L32 Clinical Pharmacology of T2DM

Insulin homeostasis: - Under fasting conditions, insulin is released in a [blank_start]pulsatile[blank_end] manner every [blank_start]10-14[blank_end] mins​. - In response to increased glucose:​ Phase 1:​ insulin release within [blank_start]seconds[blank_end]​, peak at [blank_start]3-5[blank_end] mins​ Phase 2: more [blank_start]gradual[blank_end] release with a [blank_start]lower[blank_end] peak​

Choose the incorrect statement about insulin.

Which of these is not a diabetic medication used in NZ?

Sulphonylureas stimulate insulin release by binding to a specific site on the beta islet cell's [blank_start]KATP channel[blank_end] complex (SUR) and [blank_start]inhibiting[blank_end] its activity. Inhibition causes cell membrane [blank_start]depolarisation[blank_end] and insulin [blank_start]secretion[blank_end]. Their effect declines over [blank_start]time[blank_end] because of down-regulation of cell surface [blank_start]receptors[blank_end] and​ progression of beta islet cell failure​. Side effects are hypoglycaemia and initial [blank_start]weight[blank_end] gain​, less-common side effects include nausea, vomiting, cholestatic jaundice, and agranulocytosis.​

DPP-4 is dipeptidyl peptidase 4, a serine protease that is widely distributed throughout the body​. It [blank_start]inactivates[blank_end] GLP-1​. Inhibiting [blank_start]DPP-4[blank_end] cause increase in plasma [blank_start]GLP-1[blank_end], resulting in higher insulin secretion.​

Alpha glucosidase inhibitors reduce the intestinal [blank_start]absorption[blank_end] of starch, dextrin, and disaccharides ​by inhibiting the action of [blank_start]α-glucosidase[blank_end] in the intestinal brush border​. They are taken [blank_start]before[blank_end] each meal and not absorbed​. They are often used in [blank_start]combination[blank_end] with other meds. Side effects are malabsorption, flatulence, diarrhoea, and abdominal bloating​.

Biguanides include metformin. Metformin reduces [blank_start]hepatic[blank_end] glucose production by [blank_start]reducing[blank_end] gluconeogenesis.​ It activates [blank_start]AMP-dependent protein kinase[blank_end] (AMPK), leading to stimulation of:​ - hepatic [blank_start]fatty acid[blank_end] oxidation - [blank_start]glucose[blank_end] uptake - non-oxidative glucose [blank_start]metabolism[blank_end] - [blank_start]reduction[blank_end] of lipogenesis and gluconeogenesis. ​ Side effects are GI: nausea, indigestion, abdominal cramps, bloating, diarrhoea​.

Thiazolidinediones are PPAR-gamma inhibitors that cause insulin sensitisation. The PPARγ receptor is a [blank_start]nuclear hormone receptor[blank_end] involved in the regulation of genes related to [blank_start]glucose and lipid metabolism[blank_end].​ PPARγ receptors are expressed primarily in adipose tissue. They promote uptake of circulating fatty acids into [blank_start]fat[blank_end] cells, and glucose uptake into [blank_start]muscle and adipose[blank_end] tissue.​ They [blank_start]reduce[blank_end] insulin resistance. Side effects are weight [blank_start]gain[blank_end] and oedema​.

SGLT2 is a Na+-glucose cotransporter located in the proximal portion of the [blank_start]renal[blank_end] tubule. It reabsorbs [blank_start]glucose[blank_end]. SGLT2 inhibitors [blank_start]block[blank_end] glucose transport thus [blank_start]lowering[blank_end] blood glucose.​ Side effects: - A 1%-2% increase in lower [blank_start]urinary tract[blank_end] infections.​ - A 3%-5% increase in [blank_start]genital[blank_end] mycotic infections. ​ - Mild [blank_start]diuresis[blank_end], which can lead to hypotension. ​ - Effectiveness decreases by 40%–80% in kidney disease (GFR 60–30 mL/min). ​