Ketosis-prone Diabetes Patients Research Articles

Characterizing progressive beta-cell recovery after new-onset DKA in COVID-19 provoked A-β+ KPD (ketosis-prone diabetes): A prospective study from Eastern India

BackgroundRecent literature suggests a bi-directional relationship between COVID-19 infection and diabetes mellitus, with an increasing number of previously normoglycemic adults with COVID-19 being admitted with new-onset diabetic ketoacidosis (DKA). However, the possibility of COVID-19 being a potential trigger for A-β + ketosis-prone diabetes (KPD) in these patients needs elucidation. Our study aimed at analyzing such a cohort of patients and determining their natural course of β-cell recovery on serial follow-up. MethodsAfter initial screening, n = 42 previously non-diabetic patients with new-onset DKA and RT-PCR positive COVID-19, were included in our ten-month follow-up study. Of these, n = 22 were negative (suspected A-β + KPD) and n = 20 were positive (Type 1A DM) for autoantibodies (GAD/IA-2/ZnT8). Subsequently, n = 19 suspected KPD and n = 18 Type 1A DM patients were followed-up over ten months with serial assessments of clinical, biochemical and β-cell secretion. Amongst the former, n = 15 (79%) patients achieved insulin independence, while n = 4 (21%) continued to require insulin at ten-months follow-up. ResultsOn comparison, the suspected KPD patients showed significantly greater BMI, age, Hba1c, IL-6 and worse DKA parameters at presentation. Serial C-peptide estimations demonstrated significant β-cell recovery in KPD group, with complete recovery seen in the 15 patients who became insulin independent on follow-up. Younger age, lower BMI, initial severity of DKA and inflammation (IL-6 levels), along-with reduced 25-hydroxy-Vitamin-D levels were associated with poorer recovery of β-cell secretion at ten-month follow-up amongst the KPD patients, ConclusionsThis is the first prospective study to demonstrate progressive recovery of β-cell secretion in new-onset A-β + KPD provoked by COVID-19 infection in Indian adults, with a distinctly different profile from Type 1A DM. Given their significant potential for β-cell recovery, meticulous follow-up involving C-peptide estimations can help guide treatment and avoid injudicious use of insulin.

Metabolomics Profiling of Patients With A−β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

When stable and near-normoglycemic, patients with "A-β+" ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A-β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones-a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A-β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.

Serum Branch Chain Amino Acids (BCAAs) Are Elevated Due to Decreased Catabolism in Patients With Ketosis-Prone Diabetes at the Time of Presentation With DKA

Patients with “A-β+” Ketosis-Prone Diabetes (KPD) develop diabetic ketoacidosis (DKA) despite lacking islet autoantibodies and a phenotype of T1D, have good beta cell function and can come off insulin therapy 4–8 weeks after the DKA episode. When near-normoglycemic and stable on metformin, they have accelerated BCAA catabolism which promotes ketogenesis (Patel SG et al, Diabetes 2013). Here we measured BCAAs, their metabolites and acylcarnitine esters (C5,C3) in blood samples obtained from adults with DKA (N=74) compared to those with non-ketotic hyperglycemic crisis (N=21) at the time of acute presentation to the emergency center, and to healthy controls (N=17). Of the DKA patients, 53 were classified as likely A-β+ KPD based on absence of GAD65Ab and C-peptide levels or clinical features, and the 21 patients with non-ketotic hyperglycemia were classified as T2D. Serum concentrations of leucine, isoleucine and valine and their respective branch chain keto acids (BCKA) were higher (p<0.05) in KPD patients compared to T2D and control. The ratio of each BCKA to its precursor BCAA was calculated as an index of its rate of transamination. Serum KIC/Leu, KMV/Ile and KIV/Val were significantly lower (p<0.05) in KPD compared to T2D. The ratio of each acylcarnitine to its precursor BCKA was calculated as an index of its rate of entry and metabolism within mitochondria. Serum C5/KIC, C5/KMV and C5/KIC+KMV were lower (p<0.05) in KPD patients compared to T2D patients. Serum C3/KIV, C3/KMV and C3/KIV+KMV were significantly lower (p<0.05) in KPD patients compared to controls. Since KIC can be converted to acetoacetate and then reduced to β-hydroxybutyrate (BHOB), and KIC and KMV can be metabolized to acetyl CoA, the ratios of KIC+KMV/C2 and KIC/BHOB were calculated as indicators of their relative conversion to acetyl CoA and acetoacetate respectively. KIC+KMV/C2 was significantly lower (p<0.001) in KPD than T2D and control and KIC/BOHB was lower (p<0.001) in KPD than T2D. Acetyl carnitine was markedly elevated in the KPD group, indicating accelerated production of acetyl CoA from free fatty acids. During acute DKA, KPD patients have higher serum BCAAs because their catabolism is decreased, due to slower rate of transamination in the cytosol by BCAA transaminase 1 (BCAT1) and slower rate of entry into mitochondria and metabolism to acetyl CoA and acetoacetate by BCAT2, BCKA dehydrogenase and other catabolic enzymes. This is diametrically opposite to their profile in the stable, near-normoglycemic state, when BCAA catabolism is accelerated. We propose that during acute DKA, accelerated flux of fatty acids to acetyl CoA diminishes carnitine and NAD+ availability for mitochondrial transport and metabolism of BCAA catabolites in KPD patients, whereas in the near-normoglycemic state they have heightened dependence on BCAA catabolism for energy production through acetyl CoA and ketogenesis.

