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


     

This Article
Right arrow Abstract 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 Ovalle, F.
Right arrow Articles by Bell, D. S.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ovalle, F.
Right arrow Articles by Bell, D. S.H.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Diabetes Care 27:2585-2589, 2004
© 2004 by the American Diabetes Association, Inc.

Clinical Care/Education/Nutrition
Original Article

Effect of Rosiglitazone Versus Insulin on the Pancreatic ß-Cell Function of Subjects With Type 2 Diabetes

Fernando Ovalle, MD, FACE and David S.H. Bell, MB, FACE

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama

Address correspondence and reprint requests to David S.H. Bell, MB, 510 S. 20th St., Rm. 702, Birmingham, AL 35294. E-mail: dshbell{at}uab.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—In a previous study, we found observational evidence of improvement in ß-cell function when rosiglitazone was added to a failing oral antihyperglycemic regimen consisting of sulfonylureas and metformin. To confirm our previous observations, we designed and performed a prospective, randomized, and controlled study.

RESEARCH DESIGN AND METHODS—A total of 17 subjects with type 2 diabetes, inadequately controlled on a maximized oral antihyperglycemic double regimen of glimepiride and metformin, were randomized to the addition of rosiglitazone or insulin to their treatment regimens for a period of 6 months. At baseline and at 6 months, the following were performed: measurement of fasting plasma glucose, fasting proinsulin, and insulin levels; frequently sampled intravenous glucose tolerance test; and glucagon stimulation test for C-peptide.

RESULTS—Nine subjects were randomized to the addition of 8 mg rosiglitazone, and eight subjects were randomized to the addition of one injection of insulin (premixed 70/30) before their evening meal. The treatment groups were well matched for age, duration of diabetes, and BMI. Most important, the HbA1c was well matched between groups before treatment (8.7 ± 0.3 and 9.0 ± 0.3%; NS) and at the end of the 6 months (7.8 ± 0.5 and 7.8 ± 0.3%; NS). After 6 months, at the end of the study, there was a significant improvement in acute insulin response to glucose in the rosiglitazone group (+15.3 µIU · ml–1 · 10 min–1; P < 0.001) that led to an increase in the disposition index from 0.18 at baseline to 4.18 at 6 months (P = 0.02). Furthermore, at the end of the study, the proinsulin-to-insulin ratio had decreased in the rosiglitazone group by 36% (P = 0.03) but did not change significantly in the insulin treatment group.

CONCLUSIONS—Rosiglitazone, but not insulin, induced a recovery of pancreatic ß-cell function, as evidenced by the restoration of the first-phase insulin response to glucose, improvement in the disposition index, and a decrease in the proinsulin-to-insulin ratio in subjects with type 2 diabetes in whom oral antihyperglycemic therapy failed. This improvement was independent of the correction of glucotoxicity.

Abbreviations: AIRg, acute insulin response to glucose • AUCab, area under the curve above the baseline • FFA, free fatty acid • fsIVGTT, frequently sampled intravenous glucose tolerance test • HOMA, homeostasis model assessment • TZD, thiazolidinedione


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
We have previously reported, in a prospective observational case-control study, that the addition of a thiazolidinedione (TZD) to a failing regimen of a sulfonylurea and metformin results not only in an improvement in glycemic control but also in increased endogenous insulin production (1). We have also shown, in a prospective observational study, that triple oral antihyperglycemic therapy, with a TZD, metformin, and sulfonylurea, leads to prolonged improvements in glycemic control in subjects at both 3 and 5 years and that this maintenance of control may be due to increased endogenous insulin production (2). Because of these findings, we designed and conducted this prospective, randomized, controlled study to confirm that TZDs improve pancreatic ß-cell function independent of the improvement in glycemic control.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
After approval of the study by the Institutional Review Board of the University of Alabama at Birmingham and appropriate written informed consent, we randomized 17 subjects with type 2 diabetes, who were inadequately controlled on a regimen of a sulfonylurea and metformin, to the addition of an insulin injection of 70/30 mixed human insulin administered once daily before supper or 8 mg of rosiglitazone administered once daily. The dose of rosiglitazone was fixed for the remainder of the study, whereas the 70/30 insulin was started at 0.2 units/kg and adjusted to achieve a fasting blood glucose level of ≤120 mg/dl without occurrence of severe or frequent hypoglycemia. All subjects remained on their randomized therapy for 6 months with adjustment in dose only occurring in the insulin group to correct for hypoglycemia. When titration of the insulin dose was completed, all subjects remained at this dose for 6 months unless significant and/or frequent hypoglycemia occurred when the dose was reduced and fixed at this level for the remainder of the study unless further hypoglycemia occurred.

