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Alpha- and beta-cell abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes
Salvatore Calanna1, Roberto Scicali, Antonino Di Pino
1Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy.
Insights
New HbA1c diagnostic criteria reveal distinct pathophysiological profiles for prediabetes and type 2 diabetes. Prediabetes shows defective insulin response and poor glucagon suppression, suggesting new therapeutic targets.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Diabetes Research
Background:
- Recent guidelines altered diagnostic criteria for prediabetes and type 2 diabetes using glycated haemoglobin A1c (HbA1c).
- Understanding the distinct pathophysiological characteristics of these newly defined populations is crucial for effective management.
Purpose of the Study:
- To investigate and compare the pathophysiological profiles of individuals diagnosed with prediabetes and type 2 diabetes based on HbA1c levels.
- To identify potential new targets for pharmacological interventions in prediabetes.
Main Methods:
- Studied three groups: controls (HbA1c <5.7%), prediabetes (HbA1c 5.7-6.4%), and type 2 diabetes (HbA1c ≥6.5%).
- Utilized oral glucose tolerance tests and intravenous glucose infusions over 4 hours to assess glucose, insulin, C-peptide, glucagon, and incretin hormones.
- Evaluated insulinogenic index, disposition index, glucagon suppression, and incretin effect.
Main Results:
- Prediabetes group exhibited significantly lower insulinogenic index, disposition index, and glucagon suppression compared to controls.
- Type 2 diabetes group showed significantly reduced insulinogenic index, disposition index, and glucagon suppression compared to controls.
- The incretin effect was notably diminished in type 2 diabetes patients compared to both prediabetes subjects and controls, despite similar incretin hormone levels.
Conclusions:
- HbA1c-defined type 2 diabetes demonstrates clear alpha- and beta-cell dysfunction, consistent with previous glucose-defined criteria.
- HbA1c-defined prediabetes is characterized by impaired insulin response and inadequate glucagon suppression, highlighting potential therapeutic avenues.
Abstract:
New recommendations for the use of glycated haemoglobin A1c (HbA1c) to diagnose prediabetes and type 2 diabetes have changed the constitution of the two populations. We aimed to investigate the pathophysiological characteristics of individuals with HbA1c-defined prediabetes and type 2 diabetes, respectively. Ten subjects with HbA1c-defined prediabetes, i.e. HbA1c from 5.7 to 6.4 % (39-46 mmol/mol), eight newly diagnosed patients with HbA1c-defined type 2 diabetes [HbA1c ≥6.5 % (≥48 mmol/mol)], and ten controls with HbA1c lower than 5.7 % (<39 mmol/mol), were studied. Blood was sampled over 4 h on two separate days after a 75 g-oral glucose tolerance test and an isoglycaemic intravenous glucose infusion, respectively. Blood was analysed for glucose, insulin, C-peptide, glucagon, and incretin hormones. Insulinogenic index, disposition index, glucagon suppression, and incretin effect were evaluated. Subjects with HbA1c-defined prediabetes showed significantly lower insulinogenic index (P = 0.02), disposition index (P = 0.001), and glucagon suppression compared with controls; and similar (P = NS) insulinogenic index and glucagon suppression and higher disposition index (P = 0.02) compared to HbA1c-diagnosed type 2 diabetic patients. The patients with type 2 diabetes showed lower insulinogenic index (P = 0.0003), disposition index (P < 0.0001), and glucagon suppression compared with the controls. The incretin effect was significantly (P < 0.05) reduced in patients with HbA1c-defined type 2 diabetes compared to subjects with HbA1c-defined prediabetes and controls. Plasma levels of incretin hormones were similar across the three groups. HbA1c associated negatively with insulinogenic index, disposition index, and incretin effect. Our findings show clear alpha- and beta-cell dysfunction in HbA1c-defined type 2 diabetes compatible with the previously described pathophysiology of plasma glucose-defined type 2 diabetes. Furthermore, in HbA1c-defined prediabetes, we show defective insulin response in combination with inappropriate suppression of glucagon, which may constitute new targets for pharmacological interventions.
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