose challenge followed by 1-hour glucose level): > 140 mg/dL is positive
Gestational diabetes (GDM)
- Newborn risks
o Macrosomia: insulin causes ↑ in adipose and muscle
 (1) Hyperglycemia in the fetus causes release of insulin
 (2) Insulin increases fat stored in adipose tissue
 (3) Insulin increases muscle mass by increasing amino acid uptake in muscle
o Respiratory distress syndrome (RDS): ↑ insulin inhibits fetal surfactant production
o Increased risk for open neural tube defect
o Neonatal hypoglycemia: high insulin levels at birth drives glucose into hypoglycemic range (give newborn glucose after birth)
Clinical Features of Diabetes
- Type 1 diabetes
o Primarily < 18 years, but can occur at any age
- Type 2 diabetes
o > 40 years and frequently obese
o Now in children and adolescents
o Mostly diagnosis made after routine blood testing in asymptomatic persons
- Polyuria, Polydipsia, Polyphagia
- Diabetic ketoacidosis
Diabetic ketoacidosis
- Precipitating factor – failure to take insulin, intercurrent infections, illness, trauma and certain drugs (Mostly seen in Type 1 Diabetes)
- Release of epinephrine (blocks any residual insulin action and stimulates the secretion of glucagon) – hyperglycemia (250 to 600 mg/dL), causing osmotic diuresis and
dehydration
- Ketogenesis – insulin deficiency stimulates lipoprotein lipase, free fatty acids reach liver and esterified to “acyl coA” which is oxidised to acetoacetic acid and β-
hydroxybutyric acid (Ketone bodies)
- Ketonemia, Ketonuria – Metabolic Ketoacidosis (fatigue, nausea and vomiting, severe abdominal pain, a characteristic fruity odor, and deep, labored breathing -
Kussmaul breathing)
Lab findings in Diabetic ketoacidosis
- (1) Hyperglycemia - Glucose ranges from 250 to 1000 mg/dL
- (2) Increased HbA1c≥ 6%
- (3) Dilutional hyponatremia
o Glucose overrides sodium in controlling the osmotic gradient
o Water shifts out of the ICF compartment into the ECF compartment
- (4) Hyperkalemia
o ↓ serum sodium (dilutional), ↓ bicarbonate (metabolic acidosis); ↑ serum potassium, ↑ anion gap metabolic acidosis
o Transcellular shift as excess H+ ions enter cells in exchange of potassium
- (5) Increased anion gap metabolic acidosis (due to ketoacidosis and lactic acidosis)
- (6) Pre-renal azotemia (due to volume depletion)
- Mortality rate in DKA is 5% to 10%
Hyperosmolar Hyperosmotic Syndrome
- Type 2 diabetes
- Severe dehydration from sustained osmotic diuresis
- Typically, an older diabetic, disabled by a stroke or an infection and unable to maintain adequate water intake
- Absence of ketoacidosis and its symptoms delays medical attention
- More severe hyperglycemia (600 to 1200 mg/dL)
Hypoglycemia
- Most common acute metabolic complication in either type of diabetes
- Missed meal, excessive physical exertion, an excess insulin administration, or during the phase of dose finding for antidiabetic agents
- Dizziness, confusion, sweating, palpitations, and tachycardia, can lead to loss of consciousness
- Reversal through oral or intravenous glucose intake
Chronic Complications of Diabetes
- Macrovascular disease
o Large and medium sized arteries
o Accelerated atherosclerosis resulting in increased risk of myocardial infarction, stroke, and lower-extremity gangrene
- Microvascular disease
o Small vessels
o Retinopathy, nephropathy, and neuropathy
Chronic Complications of Diabetes
- Persistent hyperglycemia (“glucotoxicity”)
o Formation of Advanced Glycation End Products
o Activation of Protein Kinase C
o Oxidative Stress and Disturbances in Polyol Pathways
o Hexosamine Pathways and Generation of Fructose-6-Phosphate
Advanced Glycation End products (AGEs)
- Non-enzymatic reactions between intracellular glucose derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) with amino groups of intracellular +
extracellular proteins
- AGEs bind to a specific receptor (RAGE) on macrophages, T cells, endothelium, and vascular smooth muscle. Receptor mediated effects include
o Release of cytokines and growth factors – TGFβ (deposition of excess basement membrane material) and VEGF (diabetic retinopathy)
o Generation of reactive oxygen species (ROS) in endothelial cells
