The pathophysiology of uninduced ketosis-prone type 1 and type 2 diabetes

Peripheral blood mononuclear cells (PBMC) producing insulin peptide-specific interferon (IFN)-γ can be detected in approximately one-third of patients with ketosis-prone type 2 diabetes (KPD), and the frequency of PBMC was similar to that of patients with acute-onset type 1 diabetes (AT1D), according to a study by the Newspaper clinical endocrinology and metabolism.

The researchers sought to assess the peripheral immunoreactivity of B:9–23rPep-specific IFN-γ in individuals with unprovoked KPD A−β+ using enzyme-linked immunoSpot assays (ELISpot ) and to clarify the immunological role of B:9–23rPep as islet-associated antigens in the pathogenesis of this phenotype.

The cross-sectional study was conducted from June 2016 to December 2020 and included blood samples from 42 patients with AT1D (median age, 43 years; 22 males) and 33 patients with KPD (median age, 42 years; 32 men). The researchers also used previous data on 25 insulin-treated participants with type 2 diabetes (T2D).

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ELISpot IFN-γ was positive in 38.1% (16/42) of patients with AT1D and 36.4% (12/33) of those with KPD, with the use of a cut-off value of 2.5 spot-forming cells (SFC) in the ELISpot assay system. The positivity rate was significantly higher in patients with AT1D and in those with KPD than in patients with type 2 diabetes (8.0%; 2/25) (P

The number of IFN-γ spot-forming cells (SFC) was negatively correlated with age and serum C-peptide levels in KPD patients, but not in AT1D patients. A significant positive correlation was found between the number of SFC IFN-γ and glycated hemoglobin (HbA1 C) levels in the KPD group (rs = 0.784, P

The investigators noted several limitations to the study, including the relatively small sample size and the cross-sectional study design. Additionally, they enrolled cases of KPD based on their own diagnostic criteria because standardized diagnostic criteria are not established.

“As with AT1D, B:9–23rPep-specific IFN-γ-related immunoreactivity may be associated with the pathophysiology of unprovoked A−β+ KPD in perhaps one-third of participants with the disease, regardless of the presence of [human leukocyte antigen] alleles linked to T1D”, specify the researchers. “Furthermore, increased immune responses may reflect a transient decrease in β-cell function and increased disease activity during onset of ketosis/diabetic ketoacidosis (DK/DKA), particularly in young individuals, thus playing a key role in the development of DK/DKA in unprovoked A. −β+ KPD.

Disclosure: This work was supported in part by the Novartis Pharma Research Grant for Young Investigators and fellowships from Astellas Pharma Inc., MSD KK, and Novo Nordisk Pharma Ltd. One of the study authors stated affiliations with pharmaceutical companies. Please see the original reference for a full list of disclosures.


Satomura A, Oikawa Y, Haisa A, et al. Clinical significance of insulin peptide-specific interferon-γ-related immune responses in ketosis-prone type 2 diabetes. J Clin Endocrinol Metab. Published online December 18, 2021. doi: 10.1210/clinem/dgab912

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