Chapter 22: Obesity

Question 1

What factors are included in the metabolic syndrome?

Answer 1

Abdominal adiposity with increased waist circumference
Mild HTN
Impaired fasting plasma glucose levels
Dyslipoproteinemia (reduced HDL, increased TG)

Question 2

The insulin receptor activates what intracellular system?

Answer 2

Tyrosine kinase -> signaling kinases -> glucose transport proteins to plasma membrane

Also MAP kinases.

Question 3

What factors contribute to insulin resistance?

Answer 3

High visceral-abdominal adiposity

Increased NEFA and TNF-alpha -> intracellular TG, DAG, and acyl-CoA derivatives -> Serine kinase activation -> blockade insulin signal

Reduced adiponectin -> reduced insulin activity

Impaired mitochondrial lipid oxidation -> increased intracellular TG

Question 4

What changes occur in type 2 diabetes mellitus?

Answer 4

Insulin resistance + inadequate insulin secretion from pancreas.

Beta-cells unable to meet body’s insulin demand.
Islet amyloid formed by amylin - also secreted by beta cells. Fibrous tissue.

Question 5

What is maturity-onset diabetes of the young?

Answer 5

MODY - rare autosomal dominant form of inherited diabetes with genetic beta-cell defects

Question 6

What are the normal actions of insulin?

Answer 6

Increased glucose uptake by skeletal muscle and adipose tissue.
Suppressed hepatic glucose production (reduced gluconeogenesis, increased glycogen synthesis, reduced hepatic glucagon response, reduced pancreatic glucagon release)

Question 7

What sorts of dysfunction might beta cells have?

Answer 7

Impaired insulin secretion after glucose uptake
Impaired release of newly synthesized insulin
Reduced beta cell mass

Question 8

What are incretins?

Answer 8

GI peptides secreted in response to carbohydrate ingestion.

Increases insulin secretion, reduces glucagon secretion, and reduces appetite.

Inactivated by DPP-4 enzyme.

Incluse GIP and GLP-1. Reduced secretion in T2DM

Question 9

What are some therapeutic options for T2DM?

Answer 9

1. Insulin-sensitizing drugs to treat insulin resistance and hyperinsulinemia
2. Treat beta-cell dysfunction and hyperglycemia with insulin secretagogues, incretin mimetics, and exogenous insulin.

Question 10

What occurs in type 1 diabetes mellitus?

Answer 10

Autoimmune destruction of beta-cells in pancreatic islets of langerhans. Significant when 90% of cells destroyed.

Question 11

What does the histology of T1DM show?

Answer 11

Destroyed islets resemble ribbonlike cords.
Little fibrosis and amylin deposition.
Exocrine pancreas has diffuse fibrosis and acinar cell atrophy.

Question 12

What are the ketone bodies?

Answer 12

Acetoacetic acid, acetone, and beta-hydroxybutyric acid.

Question 13

What is polyphagia?

Answer 13

Weight loss despite increased appetite.

Unregulated catabolism of fat, protein, and carbs.

Question 14

What can uncontrolled glucosuria and dehydration cause?

Answer 14

Progressive acidosis -> coma and death.

Question 15

What genetic factor increases susceptibility for T1DM?

Answer 15

HLA-DR3 and

HLA-DR4

Question 16

What molecules are autoantibodies against in T1DM?

Answer 16

Insulin, glutamic acid decarboxylase, and insulinoma-associated protein (IA-2)/islet cell antigen 512 (ICA-512)

Question 17

What defines pre-type 1 diabetes?

Answer 17

Anti-islet cell antibodies before insulin production decreases.

Question 18

What are the most common sells seen in a histology of insulitis?

Answer 18

Mononuclear cells - CD8+ cells against beta cells.

Question 19

What environmental factors correlate with T2DM?

Answer 19

Late fall/early winter.
Puberty age.
Acute bacterial/viral illness -> Coxsackie B and mumps viruses (molecular mimicry).

Question 20

What can be controlled with control of blood glucose (macro or micro vascular issues?)

Answer 20

Macrovascular problems - atherosclerosis - less prevented by control of blood glucose. Microvascular more successful.

Question 21

What are mechanisms of diabetic vascular damage?

Answer 21

Excess ROS

Protein glycation/nonenzymatic glycosylation (hemoglobin, crystalline lens, basement membrane)

Question 22

What is the aldose reductase pathway?

Answer 22

Needed for increased glucose uptake in non-insulin dependent tissues.

Glucose + NADPH -> Sorbitol + NADP. Sorbitol accumulates.

Question 23

What protein does DAG activate? What are the effects?

Answer 23

Protein kinase C is activated by DAG.
Increases ECM and cytokine production, increased microvascular contractility and permeability, proliferation of endothelial and smooth muscle cells, insulin resistance, activation of PLA2 and reduced Na/K ATPase activity.

Question 24

How does diabetes promote atherosclerosis?

Answer 24

Direct effect hyperglycemia on cell wall
High insulin concentration
Exacerbation of atherosclerotic risk factors (dyslipoproteinemia, HTN, hypercoagulability).

Question 25

What complications do microvascular disease cause in diabetes?

Answer 25

Arteriolosclerosis and capillary basement membrane thickening cause renal failure and blindness. Impair healing of chronic ulcers, reduce blood flow to heart, renal and retinal damage.

Question 26

What characteristic findings are seen in diabetic nephropathy?

Answer 26

Kimmelstein-Wilson nodules: Deposition of basement membrane-like material in spherical masses. Microalbuminemia and proteinuria.

Slow disease with ACEI and ARBs.

Question 27

What are the stages of diabetic nephropathy?

Answer 27

Initial increased pain sensation
Then loss of fine touch, pain, and position senses.
Autonomic dysregulation -> postural hypotension, GI problems, erectile dysfunction.

Question 28

What are common infections predisposed by diabetes?

Answer 28

TB and purulent infections.

UTI, pyelonephritis, renal papillary necrosis, mucormycosis.

Question 29

What is gestational diabetes?

Answer 29

Insulin resistance during pregnancy with a beta cell defect.
Risk for mother and child.

Poor control of gestational diabetes causes large baby -> C section. Chance of heart, great vessel, and neural tube defects.

May also have postnatal hypoglycemia.