o Increased procoagulant activity on endothelial cells and macrophages
o Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
- Can directly cross-link extracellular matrix proteins
o Decreases protein removal while enhancing protein deposition
Morphology of Chronic Complications
- Pancreas
o Type 1 diabetes
 Reduction in the number and size of islets
 Leukocytic infiltrates in the islets
o Type 2 diabetes
 Subtle reduction in islet cell mass
 Amyloid deposition within islets
o Nondiabetic newborns of diabetic mothers
 Increase in the number and size of islets
Vascular changes
- Diabetic Macrovascular Disease
o Endothelial dysfunction (persistent hyperglycemia and insulin resistance)
o Accelerated atherosclerosis (aorta, large- and medium-sized arteries)
 Myocardial infarction, Gangrene of lower extremities
o Hyaline arteriosclerosis
- Diabetic Microangiopathy
o Diffuse thickening of basement membranes of capillaries (skin, skeletal muscle, retina, renal glomeruli, and renal medulla)
 Diabetic nephropathy, retinopathy, and neuropathy
o The thickened capillaries are more leaky than normal to plasma proteins
- Diabetic Nephropathy
o Glomerular lesions
 Thickening of the glomerular capillary basement membrane (GBM)
 Diffuse Mesangial Sclerosis
 Nodular Glomerulosclerosis (Kimmelstiel-Wilson disease)
 Hyaline material in capillary loops (“fibrin caps”) or adherent to Bowman capsules (“capsular drops”)
 Nephrosclerosis (Ischemia leads to tubular atrophy and fibrosis)
- Renal vascular lesions - atherosclerosis and arteriolosclerosis
- Pyelonephritis - Necrotizing papillitis (papillary necrosis)
Diabetic Ocular Complications
- Cataract - acquired opacification of the lens
- Glaucoma (increased intraocular pressure)
- Damage to the optic nerve
- Background (pre-proliferative) diabetic retinopathy
- Proliferative diabetic retinopathy
Non-proliferative retinopathy :
- Intraretinal or preretinal hemorrhages
- Retinal exudates
- Microaneurysms
- Venous dilations, edema, and micro-angiopathy
Proliferative retinopathy :
- Neovascularization and fibrosis
- Retinal detachment
- Annual ophthalmologic examination is mandatory (photocoagulate microaneurysms)
Diabetic Neuropathy
- 50% of diabetics overall have peripheral neuropathy, 80% of those who had the disease > 15 years
- Distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function
o If upper extremities also involved – “glove and stocking” pattern
o Motor dysfunction: muscle weakness; ↓ deep tendon reflexes
o Neuropathy is the most important risk factor for pressure ulcers on the bottom of the feet (patient cannot feel pain)
- Autonomic neuropathy affecting bowel & bladder, erectile dysfunction
- Mononeuropathy - footdrop, wristdrop, or isolated cranial nerve palsy
Clinical Manifestations of Chronic Diabetes
- Macrovascular complications
o Myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality
o Hypertension found in 75% of individuals with type 2 diabetes
o Dyslipidemia
o Elevated levels of PAI-1 (inhibitor of fibrinolysis)
Diabetic nephropathy
- Leading cause of end-stage renal disease in the United States
- 30 to 40% develop nephropathy, less progress to end-stage renal disease
o Native Americans, Hispanics, and African Americans have a greater risk of developing end-stage renal disease
- Earliest manifestation of diabetic nephropathy is Microalbuminuria (>30 mg/day, but <300 mg/day)
- Without specific interventions, 80% of type 1 diabetics and 20 to 40% of type 2 diabetics develop overt nephropathy with macroalbuminuria (>300 mg of urinary albumin
per day) over 10 to 15 years, with hypertension
Other complications
- Visual impairment, sometimes even total blindness
o 60 to 80% of patients develop some form of diabetic retinopathy approximately 15 to 20 years after diagnosis
- Diabetic neuropathy
o Distal extremities, sensorimotor neuropathy. 20% to 40% - autonomic dysfunction
- Enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia and pyelonephritis
o Death in 5% cases
Skin disorders
- Necrobiosis lipoidica diabeticorum: well-demarcated yellow plaques over anterior surface of legs/dorsum of ankles
- Lipoatrophy: atrophy at insulin injection sites due to impure insulin
