Presumptive Type 1 DiabetesWith Comorbidities and RapidProgression Despite NumerousInsulin-Positive IsletsDiabetes Care 2016;39:1292–1294 | DOI: 10.2337/dc16-0737

CASE SUMMARY

c African American female died at age 26 yearsc Diabetes duration 15 years (diagnosed at age 11 years with type 1 diabetes)c Overweight; BMI 26.6 kg/m2

c Protective class II HLA (A*03:01, 03:02; DRB1*12:01, 13:03; DQA1*01:01, 05:01;DQB1*02:01, 05:01)

c Type 1 diabetes–associated autoantibodies positive for anti–glutamic acid de-carboxylase (GADA; 99 U/mL, radioimmunoassay cutoff 20) and C-peptide(0.48 ng/mL) collected at terminal hospitalization (performed 12 days after braindeath); HbA1c not availablednot recorded in chart and not obtained by the organprocurement organization (OPO)

c Medical comorbidities included hypertension, hyperlipidemia, diabetic retinop-athy, gastroparesis, end-stage renal disease on hemodialysis, cardiomyopathyand congestive heart failure with recent myocardial infarction and stent place-ment (2 months prior), history of gastrointestinal bleeding, anemia, seizures, andbipolar disorder

c Listed homemedications included insulin (dosage, type, and frequency unavailable),atorvastatin, gabapentin, clonazepam, omeprazole, digoxin, aspirin, clopidogrel,sevelamer, metoclopramide, senna, and valproic acid

c Found unresponsive, asystolic, and apneic and resuscitated several times beforeand at admission; glucose of 860 mg/dL, pH 7.07, and HCO3

2 13 mEq/Lc Head computed tomography showed diffuse cerebral edema and signs of anoxic

injury with progression to brain death 40 h after admissionc Cause of death attributed to anoxia following diabetic ketoacidosis

CASE NARRATIVE

The subject was a 26-year-old African American female diagnosed with type 1 di-abetes at the age of 11 years, treated with insulin injections, who died because of ananoxic brain injury likely secondary to diabetic ketoacidosis. The patient was foundwith agonal respirations and had acidosis alongwith severe hyperglycemia on arrivalto the emergency department. In the 15 years since being diagnosed with diabetes,she had developed significant signs of cardiovascular disease including cardiomy-opathy and congestive heart failure with recent myocardial infarction and stentplacement, hypertension, and hyperlipidemia. She was positive for anti–glutamicacid decarboxylase autoantibodies (GADA) and persistent C-peptide (0.48 ng/mL)below the normal range for healthy control subjects but detectible using standardassays. Residual C-peptide secretion of this level is generally detectable in only 3–9%of patients diagnosed prior to 18 years of age after 10–19 years duration (1);however, recent studies using ultrasensitive assays have demonstrated prolongedsecretion of small amounts of C-peptide even three to four decades after diabetesonset (2,3). The Diabetes Control and Complications Trial (DCCT) showed that thosepatients with type 1 diabetes with even low levels of persistent stimulated C-peptide

1Department of Pediatrics, University of Florida,Gainesville, FL2Department of Pathology, Immunology andLaboratory Medicine, University of Florida,Gainesville, FL

Corresponding author: DesmondA. Schatz, schatz@ufl.edu.

Received 4 April 2016 and accepted 25 April2016.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Laura M. Jacobsen,1 Mark A. Atkinson,1,2

Martha Campbell-Thompson,2 and

Desmond A. Schatz1

1292 Diabetes Care Volume 39, July 2016

CLINICALIM

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INDIABETES

developed fewer microvascular complica-tions (retinopathy, nephropathy) and lesssevere hypoglycemia (4). Despite the pres-ence of C-peptide, this donor already hadsignificantcomorbidities,mentionedabove,that were likely attributable to her diabetesand suggest a rapid progression of disease.Thus, we expected to observe significantloss of b-cells when presented with thissevere clinical picture of type 1 diabetes.Through the Network for Pancreatic

Organ Donors with Diabetes (nPOD),transplant-quality pancreas and immuno-logical tissues that are not used for trans-plantation are recovered for researchapplications. Clinical history obtained is

limited by that which is collected by theOPO, andnoearlier recordswere available.Following whole-pancreas processing, rep-resentative formalin-fixed samples werestained to evaluate organ pathology (5).The pancreas from this donor showed amajority of islets containing residualb-cells(Fig. 1A, B, and D). A large number of re-sidual b-cells is atypical in type 1 diabe-tes of 15 years duration (6). Numbers ofb-cells per islet varied widely and in-cluded islets without b-cells, so-calledpseudoatrophic islets. Pseudoatrophicislets are synonymous with type 1 diabe-tes (7). Increased proportions ofa-cell tob-cell islets were frequent (Fig. 1C). Both

cell types were reduced in islets withamyloidosis (Fig. 1D–F). Islet amyloidosisis reported in 90% of patients with type 2diabetes (8). Advanced atherosclerosiswas also observed in this patient withcalcification within the arterial wallsand subintimal proliferation (Fig. 1Gand H). Secondary complications of ath-erosclerosis are common to both type 1and type 2 diabetes (9).

