Approach to the patient with atypical diabetes

Devin W. Steenkamp; Sara M. Alexanian; Elliot Sternthal

doi:10.1503/cmaj.130185

Submit a Response to This Article

Compose Response

Title *

References

Author Information

Contributors

First Name and Middle Initial *

First or given name, e.g. 'Peter'.

Last Name *

Your last, or family, name, e.g. 'MacMoody'.

Degrees

Email Address *

Your email address, e.g. higgs-boson@gmail.com

Occupation *

Your role and/or occupation, e.g. 'Orthopedic Surgeon'. Minimum 7 characters.

Affiliation *

Your organization or institution (if applicable), e.g. 'Royal Free Hospital'. Minimum 12 characters.

Address

Your organization, institution's or residential address.

Statement of Competing Interests

Competing interests? *

Yes

Please describe the competing interests

Vertical Tabs

Jump to comment:

Re:Atypical diabetes: clarifying the muddy waters
Devin W. Steenkamp

Posted on: 08 August 2014
Atypical diabetes: clarifying the muddy waters
Elizabeth AC Sellers

Posted on: 07 July 2014

Posted on: (8 August 2014)

Re:Atypical diabetes: clarifying the muddy waters
Devin W. Steenkamp
Other Contributors:
We would like to thank Dr Sellers and colleagues for their thoughtful letter in response to our recent article and for drawing attention to the Canadian diabetes landscape.
This article was written for the practicing primary care clinician, who may occasionally take care of a patient with diabetes who doesn't seem to fit into our typical diabetes classification paradigm. We recognize that much still needs to be l...
Show More

We would like to thank Dr Sellers and colleagues for their thoughtful letter in response to our recent article and for drawing attention to the Canadian diabetes landscape.
This article was written for the practicing primary care clinician, who may occasionally take care of a patient with diabetes who doesn't seem to fit into our typical diabetes classification paradigm. We recognize that much still needs to be learned and we specifically intended to avoid onerous detail and have deliberately not attempted to provide a comprehensive review of the topic for the expert practicing endocrinologist. Our intent was to highlight phenotypic features and the limitations of lumping diverse groups of patients together - directed at the general physician. We aimed to emphasize the value in looking beyond our usual classification paradigm.
As such, we also attempted to avoid unnecessary complexity and controversy that may further 'muddy" the already complex waters. We agree that LADA is a slowly progressive form of type 1a diabetes, and while it may not be distinct from type 1 diabetes, it has certain autoimmune and phenotypic features that distinguish it from childhood type 1 diabetes. It is also the most common presentation of autoimmune diabetes in adults and therefore may initially be confused with type 2 diabetes. However, ketosis prone diabetes is not simply type 2 diabetes presenting with ketoacidosis. This group of patients is still poorly understood and much work needs to be done in furthering our understanding of the basic pathophysiology, of what constitutes this heterogeneous group of diabetes. For example, emerging metabolomics data suggest that in individuals within certain subsets of KPD, a distinctive novel pathogenic process of defective energy production and ketosis may be at play. (Patel SG et al, Diabetes 2013 Mar; 62(3):912-22.)
As adult endocrinologists, we have written this article from an adult medicine perspective and have not specifically intended to exclude important pediatric literature - and we thank the letter writer's for drawing attention to the pediatric population. We also specifically selected the three atypical diabetes phenotypes that were reviewed in this article, as we believe these are most likely to be encountered in a general primary care setting. Given space limitations, we were unable to describe specific populations with monogenic diabetes, but we hope that our focused discussion of HNF1A monogenic diabetes will stimulate consideration of this type of diabetes.
There are certainly many more atypical diabetes phenotypes to be considered and we agree that regional variation and location of practice are highly relevant. For example, in our hospital, which serves a large, under-served, heterogeneous urban population, ketosis prone diabetes is the most common reason for admission to the medical ICU with ketoacidosis. Type 1a diabetes is less common in our particular setting. In terms of the comment that we did not specifically discuss differences in prevalence in type 2 diabetes by ethnicity, we acknowledge these differences exist.
While we recognize the increasing burden of obesity in both adults and children, the literature (including the citation included by the letter writers) does support that most patients diagnosed with type 1 diabetes and HNF1A diabetes continue to be lean at diagnosis. We recognize that this may change in future, but for the purposes of helping to provide general physicians with clinical phenotypic clues to aid diagnosis, we believe there is value in this distinction.
Naturally, diet and lifestyle modification form the cornerstone of all diabetes therapeutics and we agree that metformin is the initial "pharmacologic" therapy for type 2 diabetes in most in individuals. The use of the terminology "classic juvenile form of diabetes" to describe type 1 diabetes was included for those physicians who may be more familiar with the older terminology.
We acknowledge that controversies surrounding diabetes classification continue to exist, but recognition of a possible atypical diabetes phenotype is an important part of primary diabetes care.
Devin Steenkamp, MD.
Sara Alexanian, MD.
Elliot Sternthal, MD.
Section of Endocrinology, Diabetes and Nutrition,
Boston University School of Medicine
Conflict of Interest:
None declared
Show Less

