Low levels of C-peptide have clinical significance for established Type 1 diabetes

Abstract

Aim: To determine whether the low C-peptide levels (< 50 pmol/l) produced by the pancreas for decades after onset of Type 1 diabetes have clinical significance.

Methods: We evaluated fasting C-peptide levels, duration of disease and age of onset in a large cross-sectional series (n = 1272) of people with Type 1 diabetes. We then expanded the scope of the study to include the relationship between C-peptide and HbA1c control (n = 1273), as well as diabetic complications (n = 324) and presence of hypoglycaemia (n = 323). The full range of C-peptide levels was also compared with 1,5-Anhydroglucitol, a glucose responsive marker.

Results: C-peptide levels declined for decades after diagnosis, and the rate of decline was significantly related to age of onset (P < 0.0001), after adjusting for disease duration. C-peptide levels > 10 pmol/l were associated with protection from complications (e.g. nephropathy, neuropathy, foot ulcers and retinopathy; P = 0.03). Low C-peptide levels were associated with poor metabolic control measured by HbA1c (P < 0.0001). Severe hypoglycaemia was associated with the lowest C-peptide levels compared with mild (P = 0.049) or moderate (P = 0.04) hypoglycaemia. All levels of measurable C-peptide were responsive to acute fluctuations in blood glucose levels as assessed by 1,5-Anhydroglucitol (P < 0.0001).

Conclusions: Low C-peptide levels have clinical significance and appear helpful in characterizing groups at-risk for faster C-peptide decline, complications, poorer metabolic control and severe hypoglycaemia. Low C-peptide levels may be a biomarker for characterizing at-risk patients with Type 1 diabetes.

FIGURE 1

Decades-long persistence of C-peptide in patients with Type 1 diabetes (n=1272) and more rapid fall in C-peptide levels with younger age of onset. (a) Graph showing gradual, decades-long decline in C-peptides detectable using an ultrasensitive assay. (b) Graph showing that the decline in C-peptide levels in patients with long-term diabetes is related to the age of onset of the disease. Data are stratified by diabetes duration <15 years (left) or 15–30 years (right). For a Type 1 diabetes duration of < 15 years, an age of onset of <20 years old was associated with a more rapid decline in C-peptide level (age of onset <20 years, n=292; age of onset >20 years, n=294). With a Type 1 diabetes duration of 15–30 years, a more rapid decline in C-peptide level was again associated with an age of onset of < 20 years (age of onset <20 years, n=196; age of onset >20 years, n=165). P values were calculated using a Mann–Whitney U-test (Wilcoxon rank-sum test) and the data are represented as mean ± SEM. ***P<0.0001.

FIGURE 2

Low levels of C-peptide < 10 pmol/l were predictive of diabetes-related complications (a), and levels of 2.5 pmol/l identified patients with Type 1 diabetes with poor HbA_1c control (b). (a) Development of diabetes-related complications of retinopathy, foot ulcer amputations, neuropathy or kidney disease (nephropathy or micro-albuminuria) was associated with a C-peptide level of < 10 pmol/l. This significant association (P=0.03, n = 324) was independent of disease duration. Red triangles, patients with Type 1 diabetes with complications; black circles, patients with Type 1 diabetes without any diabetes-related complications. (b) Lower risk of elevated HbA_1c was associated with a C-peptide range of >50–100 pmol/l, while higher risk was associated with a C-peptide range of >2.5–50 pmol/l (P=0.0001). A total of 1273 patients were studied.

FIGURE 3

Various degrees of hypoglycaemia (mild vs. moderate vs. severe) were compared with simultaneously evaluated C-peptide levels (n=324). Using the survey method of Clarke et al. [12] to evaluate mild, moderate and severe hypoglycaemia unawareness, the patients with Type 1 diabetes were divided into three categories and their mean C-peptide levels quantified (a). Patients with symptoms of hypoglycaemia are indicated as red dots; patients without symptoms of hypoglycaemia are represented as black dots. An absolute value for residual C-peptide level related to hypoglycaemic symptoms could not be identified in this dataset. (b) Determination of detectable C-peptide levels in patients with symptoms of mild, moderate and severe hypoglycaemia yielded a statistically significant trend when detectable C-peptide levels were compared. Mean ± SEM C-peptide levels for mild hypoglycaemia: 92.6 ± 24.8 pmol/l; moderate hypoglycaemia: 103.2 ± 36.4 pmol/l; and severe hypoglycaemia: 28.8 ± 12.3 pmol/l (*P=0.049; **P=0.04).

FIGURE 4

Significant correlations between all ranges of C-peptide with glucose, C-peptide and 1,5-Anhydroglucitol (1,5AG) in patients with Type 1 diabetes (n=50). (a) Graph showing the well-known inverse correlation between glucose levels and 1,5-AG levels, which was also observed in the present study population (Pearson r=-0.464; P=0.007). (b) Graph showing that C-peptide levels at all ranges from 1.5 to 1000 pmol/l were linearly related to 1,5-AG levels.