Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Diabetes Care 29:717-718, 2006
DOI: 10.2337/diacare.29.03.06.dc05-1538
© 2006 by the American Diabetes Association
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ritzel, R. A.
Right arrow Articles by Butler, P. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ritzel, R. A.
Right arrow Articles by Butler, P. C.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Pathophysiology/Complications
Brief Report

Relationship Between ß-Cell Mass and Fasting Blood Glucose Concentration in Humans

Robert A. Ritzel, MD1, Alexandra E. Butler, MD1, Robert A. Rizza, MD2, Johannes D. Veldhuis, MD2 and Peter C. Butler, MD1

1 Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California
2 Division of Endocrinology, Mayo Clinic, Rochester, Minnesota

Address correspondence reprint requests to Peter C. Butler, MD, Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 24-130 Warren Hall, 900 Veteran Ave., Los Angeles, CA 90095-7073. E-mail: pbutler{at}mednet.ucla.edu


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
In type 2 diabetes there is a progressive defect of insulin secretion that precedes the development of hyperglycemia (1). This defect appears to be at least in part due to a deficit in ß-cell mass (2–4). Several therapeutic strategies are now being proposed that may reverse the defect in ß-cell mass in people with type 2 diabetes, for example glucagon-like peptide 1 or glucagon-like peptide 1–like surrogates (5). However, the relationship between ß-cell mass and the blood glucose in humans is uncertain. Here we report the relative ß-cell volume in pancreata obtained at autopsy from people with well-documented blood glucose concentrations in life.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Mean ß-cell volume, ß-cell replication, and ß-cell apoptosis for the case subjects included in this analysis have been reported previously (3). Here we now show the individual data points for blood glucose versus relative ß-cell volume in obese case subjects who were nondiabetic, had impaired fasting glucose, or had type 2 diabetes. Pancreatic tissue was processed and immunostained for insulin, and the relative ß-cell volume was quantified as previously described (3). The relative ß-cell volume was used as a surrogate for ß-cell mass since whole- pancreas weight is not available.

Selection of the study subjects from autopsy files was previously described (3). In brief, all case subjects included were obese (BMI >27 kg/m2) and either nondiabetic (<110 mg/dl [6.1 mmol/l]) (n = 31, age 66.9 ± 15.2 years, BMI 36.4 ± 6.9 kg/m2), had impaired fasting glucose (≥110 mg/dl [6.1 mmol/l] but <126 mg/dl [7.0 mmol/l]) (n = 19, age 63.1 ± 10.1 years, BMI 36.8 ± 8.6 kg/m2), or were diabetic (≥126 mg/dl [7.0 mmol/l]) (n = 7, age 59.7 ± years, BMI 36.5 ± 5.3 kg/m2). We only included people with type 2 diabetes who were not taking insulin or glucose-lowering oral medications, both of which would have influenced the measured blood glucose concentrations and the relationship of these with ß-cell volume.

The relationship between fractional ß-cell volume and fasting blood glucose concentration was analyzed by nonlinear regression analysis to establish the best monoexponential fit of the relationship between the fasting blood glucose (dependent variable) and the ß-cell volume (independent variable); y = span x exp(–k x X) + plateau and the point of inflection of the hyperbole. ANOVA was used to test for the effect of ß-cell volume on fasting blood glucose.


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
There was a significant relationship between the ß-cell volume and fasting blood glucose concentration, with a point of inflection at x = 1.1 ± 0.1%. This relationship is curvilinear (Fig. 1) so that ß-cell deficiency beyond 1.1% is associated with a steep increase in blood glucose with each further decrement in ß-cell mass.


Figure 1
View larger version (23K):
[in this window]
[in a new window]
  		Figure 1— Relationship between percentage of pancreas volume occupied by ß-cells and fasting plasma glucose in obese humans without insulin or oral antidiabetic treatment. The solid line is derived from nonlinear regression analysis (monoexponential fit, r = 0.50; P < 0.0001 by ANOVA). The dashed vertical lines indicate the mean ß-cell area in obese nondiabetic subjects (OND) (right) and the computed inflection point of the curve (left).

 

   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
We report that in humans there is a curvilinear relationship between the relative ß-cell volume (and presumably the ß-cell mass) and the fasting blood glucose concentration. The present data reveal a narrow range of blood glucose over a wide range of fractional ß-cell volume (up to ~10%) and then a much wider range of blood glucose values over a narrow range of volumes at low ß-cell volumes, with the threshold set by the curve at ~1.1% defining that difference. The implications of these findings are that there is a much greater tolerance for variance in insulin sensitivity above this threshold and that below-the-threshold variance in insulin sensitivity and functional defects in insulin secretion have a much greater impact on blood glucose.

There are some important limitations with autopsy studies. The numbers of cases are frequently relatively small. The studies are inevitably cross-sectional and retrospective. We and others have presented data suggesting that the decline in ß-cell mass in type 2 diabetes is caused by increased ß-cell apoptosis (3,6). Therefore, these data suggest that inhibition of ß-cell apoptosis to avoid a ß-cell deficit might be effective to delay and/or avoid the onset of diabetes. Indeed, both metformin and thiazolidinediones have been reported to inhibit ß-cell apoptosis in vitro (6,7) and to delay onset of type 2 diabetes in clinical studies (8,9). The potential mechanisms underlying increased ß-cell apoptosis in type 2 diabetes include toxicity from islet amyloid polypeptide oligomer formation, free fatty acids (lipotoxicity), free oxygen radical toxicity and, once hyperglycemia supervenes, glucose-induced apoptosis (glucotoxicity) (10,11).