- Lipohypertrophy: increased fat synthesis at insulin injection sites
Joint disorders
- Neuropathic joint: related to lack of sensation; bone or joint deformity from repeated trauma (Charcot arthropathy)
General treatment for type 1 diabetes
- Split dose insulin mixtures: Regular insulin + neutral protamine hagedorn (NPH) twice daily (morning and evening)
- Insulin pump: allows continuous infusion of insulin throughout the day at preset levels
Insulin-induced hypoglycemia
- Most common complication
- Produces irreversible brain damage by destroying neurons
General principles in treatment of type 2 diabetes mellitus
- Oral hypoglycemic agents mostly used, because most patients are not insulin deficient
o Metformin : decreases hepatic output of glucose
o Sulfonylureas (glyburide, glipizide): increase pancreatic secretion of insulin
o Acarbose and miglitol: inhibit α-glucosidase
o Pioglitazone and rosiglitazone (thiazolidinediones): increase insulin sensitivity
o Repaglinide and nateglinide (meglitinides): acutely increase pancreatic insulin secretion
o Exenatide: synthetic peptide, stimulates release of insulin from pancreatic β-cells
- Combinations of oral hypoglycemic drugs are commonly used if one drug does not produce adequate glycemic control. If oral hypoglycemic agents alone or in
combination are still ineffective in glycemic control, then insulin is utilized
Summary of Diabetes Mellitus
- Type 1 diabetes is an autoimmune disease characterized by progressive destruction of islet β cells, leading to absolute insulin deficiency
- Type 2 diabetes - insulin resistance and β-cell dysfunction
- Obesity has an important relationship with insulin resistance , mediated through multiple factors including excess free fatty acids, cytokines released from adipose tissues
(adipocytokines), and inflammation
- Monogenic forms - single-gene defects that result in primary β-cell dysfunction or lead to abnormalities of insulin-insulin receptor signaling
- The long-term complications of diabetes are similar in both types
o Sustained hyperglycemia causes formation of advanced glycation end products (AGEs), activation of protein kinase C (PKC), disturbances in the polyol
pathways leading to oxidative stress, and overload of the hexosamine pathway
- Long term complications of diabetes - macroangiopathy (atherosclerosis, ischemic heart disease and lower extremity ischemia) and microangiopathy (retinopathy,
nephropathy and neuropathy)
Pancreatic Neuroendocrine Tumors (PanNETs)
- Only 2% of all pancreatic neoplasms
- Most common is Insulinoma (90% benign)
- Other tumors are usually malignant
- Resemble carcinoid tumors
- Recurrent somatic alterations in 3 major genes /pathways
o MEN1, which causes familial MEN syndrome, type 1
o Loss-of-function mutations in tumor suppressor genes PTEN and TSC2 resulting in activation of the oncogenic mammalian TOR (mTOR) signaling pathway
o Inactivating mutations in alpha-thalassemia/mental retardation syndrome, X-linked (ATRX) and death domain associated protein (DAXX)
Hyperinsulinism (Insulinoma)
- β-cell tumors, mostly solitary, 90% benign
- Can arise in ectopic pancreatic tissue (Electron microscopy is helpful, shows distinctive granules of β-cells)
- Hypoglycemic episodes (blood glucose level < 50 mg/dL )
o Confusion, stupor, and loss of consciousness
o Precipitated by fasting or exercise
o Promptly relieved by feeding or parenteral administration of glucose
o Tumors look like giant islets, Amyloid deposition is characteristic
Gastrinomas
- Gastrin-producing tumors
- Can arise in the duodenum, peripancreatic soft tissues and pancreas (gastrinoma triangle)
- Zollinger-Ellison Syndrome
- pancreatic islet cell lesions + hypersecretion of gastric acid + severe peptic ulceration
- > 50% are locally invasive or have already metastasized at diagnosis
- > 50% of the patients have diarrhea
- MEN-1-associated gastrinomas are frequently multifocal, while sporadic gastrinomas are usually single
Questions
- A 27-year-old man has controlled his diabetes mellitus for the past 10 years with insulin injections. This morning, his roommate is unable to awaken him. The man is
