While diabetic ketoacidosis (DKA) appears most often in people with type 1 diabetes, in African Americans, more than 50% of newly diagnosed cases feature metabolic characteristics more closely aligned with type 2 diabetes (T2D), according to a study in Endocrine Practice.1 This subtype of diabetes, ketosis-prone diabetes (KPD), arises in an estimated one-third of African Americans with T2D, in the United States.2
“We don’t know why it is seen particularly in African Americans and males. We also don’t know the antecedent of hyperglycemia in duration and extent that affects hemoglobin A1c (HbA1c), and we don’t know how long these patients have had diabetes before presentation of DKA,” senior author Priyathama Vellanki, MD, assistant professor in the division of endocrinology, metabolism, and lipids at Emory University School of Medicine in Atlanta, Georgia, told EndocrineWeb.
Given this, Dr. Vellanki said, “I am now researching the sex differences and genetics that are affecting this presentation.”
Primary ketosis-prone diabetes in patients with T2D may be provoked or unprovoked; and, stressors such as trauma or infection may precipitate the onset of DKA, while the etiology of unprovoked ketosis remains uncertain.3 However, severe hyperglycemia and ketosis are symptoms that appear to reflect unprovoked DKA as a clinical presentation of T2D.3
Characteristics of most patients with KPD include:
In addition, most patients with KPD are more likely to present with physical symptoms aligned with symptoms of T2D, including acanthosis nigricans and abdominal adiposity,1 according to findings from this study.
“KPD is seen more often in men than women, and nearly 80% of patients with KPD have a strong family history of T2D,” said Dr. Vellanki. KPD frequently affects African Americans, but it has been described also in other populations at higher susceptibility to the development of T2D, such as African, Chinese, and Hispanic populations, she said.
Despite the characteristics of KPD as consistent with T2D, time to resolution of DKA and response to insulin are more similar to what occurs in patients with type 1 diabetes.1 Yet, unlike patients with type 1 diabetes, patients with KPD are able to discontinue insulin therapy a few months after presentation (range: 2-12 weeks), with different factors affecting the amount of time each patient needs to be on insulin, according to findings from this study.1
“It’s a million dollar question to determine what affects the variability in time to remission. Insulin requirements are predicated on the type of diabetes in terms of whether it is type 1 or type 2,” Elena A. Christofides, MD, FACE, chief executive officer of Endocrinology Associates, Inc. in Columbus, OH, told EndocrineWeb. ”The second most important variable is the weight of the patient.”
“The third most important variable is everything else, such as gender, diet, age, lifestyle, and overall nutrition status,” she continued. “The first variable—type of diabetes—is non-modifiable, while the second variable—weight—is modifiable, but not immediately so.”
This initial insulin need reflects impaired insulin secretion and action at disease presentation, said Dr. Christofides. After discontinuation of insulin, these patients can maintain acceptable glycemic control for many years with diet or oral medications. Once patients with KPDM have returned to near-normoglycemic levels of insulin secretion and action have improved to levels similar to those in hyperglycemic patients with ketosis-resistant T2D, she said.
About 70% of patients with KPD return to these near-normoglycemic levels and can remain off insulin,1 according to Dr. Vellanki.
“Here, near-normoglycemia is defined as HbA1c <7% and the ability to maintain fasting blood glucose of <130 mg/dL off subcutaneous insulin therapy for at least one week,”1 Dr. Vellanki said, “Nonetheless, patients with KPD experience a long-term decrease in beta-cell function similar to that in patients with T2D. Also, they experience insulin resistance in muscle, liver, and adipose tissues over the long term.”
Factors such as the presence of pancreatic autoantibodies and beta-cell reserve affect the long-term clinical course of KPD. In patients presenting with DKA without pancreatic autoantibodies and with beta-cell reserve, beta-cell recovery and achievement of near-normoglycemia remission from insulin are possible, in contrast to patients with type 1 diabetes with pancreatic autoantibodies without beta-cell reserve.
Additionally, the presence of masked antibodies to the DPD epitope of GAD-65 (65-kDa glutamate decarboxylase) correlates with increased beta-cell reserve even with pancreatic autoantibodies.5 Patients without pancreatic autoantibodies with beta-cell reserve presenting with provoked DKA are primarily Hispanic and presented with lower glucose and HbA1c levels, and experienced lower long-term beta-cell function compared with unprovoked DKA.5
Provoked DKA was most common in African Americans, males, and patients with higher HbA1c at presentation.1-3 The clinical course of these patients typically involves recovery of insulin secretion after insulin therapy.3
“The authors did a really good job describing the variable genetics that goes into this particular population, which is not an unknown population,” Dr. Christofides said, “It’s not so much that it’s male African Americans with high HbA1c.”
“Rather, that is a feature of this kind of diabetes, not a precipitator. The genetics described are really fascinating and clearly important for the fact that these patients develop DKA that then goes away and they effectively go into remission,” she told EndocrineWeb.
“The important point is recognizing that these patients are T2D who appear type 1 because they are in DKA that then resolves and remits. Recognizing that pattern is more critical than assuming that these patients are male, African Americans with high HbA1c.”
“In patients without pancreatic autoantibodies with beta-cell reserve, biomarkers of unprovoked DKA appear at an increased frequency of the protective HLA class II DQB1*0602 allele and a lack of islet-specific T-cell response.3 These biomarkers so far are not pharmacologically targetable,” said Dr. Vellanki.
Even in patients with KPD who achieve long-term insulin remission, oral diabetic medications and continued insulin can be important for addressing declining endogenous insulin secretion that occurs in these patients, according to Dr. Vellanki. Therapy with sulfonylureas, metformin, or sitagliptin can expand the time a patient is near-normoglycemic and in insulin remission.5.6 A prolonged remission on oral medications might be due to improved beta-cell function. As in patients with T2D, deteriorating beta-cell function may necessitate escalating treatment, she said
“Identifying these patients is key because there have been studies that have evaluated the ability to restore normoglycemic remission. The first-line treatment algorithm is to pay attention to these studies, to then make sure that these medications are offered and are utilized in this patient population early, and the explanation of why therapy with these medications should be continued even when a patient is normoglycemic is necessary,” Dr. Christofides told EndocrineWeb.
“The new era of medicine is understanding how someone’s genetics might play a role in the evolution and presentation of the disease,” said Dr. Christofides, “The healthcare providers who recognize this and are actively embracing this as a way of educating and communicating with their patients and their families about future risk are the physicians of the future.”