BADERC-Lynne Levitsky

Lynne Levitsky, M.D.

Diabetes and hyperglycemia in youth

Maturity onset diabetes of the young (MODY) is a group of monogenic forms of diabetes characterized by impaired glucose-stimulated insulin secretion, usually appearing before the age of 25. Mutations in HNF1b (hepatocyte nuclear factor 1b) cause MODY5. To examine the role of HNF1b in pancreatic b cell function, we have used the Cre-LoxP strategy to generate mice deficient in this transcription factor specifically in b cells. Such mice are glucose intolerant, are defective in glucose-stimulated insulin secretion, and show derangements in b cell gene expression. Current studies are directed toward (i) defining the specific metabolic pathways affected by HNF1b deficiency and (ii) restoration of function in mutant b cells by transient expression of HNF1b or its target genes.

Type 2 diabetes mellitus (DM2) is becoming increasingly prevalent in our pediatric population. Many treatment modalities available to adults have not been tested for appropriateness or safety in children. To address this gap, we have joined in a multicenter prospective trial funded by the NICHD to assess the effectiveness of life-style and pharmaceutical interventions. It is anticipated that the results of this study will help to refine therapuetic strategies to manage DM2 in youth.

In adults, accumulation of intramyocellular lipids (IMCL) precedes insulin resistance (IR) and may etiologic in its development. Certain causes of short stature in children, e.g., Turner syndrome and intrauterine growth restriction (IUGR), are also associated with IR. Moreover, growth hormone (GH) treatment in either of these conditions can exacerbate IR despite its positive effects on body composition. To date, no studies have been performed to examine the association of IMCL with IR resulting from short stature or the impact of GH on this relationship. We hypothesize that IMCL is a marker of IR in short stature, but that GH may paradoxically alter this relationship due to changes in body composition. We are conducting studies to evaluate this hypothesis in Turner girls and IUGR children by measuring IMCL and IR at baseline and during GH therapy. IMCL is anticipated to be a valuable probe for understanding GH effects on glucose homeostasis.

References:

1. Rhoads, D. B., D. H. Rosenbaum, U. Unsal, K. J. Isselbacher, L. L. Levitsky. Circadian periodicity of intestinal SGLT1 mRNA levels is transcriptionally regulated. J Biol Chem 1998; 273: 9510-9516.

2. Soyka, L. A., S. Grinspoon, L. L. Levitsky, D. B. Herzog, and A. Klibanski. The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab1999; 84: 4489-4496.

3. Capriles C, L. L. Levitsky. Insulin-dependent Diabetes Mellitus. In: Finberg, ed., Saunders Manual of Pediatric Practice, in press.

4. Tavakkolizadeh, A., U. V. Berger, K. R. Shen, L. L. Levitsky, M. J. Zinner, M. A. Hediger, S. W. Ashley, E. E. Whang, and D. B. Rhoads. Diurnal rhythmicity in intestinal SGLT-1 function, V_max, and mRNA expression topography. Am J Physiol 2001; 280: G209-215.

5. Misra, M. L. L. Levitsky, and M. M. Lee. Transient hyperthyroidism in an adolescent with hydatidiform mole. J Pediatr 2002; 140: 362-366.

6. Freemark, M., and L. L. Levitsky. Screening for celiac disease in children with Type 1 diabetes: Two views of the controversy. Diabetes Care 2003; 26: 1932-1939.

7. Misra M., L. A. Soyka, K. K. Miller, S Grinspoon, L. L. Levitsky, A. Klibanski. Regional body Composition in adolescents with anorexia nervosa and changes with weight recovery. Am J Clin Nutr 2003;77:1361-1367

8. Yang, F., T. Agulian, J. E. Sudati, D. B. Rhoads, and L. L. Levitsky. Developmental regulation of galactokinase in suckling mouse liver by the Egr-1 transcription factor. Pediatr Res. 55: 822-829, 2004.

9. Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1{beta} (MODY5) gene in {beta} cells leads to altered gene expression and defective insulin release. Endocrinology. 145: 3941-3949, 2004.

10. Tavakkolizadeh, A., Ramsanahie, A., Levitsky, L.L., Zinner, M.J., Whang, E.E., Ashley, S.W., Rhoads, D.B. Differential role of vagus nerve in maintaining diurnal gene expression rhythms in the proximal small intestine. J Surg Res, in press 2005.