Classic type 1 diabetes clinical progres-sion is thought to eventually reach a stateof absolute insulin deficiency, and the rateatwhich this state is reached is dependenton many factors, most notably glycemiccontrol and age at onset; however, moreliterature on long-term insulin microse-cretors is emerging (2,3,10). We won-dered why this patient had such severecomorbidities, presumed rapid diseaseprogression, and early death despite thepresence of insulin-positiveb-cells, appre-ciable C-peptide, and HLA associated withprotectionagainst type1diabetes. Perhapsthese observationswere solely due to poorglycemic control; alternatively, periph-eral insulin resistance (11) and/or b-celldysfunction (related to impaired bloodglucose sensing, signal transduction, in-sulin processing, or insulin secretion) (12)might have been at play.

Flatbush diabetes, also referred to asatypical or ketosis-prone diabetes, is a sub-group of diabetes with clinical features oftype 2 diabetes but severe presentationsof ketoacidosis followed by periods of re-covery where b-cells are functioning, insu-lin is secreted, and exogenous insulintreatment is not necessary. Differentforms have been described, distinguishedby the presence or absence of autoanti-bodies in addition to variation in theamount of C-peptide secretion present(13). It is possible the patient presentedherein had Flatbush diabetes, which mayexplain the presence of numerous insulin-positive islets and detectable C-peptide.As we refine our diagnostic skills and lab-oratorymethods, wewill be able to iden-tify these cases sooner and progress tooffering specialized treatment. There is aspectrum even within these disease var-iants that dictate the level of C-peptideproduction, and this may influence theseverity as well as the speed with whichcomplications develop. Whether thesecomplications were precipitated by glu-cose toxicity, severe insulin resistance,or dysfunctional insulin secretion/actionrequires further exploration, which will

Figure 1—Representative islet images from nPOD donor 6196. Serial paraffin sections werestained by double immunohistochemistry for Ki67+Insulin (A, B, and D) or CD3+Glucagon (Cand E), Congo Red (F), or hematoxylin and eosin (G andH). Numerous insulin-positive islets wereobserved with a range of normal sizes in all sections (red, A). Islets from the boxed area in A areshown in higher magnification for b-cells (red, B and D) and a-cells (red, C and E). Rare isletsshowed scattered CD3+ cells (brown, C and E). Several islets had amyloid, seen as intraislet red-staining amorphous material by Congo Red staining (F). Arteriosclerosis was observed includingcalcificationwithin arterial walls (G) and expansion of the subintimal layer (H). Scale bars: 700mm(A),200 mm (B and C), and 100 mm (D–H).

care.diabetesjournals.org Jacobsen and Associates 1293

hopefully lead to the identification ofnew therapies for patients with similardisease characteristics.This severepresentationandprogression

of autoantibody-positive diabetes with in-congruousC-peptide andhistologicfindingsprovides another unique example of dis-ease variability and heterogeneity. Perhapsnot all long-standing diabetes reaches ab-solute insulin deficiency. It is likely that asubset of African American patients withpresumed type 1 diabetes have Flatbushdiabetes or even a hybrid form of the dis-ease. The pathogenesis may involve b-celldysfunction or other factors contributing tocardiovasculardiseaseandseverecomplica-tions despite the presence of b-cells andmeasurable C-peptide; however, thespecific underlying mechanism(s) haveyet to be elucidated. The rapid progres-sion of clinical disease discordant with thehistological analysis demonstrates amixedpicture of diabetes pathology, and furtherresearch is needed in this area.

Acknowledgments. The authors acknowledgethe nPOD staff members and OPOs that partnerwith nPOD to recover organ donors. Additionaldonor details can be obtained through the JDRFnPOD website (www.jdrfnpod.org). This studyused data from the Organ Procurement andTransplantation Network. Donor data sets areavailable through nPOD DataShare, an online

database for collaborative communication or-ganized around the nPOD specimen repository.Funding. This work was supported by JDRF(grants 25-2013-268, 17-2012-3, and 25-2012-516 to M.C.-T. and D.A.S.).Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.Author Contributions. L.M.J. researched thedata and wrote the manuscript, M.A.A. contrib-uted to the discussion and reviewed/edited themanuscript, M.C.-T. researched the data andreviewed/edited the manuscript, and D.A.S. con-ceived of the study and reviewed/edited themanuscript. D.A.S. is the guarantor of this workand, as such, had full access to all the data in thestudy and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.

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1294 Severe Diabetes Yet Numerous b-Cells and C-Peptide Diabetes Care Volume 39, July 2016