L26 Drug targets for treating type 2 diabetes

what is the fasting blood glucose level

7 mM

what is the random glucose level with signs of diabetes

11.1 mM

describe type 1 diabetes

• polygenic disorder

• autoimmune destruction of the insulin producing cells

describe type 2 diabetes

• polygenic disorder

• defects in insulin action (obsesity)

• defects in glucose-induced insulin secretion

describe monogenic diabetes

• glucokinase

• ABCC8 (SU), KCNJ11

• HNF4-alpha, HNF1-alpha, PDX1

what are the major life changing complications of diabetes

• retinopathy- sight

• nephropathy -kidneys

• peripheral neuropathy- feeling in feet

• autonomic neuropathy -cardiovascular, gut, urinary

• macrovascular -heart attack, stroke

• decreased life expectancy

• quality of life compromised as a result of chronic hyperglycaemia

what happened in 1921

fred banting and charles best injected a pancreatectomized dog with pancreatic extracts of insulin

what happened in 1922

first injection of a person with insulin

what happened in 1923

commercial production of insulin at Eli Lily and Nordisk by Krogh and Hagedorn

• novel prize to fred banting and CMcleod

what is type 2 diabetes associated with

insulin resistance and compensatory enlargement of islets

what does the genetic background of people with type 2 diabetes determine the extent by which

beta cells can compensate for insulin resistance and enlargement of islets

• individuals with good beta cell capacity can compensate better

Type 2 diabetes develops once the beta cells can no longer…

compensate for insulin resistance

what is the diabetes type 2 risk

balance between lifestyle insult and beta cell compensation (genetics)

what is obesity/calorie excess the most common driver of

T2D

describe lifestyle changes for type 2 diabetes

diet and increased exercise

what are the drugs for type 2 diabetes

either monotherapy or combination therapy

what is the first line drug in monotherapy for type 2 diabetes

Metformin (currently)

what drugs increase insulin release (targeting endocrine islets)

• insulin

• sulfonylureas

• meglitinides

what drugs increase insulin and decrease glucagon release (targeting endocrine islets)

• GLP-1R agonists

• DPP-4 inhibitors

what drugs decrease hepatic glucose production (targeting peripheral insulin resistance)

Metformin

what drugs increase insulin sensitivity (in muscle and fat- targeting peripheral insulin resistance)

Thiazolodinediones

what drugs delay gastric emptying (decreasing circulating glucose)

Pramlintide

what drugs decrease glucose absorption (decreasing circulating glucose)

alpha-glucosidase inhibitors

what drugs bind bile acids in the GI tract (decreasing circulating glucose)

Colesevelam

what drugs block glucose reabsorption in the kidney (decreasing circulating glucose)

SGLT2 inhibitors

what target carbohydrate digestion

AGI, acarbose

what target renal glucose excretion

SGLT2 inhibitors

what target insulin secretion

• sulphonylureas

• GLP-1R agonists

• DPP4 inhibitors

what targets adipose tissue: PPAR gamma

Thiazolidinediones

what targets the liver

Metformin

what are AGIs

alpha-glucose inhibitors

what do AGIs do

inhibit the conversion of oligosaccharides to glucose

what inhibitors are AGIs

competitive (pseudosubstrates)

describe 1st generation AGIs

Acarbose tetrasaccharide with nitrogen between 1st and 2nd glucose residues

• not absorbed

what is absorbed but not metabolised

iminosugar (1-deoxynokirimycin)

describe 2nd generation AGIs

Miglitol analogue of 1-deoxynokirimycin (absorbed)

what are the benefits of AGIs

• decreased intestinal glucose absorption

• decreased glycaemic index of food

• decreased post-prandial blood glucose concentration

• decreased post-prandial triacylglycerides

• no risk of hypoglycaemia

how is abdominal discomfort an adverse effect of AGIs

undigested carbohydrates pass from the small intestine to the colon, mimicking malabsorption

how is fermentation an adverse effect of AGIs

of undigested carbohydrate in the colon

why are AGIs generally used in combination therapy

not sufficiently effective alone because the effect is modest

how do we increase renal glucose excretion

by inhibiting SGLT2 in the kidney

how are GLUTs facilitative transporters

they transport glucose down a concentration gradient

how are SGLTs active transporters

symporters of glucose and Na+ using the Na+ gradient

• Na+ must be pumped out

in a non-diabetic state how much glucose is filtered by the renal glomeruli

180g/day

• all is absorbed

in a diabetic state, how much glucose is filtered and reabsorbed

increased to a maximum of 500g/day

what do SGLT2 inhibitors prevent

re-absorption of glucose

• causing excretion in urine

how much glucose is reabsorbed by SGLT2 in S1

90%

how much glucose is reabsorbed by SGLT2 in S2-3

10%

where is SGLT2 expressed

kidney and proximal kidney tubules

where is SGLT1 expressed

kidney and intestine

what are the adverse effects or risks of SGLT2 and SGLT1

• Increased urine volume (~400ml)

