Correspondence

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

N Engl J Med 2010; 362:1348-1350April 8, 2010

Article

To the Editor:

Rare, naturally occurring gene mutations provide important insights into normal human physiology. We report on a young girl with severe neonatal hypoglycemia due to a novel glucokinase mutation (V91L). Her father had a similar clinical course, but neither his DNA nor his pancreatic tissue was available for study.

V91L showed a markedly increased affinity for glucose that was more than 8.5 times as high, an enzyme efficiency that was 7 times as high, and a relative-activity index that was 30 times as high as that of the wild-type enzyme. The estimated threshold for glucose-stimulated insulin secretion was markedly lower than that of the wild-type enzyme (0.96 vs. 5.00 mmol per liter). Diazoxide and octreotide therapy did not control the patient's hypoglycemia, and a subtotal pancreatectomy was performed when she was 3 years of age.

Quantitative histologic examination revealed abnormally large islets (Figure 1AFigure 1Histologic Features of the Pancreas in the Patient and in Age-Matched Control Subjects with Normal Pancreases.) with some beta cells containing a large nucleus (Figure 1C). The mean islet area was 7705 μm² in the head of the pancreas and 7048 μm² in the tail of the pancreas. Both areas were significantly larger than those in specimens obtained from five age-matched control subjects who did not have pancreatic disease (range, 1160 to 1997 μm²; P<0.001) and in three specimens obtained from two age-matched subjects with diffuse hypoglycemia due to ABCC8 gene mutations (ATP-sensitive potassium-channel [K_ATP]–related hypoglycemia) (range, 769 to 859 μm²; P<0.001). All these subjects were in subgroups of a population from a previously published study.1 Approximately 10% of the patient's islets were larger than 13,000 μm²; this was generally larger than any islet in the pancreases of control subjects or subjects with K_ATP-related hypoglycemia. The relative beta-cell area (the percentage of the histologic section that stained positive for insulin) was 2.9% in the head of the pancreas and 6.7% in the tail of the pancreas in the patient, as compared with 1.8% in the pancreases of the control subjects and 1.1% in the pancreases of the subjects with K_ATP-related hypoglycemia. In the patient's pancreas, nine proliferating (Ki67-positive) beta cells were detected in 100 islets (Figure 1E) and apoptotic (terminal deoxynucleotidyl transferase dUTP biotin nick end labeling [TUNEL]-positive) beta cells were observed clustering within some islets (Figure 1G). Neither Ki67-positive nor TUNEL-positive cells were seen in any of the pancreases of the control subjects (Figure 1F and 1H), suggesting that increased intracellular glucose flux stimulates both proliferation and apoptosis pathways.

Normal histologic findings in four previous cases of glucokinase-related hypoglycemia have been reported, but none of these patients underwent detailed quantitative morphometric analysis.2-4 In a previously reported case that included quantitative histologic analysis, a similar increase in the mean islet profile was confirmed (it was 2.5 times larger than that of control subjects and 8.0 to 10.0 times larger than that of patients with a K_ATP-channel deficiency).5 In both that patient and our patient, the routine pathology report did not indicate any abnormality in islet size; this emphasizes the importance of quantitative morphometric analysis to determine islet size.

Thus, histologic findings in infants with hyperinsulinemic hypoglycemia may differ according to the genetic cause of the condition. Furthermore, intracellular glucose flux appears to regulate proliferation and apoptosis in human beta cells; this is consistent with previous findings in murine models. Small-molecule activators of glucokinase are currently being developed for the clinical management of diabetes. Although observations in this young child with a congenital glucokinase mutation may not be directly applicable to adults with diabetes, the effect of these glucokinase activators on human beta-cell mass may be of interest.

Sameer Kassem, M.D., Ph.D.
Hadassah–Hebrew University Medical Center, Jerusalem, Israel

Sonal Bhandari, M.D.
Weill Cornell Medical College, New York, NY

Pablo Rodríguez-Bada, M.Sc.
Carlos Haya University Hospital, Málaga, Spain

Roja Motaghedi, M.D.
Weill Cornell Medical College, New York, NY

Maayan Heyman, M.L.T.
Hadassah–Hebrew University Medical Center, Jerusalem, Israel

M. Adelaida García-Gimeno, Ph.D.
Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain

Nadia Cobo-Vuilleumier, M.Sc.
Carlos Haya University Hospital, Málaga, Spain

Pascual Sanz, Ph.D.
Consejo Superior de Investigaciones Científicas, Valencia, Spain

Noel K. Maclaren, M.D.
Weill Cornell Medical College, New York, NY

Jacques Rahier, M.D., Ph.D.
Université Catholique de Louvain, Brussels, Belgium

Benjamin Glaser, M.D.
Hadassah–Hebrew University Medical Center, Jerusalem, Israel

Antonio Luis Cuesta-Muñoz, M.D., Ph.D.
Carlos Haya University Hospital, Málaga, Spain
alcm@fundacionimabis.org

Drs. Kassem, Bhandari, and Rodríguez-Bada contributed equally to this letter.

Supported by grants (MICINN, P.I3, SAF2006-12863, SAS/PI-024/2007, and SAS/PI-0236/2009, to Dr. Cuesta-Muñoz) from the Junta de Andalucía, and a grant (to Dr. Glaser) from the Russell Berrie Foundation and D-Cure, Diabetes Care in Israel.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter (10.1056/NEJMc0909845) was updated on November 24, 2010, at NEJM.org.

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   M. Futamura, J. Yao, X. Li, R. Bergeron, J.-L. Tran, E. Zycband, J. Woods, Y. Zhu, Q. Shao, H. Maruki-Uchida, H. Goto-Shimazaki, R. B. Langdon, M. D. Erion, J. Eiki, Y.-P. Zhou. (2012) Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat. Diabetologia
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   Jorge Ferrer. (2011) Glucose as a Mitogenic Hormone. Cell Metabolism 13:4, 357-358
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   Khalid Hussain. (2010) Mutations in pancreatic ß-cell Glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus. Reviews in Endocrine and Metabolic Disorders 11:3, 179-183
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