Marian roberts Flashcards
How does obesity contribute to insulin resistance?
- Excess free fatty acids
- overwhelm the livers fatty acid oxidative capacity and they accumulate to form toxin DAG intermediates which downregulate intracellular insulin signalling by activating protein kinase C -> inhibits phosphorylation of IRS’s -> no translocation of GLUT transporters -> hyperglycemia - Adipokine imblanace
-> Insulin-sensitising hormone Adiponectin is reduced in obesity. Therefore there is unopposed action of adipokines which promote insulin-resistance. - Inflammasome activation
- Accumulation of FFA in macrophages/beta cells -> inflammasome activation -> IL-1B release -> release of more pro-inflammatory mediators -> Beta cell dysfunction and reduced insulin signalling cascade.
how do excess free fatty acids in particular cause insulin resistance/hyperglycemia
Central adipose tissue, particularly visceral fat seen in obesity, is highly lipolytic, leading to increased free fatty acids (FFAs) in the blood. This is exacerbated by disinhibition of hormone-sensitive lipase, which increases lipolysis.
Excess FFAs saturate the liver’s fatty acid beta-oxidation pathway, causing the accumulation of toxic diacylglycerol (DAG) intermediate metabolites. DAG activates protein kinase C (PKC), which impairs insulin receptor signaling by phosphorylating serine residues on insulin receptor substrate-1 (IRS-1), thereby reducing its ability to propagate insulin’s effects.
This impairment in insulin signaling leads to the disinhibition of phosphoenolpyruvate carboxykinase (PEP -CK), increasing gluconeogenesis. Elevated gluconeogenesis contributes to hyperglycemia.
Furthermore, FFAs compete with glucose for oxidation in the muscle. This competition inhibits glycolytic enzymes, leading to reduced glucose breakdown and increased blood glucose levels, contributing to hyperglycemia.
What is HbA1c and what does it tell us?
What are the ranges used?
What conditions can affects the results?
HbA1c is glycated hemoglobin - hemoglobin that is chemically/non-enzymatically bound to glucose.
It tells us the average blood glucose levels over the past 2-3 months.
Normal <39 mmol/mol
Pre-diabetic 39-47 mmol/mol
Diabetic >48 mmol/mol
Falsely high (false negs)
-Anything that prolongs the RBC lifespan
(i) Splenectomy
(ii) Iron/b12 deficiency
(iii) Aplastic anemia
False low
-pregnancy (increased blood vol)
-hemolytic anemia
-splenomegaly
3 occasions when a diagnosis of diabetes mellitus can be made
- Random glucose conc > 11mmol/L with classical signs and symptoms
- Fasting blood glucose conc >7 mmol/L on more than 1 occasion
- OGTT - Glucose levels > 11 mmol/L, 2 hours after carbohydrate loading.
What is meant by the “renal threshold for glucose”
How is glucose normally resorbed back into blood?
The renal threshold for glucose refers to the BLOOD GLUCOSE CONCENTRATION at which the kidneys begin to secrete glucose into the urine, having reached capacity of glucose resorption.
This leads to glucosuria; Rate of glucose filtrate > rate for glucose resorption.
Normal resorption
- Glucose transporters within the PCT (SGLT 1/2).
- Their activity is maintained by the sodium gradient created by Na+/K+ ATPase pumps on basolateral side (opposite side of cell to the lumen).
-Glucose exits the epithelial cells via GLUT 2 transports-> back into blood stream
List 4 common organisms that cause UTI
(i) E.coli (most common)
(ii) Pseudomonas aeruginosa
(iii) Klebsiella pneumonia
(iv) Enterococcus faecalis.
how are diabetic ulcers classified? what arteries are most commonly affected to give rise to diabetic ulcers?
Neuropathic: due to peripheral/autonomic neuropathy
Ischemic: due to PAD and microvascular changes
Neuroischemic: mixture of both
Most commonly affected:
Tibial and fibular, with sparing of the dorsalis pedis
list 4 factors that put diabetics at higher risk of ulcers
Peripheral neuropathy
Structural foot changes
Reduced healing capacity/immunity
High risk of PAD
What are the signs of hyperglycemic hyperosmolar state?
1.Hyperglycemia
2.Serum osmolality >320 mOsm/kg
3.Electrolyte imbalance, particularly low sodium and potassium
4.vomiting
5.severe dehydration + polyuria
What is meant by anion gap?
The difference between the concentration of measured cations and anions. Normal range is 6–12 mEq/L
Outline 5 ways by which exocrine glands can be classified
- Based on structure
- Cell number (unicellular/multicellular)
- Nature of secretory product (serous, mucous, mixed)
- Manner of secretion (apocrine, merocrine, holocrine)
Describe the exocrine and endocrine portion of the pancreas
The exocrine portion (>95%) is organized into clusters of acinar cells, known as acini, which surround a series of ducts
The acinar epithelial cells produce enzymes which are stored within lamellar granules at the apical surface of the cell. The enzymes include Lipases, Proteolytic, Amylolytic and nucleolytic enzymes. The acinar cells also release H+ ions. These are released when stimulated by CCK of the duodenum.
Centro-acinar (cuboidal) cells line the small ducts. These secrete bicarbonate when stimulated by secretin. Larger ducts are lined by columnar cells which produce mucous.
The contents travel to the duodenum via the intercalated duct -> intralobular duct -> main pancreatic duct.
The luminal pH is kept at 8.0. This is because with release of H+ ions/ enzymes from the acinar cells, acid sensing receptors of centro-acinar cells cause counter release of bicarbonate.
The endocrine portion (2-5%)
- 3 cell types organised into plates surrounded by vessels.
- Alpha cells (20%) on the periphery - glucagon in granules
-Beta cells (75%) on inside- insulin + C peptide
-Delta cells (5%)- somatostatin (inhibits GI hormones)
3 factors that contribute to diabetic neuropathy
- AGE - Rage
-causes basement membrane thickening, pro-inflammatory cytokine release, endothelial dysfunction, ROS production. - Increase in intracellular sorbitol
- increased uptake of glucose which is then metabolised to form sorbitol by aldose reduction -> water influx/oxidative damage. - Protein kinase C activation
- hyperglycemia causes increased intracellular diacyglycerol (DAG) which leads to activation of protein kinase c -> NADPH activity causes oxidative stress. Also causes increased VEGF release.