• Risk of UTI

• Risk of genital fungal infections

what is Phlorizin

non-selective, naturally occurring inhibitor of SGLT2 and SGLT1

what does Phlorizin do

• inhibits intestinal and renal absorption of glucose

• lowers blood glucose

what are Sergiflozin and Dapagliflozin

selective inhibitors of SGLT2

what do Sergiflozin and Dapagliflozin do

• cause 40-60% inhibition of renal glucose re-absorption

• urinary excretion of glucose is ~80-120g per day

• lower blood glucose

• weight loss

Sulphonylureas bind to…

SUR1

what is SUR1

sulphonylurea receptor

what is the K_ATP made out of

4 x Kir6.2 units + 4 x SUR1 units

what happens when glucose is low

K_ATP channel is open → no insulin secretion

what happens when glucose is high

increased ATP → channel is closed → increased insulin secretion

what do sulphonylureas do

antagonists which close the K_ATP channels to cause membrane depolarisation and increase insulin secretion

what are the benefits of sulphonylureas

• decreased blood glucose

• increased insulin secretion independently of blood glucose

what are the adverse effects of sulphonylureas

• increased risk of hypoglycaemia

• weight gain

• cardiovascular events

describe the incretin receptors

GLP-1R agonists → GLP-1 receptor

Dipeptidyl peptidase-4 inhibitors →

prevent incretin degradation

what are incretins

intestinal peptides produced in response to food that stimulate insulin secretion

where are K-cells

proximal

where are L-cells

distal

what do K-cells secrete

Glucose -dependent insulinotropic peptide (GIP)

how long is Glucose -dependent insulinotropic peptide

42 amino acids long (1-42)

what do L-cells secrete

Glucagon-like peptide-1 (GLP-1)

how long is Glucagon-like peptide-1 (GLP-1)

37 amino acid peptide (7-37;7-36)

where are GIP/GLP-1 receptors expressed

pancreas, gut, kidney, brain

what are GLP-1R agonists

• exanatide

• liraglutide

• semaglutide

what are GIPR agonists

Tirzepatide (dual GLP-1R/GIPR agonist)

how do GLP-1 receptors affect the CNS

• decreased calorie intake

  • energy expenditure

how do GLP-1 receptors affect the heart

increased heart rate

how do GLP-1 receptors affect the pancreas

• increased insulin secretion

• decreased glucagon secretion

how do GLP-1 receptors affect the stomach/gut

• decreased gastric emptying

• chylomicron production

how do GLP-1 receptors affect the adipose tissue

no prominent direct effect

how do GLP-1 receptors affect the kidneys

decreased Na excretion (transient)

how do GLP-1 receptors affect the bones

increased meal-associated bone remodelling

what are indirect effects of GLP-1 receptors in the liver

• increased glycogen and glucose uptake

• decreased hepatic glucose production

• decreased intrahepatic fat

how do GIP receptors affect the CNS

decreased calorie intake

how do GIP receptors affect the heart

increased heart rate

how do GIP receptors affect the pancreas

• increased insulin secretion

• increased glucagon secretion

how do GIP receptors affect the stomach/gut

no prominent direct effect

how do GIP receptors affect the adipose tissue

• increased glucose and TG uptake

• increased TG storage

how do GIP receptors affect the kidneys

no prominent dominant effect

how do GIP receptors affect the bones

increased meal-associated bone remodelling

how do GIP receptors affect the liver indirectly

• increased glycogen and glucose uptake

• decreased hepatic glucose production

what happens when islet beta-cells bind to GLP1-R

• increased cAMP

• increased protein kinase A

• increased cAMP guanine nucleotide exchange factor (GEF/EPAC)

• increased Ca2+

• decreased K_ATP secretion

• increased insulin secretion

• increased PI3K → AKT(PKB)

what does increasing PI3K → AKT (PKB) from GLP-1 do

• increases gene transcription

• decreases apoptosis

• stimulates cell growth

what does GLP-1 do

• enhances glucose stimulated insulin release

• increases beta-cell mass

• increases insulin biosynthesis

what are incretins degraded by

DPP-4 (dipeptidyl peptidase-4)

what happens when you degrade active incretin GIP(1-42) with DPP-4

becomes inactive incretin GIP(3-42)

what happens when you degrade active incretin GIP-1 (7-37) with DPP-4

becomes inactive incretin GLP(9-37)

what happens when you degrade active incretin GIP-1 (7-36) with DPP-4

becomes inactive incretin GLP(9-36)

both GIP and GLP-1 are inactivated by DPP-4 which cleaves…

the first 2 residues

what 2 forms does Dipeptidyl-peptidase 4 exist in

• membrane-anchored extracellular enzyme

• soluble form which also retains catalytic activity