| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Internal Medicine F (T.V., F.K.K., T.K.), Gentofte Hospital, DK-2900 Hellerup, Denmark; Department of Medical Physiology (T.V., J.J.H.), The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Steno Diabetes Center (A.J., T.H., O.P.), DK 2820 Gentofte, Copenhagen, Denmark; Department of Endocrinology (S.M.), Hvidovre Hospital, DK-2650 Hvidovre, Denmark; and Department of Gastroenterology (S.L.), Glostrup Hospital, DK-2600 Glostrup, Denmark
Address all correspondence and requests for reprints to: Tina Vilsbøll, M.D., Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: tivi{at}gentoftehosp.kbhamt.dk.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7–36)amide/kg body weight·min or 4 pmol GIP pmol/kg body weight·min. The early-phase (0–20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20–120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes. |
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
We studied five groups of patients (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis (CP); 2) lean type 2 diabetic patients (body mass index < 25 kg/m2); 3) patients with latent autoimmune diabetes in adults (LADA); 4) diabetic patients with mutations in the HNF-1 gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. The subjects studied were all diagnosed according to the 1999 criteria of the World Health Organization (10). Demographic and descriptive characteristics of the study participants are presented in Table 1
.
|
gene that was demonstrated to cosegregate with diabetes in the families. They were all Danish Caucasians by self-report and were all ICA- and GAD65-negative. The mutations included the following: Pro447Leu, Ala559fsinsA, Glu234stop, Arg159Gln, Cys241Gly, and Arg229Pro and were identified by direct sequencing as described (13). The lean type 2 diabetic patients were GAD65-negative, confirming that they were not misclassified type 1 diabetic patients or LADA patients. All LADA and type 1 diabetic patients were GAD65 positive. The type 1 diabetic patients were all newly diagnosed and were all in remission period, and they were all started on insulin treatment on the day of the diagnosis and continued, except for one patient who had been out of insulin treatment for 1 month at the time of the investigation. For the five patients treated with insulin, the mean daily dose was 18 IU (range, 10–28 IU). In all the type 1 diabetic patients, a glucagon test was performed immediately before inclusion in the study. The test showed that they were all secretors, verified by a significant increase in C-peptide after 1 mg glucagon [glucagon test: fasting plasma C-peptide, mean and (range): 0 min: 428 (230–750) pM, plasma C-peptide: 6 min: 756 (330–1530) pM, P = 0.05], indicating a significant residual ß-cell function. The clamp studies were performed within 1 month of the glucagon test. None of the included patients had impaired renal function (serum creatinine levels <130 µM and no albuminuria), proliferative retinopathy, or impaired liver function (except for two of the patients with CP, as mentioned above). All agreed to participate and gave oral and written consents. The study was approved by the Copenhagen County Ethical Committee, dated 16 October 2001 (journal number in the Committee: KA 01109gm) and conducted according to the principles of the Helsinki Declaration.
Methods
All oral antidiabetic treatment was discontinued before the study (sulfonylureas, 3 d before the study; biguanides, 7 d before the study). Insulin-treated patients did not inject long-acting insulin the evening before the experiment, and no insulin was injected in the morning of the day of the experiment. After an overnight fast (from 2200 h), the subjects were studied in the recumbent position with one cannula inserted into a cubital vein for infusion of either GIP, GLP-1, saline, or glucose. Another cannula was inserted in the retrograde direction in an opposite dorsal hand vein for collection of arterialized blood samples. The cannulated hand was kept in a heated box (42 C) throughout the experiment.
