EAST 501 Lecture Notes - Lecture 9: Gila Monster, Dipeptidyl Peptidase-4, Exenatide

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Lec 3 – Bernard Feb 23
Treatments for Diabetes Part 3
1
INCRETIN-BASED THERAPIES
- incretins = class of hormones in the gut
o the classic response to a meal is due to the convergence of signalling by glucose and also the
incretins (ex. GLP-1) there are also other members of the incretin family (other than GLP-1)
o GLP-1 binds to a Gs-coupled GPCR and activates AC (from ATP) à increase in cAMP (there will be
many AC dependent processes, many of which are mediated by PKA) à the actions only happen in
the context of what glucose is doing
§ if you only give GLP-1 then you are not going to stimulate insulin release
§ GLP-1 potentiates the normal responses that happens in a cell in response to glucose
§ GLP-1 can regulate the synthesis of insulin, can have actions on the Ca channels (voltage
gated) that open when the K channels close
there are other K channels in these cells that regulate membrane conductance,
which can be regulated by GLP-1
GLP-1 can regulate ATP sensitive channels
there are many ways in which GLP-1 mediates glucose dependent insulin secretion
à
GLP-1 and related proteins make glucose more efficient in stimulating insulin
secretion from the beta cell
- incretin is reduced in diabetics due to the decreased sensitivity to GLP-1 and related hormones
- Competitive DPP-4i inhibitors (Gliptins)
o normally: GLP-1 is degraded rather quickly by DPP4 enzymes
o e.g. Sitigliptin, saxagliptin à enzymatic inhibitors à bind to DPP4 and inhibit activity (inhibits from
cleaving GLP-1/degrading)
o DPP-4 is an ectoenzyme (serine protease)
§ cleaves N-terminal amino acids
o inhibits slow degradation of endogenous GLP-1 (and GIP) à causes fast degradation
o also affects related molecules (to GLP-1), like GIP
o inhibit glucagon secretion and hepatic glucose production
o orally available, well-tolerated
- start with Active GLP-1(7-36)amide à cleaved with Dipeptidyl Peptidase IV (DDP4) after the second aa à
inactive GLP-1(9-36)amide
- GLP1 receptor agonists
o Exexdin-4, Exenatide (t1/2 = 2-3h); twice daily SC before meals
§ there are different forms of the agonist, but all in all they bind to the GLP-1 receptor and
activate it
§ needs to be injected (peptide)
§ the Exenatide was purified from the gila monster (lizard black and orange)
a chemist was convinced that he could get bioactive molecules out of the saliva of
the monster and he was right à now very $$
there is a lot of similarity between the GLP-1 of the human and gila monster GLP-1”
aka Exenatide that allows it to bind to the human receptor à it is resistant to
degradation by DPP4 due to the sequence changes
o Liraglutide (t1/2 = 13hour); once daily SC
§ also used for obesity
§ more similarity to the human GLP-1
§ they have done different changes to alter PK = better drug-like characteristics
o Variants of endogenous GLP-1
o Resistance to DPP-4 degradation (because they are analogues)
o Increase insulin release; inhibit glucagon release
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Lec 3 – Bernard Feb 23
Treatments for Diabetes Part 3
2
SUMMARY OF DIABETES DRUGS good study guide!! use for final
* dont worry about SGLT2 inhibitors and AGIs
* the durability column refers to whether the drugs have long term effects àNo= the glycated hemoglobin effects
will go back up (because all these drugs decrease glycated hemoglobin levels initially)
NOTE: most diabetes end up having to take glucose but that doesn’t mean that they wouldnt also take these other
drugs insulin comes at the end of therapy when all else fails
- all the drugs that we have talked about have the goal of treating the hyperglycemia, but it is not just the
hyperglycemia that is the cause of all the problems
- NOTE - TZDs: increase body weight
- this flow chart shows the progression in diagnosis and treatment
o usually Metformin is the first line and is quite good at reducing the fasting glucose levels
o when Metformin is not working as well à keep them on it and add a second agent of the many
classes à Metformin + 2 other agents (ex. SU + TZD)
o usually you dont just treat with the drugs for controlling
glucose levels but also with drugs of other classes
because of the corresponding phenotypes
of the underlying disease
(ex. dyslipidemia + HT)
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Lec 3 – Bernard Feb 23
Treatments for Diabetes Part 3
3
MAJOR COMPLICATIONS OF DIABETES
- in T2DM it is not JUST hyperglycemia that is causing all the problems
- if you have good glycemic control (change in lifestyle or using any of the mentioned drugs) get euglycemia
you can treat most of the microvascular complications (retinopathy/nephropathy), BUT just treating the
hyperglycemia will not tackle the macrovascular problems that ultimately lead to the death of diabetics
(stoke, coronary heart disease) these processes are more dependent on treating atherosclerosis
- T2DM does not usually occur in isolation but with the larger syndromemetabolic syndrome
MICROVASCULAR
- just treating the diabetes does not resolve the macrovascular processes (these are most dependent on
treating the atherosclerosis)
EYE
o High blood glucose and high blood pressure can damage eye blood vessels, causing retinopathy,
cataracts and glaucoma
o >25% of TZDs
KIDNEY
o High blood pressure damages small blood vessels and excess blood glucose overworks the kidneys,
resulting in nephropathy
o 25% of TZDs, renal failure
NEUROPATHY
o Hyperglycemia damages nerves in the peripheral NS. This may result in pain and/or numbness. Feet
wounds may go undetected, get infected and lead to gangrene.
o Well treated with glycemic control
MACROVASCULAR
BRAIN
o Increased risk of stroke and cerebrovascular disease including transient ischemic attack, cognitive
impairment, etc.
o Atherosclerosis
HEART
o High blood pressure and insulin resistance increase risk of coronary heart disease
EXTREMITIES
o Peripheral vascular disease results from narrowing of blood vessels increasing the risk for reduced or
lack of blood flow in legs. Feet wounds are likely to heal slowly contributing to gangrene and other
complications
o Incompletely treated with glycemic control alone
T2DM OFTEN SEEN IN METABOLIC SYNDROME T2DM usually does not occur in isolation
- Insulin resistance
- High TG levels
- Low HDL cholesterol
- High blood pressure
o 85% of T2Ds at or above 50y will have associated HT à major risk factor for associated stroke
MAJOR CONTRIBUTORS TO MACROVASCULAR COMPLICATIONS
- Hyperglycemia
o mainly through the action of AGEs
- Insulin resistance
o think of as going beyond the control of glucose à insulin receptor expressed throughout the body à
insulin can have effect in the endothelial cells independent of the typical effects in liver, fat and
muscle à other cells also become insulin resistant
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Document Summary

Feb 23 incretins = class of hormones in the gut the classic response to a meal is due to the convergence of signalling by glucose and also the incretins (ex. Glp-1 potentiates the normal responses that happens in a cell in response to glucose. Glp-1 and related proteins make glucose more efficient in stimulating insulin secretion from the beta cell incretin is reduced in diabetics due to the decreased sensitivity to glp-1 and related hormones. Glp1 receptor agonists: exexdin-4, exenatide (t1/2 = 2-3h); twice daily sc before meals there are different forms of the agonist, but all in all they bind to the glp-1 receptor and activate it. More similarity to the human glp-1 they have done different changes to alter pk = better drug-like characteristics: variants of endogenous glp-1, resistance to dpp-4 degradation (because they are analogues) Summary of diabetes drugs good study guide!! * don"t worry about sglt2 inhibitors and agis.

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