The steep increase in blood glucose concentration with ß-cell deficiency is consistent with the well-known deleterious effects of hyperglycemia per se on ß-cell function. These include defective glucose sensing due to reduced glucokinase activity (12), impaired glucose-induced insulin secretion due to increased uncoupling protein two activity (13), and depletion of immediately secretable insulin stores (14). Also, hyperglycemia reduces insulin sensitivity, further compounding the effects of decreased insulin secretion (15). While the present data suggest that relatively small increases in ß-cell mass might have useful actions in restoring blood glucose control, it is likely that aggressive normalization of blood glucose concentrations is required to accompany the strategy to increase ß-cell mass to overcome the afore mentioned deleterious effects of hyperglycemia as well as glucose-induced ß-cell apoptosis.

In conclusion, there is a curvilinear relationship between ß-cell mass and fasting blood glucose concentration in humans. These data provide some guidelines for the efforts targeted toward restoring ß-cell mass to reverse diabetes, or prevention of diabetes by protection of ß-cell mass. The present data describe just one time point. Data regarding movement up or down the currently described curve in humans will only be available if it becomes possible to measure ß-cell mass in vivo.


   Acknowledgments
 
These studies were funded in part by the National Institutes of Health (DK59579 to P.C.B., DK61539 to P.C.B. and J.D.V., and DK29953 to R.A.R.), the Deutsche Forschungsgemeinschaft (DFG; Ri 1055/1-1), and the Larry Hillblom Foundation (to P.C.B). There were no conflicts of interest in this study.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication August 16, 2005. Accepted for publication November 18, 2005.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. UK Prospective Diabetes Study Group: U.K. Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258, 1995[Abstract]
  2. Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 4:110–125, 1985[Medline]
  3. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC: ß-Cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110, 2003[Abstract/Free Full Text]
  4. Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S: Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88:2300–2308, 2003[Abstract/Free Full Text]
  5. Nauck MA: Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm Metab Res 36:852–858, 2004[Medline]
  6. Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F, Del Prato S: Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89:5535–5541, 2004[Abstract/Free Full Text]
  7. Zeender E, Maedler K, Bosco D, Berney T, Donath MY, Halban PA: Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab 89:5059–5066, 2004[Abstract/Free Full Text]
  8. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403, 2002[Abstract/Free Full Text]
  9. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP: Preservation of pancreatic ß-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796–2803, 2002[Abstract/Free Full Text]
  10. Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC: Diabetes due to a progressive defect in ß-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. Diabetes 53:1509–1516, 2004[Abstract/Free Full Text]
  11. Donath MY, Halban PA: Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications (Review). Diabetologia 47:581–589
  12. Matschinsky FM, Glaser B, Magnuson MA: Pancreatic ß-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47:307–315, 1998[Abstract]
  13. Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB: Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 112:1831–1842, 2003[Medline]
  14. Ritzel RA, Hansen JB, Veldhuis JD, Butler PC: Induction of beta-cell rest by a Kir6.2/SUR1-selective K(ATP)-channel opener preserves beta-cell insulin stores and insulin secretion in human islets cultured at high (11 mM) glucose. J Clin Endocrinol Metab 89:795–805, 2004[Abstract/Free Full Text]
  15. Tomas E, Lin YS, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB: Hyperglycemia and insulin resistance: possible mechanisms. Ann N Y Acad Sci 967:43–51, 2002[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Diabetes CareHome page
A. F. Kumar, R. W.G. Gruessner, and E. R. Seaquist
Risk of Glucose Intolerance and Diabetes in Hemipancreatectomized Donors Selected for Normal Preoperative Glucose Metabolism
Diabetes Care, August 1, 2008; 31(8): 1639 - 1643.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J. J. Meier, A. E. Butler, Y. Saisho, T. Monchamp, R. Galasso, A. Bhushan, R. A. Rizza, and P. C. Butler
{beta}-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of {beta}-Cell Mass in Humans
Diabetes, June 1, 2008; 57(6): 1584 - 1594.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
M. Salehi, B. A. Aulinger, and D. A. D'Alessio
Targeting {beta}-Cell Mass in Type 2 Diabetes: Promise and Limitations of New Drugs Based on Incretins
Endocr. Rev., May 1, 2008; 29(3): 367 - 379.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
L. Haataja, T. Gurlo, C. J. Huang, and P. C. Butler
Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis
Endocr. Rev., May 1, 2008; 29(3): 303 - 316.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
B. A. Menge, A. Tannapfel, O. Belyaev, R. Drescher, C. Muller, W. Uhl, W. E. Schmidt, and J. J. Meier
Partial Pancreatectomy in Adult Humans Does Not Provoke -Cell Regeneration
Diabetes, January 1, 2008; 57(1): 142 - 149.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
A. V. Matveyenko and P. C. Butler
{beta}-Cell Deficit Due to Increased Apoptosis in the Human Islet Amyloid Polypeptide Transgenic (HIP) Rat Recapitulates the Metabolic Defects Present in Type 2 Diabetes.
Diabetes, July 1, 2006; 55(7): 2106 - 2114.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ritzel, R. A.
Right arrow Articles by Butler, P. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ritzel, R. A.
Right arrow Articles by Butler, P. C.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum