Ketosis-Prone Type 2 Diabetes

Updated: Jan 20, 2023
  • Author: Richard S Krause, MD; Chief Editor: George T Griffing, MD  more...
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Overview

Background

Ketosis-prone diabetes (KPD) is a global heterogeneous syndrome characterized by presentation with diabetic ketoacidosis (DKA) in persons who do not fit traditional categories of type 1 or 2 diabetes mellitus (DM). [1, 2] The original schema for classifying DM consisted of two categories known as type 1 diabetes mellitus (insulin-dependent diabetes) and type 2 diabetes mellitus (noninsulin-dependent diabetes). Individuals with type 1 diabetes have an absolute insulin deficiency due to autoimmune destruction of pancreatic beta (β) cells and thus were considered prone to develop DKA. Patients with type 2 diabetes have peripheral insulin resistance with initially normal or elevated circulating levels of endogenous insulin and thus were not considered to be at risk for DKA.

Ketosis-prone diabetes was originally described in the late 1960s as atypical diabetes and noted among African or African American patients who presented with clinical features between those of type 1 and type 2 diabetes. Later reports included cases with DKA as the initial manifestation of diabetes. However, in contrast to type 1 diabetes, patients with atypical diabetes undergo spontaneous remission and maintain long-term insulin independence. At presentation, these individuals have impairment of both insulin secretion and insulin action—but intensified diabetes management results in significant improvement in β-cell function and insulin sensitivity to allow discontinuation of insulin therapy within a few months of treatment. Because of mixed features of type 1 and type 2 diabetes, this variant has been given several names, including diabetes mellitus type 1b, idiopathic type1 diabetes, Flatbush diabetes, type 1.5 diabetes mellitus, latent autoimmune diabetes in adults (LADA), and ketosis-prone type 2 diabetes. [3]

Since the mid-1990s, the number of patients who presented with DKA but did not require long-term insulin therapy has increased. Many such patients had conditions that resembled traditionally defined type 2 diabetes in that they were obese and often had a family history of diabetes. However, subsequent to these observations, new ways to classify diabetes were devised.

The system of classification that most accurately predicts glycemic control and the need for insulin treatment 12 months after presentation with DKA is known as the Aβ system: A for autoantibody status and β for beta cell functional reserve. [1, 4] This system classifies diabetics into four groups as follows:

  • A+β+: Autoantibodies present, β-cell function present

  • A+β-: Autoantibodies present, β-cell function absent

  • A-β-: Autoantibodies absent, β-cell function absent

  • A-β+: Autoantibodies absent, β-cell function present

The most common ketosis-prone diabetes subgroup in a longitudinal study was A-β+ (54%), followed by A-β- (20%), A+β- (18%), and A+β+ (8%). [5]

Patients in the A+β- and A-β- subgroups are immunologically and genetically distinct from each other but share clinical characteristics of type 1 diabetes with very low β-cell function. These patients will require lifelong exogenous insulin therapy. [6]

Patients in the A+β+ and A-β+ subgroups have clinical characteristics of type 2 diabetes with preserved β-cell functional reserve. Those with the A+β+ subtype lose their β-cell reserve over time and eventually require lifelong exogenous insulin therapy, whereas the majority of individuals with the A-β+ subgroup can discontinue exogenous insulin therapy and can be managed with oral hypoglycemic agents long term. [6]  The American Diabetes Association (ADA) system classifies them as having type 2 diabetes. [7]  Patients with this metabolic and clinical profile who experience DKA have ketosis-prone type 2 diabetes. There is also a modified ADA system and a system based on body mass index (BMI). [8]

Patient education materials are available from various sources; an excellent resource is the American Diabetes Association.

