Development and validation of a novel nomogram for prediction of ketosis-prone type 2 diabetes
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SUBMITTER: Min R
PROVIDER: S-EPMC10565480 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Ketosis-prone diabetes (KPD) is a widespread, emerging, heterogeneous syndrome characterized by patients who present with diabetic ketoacidosis or unprovoked ketosis but do not necessarily have the typical phenotype of autoimmune type 1 diabetes. Multiple, severe forms of beta-cell dysfunction appear to underlie the pathophysiology of KPD. Until recently, the syndrome has lacked an accurate, clinically relevant and etiologically useful classification scheme. We have utilized a large, longitudinally followed, heterogeneous, multiethnic cohort of KPD patients to identify four clinically and pathophysiologically distinct subgroups that are separable by the presence or absence of beta-cell autoimmunity and the presence or absence of beta-cell functional reserve. The resulting "Abeta" classification system of KPD has proven to be highly accurate and predictive of such clinically important outcomes as glycemic control and insulin dependence, as well as an aid to biochemical and molecular investigations into novel causes of beta-cell dysfunction. In this review, we describe the current state of knowledge in regard to the natural history, pathophysiology, and treatment of the subgroups of KPD, with an emphasis on recent advances in understanding their immunological and genetic bases.
| S-EPMC2528854 | biostudies-literature
Project description:Ketosis-prone type 2 diabetes is recognized as atypical diabetes. These patients are often male, characterized by obesity, sudden onset of ketosis and a transient decrease in insulin secretion capacity that can be recovered with temporal insulin therapy. Here, we report a male patient with ketosis-prone type 2 diabetes who was followed up for 8 years. During the follow-up period, his bodyweight fluctuated and he experienced four episodes of critical ketosis recurrence in association with bodyweight gain. He discontinued insulin therapy after each ketosis episode within the first 4 years, but thereafter, he had to continue insulin therapy because of decreased insulin secretion capacity. Interestingly, his peak bodyweight just before the repeated ketosis episode gradually decreased, and the insulin secretion capacity after the recovery from repeated ketosis decreased in parallel with his peak bodyweight. This long-term clinical course might be a clue to understand the pathophysiology of ketosis-prone type 2 diabetes.
| S-EPMC7078091 | biostudies-literature
Project description:Diabetic ketoacidosis (DKA) has been considered a key clinical feature of Type 1 diabetes mellitus; however, increasing evidence indicates that DKA is also a common feature of Type 2 diabetes (T2DM). Many cases of DKA develop under stressful conditions such as trauma or infection but an increasing number of cases without precipitating cause have been reported in children and adults with T2DM. Such patients present with severe hyperglycemia and ketosis as in Type 1 diabetes mellitus but can discontinue insulin after a few months and maintain acceptable glycemic control on diet or oral agents. This subtype of diabetes has been referred to as ketosis-prone T2DM. In this article, we reviewed the literature on ketosis-prone T2DM and summarized the epidemiology, putative pathophysiology and approaches to management.
| S-EPMC3351851 | biostudies-literature
Project description:ObjectiveTo evaluate the clinical value of glycosylated hemoglobin (HbA1c) in newly diagnosed ketosis-prone type 2 diabetes (KPD).MethodsA total of 330 patients with newly diagnosed type 2 diabetes (T2DM) hospitalized in our department with an average age of 48.72 ± 13.07 years old were selected and divided into T2DM group (193 cases) and KPD group (137 cases) according to whether they were combined with ketosis. According to the quartile level of HbA1c, they were divided into group A (HbA1c < 8.90%, 84 cases), group B (8.90%≤HbA1c < 10.70%, 86 cases), group C (10.70%≤HbA1c ≤ 12.40%, 85 cases) and group D (HbA1c > 12.40%, 75 cases). The general clinical features, laboratory indicators and islet function of each group were compared. Spearman correlation analysis was used to explore the correlation between HbA1c and β- Hydroxybutyric acid (β- HB) and islet function. ROC curve was used to analyze the sensitivity and specificity of HbA1c in diagnosing KPD, and the optimal tangent point was obtained.ResultsHbA1c, β-HB, FFA, RBG, insulin dosage, GSP, OGTT (0, 0.5, 1, 2, 3h) in KPD group were significantly higher than those in T2DM group (P< 0.001). HDL-C, IRT (0, 0.5, 1, 2, 3h), HOMA-β, HOMA-IR, HOMA-IS, ΔC30/ΔG30, AUC insulin were significantly lower than those in T2DM group (P< 0.001). With the increase of HbA1c level, the incidence of ketosis, β-HB, FFA and insulin dosage increased, while IRT (0, 0.5, 1, 2, 3h), ΔC30/ΔG30, AUC insulin, HOMA-β and HOMA-IS decreased accordingly (P< 0.001). In all newly diagnosed T2DM patients, Spearman correlation analysis showed that HbA1c was positively correlated with β-HB (r=0.539, P < 0.001), and was negatively correlated with HOMA-β (r=-0.564, P < 0.001), HOMA-IS (r=-0.517, P < 0.01, P < 0.001), HOMA-IR (r=-0.177, P < 0.001), ΔC30/ΔG30 (r=-0.427, P < 0.01) and AUC insulin (r=-0.581, P < 0.001). In ROC curve analysis, the optimal threshold for the diagnosis of KPD was 10.15%, Youden index was 0.616, area under the curve (AUC) was 0.882, sensitivity = 92.70%, specificity = 70.50%.ConclusionIn newly diagnosed T2DM patients, if HbA1c > 10.15%, it is more likely to develop KPD. Monitoring HbA1c level is conducive to timely detection of high-risk individuals with KPD and taking appropriate measures to prevent the occurrence and development of the disease.