Competing Interests: None declared.
Posted on: (7 July 2014)

Atypical diabetes: clarifying the muddy waters
Elizabeth AC Sellers, Associate Professor
Other Contributors:
We are writing this letter in response to the recent review by Drs. Steenkamp, Alexanian and Sternthal entitled "Approach to the Patient with Atypical Diabetes" published in the Canadian Medical Association Journal, June 10, 2014 [1]. The authors present their approach to the diagnostic challenge presented by "atypical" diabetes. As the authors clearly state, our improved understanding of the pathophysiology of diabetes...
Show More

We are writing this letter in response to the recent review by Drs. Steenkamp, Alexanian and Sternthal entitled "Approach to the Patient with Atypical Diabetes" published in the Canadian Medical Association Journal, June 10, 2014 [1]. The authors present their approach to the diagnostic challenge presented by "atypical" diabetes. As the authors clearly state, our improved understanding of the pathophysiology of diabetes mellitus has increased the complexity and challenge associated with accurate diagnosis of a patient's type of diabetes. We acknowledge the importance of understanding each individual's pathophysiology to tailor their treatment.
The authors' stated goal was "to provide a practical approach to the heterogenous group of disorders..." Unfortunately, we believe that the authors have not successfully achieved this goal. We have several concerns about the content of this review particularly in the context of the Canadian diabetes landscape.
There is no discussion in the review around the controversy that surrounds the diagnoses of "ketosis-prone diabetes" and "latent-autoimmune diabetes of adulthood". Many clinicians believe these are not separate entities but are within the spectrum of type 2 diabetes and type 1 diabetes, respectively. In this manuscript, there is no mention of the occurrence of diabetic ketoacidosis in both adults and children with type 2 diabetes. This has been well published over the last 2 decades in both adults and children [2-4] and likely represents what the authors refer to as "ketosis prone diabetes".
Moreover, the authors use somewhat dated terminology, such as "the classic juvenile form of diabetes". Both the Canadian Diabetes Association and the American Diabetes Association discontinued the use of this terminology more than 15 years ago. Continued use of this terminology, albeit tempered by "now known as type 1 diabetes," perpetuates the confusion related to terminology.
A clearer distinction between diabetes in adult versus pediatric populations would be beneficial throughout the article for the readers of the CMAJ. Much of the data presented and literature cited pertains to adults only. For example, Table 2 defines "lean" as a BMI <25 kg/m2, an adult criterion. The Canadian Diabetes Association has worked hard to provide useful age- specific definitions and management guidelines; these are available on-line for health care providers [5].
Additionally, the authors state that both type 1 diabetes and HNF1 alpha transcription factor diabetes occur predominately in lean populations. Clinicians can no longer rely on this phenotype to help us to distinguish type of diabetes, given the increasing prevalence of overweight and obesity in the general population [6].
Table 1 refers to genetic "penetrance". This typically pertains to a monogenic disorder and refers to individuals who inherit the gene mutation and the percentage of these individuals who manifest physical signs or symptoms of the disorder [7]. It is therefore not clear to us how percentage penetrance for polygenic disorders can be reported. Table 1 also reports that type 2 diabetes has a high prevalence worldwide. While type 2 diabetes is a global disease, there are clear ethnic predispositions to this disorder [8, 9].
