Journal club presentation

Ahmed AlNahariPediatric Endocrine Fellow

McMaster Children's HospitalOct. 2nd 2015

OBJECTIVES

MEDICAL EXPERT1)Review recent literature regarding distinguish MODY from T1DM SCHOLAR2)Critically appraise reliability and applicability of a diagnostic article about MODY diagnosis

• Type 1 diabetes mellitus (T1DM) of autoimmune origin is the most prevalent form of diabetes during childhood and adolescence, although other forms of diabetes can also affect this population, resulting in different prognoses and treatments.

Maturity-onset diabetes of the young (MODY) • Is inherited in an autosomal dominant mode • 2% of all diabetes cases

• Ledermann HM. (1995). Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet:, (345: 648.)

Diabetes Metab Syndr Obes. 2012; 5: 101–108.

Various biomarkers such as

• apolipoprotein M, • transthyretin or • complement C8 have been proposed to distinguish

MODY from T1DM.

Richter, S., D. Q. Shih, E. R. Pearson, C. Wolfrum, S. S. Fajans, A. T. Hattersley, and M. Stoffel. "Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1 : Haploinsufficiency Is Associated With Reduced Serum Apolipoprotein M Levels." Diabetes, 2003, 2989-995.Cervin C. et al. An investigation of serum con- centration of apoM as a potential MODY3 marker using a novel ELISA. J Intern Med, 2010, 316-321.

• In child- hood-onset T1DM, the majority of patients are severely insulin deficient within 2–3 years of diagnosis, whereas in MODY, C-peptide is often conserved.

• In T1DM, absolute insulin deficiency usually occurs within 5 years of diagnosis.

Palmer JP, Fleming GA, Greenbaum CJ, He- rold KC, Jansa LD, Kolb H, Lachin JM, Polon- sky KS, Pozzilli P, Skyler JS, Steffes MW: C-peptide is the appropriate outcome

mea- sure for type 1 diabetes clinical trials to pre- serve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes 2004;53:250–264.

• Studies have confirmed that single serum C-peptide measurements (fasting or 90-min stimulated C-peptide) and the urinary C-peptide/creatinine ratio (UCPCR) allow for a more practical method of directly assessing beta-cell function in routine clinical practice in children .

Besser RE, Ludvigsson J, Jones AG, McDon- ald TJ, Shields BM, Knight BA, Hattersley AT: Urine C-peptide creatinine ratio is a noninva- sive alternative to the

mixed-meal tolerance test in children and adults with type 1 diabe- tes. Diabetes Care 2011;34:607–609.

• The UCPCR is a new, noninvasive and stable marker for endogenous insulin secretion.

• The most important evidence supporting the use of the UCPCR in the differential diagnosis of MODY is that the majority of patients are severely insulin deficient within 2–3 years of diagnosis in childhood-onset T1DM, whereas in MODY, C-peptide persists.

Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K; International Society for Pedi- atric and Adolescent Diabetes: ISPAD Clini- cal Practice

Consensus Guidelines 2006– 2007. The diagnosis and management of monogenic diabetes in children. Pediatr Dia- betes 2006;7:352–360.

• The aim of the present study was to compare the UCPCR and fasting C-peptide measurements in pediatric patients with genetically diagnosed MODY or T1DM who were followed up at a single center.

Urinary C-Peptide/Creatinine Ratio Can Distinguish Maturity-Onset Diabetes of the Young from Type 1 Diabetes in Children and Adolescents: A Single-Center Experience

Sebahat Yılmaz Agladioglu Elif Sagsak Zehra Aycan

Hormone Research In PeadiatricsReceived: July 25, 2014 Accepted: January 16, 2015 Published online: March 17, 2015

Horm Res Paediatr 2015;84:54–61

Method

• Patients • Fasting C-Peptide Measurement • Urine Collection • Urinary C-Peptide Measurement • Antibody Measurements

69

2742

42 ICA 042 GAD 142 IAA 1

Fasting C -peptide

• C-peptide measurements after an overnight fast, before breakfast, on the same day as the UCPCR test.

• For breakfast, patients continued their own diabetic

diet according to their age and gender, and they had their standard lunch, which contained an appropriate calorie content and was adjusted for the age and weight of the patients under hospital conditions.

• The results are expressed in nanograms per milliliter. • This assay had a lower limit of 0.08 ng/ml. • All C-peptide values <0.08 ng/ml were coded as 0.01

ng/ml.

Urine Collection

Urine samples were collected from patients 2 h after a standard lunch.Thirty-five percent of the daily calories were given at the hospital as lunch, containing 60% carbohydrates, 15% protein and 25% fat. Patients collected their urine samples in boric acid preservative 2 h after their lunch meal, following a premeal void.

Urinary C-Peptide Measurement

Urinary C-peptide was measured by electrochemiluminescence on an IMMULITE 2000 C-peptide device (USA) by the biochemistry department. The lower limit of the C-peptide assay was 0.03 nmol/l. Urinary creatinine was analyzed by mass spectrometry on the Roche P800 platform and was used to calculate the UCPCR (in nmol/mmol). All UCPCR values <0.02 nmol/mmol were coded as 0.01 nmol/mmol.

Antibody Measurements

GAD65 antibodies and ICA were measured by radioimmunoassay on a Gamma Counter StrachedNepha device (Beckman Coulter Immunotech).

IAA were measured by radioimmunoassay on a Gamma Counter StrachedNepha with DiaSource at the biochemistry department.

RESULT

Scree

• A UCPCR of 0.125 nmol/mmol had the highest sensitivity for identifying MODY (100% sensitivity, 81% specificity).

• A UCPCR of 0.19 nmol/mmol, the sensitivity was 96.3%, whereas the specificity was 85.7%.

• A UCPCR of 0.68 nmol/mmol, the sensitivity decreased to 59.3%, but the specificity increased to 90.5%.

• Serum C-peptide levels were lower in 93% (n = 39) of the patients with T1DM, and they were within normal limits in 7% (n = 3) of the patients.

• The UCPCR levels in 3 cases with normal serum C-peptide levels were found to be >0.22 nmol/mmol.

C-peptide C-peptide

Type 1DM

93%(39)7%(3)

UCPCR >0.22nmol/mmol

• The data suggest that a fasting C-peptide level of 0.62 ng/ml demonstrates a sensitivity of 93%, a specificity of 90% and an AUC of 0.967.

• Other studies in children have shown that C-peptide at diagnosis could differentiate T1DM from T2DM with sensitivities varying from 83 to 95%.

Take Home Message

• Clinical suspicion is very important. • A UCPCR ≥0.22 nmol/ mmol showed excellent

differentiation between MODY and T1DM in children. (>2y)

• Genetic Test

THANK YOU