Autoantibodies to the IA-2 Extracellular Domain Refine the Definition of "A+" Subtypes of Ketosis-Prone Diabetes.

Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodies-IA-2, GAD65, and ZnT8 Abs-associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative ("A-") KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC). We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A- KPD. Ten A- KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes. Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aβ classification of KPD patients.

Acute phase ketosis-prone atypical diabetes is associated with a pro-inflammatory profile: a case-control study in a sub-Saharan African population.

It is unknown whether inflammation plays a role in metabolic dysfunction on ketosis-prone diabetes (KPD). We aimed to assess the inflammatory profile in sub-Saharan African patients with KPD during the acute ketotic phase as well as during non-ketotic hyperglycemic crises.We studied 72 patients with non-autoimmune diabetes: 23 with type 2 diabetes mellitus (T2D), and 49 with KPD, all admitted in hyperglycemic crisis (plasma glucose ≥250 mg/dl). The T2D and KPD groups were matched by sex, age, and Body Mass Index. KPD was sub-classified into new-onset ketotic phase (n = 34) or non-ketotic phase (n = 15). We measured TNF-α, MCP-1, MIP1-α, IL-8, MIP1-β, and VEGF in the serum of all participants.TNF-α and IL-8 were higher in participants with KPD compared to those with T2D (p = 0.02 TNF-α; p = 0.03 IL-8). TNF-α and IL-8 were also higher in the ketotic phase KPD group compared to the T2D group (p = 0.03 TNF-α; p < 0.001 IL-8) while MIP1-α was lower in people with ketotic phase KPD compared to their T2D counterparts (p = 0.03). MIP1-α was lower in the ketotic phase KPD group compared to the non-ketotic phase KPD group (p = 0.04). MCP-1 was lower in non-ketotic phase KPD compared to T2D (p = 0.04), and IL-8 was higher in non-ketotic phase KPD compared to T2D (p = 0.02).Participants with KPD had elevated pro-inflammatory cytokines compared to their T2D counterparts. Ketotic phase KPD is associated with a different pro-inflammatory profile compared to non-ketotic phase KPD, and the inflammatory profile appears to be comparable between non-ketotic phase KPD and T2D patients.

Arginine Metabolism Is Altered in Adults with A-β + Ketosis-Prone Diabetes

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. 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. 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. 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. 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.

Clinical characteristics, beta-cell dysfunction and treatment outcomes in patients with A − β + Ketosis-Prone Diabetes (KPD): The first identified cohort amongst Asian Indians

ObjectiveKetosis-prone diabetes (KPD), an atypical form of diabetes, has emerged as a heterogeneous syndrome in multiple ethnic groups. The objectives of this study were to look into the clinical characteristics of adult Asian Indian patients with recently diagnosed, antibody negative diabetes presenting with unprovoked ketoacidosis (A−β+ KPD) and to determine the natural course of recovery of beta-cell functions on serial follow-up over one year. Research design and methodsNewly diagnosed adult diabetes patients (n=11) with suspected KPD (A−β+) were prospectively studied over a period of 1-year with serial evaluations of clinical, biochemical and beta-cell secretion characteristics. These were compared with a control group (n=23) of KPD (A+β−) (classical Type 1A diabetes) with similar presentation. Beta-cell secretion was assessed by fasting and stimulated C-peptide values after a standard mixed meal challenge. Glycaemic control and treatment outcomes were also documented. ResultsIn comparison to the A+β− KPD controls, the A−β+ KPD patients had a significantly older age, higher BMI, stronger family history of type 2 diabetes, more severe ketoacidosis and higher fasting and stimulated C-peptide level at presentation. On serial follow-up, the patients with KPD achieved complete recovery of their beta-cell function with remission from insulin-dependence within 3–4months without further recurrences of DKA. ConclusionsThis is the first reported series of A−β+ KPD from India. The phenotype of Indian A−β+ KPD patients differs from their Western counterparts in that they are relatively younger and leaner, though the male preponderance and natural history of recovery of beta-cell dysfunction bears similarity.

