Pathology of Diabetes and Diabetes-Related Pathologies

Question 1

Of what is the endocrine pancreas composed?

Answer 1

• clusters of cells termed islets of Langerhans.
• a single islet consists of multiple cell types, each producing one type of hormone.
• INSULIN is secreted by BETA cells; lie in the CENTER of islets.

Question 2

What is INSULIN?

Answer 2

• the major anabolic hormone, which up-regulates insulin-dependent GLUT4 on skeletal muscle and adipose tissue (decreasing serum glucose).
• increased glucose uptake by tissues leads to increased glycogen synthesis, protein synthesis, and lipogenesis.

Question 3

What is GLUCAGON?

Answer 3

• hormone secreted by ALPHA cells, which opposes insulin in order to increase blood glucose (e.g. states of fasting) via glycogenolysis and lipolysis.

Question 4

** What is Type 1 Diabetes Mellitus (T1DM)?

Answer 4

• AUTOIMMUNE DESTRUCTION of BETA cells by T LYMPHOCYTES (type IV hypersensitivity) causing an insulin deficiency, which leads to a metabolic disorder characterized by hyperglycemia.
• characterized by INFLAMMATION of ISLETS.
• INSULINITIS= necrosis of islets and lymphocytic infiltration.

Question 5

With what HLAs is T1DM associated?

Answer 5

• HLA-DR3 and DR4

Question 6

In T1DM, can autoantibodies against insulin be present years before clinical disease develops?

Answer 6

• YES often.

Question 7

When does T1DM manifest?

Answer 7

• in CHILDHOOD with features of insulin deficiency.

Question 8

** What are the clinical signs of T1DM?

Answer 8

• high serum glucose (lack of insulin leads to decreased glucose uptake by fat and skeletal muscle).
• weight loss, low muscle mass, and polyphagia (unopposed glucagon leads to gluconeogenesis, glycogenolysis, and lipolysis, which further exacerbates hyperglycemia).
• polyuria, polydispsia, and glycosuria (hyperglycemia exceeds renal ability to resorb glucose; excess filtered glucose leads to osmotic diuresis).

Question 9

How do you treat T1DM?

Answer 9

• life long insulin

Question 10

What is a feared complication of T1DM?

Answer 10

• diabetic ketoacidosis (DKA)

Question 11

** What is diabetic ketoacidosis (DKA)?

Answer 11

• excessive serum ketones that often arises with stress (e.g. infection); epinephrine stimulates GLUCAGON secretion, increasing lipolysis, along with gluconeogenesis and glycogenolysis.

Question 12

What happens in DKA with increased lipolysis?

Answer 12

• increased FFAs, which the liver converts to KETONE BODIES (B-hydroxybutyric acid and acetoacetic acid).

Question 13

** What are the clinical features of DKA?

Answer 13

• HYPERGLYCEMIA (greater than 300 mg/dL) due to stimulation of gluconeogenesis and glycogenolysis.
• anion gap METABOLIC ACIDOSIS (due to excess ketones in the blood)
• HYPERKALEMIA bc insulin is required for driving K+ into cells, and the body tries to buffer the acidic blood by driving H+ into the cells in exchange for K+ out into the blood; note much of the K+ will be lost in the urine.
• KUSSMAUL RESPIRATIONS (trying to blow off the acidosis), dehydration, nausea, vomiting, mental status changes, and FRUITY SMELLING BREATH

Question 14

*** How do you treat DKA?

Answer 14

• FLUIDS (corrects dehydration from plyuria)
• INSULIN
• ELECTROLYTES (potassium)

Question 15

** What is type 2 Diabetes Mellitus (T2DM)?

Answer 15

• end-organ INSULIN RESISTANCE leading to metabolic disorder characterized by HYPERGLYCEMIA.

Question 16

Is T1DM or T2DM more common?

Answer 16

• T2DM by FAR

* incidence is rising!

Question 17

In whom does T2DM arise?

Answer 17

• OBESE middle-aged adults.

- Obesity leads to DECREASED numbers of insulin-RECEPTORS.

Question 18

Is there a genetic predisposition for T2DM?

Answer 18

• YES, higher than T1DM

Question 19

Will insulin levels be high or low, in the early stages of T2DM?

Answer 19

• HIGH bc the islet cells of the pancreas are producing more in an attempt to overcome the insulin resistance of the cells.

Question 20

What happens to insulin later in T2DM?

Answer 20

• insulin deficiency due to BETA cell EXHAUSTION.

Question 21

** What will you see on histology of the pancreas in T2DM?

Answer 21

• AMYLOID deposition in islets.

Question 22

** What are the clinical features of T2DM?

Answer 22

• polyuria
• polydipsia
• hyperglycemia
• often clinically silent

Question 23

How do you diagnose T2DM?

Answer 23

• random glucose greater than 200 mg/dL
• fasting glucose greater than 126 mg/dL
• glucose tolerance test greater than 200 mg/dL 2 hours after glucose load.

Question 24

How do you treat T2DM?