			Lynne Levitsky, M.D. Diabetes and hyperglycemia in youth Maturity onset diabetes of the young (MODY) is a group of monogenic forms of diabetes characterized by impaired glucose-stimulated insulin secretion, usually appearing before the age of 25. Mutations in HNF1b (hepatocyte nuclear factor 1b) cause MODY5. To examine the role of HNF1b in pancreatic b cell function, we have used the Cre-LoxP strategy to generate mice deficient in this transcription factor specifically in b cells. Such mice are glucose intolerant, are defective in glucose-stimulated insulin secretion, and show derangements in b cell gene expression. Current studies are directed toward (i) defining the specific metabolic pathways affected by HNF1b deficiency and (ii) restoration of function in mutant b cells by transient expression of HNF1b or its target genes. Type 2 diabetes mellitus (DM2) is becoming increasingly prevalent in our pediatric population. Many treatment modalities available to adults have not been tested for appropriateness or safety in children. To address this gap, we have joined in a multicenter prospective trial funded by the NICHD to assess the effectiveness of life-style and pharmaceutical interventions. It is anticipated that the results of this study will help to refine therapuetic strategies to manage DM2 in youth. In adults, accumulation of intramyocellular lipids (IMCL) precedes insulin resistance (IR) and may etiologic in its development. Certain causes of short stature in children, e.g., Turner syndrome and intrauterine growth restriction (IUGR), are also associated with IR. Moreover, growth hormone (GH) treatment in either of these conditions can exacerbate IR despite its positive effects on body composition. To date, no studies have been performed to examine the association of IMCL with IR resulting from short stature or the impact of GH on this relationship. We hypothesize that IMCL is a marker of IR in short stature, but that GH may paradoxically alter this relationship due to changes in body composition. We are conducting studies to evaluate this hypothesis in Turner girls and IUGR children by measuring IMCL and IR at baseline and during GH therapy. IMCL is anticipated to be a valuable probe for understanding GH effects on glucose homeostasis. References: 1. Rhoads, D. B., D. H. Rosenbaum, U. Unsal, K. J. Isselbacher, L. L. Levitsky. Circadian periodicity of intestinal SGLT1 mRNA levels is transcriptionally regulated. J Biol Chem 1998; 273: 9510-9516. 2. Soyka, L. A., S. Grinspoon, L. L. Levitsky, D. B. Herzog, and A. Klibanski. The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab1999; 84: 4489-4496. 3. Capriles C, L. L. Levitsky. Insulin-dependent Diabetes Mellitus. In: Finberg, ed., Saunders Manual of Pediatric Practice, in press. 4. Tavakkolizadeh, A., U. V. Berger, K. R. Shen, L. L. Levitsky, M. J. Zinner, M. A. Hediger, S. W. Ashley, E. E. Whang, and D. B. Rhoads. Diurnal rhythmicity in intestinal SGLT-1 function, V_max, and mRNA expression topography. Am J Physiol 2001; 280: G209-215. 5. Misra, M. L. L. Levitsky, and M. M. Lee. Transient hyperthyroidism in an adolescent with hydatidiform mole. J Pediatr 2002; 140: 362-366. 6. Freemark, M., and L. L. Levitsky. Screening for celiac disease in children with Type 1 diabetes: Two views of the controversy. Diabetes Care 2003; 26: 1932-1939. 7. Misra M., L. A. Soyka, K. K. Miller, S Grinspoon, L. L. Levitsky, A. Klibanski. Regional body Composition in adolescents with anorexia nervosa and changes with weight recovery. Am J Clin Nutr 2003;77:1361-1367 8. Yang, F., T. Agulian, J. E. Sudati, D. B. Rhoads, and L. L. Levitsky. Developmental regulation of galactokinase in suckling mouse liver by the Egr-1 transcription factor. Pediatr Res. 55: 822-829, 2004. 9. Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1{beta} (MODY5) gene in {beta} cells leads to altered gene expression and defective insulin release. Endocrinology. 145: 3941-3949, 2004. 10. Tavakkolizadeh, A., Ramsanahie, A., Levitsky, L.L., Zinner, M.J., Whang, E.E., Ashley, S.W., Rhoads, D.B. Differential role of vagus nerve in maintaining diurnal gene expression rhythms in the proximal small intestine. J Surg Res, in press 2005.