Kaarten: CAT1: minor; internal medicine | Quizlet

Type 1 diabetes is a heterogenous disease where an event in combination with genetical predisposition leads to auto-immuun T-cell activation. This activation targets the beta-cells in the pancreas. Beta-cell destruction is further exacerbated by pro-inflammatory cytokines and reactive oxygen which attract cells lymfoid cells. A number of auto-antigen may play a role in the initiation or progression of islet damage.

During the progression of beta-cell destruction (which can take month or years) a subject remains asymptomatic until a large number of beta-cells is lost.

Can you explain the pathogenesis of type 1 diabetes?

The classic triumvirate is; pancreas, liver and skeletal muscle.

pancreas; impaired insuline secretion

liver; increased hepatic glucose production (HGP)

muscles; decreases glucose uptake

Name 3 organs involved in the pathogenesis of type 2 diabetes.

Known type 2 diabetes genes only explain 10% of the genetic predisposition. Type 2 diabetes is "more" inheritable than type 1 diabetes. Many genetic factors are involved and a large part of the genetic risk is related to obesity.

What is the genetic factor of type 2 diabetes?

In the endothelial cells insuline starts a pathway via PI-3-kinase and AKT which leads to NO. This leads to vasodilatation. Insuline also starts another pathway resulting in endotheline-1 which leads to vasoconstriction. In type 2 diabetes TNF-alfa and free fatty acids inhibit the NO pathway but not the ET-1 pathway. This leads to less vasodilatation and more vasocontriction and therefore leading to hypertension.

Through which pathway are hypertension and diabetes type 2 connected?

T Cells (Adaptive Immune Response)

Which immuun cells are involved in the pathogenesis of type 1 diabetes?

No

Is type 1 diabetes associated with obesity?

viral infections (CMV, EBV, RS, Aden, rotavirus)

family history

diets (coeliac disease and cow-milk)

Which envoirmental factors play a role in the pathogenesis of type 1 diabetes?

classical triumvirate: pancreas, liver, skeletal muscle

adipose tissue, endothelia, gut, kidneys, brain

Which organs (more than 3) are associated with type 2 diabetes?

Toename In De Mooie Seizoenen:

- telemore attrition

- inflammation

- DNA damage

- mitochondrial dysfunction and Stem cell exhaustion

which characteristics of human genetics facilitate biological ageing?

Grote Tijgers Eten Met Plezier Negen Smakelijke Stukken Ijs.

- Genomic instability

- Telemore attrition

- Epigenetic alterations

- Mitochondrial dysfunction

- Proteostasis loss

- Nutrients deregulations

- Senescence

- Stem cell exhaustion

- Intercellulair communications alterations

******first four are primary hallmarks*******

What are the nine hallmarks of ageing?

C. difficile

Which disease is the only indication for a fecal transplant?

the incretin effect is the difference in insulin secretion when glucose is consumed orally compared to intraveneus administation. This difference is due to hormones in the small intestine. Well known incretins are GLP-1 and GIP.

Explain the concept of the incretin-effect.

The half life time of GLP-1 naturally is 3 minutes. By linking the synthetic GLP-1 to a fatty acid to lower renal clearance. DPP-4 can also be inhibited

What is half-life time of GLP-1 and how did farmaceutic companies handle this?

brain --> inhibits limbic system and therefore ones appetite.

stomach --> inhibits gastric emptying making one nauseous, contributing to weight lose

muscle --> making muscles more sensitive to insulin leading to more glucose uptake by the muscles

liver --> increasing insuline sensitivity leading to less glucose production

pancreas --> stimulating insulin production

kidneys --> I don't know

adipose tissue --> more insuline sensitive

heart --> lower blood pressure

Which organs have GLP-1 receptors an how does that contribute to the mechanism of action?

There is an on going discussion if more traditional medication for diabetes such as metformin and insulin decrease the risk of cardiovascular disease. In a recent meta analysis there was found no significant effect however Erik Serne believes that in people who have had diabetes for a long time it does have an effect.

Does strictly controlling glucose levels in elder patients help with cardiovascular disease?

whole organ attached to small intestine and Islets in liver

Which two ways of pancreas transplantation are used?

metabolic: compared to people without depression, most, but not all, depressed patients are less actively engaged in health lifestyle, such as diet and physical activity.

chrono-dysregulated: problems with sleeping are common, classic symptoms of depression have led to the hypothesis that depression results from an abnormal regulation of circadian rhythm.

anxious: the comorbid anxiety is associated with more severe depression, more disability and and a worse outcome for either disorder.

There are three candidates profiles relevant for the co-occurance of depression and diabetes, what are those?

A foot that has been broken, and, due to the neuropathy in diabetes patient, has come unnoticed. The patient keeps walking on this feet leading to extra stress on the foot. This can eventually lead to permanent deformation.

