A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome

Abstract

OBJECTIVE -Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the AϪ␤Ϫ subgroup of KPD, characterized by complete insulin dependence, absent ␤-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.RESEARCH DESIGN AND METHODS -Over 8 years, 37 patients with an AϪ␤Ϫ phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.RESULTS -The majority (70%) of the AϪ␤Ϫ KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1␣ (A174V or G574S), PDX1 (putative 5Ј-untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.CONCLUSIONS -Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated ␤-cell dysfunction, AϪ␤Ϫ KPD is most likely not a predominantly monogenic diabetic syndrome. Several AϪ␤Ϫ KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

HbA1c as a Screening tool for Ketosis in Patients with Type 2 Diabetes Mellitus

“…The mean HbA 1c of T2DM patients reported in this study is similar to that reported in previous studies9192021. DKA was demonstrated to be associated with increased HbA 1c levels which reflect both fasting and postprandial hyperglycemia24 in T1DM23252627 and T2DM28.…”

“…Several reports have indicated the utility of HbA 1c in predicting the development of diabetic retinopathy and nephropathy15161718. The mean HbA 1c is reported to be higher than 10% in T2DM patients with ketosis9192021. Considering the fact that ketosis is the end result of prolonged uncontrolled diabetes2223, we hypothesized that HbA 1c could be used as a screening tool for ketosis in T2DM patients.…”

Male predominance in ketosis-prone diabetes mellitus

“…In conclusion, KPDM is a complex and heterogeneous disease with environmental and genetic factors influencing pathophysiology and clinical progression significantly (32). Currently, the syndromes of KPDM and its specific complications appear to be increasingly recognized worldwide.…”

“…A previous study confirmed that the majority (70%) of the A-β-KPDM patients had no significant causal polymorphisms in either the proximal promoter or coding regions of 7 genes, including glucokinase, HNF1A and HNF1B, pancreatic and duodenal homeobox 1, β2/NeuroD1 and paired box gene 4. The investigators regarded that A-β-KPDM is more likely to not be a predominantly monogenic diabetic syndrome (31,32). The previous study by Louet et al (33) showed that neurogenin-3 variations may influence the pathogenesis of KPDM in West African populations but did not show an association with gender distribution.…”

Precision Medicine in Diabetes: Is It Time?

“…For example, we see lean members of specific ethnic groups with antibody-negative, nonketotic diabetes; we treat patients with childhood-onset, antibody-positive diabetes who become insulin resistant as they age; we do not fully understand why some patients progress rapidly to microvascular and/or macrovascular complications or require aggressive escalation of therapy; and we cannot predict the rate of b-cell failure, the degree of weight loss required to normalize glycemia, or the type of medication best suited for a given patient. Attempts at capturing greater granularity have resulted in the creation of new entities, such as latent autoimmune diabetes in the adult to describe autoimmune diabetes with onset after age 30 (1), and ketosis-prone diabetes to describe antibody-negative diabetes with a ketotic onset but only transient insulin requirements (2,3); however, absent a full understanding of the mechanism and its implications, these subtypes emerge mired in controversy or fail to penetrate clinical care (4,5).…”