Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?
S M Marren, S Hammersley, T J McDonald, B M Shields, B A Knight, A Hill, R Bolt, T I Tree, B O Roep, A T Hattersley, A G Jones, R A Oram, TIGI consortium, S M Marren, S Hammersley, T J McDonald, B M Shields, B A Knight, A Hill, R Bolt, T I Tree, B O Roep, A T Hattersley, A G Jones, R A Oram, TIGI consortium
Abstract
Aims: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes.
Methods: We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide.
Results: Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C-peptide respectively. Participants with preserved C-peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C-peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06).
Conclusions: Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self-reported hypoglycaemic episodes, but no difference in HbA1c . This is consistent with non-intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin.
© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.
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References
- Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 1986; 314: 1360–1368.
- Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H et al C‐peptide is the appropriate outcome measure for Type 1 diabetes clinical trials to preserve beta‐cell function: report of an ADA workshop, 21‐22 October 2001. Diabetes 2004; 53: 250–264.
- Wang L, Lovejoy NF, Faustman DL. Persistence of prolonged C‐peptide production in Type 1 diabetes as measured with an ultrasensitive C‐peptide assay. Diabetes Care 2012; 35: 465–470.
- Oram RA, Jones AG, Besser REJ, Knight BA, Shields BM, Brown RJ et al The majority of patients with long‐duration Type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia 2014; 57: 187–191.
- Oram RA, McDonald TJ, Shields BM, Hudson MM, Shepherd MH, Hammersley S et al Most people with long‐duration Type 1 diabetes in a large population‐based study are insulin microsecretors. Diabetes Care 2015; 38: 323–328.
- Davis AK, DuBose SN, Haller MJ, Miller KM, DiMeglio LA, Bethin KE et al Prevalence of detectable C‐peptide according to age at diagnosis and duration of Type 1 diabetes. Diabetes Care 2015; 38: 476–81.
- Shields BM, McDonald TJ, Oram R, Hill A, Hudson M, Leete P et al C‐peptide decline in Type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care 2018; 41: 1486–1492.
- Kuhtreiber WM, Washer SLL, Hsu E, Zhao M, Reinhold P, Burger D et al Low levels of C‐peptide have clinical significance for established Type 1 diabetes. Diabet Med 2015; 32: 1346–1353.
- Effect of intensive therapy on residual beta‐cell function in patients with Type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1998; 128: 517–523.
- Steffes MW, Sibley S, Jackson M, Thomas W. Beta‐cell function and the development of diabetes‐related complications in the diabetes control and complications trial. Diabetes Care 2003; 26: 832–836.
- Lachin JM, McGee P, Palmer JP; DCCT/EDIC Research Group . Impact of C‐peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial. Diabetes 2014; 63: 739–748.
- Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL et al Islet transplantation in seven patients with Type 1 diabetes mellitus using a glucocorticoid‐free immunosuppressive regimen. N Engl J Med 2000; 343: 230–238.
- Vantyghem M‐C, Raverdy V, Balavoine A‐S, Defrance F, Caiazzo R, Arnalsteen L et al Continuous glucose monitoring after islet transplantation in Type 1 diabetes: an excellent graft function (β‐score greater than 7) is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (β‐score greater than 3). J Clin Endocrinol Metab 2012; 97: E2078–E2083.
- Brooks AM, Walker N, Aldibbiat A, Hughes S, Jones G, de Havilland J et al Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations. Am J Transplant 2013; 13: 3236–3243.
- Ryan EA, Paty BW, Senior PA, Lakey JRT, Bigam D, Shapiro AMJ. Beta‐score: an assessment of beta‐cell function after islet transplantation. Diabetes Care 2005; 28: 343–347.
- Brooks AM, Oram R, Home P, Steen N, Shaw JAM. Demonstration of an intrinsic relationship between endogenous C‐peptide concentration and determinants of glycemic control in Type 1 diabetes following islet transplantation. Diabetes Care 2015; 38: 105–112.
- Wahren J, Larsson C. C‐peptide: new findings and therapeutic possibilities. Diabetes Res Clin Pract 2015; 107: 309–319.
- Wahren J, Foyt H, Daniels M, Arezzo JC. Long‐acting C‐peptide and neuropathy in Type 1 diabetes: a 12‐month clinical trial. Diabetes Care 2016; 39: 596–602.
- Skyler JS. Hope vs. hype: where are we in Type 1 diabetes? Diabetologia 2017; 61: 509–516.
- Jones AG, Hattersley AT. The clinical utility of C‐peptide measurement in the care of patients with diabetes. Diabet Med 2013; 30: 803–817.
- Shepherd M, Shields B, Hammersley S, Hudson M, McDonald TJ, Colclough K et al Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes. Diabetes Care 2016; 39: 1879–1888.
- Clarke WL, Cox DJ, Gonder‐Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 1995; 18: 517–522.
- Hope SV, Knight BA, Shields BM, Hill AV, Choudhary P, Strain WD et al Random non‐fasting C‐peptide testing can identify patients with insulin‐treated Type 2 diabetes at high risk of hypoglycaemia. Diabetologia 2018; 61: 66–74.
- Fukuda M, Tanaka A, Tahara Y, Ikegami H, Yamamoto Y, Kumahara Y et al Correlation between minimal secretory capacity of pancreatic β‐cells and stability of diabetic control. Diabetes 1988; 37: 81–88.
- Pinckney A, Rigby MR, Keyes‐Elstein L, Soppe CL, Nepom GT, Ehlers MR. Correlation among hypoglycemia, glycemic variability, and C‐peptide preservation after alefacept therapy in patients with Type 1 diabetes mellitus: analysis of data from the Immune Tolerance Network T1DAL Trial. Clin Ther 2016; 38: 1327–1339.
Source: PubMed