The authors state that metformin is first line therapy for most patients with type 2 diabetes. This is not consistent with the Canadian Diabetes Association Clinical Practice Guidelines where lifestyle modification is first line therapy in children and also in adults (with consideration to the use of metformin in addition to lifestyle modification at diagnosis in adults) [9,10]. Perhaps this should have been clarified that metformin would be the first line pharmacotherapeutic agent.
Our location of practice may bias us, but given the review's publication in the journal of the Canadian Medical Association, mention of the polymorphism of the HNF 1 alpha gene found in the Oji-Cree of northeastern Manitoba and northwestern Ontario is warranted. This polymorphism contributes to the development of type 2 diabetes in the Oji- Cree, who have amongst the highest reported rates of type 2 diabetes in both adults and youth [11,12]. The authors provided a brief overview of MODY2 and 3; however regional differences are important to reinforce to ensure optimal diagnoses and intervention.
We agree with the authors that there are many important reasons to differentiate diabetes types, to guide treatment, prognosis and genetic counseling. This is an ongoing area of active research and knowledge translation. We trust that this letter has helped to augment your readers' understanding of diabetes in Canada, for all age groups.
Sincerely,
Elizabeth Sellers, MD., MSc., FRCPC Associate Professor
Seth Marks, MD., MSc., FRCPC Associate Professor
Celia Rodd MD., MD., MSc., FRCPC Associate Professor
Brandy Wicklow MD., MSc., FRCPC Assistant Professor
Heather Dean MD., FRCPC Professor
Section of Pediatric Endocrinology & Metabolism Department of Pediatrics and Child Health University of Manitoba
References
1. Steenkamp DW, Alexanian SM, Sternthal E. Approach to the patient with atypical diabetes. CMAJ 2014;186; 678-684.
2. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus. Arch Intern Med 2004; 164: 1925-1931.
3. Rewers A, Klingensmith G, Davis C et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics 2008; 121: 1258-1266.
4. Amed S, Dean HJ, Panagiotopoulos C, et al. Type 2 diabetes, medication-induced diabetes and monogenic diabetes in Canadian children: a prospective national surveillance study. Diabetes Care 2010;33:786-91.
5. http://www.diabetes.ca/clinical-practice-education/clinical- practice-guidelines
6. Kaminski BM, Klingensmith GJ, Beck RW, Tamborlane WV, Lee J, Hassan K, Schtz D, Kollman C, Redondo MJ. Body mass index at the time of diagnosis of autoimmune type 1 diabetes in children. J Peds 2013; 162: 736 -740.
7. Nussbaum RL, McInnes RR, Willard HF. Thompson and Thompson: Genetics in Medicine 7th edition 2007. Saunders, Philadelphia, PA
8. Ekoe JM, Punthakee Z, Ransome T, Prebtani APH, Goldenberg R. Screening for type 1 and type 2 diabetes. Can J Diabetes 2013; 37: S8-S11.
9. Panagiotopoulos C, Riddell MC, Sellers EAC. Type 2 diabetes in children and adolescents. Can J Diabetes 2013; 37: S163-S167.
10. Harper W, Clement M, Goldenberg R, Hanna A, Main A, Retnakaran R, Sherifali D, Woo V, Yale JF. Pharmacologic management of type 2 diabetes. Can J Diabetes 2013;37: S61-S68.
11. Hegele RA, Zinman B, Hanley AJ, Harris SB, Barrett PH, Cao H. Genes, environment and Oji-Cree type 2 diabetes. Clin Biochem 2003; 36: 163-170.
12. Dean HJ, Young TK, Flett B, Wood-Steiman P. Screening for type-2 diabetes in aboriginal children in northern Canada. The Lancet. 1998;352(9139):1523-1524.
Conflict of Interest:
None declared
Show Less

Competing Interests: None declared.