BC ADM Diabetes Pathophysiology 4 — Questions and Answers
Question 1: In hyperosmolar hyperglycemic state (HHS), why is ketoacidosis typically absent despite severe hyperglycemia?
- Counter-regulatory hormones are suppressed in HHS
- Residual insulin secretion is sufficient to suppress lipolysis and ketogenesis but not to control glucose (Correct answer)
- The kidneys clear ketones more efficiently at higher glucose levels
- HHS patients have normal glucagon levels that do not stimulate lipolysis
Correct answer: Residual insulin secretion is sufficient to suppress lipolysis and ketogenesis but not to control glucose
In HHS, enough endogenous insulin remains to inhibit lipolysis and hepatic ketogenesis, preventing significant ketone accumulation despite extreme hyperglycemia.
Question 2: Which pathway of glucose metabolism is responsible for the synthesis of diacylglycerol (DAG), which activates protein kinase C (PKC) and contributes to diabetic vascular complications?
- Pentose phosphate pathway
- De novo glycerol-3-phosphate synthesis from excess glucose (Correct answer)
- Beta-oxidation of fatty acids in endothelial cells
- Hexokinase saturation leading to glucose-6-phosphate accumulation
Correct answer: De novo glycerol-3-phosphate synthesis from excess glucose
Excess intracellular glucose is diverted to glycerol-3-phosphate synthesis, increasing DAG levels that activate PKC isoforms driving vascular inflammation and permeability changes.
Question 3: What is the primary mechanism by which the hexosamine biosynthesis pathway contributes to insulin resistance?
- UDP-GlcNAc O-glycosylates serine/threonine residues on IRS-1, blocking insulin signaling (Correct answer)
- The hexosamine pathway increases ceramide synthesis that inhibits Akt
- Glucosamine directly binds the insulin receptor tyrosine kinase domain
- Excess fructose-6-phosphate diverted to this pathway reduces NADH availability
Correct answer: UDP-GlcNAc O-glycosylates serine/threonine residues on IRS-1, blocking insulin signaling
Excess glucose flux through the hexosamine pathway elevates UDP-GlcNAc, which O-GlcNAc–modifies IRS-1 at sites that compete with phosphorylation, impairing downstream insulin signal transduction.
Question 4: Which type of diabetes results from exocrine pancreatic disease (e.g., chronic pancreatitis or cystic fibrosis) affecting both insulin and glucagon secretion?
- Type 3c diabetes (pancreatogenic diabetes) (Correct answer)
- MODY type 3
- Fibrocalculous pancreatic diabetes
- Type 1.5 diabetes
Correct answer: Type 3c diabetes (pancreatogenic diabetes)
Type 3c diabetes occurs secondary to pancreatic exocrine disease; loss of both alpha and beta cells creates a brittle, hypoglycemia-prone state distinct from type 1 or 2.
Question 5: In mitochondrial diabetes (MIDD), which mutation is most commonly responsible and what clinical feature distinguishes it?
- GCK mutation causing fasting hyperglycemia without progression
- m.3243A>G tRNA-Leu mutation associated with maternally inherited deafness (Correct answer)
- KCNJ11 activating mutation causing neonatal presentation
- PDX1 homozygous mutation causing pancreatic agenesis
Correct answer: m.3243A>G tRNA-Leu mutation associated with maternally inherited deafness
The m.3243A>G mitochondrial mutation impairs oxidative phosphorylation in beta cells and cochlear cells, causing maternally inherited diabetes with sensorineural hearing loss (MIDD).
Question 6: Which mechanism accounts for the increased susceptibility to infections — particularly fungal — in poorly controlled diabetes?
- Hyperglycemia induces lymphocytopenia by osmotic lysis of T cells
- Elevated glucose impairs neutrophil chemotaxis, phagocytosis, and oxidative burst, and provides a rich substrate for pathogen growth (Correct answer)
- Glycosylated complement proteins cannot bind bacterial surfaces
- Insulin deficiency reduces IgG synthesis in plasma cells
Correct answer: Elevated glucose impairs neutrophil chemotaxis, phagocytosis, and oxidative burst, and provides a rich substrate for pathogen growth
Hyperglycemia directly impairs multiple neutrophil functions and creates a high-glucose environment that promotes growth of Candida and other opportunistic pathogens.
Question 7: What is the predominant fuel source used by the brain during prolonged diabetic ketoacidosis once glucose uptake is impaired?
- Lactate derived from anaerobic glycolysis in muscle
- Ketone bodies (beta-hydroxybutyrate and acetoacetate) (Correct answer)
- Branched-chain amino acids released from muscle proteolysis
- Free fatty acids transported across the blood-brain barrier
Correct answer: Ketone bodies (beta-hydroxybutyrate and acetoacetate)
The brain, which normally cannot use free fatty acids, can upregulate ketone body utilization; in DKA, ketones become the primary alternative fuel for cerebral metabolism.
BC ADM Diabetes Pathophysiology 4
In hyperosmolar hyperglycemic state (HHS), why is ketoacidosis typically absent despite severe hyperglycemia?