The study included 3 experimental days. The experiments were performed in randomized order and consisted of hyperglycemic clamps (15 mM) with or without continuous infusion of incretin hormones. At time zero (0 min), 50% glucose (wt/vol) was infused during 1 min to increase the plasma glucose to 15 mM; the amount of glucose given was calculated as follows: [15 mM - fasting plasma glucose (FPG)] x 35 mg glucose x weight in kilograms. Plasma glucose was kept at 15 mM by continuous infusion of glucose, which was adjusted every 5 min according to bedside measurements of plasma glucose. After 3 min, a continuous infusion of incretin hormone or saline was initiated: GLP-1 (7–36)amide, 1 pmol/kg body weight·min; GIP, 4 pmol/kg body weight·min; or a saline infusion (25 ml/h). Blood was sampled 15, 10, and 0 min before and 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, and 120 min after elevation of plasma glucose. Blood was sampled into fluoride tubes for plasma glucose analysis and into tubes containing heparin or EDTA (6 mM) plus aprotinin (500 KIU/ml blood; Trasylol, Bayer, Leverkusen, Germany) and a specific dipeptidyl peptidase IV inhibitor (valine-pyrrolidide; 0.01 mM, final concentration; a gift from Drs. R. D. Carr and L. B. Christiansen, Novo Nordisk A/S, Bagsværd, Denmark) for hormone analyses. Tubes were immediately cooled on ice and centrifuged at 4 C within 20 min. Plasma was stored at -20 C until analysis (plasma for insulin and C-peptide analysis was stored at -80 C).
Peptides
Synthetic GLP-1 (7–36)amide was a generous gift from Bionebraska, Inc. (now Restoragen, Lincoln, NE), and synthetic GIP was purchased from PolyPeptide Laboratories GmbH (Wolfenbüttel, Germany). The peptides were dissolved in sterilized water containing 2% human serum albumin (Human Albumin, Statens Serum Institute, Copenhagen, Denmark, guaranteed to be free of hepatitis-B surface antigen, hepatitis-C virus antibodies, and human immunodeficiency virus antibodies) and subjected to sterile filtration. Appropriate amounts of peptide for each experimental subject were dispensed into glass ampoules and stored frozen under sterile conditions until the day of the experiment. The peptides were demonstrated to be more than 97% pure and identical to the natural human peptides, by HPLC, mass, and sequence analysis.
Analysis
Plasma glucose concentrations were measured during the experiments using a glucose oxidase method and a Glucose Analyser (Yellow Springs Instrument Model YSI 2300 STAT plus analyzer, Yellow Springs Instruments, Yellow Springs, OH). Plasma insulin and C-peptide concentrations were measured by auto-DELPHIA automatic fluoroimmunoassay (Wallac Oy, Turku, Finland). The detection limit is approximately 3 pM for plasma insulin and 17 pM for plasma C-peptide. Intra- and interassay coefficients of variation for plasma insulin are 0.04–0.10 at 39–1240 pM. Intra- and interassay coefficients of variation for plasma C-peptide are 0.03–0.06 at 380-2700 pM. The cross-reactivity with intact and split proinsulin in the plasma C-peptide assay is 63–87%. Total GIP was measured using the C-terminally directed antiserum R65 (14, 15), which reacts fully with intact GIP and the N-terminally truncated metabolite, GIP (3–42). The assay has a detection limit of 2 pM and intra- and interassay coefficients of variation of approximately 0.06 and 0.15. Plasma samples were assayed for C-terminal immunoreactivity of GLP-1 (total), measuring the sum of the intact peptide plus the primary metabolite, as described previously (16), using standards of synthetic GLP-1 (7–36)amide (= proglucagon 78–107amide) and antiserum no. 89390. The assay cross-reacts less than 0.01% with C-terminally truncated fragments, and 83% with GLP-1 (9–36)amide, and has a detection limit less than 1 pM. Intraassay and interassay coefficients of variation were less than 0.06 and 0.16 at 40 pM. The glucagon assay is directed against the C terminus of the glucagon molecule (antibody code no. 4305) and therefore measures glucagon of mainly pancreatic origin. The sensitivity is approximately 1 pM, and the intra- and interassay coefficients of variation are less than 0.06 and 0.12 in the range between 10 and 25 pM (17).
Statistical analysis and calculations
All results are presented as the mean ± SEM. Area under the curve (AUC) values were calculated using the trapezoidal rule, and statistical analysis were carried out as two-way ANOVA for repeated measurements with post hoc analysis (Fisher’s test) contrasting the results of the different days using the software Statistica (Statsoft, Tulsa, OK). Differences between the groups, with respect to the relative insulin response to GIP vs. GLP-1, were calculated using a one-way ANOVA with post hoc analysis (Fisher’s test, Statistica).