Factors associated with early relapse to insulin dependence in unprovoked A-β + ketosis-prone diabetes

ObjectiveUnprovoked “A-β+” Ketosis-Prone Diabetes (KPD), a unique diabetic syndrome of adult-onset, obesity and proneness to ketoacidosis, is associated with rapid recovery of β cell function and insulin-independence. Whereas most patients experience prolonged remission, a subset relapses early to insulin dependence. We sought to define factors associated with early relapse. MethodsWe utilized a prospective, longitudinal database to analyze 50 unprovoked A-β+ KPD patients with >2 measurements of β cell function and glycemia following baseline assessment. Results19 patients (38%) relapsed to insulin dependence <1 year after the index DKA episode, while 31 (62%) remained insulin-independent for >1 year (median 4.2 years). Younger age at baseline (OR=0.947, P=0.033), and lower HOMA2-%β (OR=0.982, P=0.001), lower HOMA2-IR (OR=0.582, P=0.046) and higher HbA1c at 1 year (OR=1.71, P=0.002) were associated with early relapse. A multivariate model with these variables and the interaction of HOMA2-%β and HbA1c at 1 year provided a good fit (P<0.05). ConclusionsRelapse to insulin dependence in unprovoked A-β+ KPD patients is associated with younger age and, after 1 year, lack of robust increase in β cell functional reserve, and suboptimal glycemic control. Measurements of these parameters 1 year after the index DKA episode can be used to assess the need for insulin therapy.

Clinical characteristics and insulin independence of Koreans with new‐onset type 2 diabetes presenting with diabetic ketoacidosis

We evaluated the incidence, characteristics and insulin independence of Koreans with new-onset type 2 diabetes (T2D) initially presenting with diabetic ketoacidosis (DKA). We analysed clinical and biochemical data from diabetic patients presenting with DKA. They were classified into ketosis-prone diabetes (KPD) type 1A (KPD-T1A) (A+β-), type 1B (KPD-T1B) (A-β-), type 2A (KPD-T2A) (A+β+) or type 2B (KPD-T2B) (A-β+) according to the presence or absence of an autoantibody and β-cell reserve. Changes in therapy after insulin discontinuation were evaluated for up to 4 years. We also compared clinical and biochemical characteristics between newly diagnosed T2D patients presenting with DKA and previously diagnosed T2D patients presenting with DKA. Among 60 newly diagnosed KPD patients, 18, 21 and 21 patients were classified as KPD-T1A, KPD-T1B and KPD-T2B, respectively. In the KPD-T2B group, both fasting and stimulated C-peptide were recovered over 6 months. After 4 years of DKA development, 75% of KPD-T2B subjects no longer required insulin. Compared with previously diagnosed T2D patients presenting with DKA, newly diagnosed KPD-T2B patients tended to be younger, more obese and showed better insulin secretory function after recovery from DKA. New-onset T2D patients presenting with DKA was not uncommon among the Korean population. In contrast to previously diagnosed T2D patients presenting with DKA, who showed a progressive decrease in insulin secretory function, new-onset KPD-T2B patients recovered insulin secretory function over time, and insulin independence could be expected.

Characteristics Of Patients With Ketosis-Prone Diabetes (Kpd) Presenting With Acute Pancreatitis: Implications For The Natural History And Etiology Of A Kpd Subgroup

Reports of concomitant diabetic ketoacidosis (DKA) and acute pancreatitis (AP) are lacking among emerging forms of diabetes. This longitudinal study characterized ketosis-prone diabetes (KPD) in patients presenting with concomitant AP and DKA. Multi-ethnic KPD patients (N = 755) were followed prospectively for 1 year from the time of index DKA using repeated metabolic and beta cell functional reserve measures. Baseline and longitudinal characteristics were compared between KPD patients whose index DKA was associated with (n = 54) or without (n = 701) AP. The AP group had significantly higher baseline serum amylase, lipase, and triglyceride levels and significantly lower bicarbonate levels than the non-AP group. AP patients had significantly greater C-peptide area-under-the-curve with glucagon stimulation shortly after the index DKA, and higher fasting C-peptide (FCP) levels 6 to 12 months later. Using the validated "Aβ" KPD classification, 85% of AP patients had β+ status (preserved beta cell functional reserve), compared to 60% of non-AP patients (P = .04). Multivariate analysis revealed that among the β+ KPD subgroup with an identifiable precipitating factor for DKA ("provoked" DKA), patients with AP had worse long-term glycemic outcomes than patients whose DKA was associated with other factors. Despite greater clinical severity at presentation, KPD patients with AP have better preserved beta cell function than those without AP. β+ KPD patients presenting with AP have worse long-term glycemic control than those with other causes of provoked DKA. Factors other than beta cell function negatively impact glycemic control in KPD patients presenting with AP.