Fasting glucose, serum insulin, and proinsulin levels were measured at baseline and at the end of the study. Plasma glucose level was measured by a glucose oxidase method using a YSI glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH). Serum insulin was assayed using a competitive chemiluminescent immunoassay (DPC, Los Angeles, CA). Proinsulin was measured by enzyme-linked immunosorbent immunoassay (Nichols Institute, San Clemente, CA). At baseline and after 6 months of therapy, a intravenous glucose tolerance test (fsIVGTT) was performed to determine the acute insulin response to glucose (AIRg) as a way to evaluate first-phase insulin response to glucose. Additionally, a glucagon stimulation test for C-peptide was performed 1 week after the fsIVGTT. C-peptide was measured using a double-antibody C-peptide kit (reference range 1.0–5.0 ng/ml). All tests were performed in the fasting state, and the subjects in the insulin group were asked to withhold their insulin injection the night before testing.

During the fsIVGTT, venous blood samples for measurement of serum insulin were collected at baseline (average of –10 and –4 min samples) and at +2, +3, +4, +5, +6, +8, and +10 min after an intravenous bolus of glucose calculated at a dose of 300 mg/kg of body weight given over 60 s starting at time 0. The AIRg was calculated as the area under the curve above the baseline (AUCab) during the first 10 min after the glucose infusion.

During the glucagon stimulation test, venous blood samples for the measurement of C-peptide were collected at baseline and 6 min after an intramuscular injection of glucagon.

Insulin resistance was calculated at baseline and at 6 months using the following homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) formula: (insulin [micro–International Units/milliliter] x glucose [millimoles/liter])/22.5. For calculation purposes, the reciprocal of IR (1/IR) was used as the insulin sensitivity index (Si).

ß-Cell function was determined by the disposition index, which was calculated as the product of AIRg and Si. Statistical analysis was performed using two-tailed Student’s t tests for most comparisons except for the fsIVGTT, which was analyzed using a one-way ANOVA and performed using GraphPad Prism Version 4.00 for Windows (GraphPad Software, San Diego, CA). Data are shown as means ± SE. P values <0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
As shown in Table 1, the groups were well matched for age, BMI, and duration of diabetes. Furthermore, and most importantly, HbA1c was well matched among study groups before the start of the study and decreased to the same level after treatment in both groups (Table 2, Fig. 1).


View this table:
[in this window]
[in a new window]
  		Table 1— Baseline characteristics of treatment groups

 

View this table:
[in this window]
[in a new window]
  		Table 2— Mean HbA1c and FPG at baseline and end of study

 


View larger version (39K):
[in this window]
[in a new window]
  		Figure 1— Insulin and rosiglitazone both reduce HbA1c levels. Insulin (INS) and rosiglitazone (RSG) therapy achieve similar levels of glycemic control. Values are means ± SE.

 
The AIRg increased significantly, from a baseline of 1.42 to 16.71 µIU · ml–1 · 10 min–1 at 6 months (+15.3 µIU · ml–1 · 10 min–1 [AUCab]; P ≤ 0.001), in the rosiglitazone group but not in the insulin group, in which there was a nonsignificant decrease from a baseline of 8.43 to 7.23 µIU · ml–1 · 10 min–1 at 6 months (–1.2 µIU · ml–1 · 10 min–1 [AUBab]; NS) (Fig. 2).



View larger version (28K):
[in this window]
[in a new window]
  		Figure 2— Rosiglitazone therapy provides a significant improvement in AIRg and thus ß-cell function. The AIRg increased by 15.3 µIU · ml–1 · 10 min–1 (AUCab), from a baseline of 1.42 to 16.71 µIU · ml–1 · 10 min–1 at 6 months (P ≤ 0.001) in the rosiglitazone (RSG) group (n = 8). In the insulin (INS) group (n = 9), there was a nonsignificant decrease of 1.2 µIU · ml–1 · 10 min–1 (AUBab), from a baseline of 8.43 to 7.23 µIU · ml–1 · 10 min–1 at 6 months (NS). The AIRg was calculated as the AUCab during the first 10 min after the glucose infusion.

