Many People With Type 1 Diabetes Still Produce Insulin

Miriam E Tucker

December 29, 2014

Many people with type 1 diabetes continue to secrete small amounts of insulin long after diagnosis, particularly those who develop the condition in adolescence or adulthood.

That was the finding of two studies published online December 17, 2014 in Diabetes Care. One study, led by Dr Asa K Davis (Benaroya Research Institute, Seattle, Washington) and colleagues, found that residual insulin secretion was present in one of three people diagnosed with type 1 diabetes 3 years or more earlier.

In the other study, by Dr Richard A Oram (National Institute for Health Research, University of Exeter Medical School, UK), 80% of patients aged less than 30 years when diagnosed with type 1 diabetes and a disease duration of 5 years or longer still had detectable C-peptide levels.

"The old dictum is that if you have type 1 diabetes long enough you don't have any C-peptide, yet if you have a sensitive enough assay, many people do," Dr Anne L Peters (Keck School of Medicine, University of Southern California, Los Angeles, California) told Medscape Medical News.

The finding, which has been previously reported but not in large studies — each of these new studies involved more than 900 patients — suggests that one day it may be possible to recover and reharness beta-cell production. But the finding also has immediate clinical relevance, particularly with regard to diagnosing type 1 diabetes, according to Dr Peters, a coauthor of the first study.

"People with type 1 diabetes still have beta cells and still make some insulin because the autoimmune process may not cause complete beta-cell destruction. It's interesting and confuses the diagnosis, but doesn't take away that this is an autoimmune disease," she told Medscape Medical News.

Importantly, the study she was involved with showed that C-peptide levels tend to be higher among people who develop type 1 diabetes in adulthood, a scenario that may be unfamiliar to many clinicians who trained in the era when type 1 diabetes was called juvenile diabetes. Indeed, Dr Peters often sees patients with adult-onset autoimmune diabetes who had been misdiagnosed with type 2 diabetes and inappropriately prescribed metformin instead of insulin.

"People need to know that autoimmune type 1 diabetes can occur at any age and that older-onset type 1 patients retain the ability to make C-peptide longer than those who get it younger. This is not the cut-and-dried C-peptide-negative and -positive story we once thought….Think of type 1 in adults who don't fit the typical type2 picture, and if you're confused send the patient to an endocrinologist, because this isn't simple," she advised.

Microsecretors Common

Davis and colleagues measured C-peptide levels in 919 patients at 28 sites participating in the T1D Exchange Clinic Network. Patients were aged 6 months to 46 years (median, 14 years) when they were diagnosed with autoimmune type 1 diabetes and had a disease duration of at least 3 years (median, 13 years).

Overall, 29% had detectable nonfasting C-peptide levels of 0.017 nmol/L or greater, and 10% had levels of 0.2 nmol/L or greater.

The proportion of patients with detectable nonfasting C-peptide decreased with longer duration of type 1 diabetes, but remained consistently and significantly higher among those diagnosed as adults than those aged 18 years or younger at diagnosis (P < .001 for duration of diabetes and age at diagnosis).

Among those with 3 to 5 years' duration of type 1 diabetes, C-peptide was detected in 78% of those aged more than 18 years at diagnosis and 46% of those aged 18 years or younger at diagnosis. Even after 40 years' duration, 16% and 6%, respectively, still had detectable levels.

A subsample of 269 patients underwent a mixed-meal tolerance test for stimulated C-peptide. Of 78 patients who had undetectable C-peptide levels in the nonfasting test, 15 (19%) were now positive. Taking into account that value and a 5% false-negative rate, researchers estimated the true frequency of residual C-peptide to be 40%, Davis and colleagues write.

The authors note that in the United States Medicare uses low or absent C-peptide a criterion to determine coverage eligibility for insulin pumps. "Our data suggest that this restriction would exclude coverage for at least 10% of type 1 diabetes patients, disproportionately impacting those diagnosed as adults."

Moreover, they add, "Many clinicians use the presence of C-peptide as an exclusion criterion for the diagnosis of type 1 diabetes and explain to patients with C-peptide and antibodies that their diagnosis is uncertain. The inconsistencies in diagnosis are likely to confound new initiatives evaluating care and outcomes using ICD-9 or ICD-10 coding and electronic medical records."

The study by Oram and colleagues included 924 patients recruited from primary and secondary care at two UK centers, all of whom had a clinical diagnosis of type 1 diabetes, were aged less than 30 years at diagnosis (median, 11 years), and had a diabetes duration longer than 5 years (median, 19 years).

Home postmeal-stimulated urine C-peptide-to-creatinine ratios (UCPCR) of 0.001 nmol/mmol or greater (ie, detectable) were found in 80% (740) of patients. The majority of patients (52%) had ratios between 0.001 and 0.03 nmol/mmol, 20% had ratios of 0.03 to 0.2 nmol/mmol, and 8% had ratios above 0.2 nmol/mmol.

"The presence of a detectable C-peptide level was inversely associated with a shorter duration of diabetes but unrelated to age at diagnosis or [body mass index]," the authors write. Patients with detectable UCPCR had an average type 1 diabetes duration of 17.8 years vs 20.9 years for those without (P = .0003).

Insulin dose and glycemia were similar in those with and without detectable C-peptide.

Is Measuring C-peptide Useful?

For adult patients with new-onset diabetes who don't fit the classic type 2 diabetes picture (those without insulin resistance and without strong family history of type 2 diabetes) Dr Peters does not use C-peptide to try to determine whether they have type 1 or type 2 diabetes, because — as these studies suggest — many with type 1 diabetes will still test positive.

Instead, she looks for evidence of autoimmunity. First, she orders an anti–glutamic-acid-decarboxylase (GAD) test, because about 80% of people with autoimmune type 1 diabetes will be positive for the antibody. If the anti-GAD test is negative, she'll order a zinc-transporter-antibody test, which will usually be positive if the patient has type 1 diabetes.

However, she cautions, "None of this is standard....We don't really know the natural history of type 1 diabetes in an adult population or what all levels of anti-GAD mean."

She uses C-peptide more often as an adjunctive test in patients referred to her who have had diabetes for several years but in whom the diagnosis of type 1 or type 2 diabetes isn't clear.

Although neither of these studies looked at prognosis related to C-peptide level, other data have suggested that those with higher levels do better. Dr Peters said, "The good news is, for some with type 1 diabetes — whether they've had it for 5 or 40 years and even [those] getting it young — some still make insulin and that's a good prognostic factor and seems to be beneficial."

Funding for Dr Davis's study was provided by the Leona M and Harry B Helmsley Charitable Trust. Dr Davis had no additional disclosures; coauthors' disclosures are listed in the article. Dr Oram's study was supported by a grant from the Wellcome Trust and UK Department of Health. Dr Oram and coauthors had no relevant financial disclosures. Dr Peters's nonprofit employer has a research grant from Sanofi.

Diabetes Care. Published online December 17, 2014. Abstract Study 1, Abstract Study 2

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