What is a Charcot foot?

0 = no loss of protective sensitivity and no peripheral arterial disease

1 = loss of PS or PAD without signs of increased pressure

2 = loss of PS or PAD with signs of increased pressure OR loss of PS and PAD

3 = ulcer or amputation in medical history or renal failure (

Can you explain the SIMs classification?

Due to artherosclerosis in the intima-media, arteries become less compressible. This can lead to a higher measured bloodpressure in the ankle leading to an overestimation of the ankle-brachial-index.

Why is the ankle-brachial-index less reliable in diabetic patients?

weight loss of over 5%

bariatric surgery

Name two interventions that can cure type 2 diabetes

somatic

cognitieve

functional

social

Geriatric assessment takes place in four domains, explain these domains.

- MoCa = montreal cognitive assessment which test 8 domains (language, concentration, attention, working pase, short term memory, orientation, executive function, visuopatial skills). The max. score is 30 and it is considered abnormal

Which tools can be used to assess cognitive domain?

Katz ADL = independent with a score of 2 or lower

iADL = instrumental activities of daily living = cooking, doing finances, calling people etc.

nutrition score --> BMI or MNA (mini nutritional assessment)

visual impairment --> eye doctor or optician

hearing impairment

Which actions fall under functional domain and which tools can be used to asses functional domain?

social care network can be charted.

Social Support Questionnaire

What falls under the social domain and how can you asses this domain?

- falling

- delirium

- unexpected weight loss

- frequent infections

- fatigue

Frailty can present clinically. Which "symptoms" are common in frail patients?

chronic use of 5 or more drugs used for a minimal of 3 months

What is the definition of polypharmacy?

prescribing optimization method (POM)

1. which drug are used (including herbs and over the counter) and how are they used?

2. for which indication are they used?

3. are there ADE or problems with the drug that are being taken?

4. START/STOP criteria

5. interactions between the drugs?

6. do we need to adjust the dose/frequency or form?

What can you do to optimize drug use in patients?

the distribution changes --> less muscle and more fat --> lipophilic drugs have reduced clearance and hydrophilic drugs have higher plasma concentrations.

the metabolism changes --> less active drugs derive from pro-drugs and there is an increased biological availability since the first pass effect becomes less.

if kidney function declines the clearance of water soluble drugs becomes less leading to higher plasma concentration

what changes in pharmacokinetic with age?

the number of receptors changes and the affinity drugs have with these receptors changes

What changes in pharmacodynamic with age?

reduces SA nodes automaticity which reduces heart rate.

left ventriculair and atrial hypertrophy

higher risk of rhythm problems and heart failure

sclerosis of the valve leading to aortic stenosis

What changes in a hearth at old age?

wall become thicker and stiffer due to atherosclerosis

reduces arterial compliance

reduced baro-receptor sensititity leading to orthostatic hypotension

less beta-adrenergic response leading to a decreased fight or flight reaction.

What changes in arteries at old age?

The arteries are capable of expanding and tightening. This way pressure can stay controled during diastole and systole.

What is the windkessel function?

The velocity at which the reflecting wave, created by stumbling upon the bifurcation of the aorta, is reflected back. In elder patients this rises due to the stiffness of the arteries. If the waves comes back during the systole in stead of the diastole the hearth has less time to relax. The heart itself get blood during relaxation time. Less relaxation time is related to heart disease.

What is pulse wave velocity?

The thickness of the intima media wall in the carotid artery measured bij echo. This is in indicator of the level of atherosclerosis.

What is the carotid intima media thickness?

the hemodynamic instability and impaired auto-regulation leads to cerebral hypo-perfusion leading to structural brain damage and functional decline.

How does heart failure lead to cognitive decline?

ending with -olol

How do you recognize beta blockers?

ending with -pril

How do you recognize ACE-inhibitors?

ending with -sartan

How do you recognize ARB?

ending with -dipine

How do you recognize calcium antagonists?

hypotension and being less able to start explosive motions (such as sprinting during sports)

What is a typical side effect of beta-blocker?

irritable cough

what is a typical side effect of ACE-inhibitors?

ACE-inhibitors of ARBs because of the nefroprotective mechanism.

Which anti-hypertension drugs is preffered in patients with diabetes and why?

Hypoglycemia increases the risk of cognitive decline. Cognitive decline increases the risk of hypoglycemia.

Poor glycemic control is associated with cognitive decline. However, studies examining the effect of intensive glycemic control have not demonstrated a reduction in brain function decline.

how do diabetes and cognitive decline correlate?

screening for cognitive impairment and desintensificate regimes for diabeteses patients/ simplify treatment.

What should you recommend older patients with diabetes?

atherosclorosis disease/event in patient history

What is a clear indication for the use of statin?

simvastatin 40mg

Which statin is most common?

atorvastatine 20 mg and rosuvastatine 10mg

Which statin is most potent (used for a decline over 40%)?