| S-EPMC10667908 | biostudies-literature
Project description:Background:A-β + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible β cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. Objective:The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and β cell function in KPD patients compared with control participants. Methods:Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index-matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants. Results:Arginine availability was higher in KPD patients during euglycemia [53.5 ± 4.3 (mean ± SEM) compared with 40.3 ± 2.4 μmol · kg lean body mass (LBM)-1 · h-1, P = 0.03] but declined more in response to hyperglycemia (Δ 10.15 ± 2.6 compared with Δ 3.20 ± 1.3 μmol · kg LBM-1 · h-1, P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 ± 294 compared with 2584 ± 259 min · μmol · L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 ± 108 compared with 926 ± 257 min · μU · mL-1, P = 0.02; hyperglycemic insulin AUC 358 ± 79 compared with 866 ± 292 min · μU · mL-1, P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants. Conclusion:Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.
| S-EPMC6251649 | biostudies-literature
Project description:Unprovoked A-β+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies ("A- "), and preservation of β-cell function ("β+ ") after recovery from DKA using insulin therapy. However, there have been few reports on glucose tolerance after recovery. We present a case of KPD with nearly normalized glucose tolerance after recovery from severe DKA. A 41-year-old obese woman first presented with unprovoked severe DKA, i.e., ketonuria, plasma glucose 570 mg/dL, pH 7.18, and HCO3 - 5.2 mmol/L, without anti-islet autoantibodies. She achieved insulin-free glycemic remission after recovery from DKA, leading to the diagnosis of KPD. Thereafter, 75 g oral glucose tolerance test showed impaired fasting glucose and time-in-range using intermittently scanned continuous glucose monitoring was 97% without medication. These findings suggest that, despite the initial severe DKA, some patients with KPD might achieve normalized glucose tolerance after recovery. The similar onset patterns of DKA necessitates appropriately distinguishing KPD from acute-onset type 1B (idiopathic) diabetes.Supplementary informationThe online version contains supplementary material available at 10.1007/s13340-022-00599-6.
| S-EPMC9829925 | biostudies-literature
Project description:Aims/hypothesisWe aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes.MethodsA cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., ≥10%) using the model with the percentage eligible for statins using current guidelines by age.ResultsThe age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer-Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic from 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and ≥ 60 years, respectively (all p values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those ≥40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD ≥10% in 10 years.Conclusions/interpretationA prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention, the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.
| S-EPMC8382639 | biostudies-literature
Project description:We describe an unusual course of Ketosis Prone Diabetes and investigate potential mechanisms using induced pluripotent stem cell technology with high throughput mRNA sequencing and validation of a lecuine sensitive mTOR pathway.
2021-06-01 | GSE165385 | GEO
Project description:ObjectiveKetosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A-beta- subgroup of KPD, characterized by complete insulin dependence, absent beta-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 methodsOver 8 years, 37 patients with an A-beta- 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.ResultsThe majority (70%) of the A-beta- 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 alpha (A174V or G574S), PDX1 (putative 5'-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.ConclusionsDespite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated beta-cell dysfunction, A-beta- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-beta- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.
| S-EPMC2671096 | biostudies-literature
Project description:Genetic analysis of an adult patient with an unusual course of ketosis-prone diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5'-untranslated region (UTR) of PDX1, a β-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm (DE) stage. Metabolomics analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the DE to the pancreatic progenitor (PP) stage, and RNA sequencing showed that defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR/Cas9 manipulation of the PDX1 variant demonstrated that it is necessary and sufficient to confer leucine sensitivity and the differentiation block, likely due to disruption of binding of the transcriptional regulator NFY to the PDX1 5'-UTR, leading to decreased PDX1 expression at the early PP stage. Thus, the combination of an underlying defect in leucine catabolism characteristic of KPD with a functionally relevant heterozygous variant in a critical β-cell gene that confers increased leucine sensitivity and inhibits endocrine cell differentiation resulted in the phenotype of late-onset β-cell failure in this patient. We define the molecular pathogenesis of a diabetes syndrome and demonstrate the power of multiomics analysis of patient-specific stem cells for clinical discovery.
| S-EPMC8576504 | biostudies-literature