Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown.

Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses.

Results: At enrolment, 32% had low CP (<250 pmol/L) and 5% were GADA+. In the low CP group, 7% were GADA+. In the GADA+ group, 50% had low CP. During a mean follow-up of 10.8 years, 58.6% were started on insulin after a median of 6.5 years. The GADA+ group was more likely to initiate insulin [adjusted HR (95% CI) 1.55 (1.26-1.91) ] and experienced SHE [HR 1.45 (1.08-1.95) ] than the GADA- group. In the GADA- group, low CP had lower hazards of insulin use [HR 0.86 (0.77-0.97) ] than high CP especially in patients with HOMA2-IR (insulin resistance) above median. The low CP group had higher HR of 1.34 (1.13-1.59) of SHE than the high CP group. In the GADA+ group, low CP was associated with increased risk of SHE [HR 1.81 (1.25, 2.62) ] but not in patients with high CP (Pinteraction= 0.01) . Both CP and GADA did not predict glycemia response after controlling for baseline HbA1c.

Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment.


B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.


The HKG Health Medical and Research Fund and RGC Research Impact Fund

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