The Pathophysiology of Unprovoked Ketosis-Prone Type 1 and Type 2 Diabetes

A woman discusses with her doctor about possibilities for diabetes treatment in a well lit medical facility.
The cross-sectional study included blood samples from 42 patients with acute-onset type 1 diabetes and 33 patients with ketosis-prone type 2 diabetes. Previous data on 25 insulin-treated participants with type 2 diabetes was also used.

Insulin peptide-specific interferon (IFN)-γ-producing peripheral blood mononuclear cells (PBMCs) can be detected in about one-third of patients with ketosis-prone type 2 diabetes (KPD), and the PBMC frequency was similar to that in patients with acute-onset type 1 diabetes (AT1D), according to a study in the Journal of Clinical Endocrinology and Metabolism.

Investigators sought to evaluate peripheral B:9–23rPep-specific IFN-γ immunoreactivity in individuals with unprovoked A−β+ KPD using enzyme-linked immunoSpot (ELISpot) assays 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 male) and 33 patients with KPD (median age, 42 years; 32 male). The researchers also used previous data on 25 insulin-treated participants with type 2 diabetes (T2D).

IFN-γ ELISpot was positive in 38.1% (16/42) of patients with AT1D and in 36.4% (12/33) of those with KPD, with use of a cutoff value of 2.5 spot-forming cells (SFCs) in the ELISpot assay system. The positivity rate was significantly greater among patients with AT1D and in those with KPD vs in patients with type 2 diabetes (8.0%; 2/25) (P < .0167).

The number of IFN-γ spot-forming cells (SFCs) were negatively correlated with age and serum C-peptide levels in patients with KPD, but not in patients with AT1D. A significant positive correlation was found between the number of IFN-γ SFCs and glycated hemoglobin (HbA1c) levels in the KPD group (rs = 0.784, P < 0.01, Spearman’s rank correlation test), but not in the AT1D group, when analysis was limited to participants with a positive result for the IFN-γ ELISpot assay (n = 12 in the KPD group and n = 16 in the AT1D group).

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

“As with AT1D, B:9–23rPep-specific IFN-γ-related immunoreactivity might be associated with the pathophysiology of unprovoked A−β+ KPD in perhaps one-third of participants with the disease, irrespective of the presence of [human leukocyte antigen] alleles linked to T1D,” stated the researchers. “Moreover, increased immune responses may reflect transiently decreased β-cell function and increased disease activity at the onset of diabetic ketosis/ketoacidosis (DK/DKA), especially in young individuals, thereby playing a key role in developing DK/DKA in unprovoked A−β+ KPD.”

Disclosure: This work was supported in part by the Novartis Pharma Research Grant–in-Aid for Young Researchers and scholarship grants from Astellas Pharma Inc., MSD K.K., and Novo Nordisk Pharma Ltd. One of the study authors declared 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