unconscious when brought to the emergency department. On physical examination, his temperature is 37Åã C, pulse is 91/min, respirations are 30/min, and blood
pressure is 90/65 mm Hg. Laboratory findings include a high plasma level of insulin and a lack of detectable C peptide. Urinalysis shows no blood, protein, or glucose, but
4+ ketonuria. Which of the following conditions is most likely to be present? Hypoglycemic coma
- Blood relatives of individuals diagnosed with type 1 or type 2 diabetes mellitus are studied for 10 years. Laboratory testing for glucose and insulin levels and autoantibody
formation is performed on a periodic basis. The HLA types of the subjects are determined. A cohort of the subjects who are 8 to 22 years old has no overt clinical illnesses
and no hyperglycemia; however, autoantibodies to glutamic acid decarboxylase are present. Many subjects in this cohort have the HLA-DR3 and HLA-DR4 alleles. Which
of the following pancreatic abnormalities is most likely to be found in this cohort of study subjects? Insulitis
- A 23-year-old woman has a routine health status examination. Her body mass index is 22. Laboratory studies show fasting plasma glucose is 130 mg/dL. Urinalysis shows
mild glucosuria, but no ketonuria or proteinuria. She has no detectable insulin autoantibodies. Her father was similarly affected at age 20 years. She is most likely to have
a mutation in a gene encoding for which of the following? Glucokinase
- A 13-year-old girl collapses while playing basketball. On arrival at the emergency department, she is obtunded. On physical examination, she is hypotensive and
tachycardic with deep, rapid, labored respirations. Laboratory studies show serum Na+, 151 mmol/L; K+, 4.6 mmol/L; Cl–, 98 mmol/L; CO2, 7 mmol/L; and glucose, 521
mg/dL. Urinalysis shows 4+ glucosuria and 4+ ketonuria levels, but no protein, blood, or nitrite. Which pathologic abnormality is most likely to be present in her pancreas
at the time of her collapse? Loss of islet beta cells
- A study of patients more than 25 years of age with body mass index above 30, dyslipidemia, hypertension, and fasting glucose averaging 115 mg/dL is performed. They
have adipose tissue abnormalities including increased nonesterified fatty acid release, altered adipokines with decreased adiponectin, greater proinflammatory cytokine
release, and diminished peroxisome proliferator-activated receptor gamma (PPARγ) function. Which of the following is the best initial therapeutic intervention for these
patients? Caloric restriction
- An infant is born following premature delivery. Multiple external congenital anomalies are noted. The infant exhibits a seizure soon after birth. The blood glucose is 19
mg/dL. Which of the following maternal diseases is the most likely cause for the observed findings in this infant? Diabetes mellitus, type 2
- A clinical study is conducted in patients diagnosed with either type 1 or type 2 diabetes mellitus. Persons with either type develop complications of accelerated and
advanced atherosclerosis. All untreated patients have an elevated hemoglobin A1c. Which of the following features common to patients with either type 1 or type 2
diabetes mellitus is most likely to be found by this study? Nonenzymatic glycosylation of proteins
- A 50-year-old man with fasting blood glucose >140 mg/dL on two occasions is put on a restricted caloric diet and started on a glucagon-like peptide-1 (GLP-1) receptor
agonist. Which of the following laboratory studies is most likely to afford the best method of monitoring disease control in this man? Glucosuria
- A 52-year-old man has been concerned about a gradual weight gain over the past 30 years. He is 174 cm (5 feet 7 inches) tall and weighs 91 kg (body mass index 30). He is
taking no medications. On physical examination, he has decreased sensation to pinprick and light touch over the lower extremities. Patellar reflexes are reduced. Motor
strength seems to be normal in all extremities. Laboratory studies show blood glucose of 169 mg/dL, creatinine of 1.9 mg/dL, total cholesterol of 220 mg/dL, HDL
cholesterol of 27 mg/dL, and triglycerides of 261 mg/dL. A chest radiograph shows mild cardiomegaly. Five years later, he has
