Journal clubYassin M Alsaleh

Introduction

• Hyperinsulinemic hypoglycemia, a

major cause of severe hypoglycemia

during the neonatal period.

• is characterized by inappropriate

insulin secretion.

Introduction

• The condition may result from defects

in many genes including :

• ABCC8, KCNJ11, GLUD1, GCK,HADH, SLC16A1, HNF4A, HNF1A, and UCP2.

• Two major histologic subtypes have

been described: diffuse and focal.

• Mutations in ABCC8 and KCNJ11 are

associated with severe hyperinsulinemic

hypoglycemia that is unresponsive to

medical treatment with diazoxide and

octreotide.

• The only alternative treatment currently

available for patients with medically

unresponsive forms of diffuse

hyperinsulinemic hypoglycemia is a

subtotal pancreatectomy.

Introduction

Introduction

• However, some patients who have

undergone surgery continue to have

recurrent hyperinsulinemic

hypoglycemia.

• whereas diabetes mellitus and

exocrine pancreatic insufficiency

develop in others..

• A possible mechanism of diffuse

hyperinsulinemic hypoglycemia

involves the constitutive activation of

the mammalian target of rapamycin

mTOR pathway.

• The serine–threonine protein kinase

mTOR has been implicated in the

cellular response to nutrients and

growth factor signaling

Introduction

• The mTOR pathway is abnormally

activated in several neoplasms,

including insulinoma.

• inhibitors of mTOR have been

increasingly recognized as a

treatment option in patients with

cancer...

Introduction

Introduction

• Long-term treatment with sirolimus in

recipients of renal transplants has

been noted to induce peripheral

insulin resistance by impairing the

activation and signaling of protein

kinase B through the insulin-receptor

substrate pathway

• potential role for mTOR inhibitors

include:

• the reduction of beta-cell proliferation.

• induce the apoptosis of Beta cells.

• the inhibition of insulin production.

• induce peripheral insulin resistance.

• up-regulating hepatic

gluconeogenesis

Introduction

PHARMACOLOGY

• Sirolimus also known as rapamycin.

• is a macrolide produced by

the bacteria streptomyces

hygroscopicus .

• It has potent immunosuppressive

and antiproliferative properties

• USES:

• Post renal transplant, insulinoma.

• Coronary artery stent coating.

• ? TS,SLE,Alzhimer,Porgeria.

The adverse effects of mTOR

inhibitors• increased risk of infection,

immunosuppression,

• abnormalities in renal function

• Fatigue.

• pneumonitis.

• Stomatitis.

Methods

• AIM:

• To study the glycemic response to

sirolimus in four consecutive patients

with diffuse hyperinsulinemic

hypoglycemia that had been

unresponsive to diazoxide and

octreotide.

• INCLUSION criteria:

• patients with severe hyperinsulinemic

hypoglycemia that was unresponsive

to maximal doses of diazoxide (20 mg

per kilogram per day) and octreotide

(35 μg per kilogram per day) were

recruited to participate in the study.

Methods

• Approval for the study was obtained

from the drugs and therapeutics

committee at the hospital.

• written informed consent was taken

from parents.

Methods

• All the patients received sirolimus at an

initial dose of 0.5 mg/m2/day.

• The dose was gradually increased with

the goal of reaching a serum trough level

of 5 to 15 ng per milliliter.

• The serum trough level was measured

every 5 days.

• Once the desired serum drug level had

been reached and blood glucose levels

were stable, intravenous glucose and

glucagon infusions were gradually tapered

Methods

• Regular monitoring was performed

including :

• CBC,lipid levels, renal and liver

function.

• After discharge,patients were

followed up regularly for assessment

of glycemic control and measurement

of serum sirolimus levels.

Methods

Critical

appraisal

PICO• Population: patients with

diffuse hyperinsulinemichypoglycemia that had been unresponsive to diazoxideand octreotide

• Intervention: sirolimus

• Control:

• Out come: glycemic response

Relevance1. Does the study address a common

problem in your practice?

YES

2. Does the study address an important outcome to you or to your patient? (DOE vs. POEM).

YES

Validity1. Was the assignment of patients

to treatment randomized?

NO

2- Was the assignment concealed?

NO

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Validity3- Were patients analyzed in the

groups to which they were randomized (intention to treat analysis)?

NA

• Was follow-up complete& long enough?complete but long enough ??

30

Validity3. Were the groups similar at the start

of the trial? Baseline prognostic factors (demographics, co-morditity, disease severity, other known confounders) balanced?

NA

4. Were patients, their clinicians, and study personnel 'blind' to treatment?

• NO 31

Validity5. Aside from the experimental

intervention, were the groups treated

equally?

• Co-intervention?

• Contamination?

• Compliance?

yes

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Validity6. Were all clinically important

outcomes considered?

NO,

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Results clinical significance

• Precision of the effect:

• Confidence intervals?

• NO

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Applicability

1. Can you do the Intervention exactly as it is described in the paper

YES

2. Is your Patient is similar to the population of the study?

YES

3. Are the likely treatment benefits worth the potential harms and costs?yes

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Assuming that the study conclusion is true ,would it lead to a change in your practice?

YES

• Treatment with mTOR inhibitors,

alone or in combination with

somatostatin analogues, may be a

feasible option for selected patients

with no contraindication, although the

longterm adverse effects and efficacy

of such treatment require further

study.

Conclusion