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Pathophysiology

The triggering mechanisms leading to diabetic ketoacidosis (DKA) in the A-β+ subgroup of those with ketosis-prone diabetes (KPD) are not well defined. Viral infections, other metabolic factors such as oxidative stress with concomitant glucose-6-phosphate-dehydrogenase (G6PD) deficiency, and genetic factors have been implicated. [9]

Investigators analyzed the roles of glucotoxicity and lipotoxicity in causing a severe but partially reversible β-cell functional defect following the initial episode of DKA in a group of African Americans with the A-β+ variant. [6] They found that acute hyperglycemia but not acute hyperlipidemia caused severe blunting of the C-peptide response to glucose stimulation, and chronic hyperglycemia was associated with reduced expression and insulin-stimulated threonine-308 phosphorylation of Akt2 in skeletal muscle. Severe glucotoxic blunting of an intracellular pathway that leads to insulin secretion may contribute to the reversible β-cell dysfunction characteristic of the A-β+ subtype, and hyperglycemia may be exacerbated by defects in skeletal muscle glucose uptake as a result of glucotoxic downregulation of skeletal muscle insulin signaling. One possible mechanism of glucotoxic β-cell dysfunction is increased oxidant stress in the pancreatic islet cells. [6]

The pathophysiology of some cases of unprovoked A-β+ ketosis-prone type 2 diabetes may potentially involve B-chain amino acid 9-23-related peptide (B:9-23rPep)–specific interferon (IFN)-ϒ-related immunoreactivity. [10]  The increase in immunoreactivity may be a reflection of transiently lowered β-cell function and heightened disease activity at the onset of diabetic ketosis/ketoacidosis (DK/DKA), all of which could contribute to the development of DK/DKA in those with the A-β+ subtype. [10]

The possibility of X-linked G6PD deficiency as a genetic basis for the male predominant A-β+ phenotype in West African patients has been investigated. The prevalence of functional G6PD deficiency was found to be higher in individuals with ketosis-prone diabetes as compared to those with type 2 diabeties, along with a relationship between β-cell functional reserve and erythrocyte G6PD activity. [6]

In a study that analyzed the relationship between 25-hydroxyvitamin D (25OHD) and episodes of ketosis in 162 patients with nonautoimmune, newly diagnosed diabetes, it appears that a higher level of serum 25OHD may be an independent protective factor for episodes of ketosis or ketoacidosis in those with ketosis-prone type 2. [11]

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Etiology

The etiology of different diabetic conditions is an area of active research. Antibodies to glutamic acid decarboxylase exhibit different epitopes (antigenic determinants). The differences in antigenic specificity of these epitopes are related to the degree of β-cell destruction and, thus, to the severity of the clinical syndrome. [12]

When antibodies are absent (A-β+ phenotype), multiple etiologies have been proposed. These include viral infection, genetic variations, and oxidative stress. [9] As with type 2 diabetes, most patients with ketosis-prone type 2 diabetes are obese and have a family history of diabetes.

There is a two- or three-fold higher prevalence of ketosis-prone diabetes in men independent of the degree of obesity and age. The reason for the sex difference has been ascribed to hormonal factors, body-fat distribution, and changes in insulin sensitivity. [13]

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Epidemiology

In the United States, the prevalence of ketosis-prone diabetes (KPD) has been estimated to be between 20% and 50% in African American and Hispanic patients who present with diabetic ketoacidosis (DKA). Half of these patients have the A-β+ phenotype. [14] African studies have reported a similar incidence. [15] Asian and White populations show a lower prevalence and may represent fewer than 10% of individuals presenting with DKA. [16]

The incidence of ketosis-prone shows a two- or third-fold higher prevalence in men compared to women. [13] Diagnosis is most often made in the third to fifth decade of life, but cases in children have been reported. [6]

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Prognosis

The long-term prognosis of ketosis-prone diabetes varies with the Aβ status. Patients who are β- require long-term insulin therapy for glycemic control. Most patients in the A-β+ subgroup have-long term remission (ie, do not continue to require insulin) after treatment of an initial diabetic ketoacidosis episode followed by a period of insulin therapy.

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