claudication in the lower extremities when he exercises. Based on these findings, which of the following complications is most
likely to occur in this man? Gangrene
- A 45-year-old woman has had angina pectoris, polyuria, and polydipsia for the past 5 years. On physical examination, she has a
body mass index of 32. Laboratory studies show her hemoglobin A1c is 10%. Urinalysis shows proteinuria, but no ketonuria. The
representative microscopic appearance of her kidneys is shown in the figure. Which of the following is the most likely mechanism
leading to the disease causing her findings? Insulin resistance
- A 50-year-old man has a 35-year history of diabetes mellitus. During this time, he has had hemoglobin A1c values between 7% and
10%. He now has problems with sexual function, including difficulty attaining an erection. He also is plagued by mild but recurrent
low-volume diarrhea and difficulty with urination. He has delayed gastric emptying. These problems are most likely to originate
from which of the following mechanisms of cellular injury? Polyol-induced susceptibility to oxidative stress
- A 74-year-old woman is admitted to the hospital in an obtunded condition. Her temperature is 37Åã C, pulse is 95/ min, respirations are 22/min, and blood pressure is
90/60 mm Hg. She appears dehydrated and has poor skin turgor. Her serum glucose level is 872 mg/dL. Urinalysis shows 4+ glucosuria, but no ketones, protein, or blood.
Which of the following factors is most important in the pathogenesis of this patient’s condition? Peripheral insulin resistance
- A 40-year-old woman has experienced chest pain on exertion for the past 2 months. A month ago, she had pneumonia with Streptococcus pneumoniae cultured from her
sputum. On physical examination, she has a body mass index of 35. A random blood glucose value is 132 mg/dL. The next day, a fasting blood glucose is 120 mg/dL,
followed by a value of 122 mg/ dL on the following day. She is given an oral glucose tolerance test, and her blood glucose is 240 mg/dL 2 hours after receiving the
standard 75-g glucose dose. On the basis of these findings, she is prescribed an oral thiazolidinedione (TZD) drug. After 2 months of therapy, her fasting blood glucose is
90 mg/ dL. The beneficial effect of TZD in this patient is most likely related to which of the following processes? Activation of PPARγ nuclear receptor in adipocytes
- A family is followed longitudinally for two generations. Four of eight children develop hyperglycemia by age 18 years. They are found to have serum islet autoantibodies.
They have similar MHC I and MHC II loci. Treatment with insulin injections normalizes their Hgb A1c levels. Which of the following is the most likely mechanism leading to
their disease? Loss of T-cell tolerance
- A 33-year-old woman has had several “fainting spells” over the past 6 months. Each time, she has a prodrome of lightheadedness followed by a brief loss of
consciousness. After each episode, she awakens and on examination has no loss of motor or sensory function. Physical
examination after the current episode shows that she is afebrile, with a pulse of 72/min, respirations of 17/min, and blood
pressure of 120/80 mm Hg. Imaging studies reveal a 0.5-cm lesion in the head of the pancreas. The microscopic appearance of this
lesion is shown in the figure. Which of the following pancreatic disorders is most likely to be present in this patient?
Neuroendocrine tumor
- A 43-year-old man from Stockholm, Sweden, has had low-volume watery diarrhea for the past 3 months. He now has midepigastric
pain. Over-the-counter antacid medications do not relieve the pain. On physical examination, he is afebrile; on palpation, there is
no abdominal tenderness and no masses. An upper gastrointestinal endoscopy shows multiple 0.5- to 1.1-cm, shallow, sharply
demarcated ulcerations in the first and second portions of the duodenum. He is given omeprazole. Three months later, repeat
endoscopy shows that the ulcerations are still present. Which of the following analytes is most likely to be increased in his in serum or plasma? Gastrin