Daniel M. Keller, PhD

September 14, 2011

September 14, 2011 (Lisbon, Portugal) — A measure of the postprandial ratio of urinary C-peptide to creatinine (UCPCR) can distinguish maturity-onset diabetes of the young (MODY) from type 1 diabetes mellitus (T1DM), allowing some children who would otherwise be treated with insulin to receive oral antidiabetic agents alone, Rachel Besser, MBBS, from the clinical research faculty at Peninsula Medical School in Exeter, United Kingdom, told delegates here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting.

Dr. Besser said the UCPCR test is 100% sensitive for identifying MODY, with 78% specificity, and it may be useful even close to the time of diagnosis.

MODY, an autosomal dominant condition that alters beta-cell function, is the most common monogenic cause of diabetes and accounts for 1% to 3% of cases. Various genes have been implicated, and the HNF1A and HNF4A forms are sensitive to treatment with sulfonylurea drugs, whereas the glucokinase form is not. Onset is typically at ages younger than 25 years. About 30% of patients are misdiagnosed as having T1DM and are therefore treated with insulin.

Persistent insulin secretion occurs in MODY but not in T1DM. The mixed-meal tolerance test is the gold standard to distinguish between them, but it is limited by the need to come to a medical setting in a fasting state and stay for 2 hours after a test meal for blood sampling.

Urine Test Performed at Home

"In Exeter, we've developed a urine test, urine C-peptide creatinine ratio, which is stable at room temperature for 3 days in boric acid preservative," Dr. Besser said.

Patients can do the test at home and drop the sample in the mail the next morning. Using the creatinine ratio accounts for the concentration of the urine. "We showed that postprandial collection after a normal home meal is well correlated to the 90-minute serum peptide in the mixed-meal tolerance test," she said.

Dr. Besser showed that the test reliably discriminates between T1DM patients (n = 69) and MODY patients (n = 77), with median UCPCRs of less than 0.02 and 1.72, respectively (P < .001). On the basis of a receiver-operator curve analysis, the investigators found that the optimal cutoff of UCPCR for discriminating MODY from T1DM in adults was 0.2.

Test Accurate in Children

To see whether the test could be applied to children, even close to the time of diagnosis, the researchers performed a cross-sectional study involving children with a clinical diagnosis of T1D (n = 135) or MODY (n = 52). Patients were younger than 18 years of age and had normal renal function. Participants emptied their bladders before eating an evening meal and submitted a 2-hour postprandial urine sample through the mail the next day.

The UCPCR median values for the HNF1A/HNF4A and glucokinase forms were similar, at 3.9 and 3.4 nmol/mmol (P = .4), but the value for the MODY groups combined was significantly different from the value for the T1D patients (0.07 nmol/mmol; P < .0001).

Dr. Besser said there is some crossover in UCPCR values between the MODY and T1D groups close to diagnosis, but for the T1D patients the UCPCR quickly drops to 0 by about 2.5 years. The MODY patients continue to have a positive ratio because they are still producing insulin and, therefore, C-peptide.

Dr. Besser concluded that postprandial UCPCR may be useful in distinguishing MODY from T1D in pediatric diabetes, particularly to exclude MODY. A ratio greater than 0.79 nmol/mmol identified MODY with 100% sensitivity and 78% specificity. Twenty-one percent of T1DM patients had a UCPCR greater than 0.79, but all were within 5 years of diagnosis.

She recommended that any patient with a UCPCR below 0.79 should not be selected for MODY testing, and any patient with a value above this cut-point should be considered for antibody testing before testing for MODY.

Session moderator Henk-Jan Anstoot, MD, PhD, a pediatrician in Rotterdam, the Netherlands, commented to Medscape Medical News that physicians probably jump to a diagnosis of T1DM too quickly because the diabetes is occurring in a child. He said family history is still important since MODY is an autosomal dominant condition and therefore tends to run in families.

"We know all the genes of our body, we have the Human Genome Project, but we now found out that what has happened in our family is probably one of the most important predictors of our life...and that was one of the things in the MODY study that was clear, that you still have to look at the family," Dr. Anstoot advised.

He said the UCPCR test still needs validation. One member of the audience commented that exogenous insulin can suppress the processing of endogenous insulin, resulting in lower plasma and urine levels of C-peptide.

"The importance [of distinguishing MODY from T1DM] is that you can treat it in such a different way, with tablets rather than with insulin," he said. Some patients in his clinic have switched to oral therapy after as long as 30 years on insulin. And sulfonylurea therapy is much safer in terms of the risk for hypoglycemia.

The study received no commercial funding. Dr. Besser and Dr. Anstoot have disclosed no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 47th Annual Meeting; Oral Session: OP 03 Nutrition and diet. Presented September 14, 2011.


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