Answer 24

• weight loss
• drug therapy to counter insulin resistance
• insulin in later stages of disease

Question 25

What is hyperosmolar non-ketotic coma? (risk of T2DM)

Answer 25

• high glucose (greater than 500 mg/dL) leads to life-threatening diuresis (due to overwhelming glucose in the filtrate, pulling water along with it) with hypotension and coma.
• ketones are absent due to small amounts of circulating insulin.

Question 26

** What are the 2 long-term consequences of diabetes?

Answer 26

1. NONENZYMATIC GLYCOSYLATION (NEG) of vascular basement membranes (aka you are just sticking sugar to the vessel walls).
2. OSMOTIC DAMAGE

Question 27

** What complications can arise from nonenzymatic glycosylation (NEG) caused by diabetes?

Answer 27

• NEG of large and medium sized vessels MACROvascular disease= ATHEROSCLEROSIS; CVD is the leading cause of death among diabetics and PVD is the leading cause of nontraumatic amputations in diabetics.
• NEG of small vessels (MICROvascular disease)= HYALINE ARTERIOLOSCLEROSIS.
• NEG of hemoglobin= HbA1c

Question 28

** What complications can arise in the kidneys due to NEG of small vessels (MICROvascular disease) in diabetes causing hyaline arteriolosclerosis (thickening of basement membrane; mostly type IV collagen)?

Answer 28

• small scarred kidneys with a granular surface
• preferential involvement of the EFFERENT arterioles leads to glomerular hyperfiltration injury with microalbuminuria that eventually progresses to NEPHROTIC syndrome (characterized by KIMMELSTIEL-WILSON nodules in glomeruli).
• can eventually lead to chronic renal failure.

Question 29

What is important about HbA1c?

Answer 29

• it is an important marker of glycemic control

Question 30

** How does osmotic damage occur as a long-term consequences of diabetes? (VERY HIGH YIELD)

Answer 30

• glucose freely enters into Schwann cells (which myelinate peripheral nerves), pericytes of retinal blood vessels, and the lens.
• ALDOSE REDUCTASE converts glucose to SORBITOL, resulting in osmotic damage.
• this leads to PERIPHERAL NEUROPATHY (can lead to infections), IMPOTENCE, BLINDNESS, AND CATARACTS.

Question 31

What is the leading cause of blindness in the developed world?

Answer 31

• diabetes

Question 32

What are pancreatic endocrine tumors?

Answer 32

• tumors of the islet cells of the pancreas

Question 33

Of what are pancreatic tumors often a component?

Answer 33

• MEN1 (along with parathyroid hyperplasia and pituitary adenoma).
• REMEMBER THE 3 P’s

Question 34

What is an insulinoma?

Answer 34

• tumor that produces insulin causing episodic hypoglycemia with mental status changes that are relieved by glucose.

Question 35

What lab studies will you see with insulinoma?

Answer 35

• increased insulin
• decreased glucose
• increased C-peptide (produced along with insulin)

Question 36

What if insulin is high but C-peptide is low?

Answer 36

• pt is likely injecting them-self with insulin to seek the attention of medical professionals.

Question 37

What is a gastrinoma?

Answer 37

• tumor that produces gastrin (goes to the parietal cells of the stomach, causing them to produce HCl via proton pumps).
• will see treatment-resistant peptic ulcers (ZE syndrome)
• ulcers may be multiple and can extend into the jejunum.

Question 38

What is a somatostatinoma?

Answer 38

• tumor that produces somatostain (inhibits gastrin causing ACHLORHYDRIA, and also inhibits cholecystokinin leading to cholelithiasis and steatorrhea due to lack of gallbladder contraction).

Question 39

What is a VIPoma?

Answer 39

• tumor that produces vasoactive intestinal peptide (VIP) resulting in watery diarrhea, achlorhydria (due to inhibition of gastric acid secretion), and hypokalemia.

Question 40

In T1DM, what may be a target of autoantibodies?

Answer 40

• glutamic acid decarboxylase (GAD) in the islets of langerhans

Question 41

What cytokines can induce BETA cell apoptosis in T1DM?

Answer 41

• IFN, TNF, and IL-1

Question 42

In T1DM, is there a linkage to MHC Class II HLA genes?

Answer 42

• YES

* not in T2DM

Question 43

** What are the 3 metabolic pathways by which damage occurs in diabetes?

Answer 43

1. advanced glycation end products= formed from reaction between intracellular glucose derived dicarbonyl precursors with amino group of intracellular and extracellular proteins, leading to cross linking between peptides of the ECM (decreasing elastin, contribute to endothelial injury, trap LDL, increase endothelial permeability, and increase procoagulant activity).
2. activation of protein kinase C= intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC, producing VEGF (leads to neovascularaiztion in diabetic retinopathy), increases activity of vasoconstrictor endothelin 1, and decreases vasodilator endothelin nitric oxide synthase.
3. disturbance in polyol pathways= increases cell response to oxidative injury as glucose is converted to fructose, which requires NADPH as a cofactor; NADPH is also a cofactor in the production of glutathione, an antioxidant. Thus you are depleting this important cofactor.

Question 44

What is the major cause of death in DM?

Answer 44

• MI from atherosclerosis

Question 45

Does pyelonephritis (inflammation of kidneys) occur more frequently in diabetics?

Answer 45

• YES leading more frequently to NECROTIZING PAPILLITS.