In the proces of producing cholesterol, acetyl-CoA becomes cholesterol in the liver. Statin inhibit the conversion of HMG-CoA by competing with HMG-CoA-reductase. Statin therefore inhibit the production of cholesterol. Leading to increased number of LDL-receptors on the liver resulting in lowered LDL-concentration

Explain the mechanisme of statin treatment.

life expectancy, goals of care, treatment target and time until benefit

Which aspects should be considered when prescribing to older patients?

2-3 years

What is the time until benefit for statin treatment?

Yes, an HR of below zero (protective working mechanism) was found for Myocardial infarct, coronary events and TIA. However, no difference was found in the ischemic stroke (major risk factor is high blood pressure)

Does statin treatment effect cardiac events?

10%

What percentage of cholesterol is influenced by diet?

People expect a certain side effect of adverse drug event to happen. When these people are given a placebo they still experience these symptoms.

Explain the nocebo effect

1. statin

2. higher dose or +ezetimibe

3. consider PCSK-9-inhibitors

What is the protocol for medication in primary prevention or if someone is > 70 years old?

1. high potent statin or normal statin + ezetimibe

2. higher dose

3. consider PCSK-9-inhibitors

What is the protocol for medication in secundaire prevention and <70 years old

What is the LDL-target in primary prevention?

under 70 years old —> <1.8 mmol/l

over 70 years old but not frail —> <2.6 mmol/l

over 70 years old and frail —> <2.6 mmol/l is medication if medication is endured and life expectancy is long enough

What is the LDL-target in secundairy prevention?

1. orthostatic hypotension

2. vasovagal

3. sinus carotic syndrome

4. rhythm disorders

What are the most common cardiovascular related fall reasons?

It is common, however it is not normal and should always be investigated. It is a red flag. Since there are multiple risk factors always do a multi factorial assessment.

Is falling normal in older age?

aspirin and carbasalate calcium --> platelet aggregation inhibitors

What are salicylates?

By irreversibly binding to COX they inhibit TX2, therefore inhibiting recruitment of platelets in the primary hemostatis.

How do salicylates work?

Side effect include a higher risk of bleeding and gastic acid complaints / gastric ulceration. Higher bleeding risk is a cause of the working mechanisme leading to reduces platelet aggregation in the primary hemostatis. Gastric complaints are explained because by inhibiting COX, COX1 is also inhibited. COX1 is responsible for the mucosa protecting the stomach.

What are side effects of salicylates and how can you explain these side effect by the working mechanism?

other anti-coagulants, other agents that reduce gastric mucosa (NSAIDs and steroids) and reversible cox inhibitor (especially ibuprofen) because of competitiveness.

What are interactions salicylates have?

active bleeding or bleeding disorders in history. Renal,liver or hearth insufficiency. Overreaction to salicylates or NSAIDs.

What is an contra-indication for salicylates?

indicated 10 years later than NSAIDs so at 80 years old or with ulces in history probably yes.

Should you prescribe a PPI with aspirin or carbasalate calcium?

clopidogrel, ticagrelor, prasugrel --> platelet aggregation inhibitors

What are P2Y12-inhibitors?

By inhibiting P2Y12-receptor, ADP dependent platelet aggregation is inhibited. Clopidogrel binds irreversible. More potent than salicylates

How do P2Y12-inhibitors work?

higher bleeding risk

What are possible ADE for P2Y12-inhibitors?

other anticoagulants and clopidogrel is given as a pro-drug, CYP2C19 converts this pro-drug into the active metabolite. Omeprazol inhibits CYP2C19 leading to less active metabolite and decrease in function.

What are interactions P2Y12 inhibitors have?

having a bad liver function. Clopidogrel is activated in the liver.

What contra-indication can be seen with P2Y12-inhibitors?

Dipyridamole

Platelet aggregation inhibitor

What are phosfodiesterase-inhibitors?

it inhibits cAMP and gGMP leading to reduced platelet aggregation

working mechanism of phosfodiesterase inhibitors?

approxiamately 12 hours

Working time of phosfodiesterase inhibitors?

bring systolic blood pressure back to

A bleeding CVA within 6 hours presented, what do you do?

bring systolic blood pressure back to

A bleeding CVA after 6 hours presented, what do you do?

alteplase if possible (check contra-indications)

Ischemic CVA presenting within 4,5 hours, what do you do?

endovascular thrombectomy

Ischemic CVA presenting within 6 hours, what do you do?

intercranial hemorrhage

moderate or severe cranial brain injury in previous two months

cerebral infestation in previous two months

Intracranial haemorrhage in the previous three months or gastrointestinal or urinary tract bleeding in the previous two weeks

major surgery in previous two weeks

bloodpressure >185 mmHg systolic or diastolic >110 mmHg

active bleeding

Use of vitamin K antagonist and INR > 1.7

use of DOAC

use of heparin

Platelets < 100 x 109/L

Serum glucose < 2.7 mmol/L

serum glucose >22.0 mmol/L

What are some contra-indications for use of alteplase?