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Mean FPG in the five groups on the day of the saline clamp is shown in Table 1
. Peak plasma glucose concentrations were similar after glucose administration in all five groups, and time courses of PG during the hyperglycemic clamps were not significantly different on the experimental days (Fig. 1A). Time courses of plasma insulin and C-peptide responses during the clamps are presented in Fig. 1, B and C. Fasting plasma insulin and C-peptide concentrations were similar on the 3 experimental days within the groups [not statistically significant (NS)]. Fasting plasma C-peptide concentrations on the day of the saline clamp amounted to 389 ± 102, 604 ± 71, 706 ± 116, 389 ± 17, and 391 ± 76 pM in CP patients, lean type 2 diabetic patients, LADA patients, MODY patients, and type 1 diabetic patients, respectively. Plasma insulin and C-peptide responses were divided into early-phase [total AUC(0–20 min)] and late-phase [total AUC(20–120 min)] responses for all five groups of diabetic patients (Fig. 2). All groups had a higher early-phase plasma insulin response to both GLP-1 and GIP, compared with saline (P values, two-way ANOVA with post hoc analysis by Fisher’s test) (GLP-1/saline and GIP/saline): CP patients, P < 0.05 for GLP-1 vs. saline and P = 0.21 for GIP vs. saline [however, all subjects showed an increase during GIP (P = 0.05 by Wilcoxon analysis)]; type 2 diabetic patients, P < 0.05 and P < 0.05; LADA patients, P < 0.05 and P = 0.09 (P = 0.05 by Wilcoxon); MODY3 patients, P < 0.05 and P < 0.05; type 1 diabetic patients, P < 0.05 and P = 0.065. In four of the groups, there was no significant difference between the early-phase plasma insulin responses to GIP and GLP-1 [total AUC(0–20 min)], but the LADA patients showed slightly lower early-phase plasma insulin response during GIP stimulation, compared with GLP-1 stimulation (P = 0.04). In contrast, late-phase plasma insulin responses [AUC(20–120 min)] were higher after GLP-1 stimulation, compared with GIP and saline in all five groups [P values (GLP-1/GIP and GLP-1/saline): CP patients, P = 0.063 and P < 0.05; type 2 diabetic patients, P < 0.05 and P < 0.05; LADA patients, P < 0.05 and P < 0.05; MODY3 patients, P = 0.054 and P < 0.05; type 1 diabetic patients, P < 0.05 and P < 0.05 (Fig. 2)]. In Fig. 3, the relative plasma insulin responses to GIP vs. GLP-1, estimated during the early phase (0–20 min) and during the late phase (20–120 min), are shown. During the early-phase plasma insulin response, there was no significant difference in the relative plasma insulin response to GIP vs. GLP-1 among the five groups [one-way ANOVA with post hoc analysis (Fisher’s test)]. In contrast, a significantly higher relative plasma insulin response (GIP vs. GLP-1) in the late-phase plasma insulin response (ANOVA, P < 0.02) was seen in the MODY3 patients, compared with the other four groups, with values amounting to 68 ± 5% in the MODY patients, compared with 40 ± 8% (CP), 33 ± 6% (lean, type 2 diabetic patients), 41 ± 6% (LADA patients), and 43 ± 9% (type 1 diabetic patients) (Fig. 3). We have previously shown that healthy subjects have a large late-phase plasma insulin response to GIP during the conditions of a hyperglycemic clamp [total AUC(insulin, 20–120 min), 230 ± 47 (100 min x nM) (mean ± SEM)], which is markedly higher than the responses shown in Fig. 2 (7).
|
|
|
Basal total GLP-1 concentrations amounted to 7 ± 2, 7 ± 1, 9 ± 3, 5 ± 1, and 6 ± 1 pM in CP patients, lean type 2 diabetic patients, LADA patients, MODY patients, and type 1 diabetic patients, respectively (Fig. 4A). Total GLP-1 plasma concentrations increased rapidly during the first 20 min of GLP-1 stimulation, and peak concentrations were reached between 90 and 120 min and amounted to 132 ± 25, 176 ± 18, 197 ± 26, 156 ± 13, and 125 ± 12 pM, respectively (Fig. 4A). Basal total GIP concentrations were 11 ± 3, 5 ± 2, 5 ± 1, 6 ± 2, and 8 ± 2 pM in CP patients, lean type 2 diabetic patients, LADA patients, MODY patients, and type 1 diabetic patients, respectively (Fig. 4B). Total GIP plasma concentrations increased rapidly during the first 20 min of GIP stimulation, and peak concentrations were reached between 90 and 105 min and amounted to 481 ± 53, 592 ± 25, 607 ± 21, 594 ± 34, and 558 ± 50 pM, respectively (Fig. 4B).