 
As expected, rosiglitazone induced a significant improvement (92.3% increase) in insulin sensitivity (Table 3). Si was calculated using the reciprocal of the HOMA method as described above.


View this table:
[in this window]
[in a new window]
  		Table 3— Baseline and changes in Si (1/HOMA-IR)

 
Furthermore, the disposition index increased significantly in the rosiglitazone-treated group from a baseline of 0.18 to 4.18 at 6 months (P = 0.02); meanwhile, the insulin-treated group experienced a nonsignificant decrease from a baseline of 1.86 to 1.23 at 6 months (NS) (Fig. 3).



View larger version (46K):
[in this window]
[in a new window]
  		Figure 3— Absolute change in disposition index. Rosiglitazone (RSG) therapy produces a significant improvement in the disposition index, which was calculated as follows: AIRg * Si. Si was calculated as the reciprocal of HOMA-IR. INS, insulin.

 
Although no differences between groups were observed when looking at the raw C-peptide data obtained during the glucagon-stimulated C-peptide tests, we found significant differences when adjusting for the differences in insulin sensitivity and calculating the disposition index. The rosiglitazone-treated group demonstrated a significant (+43%) increase in the disposition index compared with a nonsignificant decrease (–9.4%) in the insulin group after 6 months of therapy (Table 4).


View this table:
[in this window]
[in a new window]
  		Table 4— ß-Cell function assessed by the C-peptide response to glucagon

 
Furthermore, the proinsulin-to-insulin ratio, which was equally elevated in both groups at baseline, decreased significantly in the rosiglitazone group after treatment (Fig. 4).



View larger version (53K):
[in this window]
[in a new window]
  		Figure 4— Rosiglitazone but not insulin reduces proinsulin-to-insulin ratio. *P < 0.05 vs. baseline.

 

   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
We have therefore demonstrated, in a prospective randomized and controlled study, that rosiglitazone improves pancreatic ß-cell function after 6 months of therapy and that this improvement is independent of glycemic control because with a similar reduction in HbA1c no improvement in ß-cell function was found in the insulin-treated group.

Dysfunctional pancreatic ß-cells are known to release more proinsulin; therefore, the ratio of proinsulin to insulin generally increases when ß-cell function decreases. Therefore, the decrease in the proinsulin-to-insulin ratio observed in this study may be interpreted as evidence of improved ß-cell function confirming previous studies in which the HOMA-ß improved and the proinsulin-to-insulin ratio decreased with rosiglitazone but remained unchanged or increased with placebo, metformin, or sulfonylurea (3,4).

A defect in the first phase of insulin release is usually the first measurable sign of ß-cell dysfunction that can be observed in both type 1 and type 2 diabetes. A return or improvement of the first-phase insulin secretory response to glucose has not been previously demonstrated with other antihyperglycemic agents including secretagogues, metformin, or {alpha}-glucosidase inhibitors. Although others have reported that therapy with multiple daily injections of insulin can lead to improvement in the proinsulin-to-insulin ratio similar to that we observed with rosiglitazone, these improvements have been short-lived (9 weeks) and failed to demonstrate improvements by other methods (5).

Alternatively, other investigators have reported no improvement in insulin secretion after treatment with rosiglitazone; however, this study was probably too short in duration to demonstrate an effect on ß-cell function. Furthermore, the small number of subjects might have caused a type 1 error because the investigators reported an improvement on insulin sensitivity and a tendency to an increase in the disposition index in the rosiglitazone-treated group (6).

Therefore, this is the first study to demonstrate an improvement in the first phase of the insulin secretory response to glucose in subjects with long-standing type 2 diabetes receiving oral pharmacological therapy. This study confirms our previous observational finding in a case-control study that the addition of a TZD, but not the addition of metformin, improves glycemic control as well as endogenous insulin production (1). This is consistent with our findings in a continuing long-term observational study demonstrating that the addition of a TZD to a failing oral regimen of sulfonylurea and metformin results in significant improvements in glycemic control in most subjects with type 2 diabetes. Furthermore, this improvement is maintained for a prolonged period of time, as long as 5 years, which we hypothesize is due to improved endogenous insulin production (2).