Metabolomics, Stable Isotopes, and A−β+ Ketosis-Prone Diabetes

First described in 1987 by Winter et al. as “atypical diabetes” (1), A−β+ ketosis-prone diabetes (KPD) describes a group of primarily middle-aged individuals brought to medical attention by an episode of spontaneous ketoacidosis (i.e., without evidence of infection, alcohol abuse, etc.) and subsequently diagnosed with diabetes (2,3). Although not exclusive to a particular ethnic group, KPD has primarily been described in individuals of African descent, Hispanics, and groups traditionally classified as ethnic minorities. Experience from our county hospital in Dallas, Texas, suggests that among those who present with new-onset diabetes and ketoacidosis, 60% meet criteria for the diagnosis of KPD (4). These patients generally lack evidence of endocrine pancreas autoimmunity (A−) and experience improved insulin secretory capacity (β+) and sensitivity after near-normalization of glycemia (5). Patients with KPD tend to be male and obese, and they typically have a family history of diabetes (3). Over time, this condition is characterized by a period of near-normoglycemia followed by sustained deterioration in glucose control and episodes of ketoacidosis. The metabolic perturbations that lead to transient β-cell dysfunction and spontaneous ketoacidosis in individuals with KPD remain unclear. Insights on the extreme metabolic phenotype of KPD have the potential to improve our understanding of more subtle metabolic derangements of type 2 diabetes. The fluctuating β-cell function that is characteristic of KPD suggests that acute glucose and fatty acid toxicity may play a role in its pathogenesis. However, recent studies of KPD patients during near-normoglycemic remission demonstrated that a 48-h exposure to excess fatty acids …

Pathogenesis of A−β+ Ketosis-Prone Diabetes

A−β+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible β-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnitines, and amino acids were quantified in 20 KPD patients compared with 19 nondiabetic control subjects. Unique signatures in KPD—higher glutamate but lower glutamine and citrulline concentrations, increased β-hydroxybutyryl-carnitine, decreased isovaleryl-carnitine (a leucine catabolite), and decreased tricarboxylic acid (TCA) cycle intermediates—generated hypotheses that were tested through stable isotope/mass spectrometry protocols in nine new-onset, stable KPD patients compared with seven nondiabetic control subjects. Free fatty acid flux and acetyl CoA flux and oxidation were similar, but KPD had slower acetyl CoA conversion to β-hydroxybutyrate; higher fasting β-hydroxybutyrate concentration; slower β-hydroxybutyrate oxidation; faster leucine oxidative decarboxylation; accelerated glutamine conversion to glutamate without increase in glutamate carbon oxidation; and slower citrulline flux, with diminished glutamine amide–nitrogen transfer to citrulline. The confluence of metabolomic and kinetic data indicate a distinctive pathogenic sequence: impaired ketone oxidation and fatty acid utilization for energy, leading to accelerated leucine catabolism and transamination of α-ketoglutarate to glutamate, with impaired TCA anaplerosis of glutamate carbon. They highlight a novel process of defective energy production and ketosis in A−β+ KPD.

Ketosis-Onset Diabetes and Ketosis-Prone Diabetes: Same or Not?

Objective. To compare clinical characteristics, immunological markers, and β-cell functions of 4 subgroups (“Aβ” classification system) of ketosis-onset diabetes and ketosis prone diabetes patients without known diabetes, presenting with ketosis or diabetic ketoacidosis (DKA) and admitted to our department from March 2011 to December 2011 in China, with 50 healthy persons as control group. Results. β-cell functional reserve was preserved in 63.52% of patients. In almost each subgroup (except A− β− subgroup of ketosis prone group), male patients were more than female ones. The age of the majority of patients in ketosis prone group was older than that of ketosis-onset group, except A− β− subgroup of ketosis prone group. The durations from the patient first time ketosis or DKA onset to admitting to the hospital have significant difference, which were much longer for the ketosis prone group except the A+ β+ subgroup. BMI has no significant difference among subgroups. FPG of ketosis prone group was lower than that of A− β+ subgroup and A+ β+ subgroup in ketosis-onset group. A− β− subgroup and A+ β+ subgroup of ketosis prone group have lower HbA1c than ketosis-onset group. Conclusions. Ketosis-onset diabetes and ketosis prone diabetes do not absolutely have the same clinical characteristics. Each subgroup shows different specialty.

Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of “A- β+” ketosis-prone diabetes based on long-term β-cell function, human leukocyte antigen class II alleles, and sex predilection

Abstract Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with “A- β+” KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A- β+ KPD patients presenting with “provoked” compared with “unprovoked” DKA. Clinical, biochemical, and β-cell functional characteristics were compared between provoked and unprovoked A- β+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A- β+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A- β+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. β-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. “Unprovoked” A- β+ KPD is a distinct syndrome characterized by reversible β-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas “provoked” A- β+ KPD is characterized by progressive loss of β-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term β-cell functional reserve, insulin independence, and glycemic control in KPD.

Gender and neurogenin3 influence the pathogenesis of ketosis‐prone diabetes

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

HLA class II alleles specify phenotypes of ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of beta-cell autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes. A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, beta-cell functional reserve, insulin sensitivity, and insulin requirement. Frequencies of susceptibility and resistance alleles at HLA DQA1, DQB1, and DRB1 loci were correlated with clinical and phenotypic features of KPD subgroups and compared with those of ethnic-specific population control subjects. Susceptibility alleles were more frequent (P < 0.0001) in the two A+ than the two A- KPD subgroups; in the latter, the frequency was no greater than in population control subjects (except for DQB1*0302). Susceptibility alleles differentiated the two clinically similar beta- subgroups (more frequent in A+beta- than A-beta- KPD; P < 0.01). Resistance alleles were more frequent in the two beta+ than the two beta- KPD subgroups (P < 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American A-beta+ KPD patients than in African-American control subjects. DQB1*0302 was more frequent in all KPD subgroups compared with control subjects. HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPD. Inheritance of these alleles may influence long-term beta-cell functional reserve.

Syndromes of Ketosis-Prone Diabetes Mellitus

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.

Accuracy and Predictive Value of Classification Schemes for Ketosis-Prone Diabetes

Ketosis-prone diabetes (KPD) is an emerging, heterogeneous syndrome. A sound classification scheme for KPD is essential to guide clinical practice and pathophysiologic studies. Four schemes have been used and are based on immunologic criteria, immunologic criteria and insulin requirement, BMI, and immunologic criteria and beta-cell function (Abeta classification). The aim of the present study is to compare the four schemes for accuracy and predictive value in determining whether KPD patients have absent or preserved beta-cell function, which is a strong determinant of long-term insulin dependence and clinical phenotype. Consecutive patients (n = 294) presenting with diabetic ketoacidosis and followed for 12-60 months were classified according to all four schemes. They were evaluated longitudinally for beta-cell autoimmunity, clinical and biochemical features, beta-cell function, and insulin dependence. beta-Cell function was defined by peak plasma C-peptide response to glucagon >or=1.5 ng/ml. The accuracy of each scheme to predict absent or preserved beta-cell function after 12 months of follow-up was tested using multiple statistical analyses. The "Abeta" classification scheme was the most accurate overall, with a sensitivity and specificity of 99.4 and 95.9%, respectively, positive and negative likelihood ratios of 24.55 and 0.01, respectively, and an area under the receiver operator characteristic curve of 0.972. The Abeta scheme has the highest accuracy and predictive value in classifying KPD patients with regard to clinical outcomes and pathophysiologic subtypes.

High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes

Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in beta-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation. This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

Effect of control of hyperglycemia on plasma insulin responses to various stimuli in newly diagnosed ketosis-prone diabetic patients.

ABSTRACT The effect of prompt re-establishment of normoglycemia on insulin was examined in newly diagnosed, ketosis-prone diabetic patients. The patients were studied with an oral glucose tolerance test (GTT), a tolbutamide tolerance test (TTT), and a maximum insulin stimulation test (MIST) at the initiation of insulin treatment (mean fasting blood glucose = 268 ± 26 mg/100 ml), and again after control of hyperglycemia (mean fasting blood glucose = 142 ±: 13 mg/100 ml). Initially the patients' insulin responses to the three tests were absent or markedly below normal except for three patients' responses to tolbutamide. Glucose administration prior to control of hyperglycemia induced a mean insulin response which was only 6.7% of the normals' response. Treatment of hyperglycemia was followed by variable insulin responses. Three patients experienced a temporary remission of their diabetes and had insulin responses on the second GTT of 241%, 204%, and 82% of the normals' response. These patients also demonstr...