Ketosis-prone Diabetes (KPD) is an emerging, widespread form of diabetes characterized by presentation with diabetic ketoacidosis (DKA). The most common form of KPD is a subgroup termed """"""""A-2+"""""""" KPD. Apart from their proneness to ketosis and non-immune mediated, severe beta cell dysfunction at the time of initial presentation, the clinical features of A-2+ KPD patients are very similar to those of """"""""typical"""""""" patients with type 2 diabetes - they are middle-aged, overweight or obese, have a high frequency of metabolic syndrome, and have residual beta cell functional reserve. The pathophysiology of this novel syndrome is unknown. Using a metabolomic approach in carefully phenotyped patients compared to lean and obese non-diabetic controls, we have found that clinically stable, new onset A-2+ KPD patients have lower concentrations of total fatty acids and acyl carnitines, higher concentrations of an acyl carnitine marker of beta-hydroxybutyrate, and markedly higher concentrations of glutamine / glutamate, together with higher ornithine, lower citrulline and arginine, and depressed levels of amino acids that enter the TCA cycle via anaplerosis. We hypothesize that A-2+ KPD patients have a high rate of disposal of fatty acids, marked by an increased shunt towards ketogenesis associated with impaired oxidative flux through the TCA cycle, and defects in transfering nitrogen from glutamine / glutamate to the urea cycle and carbon from glutamine / glutamate to the TCA cycle. Collectively, these defects could result in impaired TCA cycling and decreased ATP generation in mitochondria, leading to increased ketogenesis (in the liver) and impaired insulin secretion (in beta cells). We propose to test these hypotheses using stable isotope / mass spectrometric protocols by carrying out, in 10 men with new onset A- 2+ KPD on stable insulin therapy 8 weeks after the defining episode of DKA, 10 age-, BMI-, gender- and glycemia-matched, recently diagnosed type 2 diabetic patients on stable insulin therapy, and 10 age-, BMI- and gender-matched non-diabetic controls, the following Specific Aims: 1. Measure whole body total and net lipolysis and fat oxidation;2. Determine acetyl CoA production, oxidation and its utilization for ketogenesis;3. Determine whole body rate of production of glutamine, its deamidation to glutamate and rate of transfer of its amide nitrogen to citrulline. The results of these investigations could specify the pathophysiology of a unique form of diabetes, and also shed light on possible mechanisms of beta cell failure in common forms of type 2 diabetes.
Failure of the pancreatic beta cell to secrete insulin is critical to the development of type 2 diabetes, but the causes of beta cell dysfunction are unknown. We have characterized patients with a distinct syndrome of type 2 diabetes termed """"""""A-2+ Ketosis-prone Diabetes"""""""", who have patterns of blood metabolites that point to unique mechanisms of beta cell failure. We propose to identify these novel mechanisms, and thereby shed light on how the beta cell fails to secrete insulin in type 2 diabetes.
|Redondo, Maria J; Muniz, Jesse; Rodriguez, Luisa M et al. (2014) Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes. BMJ Open Diabetes Res Care 2:e000008|
|Redondo, M J; Rodriguez, L M; Haymond, M W et al. (2014) Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes. Pediatr Diabetes 15:543-9|
|Balasubramanyam, Ashok (2014) The villain with a thousand faces. J Diabetes Complications 28:434-5|
|Oak, Shilpa; Gaur, Lakshmi K; Radtke, Jared et al. (2014) Masked and overt autoantibodies specific to the DPD epitope of 65-kDa glutamate decarboxylase (GAD65-DPD) are associated with preserved ?-cell functional reserve in ketosis-prone diabetes. J Clin Endocrinol Metab 99:E1040-4|
|Redondo, Maria J; Rodriguez, Luisa M; Escalante, Mirna et al. (2013) Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis. Pediatr Diabetes 14:333-40|
|Fernandez, Ramiro; Misra, Ranjita; Nalini, Ramaswami et al. (2013) Characteristics of patients with ketosis-prone diabetes (KPD) presenting with acute pancreatitis: implications for the natural history and etiology of a KPD subgroup. Endocr Pract 19:243-51|
|Patel, Sanjeet G; Hsu, Jean W; Jahoor, Farook et al. (2013) Pathogenesis of A??? ketosis-prone diabetes. Diabetes 62:912-22|
|Brooks-Worrell, Barbara M; Iyer, Dinakar; Coraza, Ivonne et al. (2013) Islet-specific T-cell responses and proinflammatory monocytes define subtypes of autoantibody-negative ketosis-prone diabetes. Diabetes Care 36:4098-103|
|Redondo, Maria J; Rodriguez, Luisa M; Escalante, Mirna et al. (2012) Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes. Pediatr Diabetes 13:564-71|
|Nalini, Ramaswami; Ozer, Kerem; Maldonado, Mario et al. (2010) Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of ""A-?+"" ketosis-prone diabetes based on long-term ?-cell function, human leukocyte antigen class II alleles, and sex predilection. Metabolism 59:1448-55|