We believe that the mechanism responsible for the improvement in endogenous insulin production is directly related to the lowering of serum and tissue free fatty acid (FFA) levels that is known to occur with TZDs but not with other antihyperglycemic agents including insulin secretagogues, {alpha}-glucosidase inhibitors, and biguanides. Animal studies have shown that ß-cell failure is preceded by an increase in plasma FFAs and accumulation of triglyceride in ß-cells (7). In addition, if lipid accumulation in the ß-cell is reversed by creating a hyperleptinemic state, ß-cell function improves and development of diabetes is avoided (8). The damage to the ß-cell is caused by elevated ß-cell levels of FFA, its metabolite ceramide, nitric oxide, and peroxinitrite levels, leading to accelerated ß-cell apoptosis (9,10). In addition, increased FFA levels decrease the expression of the IDX-1 gene, which is responsible for the formation of new ß-cells from stem cells in the pancreatic duct (11). Rosiglitazone has been shown in animal studies to decrease islet cell triglyceride levels and increase stainable insulin in both the db/db mouse and the Zucker diabetic fatty rat models (12,13).

Autopsy studies of human ß-cells have shown that with aging, more fat accumulates in the pancreatic ß-cells of the islets of Langherhans than in the {alpha}-cells or the pancreatic duct cells and that apoptosis rather than decreased formation of ß-cells is responsible for the decreasing ß-cell mass seen in type 2 diabetes (14,15). Therefore, in the absence of unethical pancreatic biopsy studies in type 2 diabetic patients, we must assume that the mechanism of pancreatic ß-cell destruction and its correction with rosiglitazone is similar to that seen in animal models.

Because rosiglitazone and perhaps other TZDs differ from the currently available therapies for type 2 diabetes in their ability to rejuvenate pancreatic ß-cells, these drugs should be used at the earliest possible opportunity in the course of type 2 diabetes and not withheld until the later stages of the disease (16). In this study, the average duration of diabetes was 7.6 years. It should be noted that determining the exact date of onset of type 2 diabetes may be a difficult task and, in general, type 2 diabetes goes unrecognized for several years before being diagnosed. In this study, the time of onset was determined by patient recollection and review of medical records.

There are potential limitations of this study that need to be discussed. One of these is the difference (9 years) in the mean age between the two treatment groups; although this difference was not statistically different, a negative effect of aging on ß-cell function has been shown by some investigators (17). Nonetheless, the fact that the baseline AIRg was better in the insulin group and that both groups had similar proinsulin-to-insulin ratios at baseline seems to make this age difference irrelevant. Another potential limitation of this study is the lack of determination of hepatic insulin extraction, which can potentially account for differences in proinsulin-to-insulin ratio (18).

In conclusion, this study demonstrates that rosiglitazone, but not insulin, helps to induce a recovery of pancreatic ß-cell function, as evidenced by the restoration of the first-phase insulin response to glucose. This effect was in independent of the correction of glucose toxicity.


   Acknowledgments
 
This work was supported by a research grant from GlaxoSmithKline Pharmaceuticals.


   Footnotes
 
F.O. has received consulting fees, honoraria, and grant support from GlaxoSmithKline. D.S.H.B. has received consulting fees, honoraria, and grant support from GlaxoSmithKline, Sankyo, BMS, KOS, Amgen, Aventis, and Novo Nordisk.