Grapefruit-CYP3A4 interaction

CYP3a4 breaks down statin. Grapefruit blocks CYP3A4 and therefore the breaking down of statin resulting in higher plasma concentration

explain an interaction statin have.

only simvastatin and pravastatin because of the short working mechanism. Cholesterol is mostly produced at nighttime.

Should you take statin "ante noctem"

reduces cholesterol uptake by the small intestine

How does ezetimibe work?

PCSK-9 is an enzym that breaks down LDL-receptors, by inhibiting this there is more expression of LDL-receptors in the liver

How do PCSK9-inhibitors work?

age at diagnosis

BMI

time till insulin therapy

antibodies anti-GAD or anti-Islet

family history

On what characters can you defer between type 1 and type 2 diabetes?

C-peptide test,

C-peptide is a byproduct of insulin production and can be used to determine if there is insulin production. Type 1 diabetes does not have this.

what test can be used to differentiate between type 1 and type 2 diabetes?

MIDD = maternally inherited diabetes and deafness

--> problems in mitochondrial DNA

Diabetes and deafness

MODY (= Maturity-Onset Diabetes of the Young)

MODY2 = problem with glucokinase leading to a sensing defect resulting in a mild hyperglycemia and no microvascular complications

MODY3 = problem with HNF-alfa lowering insulin secretion, resulting in microvascular complications. This should be treated with SU-derivates.

When there is a atypical presentation of diabetes, what disease should you be aware of?

Insulin

Glutamic acid decarboxylase (GAD)

Insulinoma-associated protein 2 (IA-2)

Zinc transporter ZnT8

Islet Cell Cytoplasmic Autoantibodies (ICA)

which autoantigens are identified with Islet injury?

Firmicutes and bacteriodetes

90% of gutmicrobiota consist of two phyla, name those two.

They miss the function to produces short chain fatty acids

Which characteristic function is missing in the bacterial strains found in obese and subjects with diabetes?

probably only weakly; all kinds of disease demonstrate a change in gut microbiota, as well as a decrease in the production of short chain fatty acids

Is the gut microbiota causally associated with disease, please explain

1. blood pressure controle

2. reduction of albuminuria

3. reduction of inflammation by targeting hyperfiltration

RAAS-therapy has nephroprotective mechanism, name these mechanisms.

tubular-glomerular-feedback refers to the feedback system involving the macula densa and the glomeruli. Depending on the Na-concentration the cell around the macula densa signal for action resulting in more or less filtration (GFR).

In diabetic patients the glomeruli filters a lot of glucose. SGLT-2 then reabsorbs this glucose with Na. The Na concentration in the distal tubuli is now lower, which leads to the macula densa sensing a lower Na-concentration and result in vasodilatation of the afferent arterie and vasoconstriction in the efferent arterie of the glomeruli. The filtration rate then rises (higher GFR), this is called hyperfiltration.

When SGLT-2 is inhibited (by a drug ending in -flozine) the glucose reabsorption and the Na (sodium) reabsorption decreases, leading to a higher concentration of Na in the distal tubuli. The macula densa sences this concentration and signals for actions leading to less filtration. The afferent arteriol constricts and the efferent arteriol dialates. Resulting in a lower GFR —> less filtration.

Explain what tubular-glomerular-feedback is, how is works in diabetic patient and the influence of SGLT-2-inhibitors.

The trias of whipple

1. glucose below 3.9 mmol/l

2. symptoms consistent with hypoglycemia

3. relief of symptoms after raising of the plasma glucose levels

What is the definition of hypoglycemia?

• drop of insuline production (glucose level <4,5 mmol/l)

• increase of glucagon production (glucose level <3,5 mmol/l)

• adrenelin production increase (glucose level <3,5 mmol/l)

What is the hormonal counterregulation in case of hypoglycemia?

Gold score of >4 and at least one severe hypoglycemic event

Define hypoglycemia unawareness

• patient education on diet and exercise

• frequent glucose monitoring (CGM)

• insulin pomps

• appropriate adjustments for therapy

How can you prevent hypoglycemia?

• roux y gastric bypass

• gastric sleeve

• gastric banding

• duodenal switch

• distal gastric bypass

Name types of bariatric surgeries

roux y gastric bypass

which bariatric procedure is the preferred one?

The succes of the procedure is a combination of volume restriction and malabsorption procedures that affect satiety, absorption and insulin resistance or enteric derived factors

what explains the succes of gastric bypass?