lecture 26 Flashcards by abbie forsyth

what is type 1 diabetes?

-polygenic disorder
-autoimmune destruction of insulin producing cells

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what is type 2 diabetes?

-polygenic disorder
-defects in insulin action (obesity)
-defects in glucose-induced insulin secretion

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what are the complications with diabetes?

retinopathy (sight)
nephropathy (kidney function)
peripheral neuropathy (feet)
autonomic neuropathy (cardiovascular, gut)
macrovascular (heart attack, stroke)

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which type of diabetes associates with obesity?

type 2

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why does obesity increase diabetes risk?

-associated with insulin resistance and enlargement of islets
-balance between lifestyle and B cell compensation (genetics)

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when does type 2 diabetes develop?

once beta cells can no longer compensate for insulin resistance

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how is type 2 diabetes developed from unhealthy lifestyle?

-increased obesity
-increased insulin resistance
-susceptible beta cells
-beta cell dysfunction and failure
-hyperglycaemia
-type 2 diabetes

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what is the therapy for type 2 diabetes?

-lifestyle changes (diet and increased exercise)
-drugs - mono therapy (metformin) or combination

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how is carbohydrate absorption targeted?

-inhibiting carb digestion with alpha-glucoside inhibitors (AGIs)

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what are AGIs?

competitive inhibitors
convert oligosaccharides to glucose
1st gen -> acarbose -> not abosrbed
2nd gen -> miglitol ->absorbed

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what are the benefits of AGI?

-decreases intestinal glucose absorption
-decreases glycemic index of food
-decreases post prandial blood (glucose) and triglycerides
-no risk of hypoglycaemia (too low glucose levels)

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what are the adverse effects of AGI?

-abdominal discomfort as undigested carbs move from small intestine to colon
-fermentation of undigested carbs in colon

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how is renal glucose excretion increased?

-by inhibiting SGLT2 in kidney

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what do SGLTs do?

They are symporters of glucose and sodium > use sodium gradient (‘active transporter’ > Na+ must be pumped out)

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what is the function of SGLT2 inhibitors?

prevent reabsorption of glucose causing excretion in urine

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where is SGLT2 expressed?

kidney

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where is SGLT1 expressed?

kidney and intestine

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what are the inhibitors of SGLT2?

-phlorizin (non selective naturally occuring)
-sergiflozin and dapagliflozin (selective inhibitor)

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what does phlorizin do?

inhibits intestinal and renal absorption of glucose
lowers blood glucose
inhibits SGLT1 and 2

what does sergiflozin and dapagliflozin do?

-cause inhibition of renal glucose re-absorption
-lower blood glucose
-weight loss
-inhibits SGLT2

what are the adverse effects/risks of using SGLTs?

increased urine volume
risk of urinary tract infections (UTIs)
risk of genital fungal infections

how is insulin secretion targeted?

sulphonylureas
GLP-1R agonists
DPP4 inhibitors

how do sulphonylureas work?

-bind to SUR1
-close the K-ATP channel
-membrane depolarisation
-increase insulin secretion

what are incretins?

intestinal peptides produced in response to food that stimulate insulin secretion
GIP and GLP1

what is GIP?

-glucose dependent insulinotropic peptide -secreted from K cells in small intestine -inhibits gastric motility, stimulates insulin secretion -has inhibitory effect on appetite

what is GLP1?

-glucagon like peptide 1 -secreted from L cells of colon -stimulates insulin secretion by beta cells -suppresses appetite in brain -used in treatment of obesity

what is an example of a GIP agonist?

tirzepatide

what is an example of a GLP-1 agonist?

-exenatide -liraglutide -semaglutide

what is the mechanism of action of GLP-1 on islet beta cells?

1. bind to GLP-1 receptor 2. increases cAMP 3. increases PKA 4. increases cAMP guanine nucleotide exchange factor 5. increased ca2+ 6. decreased K ATP channel 7. increased insulin secretion

what causes degradation of incretins?

DPP-4 (dipeptidyl peptidase 4) cleaves the first 2 residues to become inactive

what 2 forms does DPP4 exist as?

1. membrane anchored extracellular enzyme 2. soluble form (retains catalytic activity)

what are the benefits of sulphonylureas?

-decreases blood glucose -increases insulin secretion

what are the risks of sulphonylureas?

-increased risk of hypoglycaemia -increased weight gain -increased cardiovascular events

what are the benefits of GLP-1R agonists and DPP4 inhibitors?

-decrease blood gluciose -increased insulin secretion -decrease glucagon secretion -no risk of hypoglycaemia -decreased food intake and body weight

what are the potential risks of GLP-1R agonists and DPP4 inhibitors?

pancreatitis or pancreatic cancer gastric discomfort

what are the two ways adipose tissue expands in obesity?

1. fat cell hypertrophy (increases in cell volume) 2. fat cell hyperplasia (increase in cell number/adipogenesis)

what happens when adipocytes attain their max capacity of lipid storage?

lipid leaves are raised in blood and other tissues

what are PPAR-gamma drugs?

favour adipocyte proliferation and further lipid storage prevents damage by lipids in other organs

what do TZDs do?

-decrease blood glucose -decrease blood insulin -decrease blood triglycerides -increase insulin sensitivity

what does PPAR gamma do?

transcription factors that promotes adipocyte proliferation and differentiation

how is PPAR gamma activated?

1. ligand binding to PPAR gamma 2. heterodimer with retinoid acid receptor 3. recruitment to PPRE on DNA promoter 4. recruitment of co-activator (eg. P300-histone acetylase) 5. acetylation of histones exposes chromatin 6. increased transcription of PPAR gamma target genes

what are the benefits of TZDs?

-lower blood glucose and insulin -increased insulin sensitivity in obesity

what are the risks of TZDs?

increases body weight can cause liver damage heart attack risk

which TZD is currently in clinical use?

pioglitazone

what are the biological effects of metformin?

-decreased hepatic glucose production -increased fatty acid oxidation -increased insulin sensitivity -increased glucose utilisation

what is the mechanism of metformin?

1. enter cells via OCT1 2. accumulates in energised mitochondria (-ve charge inside) 3. inhibits complex I 4. decreases ATP/ADP (decreases energy for gluconeogenesis) 5. increases AMP (inactivates adenyl cyclase, prevents glucagon signalling, decreases gluconeogenesis) 6. AMPK activation (increased fatty acid oxidation, decreased fatty acid synthesis)