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

Received for publication March 3, 2004. Accepted for publication August 2, 2004.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Ovalle F, Bell DSH: Clinical evidence of thiazolidinedione-induced improvement of pancreatic beta cell function in patients with type 2 diabetes mellitus. Diabet Obes Metab 4:56–59, 2002
  2. Bell DSH, Ovalle F: Long-term efficacy of triple oral therapy for type 2 diabetes mellitus. Endocr Pract 8:271–275, 2002[Medline]
  3. Porter LE, Freed MI, Jones NP, Biswas N: Rosiglitazone improves B cell function as measured by proinsulin/insulin ratio in patients with type 2 diabetes (Abstract). Diabetes 49 (Suppl. 1):A122, 2000
  4. Fonseca V, Rosenstock J, Patwardhan R, Salzman A: Effects of metformin and rosiglitazone therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283:1695–1702, 2000[Abstract/Free Full Text]
  5. Karvestedt L, Andersson G, Efendic S, Grill V: A rapid increase in ß-cell function by multiple insulin injections in type 2 diabetic patients is not further enhanced by prolonging treatment. J Intern Med 251:307–316, 2002[Medline]
  6. Juhl CB, Hollingdale M, Porksen N, Prange A, Lonnqvist F, Schmitz O: Influence of rosiglitazone treatment on ß-cell function in type 2 diabetes: evidence of an increased ability of glucose to entrain high-frequency insulin pulsativity. J Clin Endocrinol Metab 88:3794–3800, 2003[Abstract/Free Full Text]
  7. Lee Y, Hirosel T, Ohneda M, Johnson JH, McGarry JD, Unger RH: Beta cell lipotoxicity of non-insulin dependent diabetes mellitus of obese rats: impairment in adipocyte-beta cell relationships. Proc Natl Acad Sci U S A 91:10878–10882, 1994[Abstract/Free Full Text]
  8. Shimabukura M, Koyama K, Chen G, Wang M-Y, Trieu F, Lee Y, Newgard CB, Unger RH: Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A 94:4637–4641, 1997[Abstract/Free Full Text]
  9. Winzell MS, Sversson H, Enerback S, Ravnskjaer K, Mandrup S, Esser V, Arner P, Alves-Guerra M-C, Miroux B, Sundler F, Ahren B, Holm C: Pancreatic ß-cell lipotoxicity induced by overexpression of hormone sensitive lipase. Diabetes 52:2057–2065, 2003[Abstract/Free Full Text]
  10. Shimabukuro M, Ohneda M, Lee Y, Unger RH: Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 100:290–295, 1991
  11. Gremlich S, Bonny C, Waeber G, Thorens B: Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase insulin and somatostatin levels. J Biol Chem 272:30261–30269, 1997[Abstract/Free Full Text]
  12. Lister CA, Moore GBT, Pierce V, Newman M, Chapman H, Smith SA: Rosiglitazone but not metformin or glibenclamide improves glycemic control and increases islet cell content (Abstract). Diabetologia 42 (Suppl. 1):A150, 1999
  13. Finegood DT, McArthur MD, Kojwang D, Topp BG, Leonard T: ß-Cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes 50:1021–1029, 2001[Abstract/Free Full Text]
  14. Chop M, Grupping A, Hooren A, Bouwers L, Pipeleers-Marichal M, Pipeleers D: Endocytosis of low-density lipoprotein by human pancreatic beta cells and uptake in lipid-storing vesicles which increases with age. Am J Pathol 156:237–244, 2000[Abstract/Free Full Text]
  15. Butler AE, Jurson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC: ß-Cell deficit and increased beta cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110, 2003[Abstract/Free Full Text]
  16. Wallace TM, Matthews DR: Poor glycemic control in type 2 diabetes: a conspiracy of disease, sub-optimal therapy and attitude. Q J Med 93:369–374, 2000
  17. Fritsche A, Madaus A, Stefan N, Tschritter O, Maerker E, Teigeler A, Haring H, Stumvoll M: Relationships among age, proinsulin conversion, and ß-cell function in nondiabetic humans. Diabetes 51 (Suppl. 1):S234–S239, 2002
  18. Tura A, Pacini G, Kautzky-Willer A, Ludvik B, Prager R, Thomaseth K: Basal and dynamic proinsulin-insulin relationship to assess ß-cell function during OGTT in metabolic disorders. Am J Physiol Endocrinol Metab 285:E155–E162, 2003[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
 Eur J EndocrinolHome page
L. F Van Gaal, S. W Gutkin, and M. A Nauck
Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?
Eur. J. Endocrinol., June 1, 2008; 158(6): 773 - 784.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
K. Kos, A. L. Harte, S. James, D. R. Snead, J. P. O'Hare, P. G. McTernan, and S. Kumar
Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass
Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1335 - E1340.
[Abstract] [Full Text] [PDF]

Home page
 DOC NewsHome page
B. M. Law
Avandia Meta-analysis Sparks Confusion, Questions
DOC News, July 1, 2007; 4(7): 1 - 21.
[Full Text]

Home page
 Arch Intern MedHome page
P. Hollander, D. Yu, and H. S. Chou
Low-Dose Rosiglitazone in Patients With Insulin-Requiring Type 2 Diabetes
Arch Intern Med, June 25, 2007; 167(12): 1284 - 1290.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
B. L. Wajchenberg
{beta}-Cell Failure in Diabetes and Preservation by Clinical Treatment
Endocr. Rev., April 1, 2007; 28(2): 187 - 218.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract 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 Ovalle, F.
Right arrow Articles by Bell, D. S.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ovalle, F.
Right arrow Articles by Bell, D. S.H.
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