|
In Fig. 5A, the amounts of glucose needed to maintain the hyperglycemic clamp at 15 mM are shown. For all groups, there was no significant difference between the amount of glucose needed during the first half hour of the GLP-1 and the GIP clamp. The amount of glucose infused during the first half hour of the hyperglycemic clamp was higher during both GLP-1 stimulation and GIP stimulation, compared with the saline clamp (P < 0.05), except for the MODY3 patients and the type 1 diabetic patients [saline vs. GIP (NS)]. In contrast, a significantly higher amount of glucose was needed to maintain the clamp during the late phase of the clamp (P < 0.05) during the GLP-1 stimulation, compared with the GIP stimulation in all five groups (P < 0.05). For all groups, there was no significant difference between the amounts of glucose infused in the late phase during the GIP and the saline stimulation.
|
On the day of GLP-1 stimulation, basal glucagon concentrations were 6 ± 1, 7 ± 1, 12 ± 1, 7 ± 1, and 11 ± 2 pM in CP patients, lean type 2 diabetic patients, LADA patients, MODY patients, and type 1 diabetic patients, respectively. Corresponding results were 5 ± 1, 6 ± 2, 10 ± 1, 8 ± 1, and 9 ± 2 pM on the day of the GIP stimulation and 5 ± 1, 7 ± 1, 11 ± 1, 8 ± 1, and 10 ± 2 pM, respectively, on the day of the hyperglycemic clamp without incretin hormone (Fig. 5B). In all five groups, a decrease was seen during all three hyperglycemic clamps; but in the LADA patients, MODY patients, and type 1 diabetic patients, the decrease was more pronounced during the GLP-1 stimulation, compared with the GIP stimulation and with the hyperglycemic clamp without infusion of incretin hormones.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In the present study, all groups of diabetic patients (except CP patients, in which fasting glucagon values were already lower than in the other groups) responded with a decrease in glucagon concentration during the glucose + saline infusions. The addition of GIP did not influence this response in any of the groups. A similar finding was previously made in obese type 2 diabetic patients (7). In contrast, in the MODY3 patients, in the LADA patients, and in the type 1 diabetic patients, addition of GLP-1 stimulation further inhibited glucagon secretion at the end of the clamp. The results demonstrate that GLP-1 is capable of conveying enhanced responsiveness to glucose to the -cells of the pancreatic islets in the MODY3, LADA, and type 1 diabetic patients, just as in the obese type 2 diabetic subjects (7). The powerful inhibitory effect of GLP-1 on -cell secretion in the majority of diabetic patients is consistent with its pronounced glucose-lowering effect and its potential application as a therapeutic agent in diabetes treatment.
The absolute ß-cell response in the MODY3 patients to both GIP and GLP-1 stimulation was markedly lower, compared with the other groups. This impaired ß-cell function could simply be explained by the fact that MODY3 patients, because of a longer duration of diabetes, have a decreased ß-cell mass (four of the six patients are plasma insulin treated). MODY3 patients are normally characterized by having a progressive disease, where the ß-cell function is known to decrease markedly with time (22). As mentioned in the results section, the relative insulin response to GIP vs. GLP-1 in the late phase (20–120 min) in the MODY3 patients was significantly higher, compared with the other four groups of patients. The reason for this difference is not obvious but may be explained by the fact that the surviving ß-cells of the MODY3 patients might be functioning more like the ß-cells of healthy subjects (7, 22). Studies of hnf-1 -/- mice indicate that loss of hnf-1-function leads to altered expression of genes involved in glucose-stimulated insulin secretion, and physiological studies using pancreatic islets from hnf-1-deficient mice have shown that ß-cell dysfunction in these animals is likely to result from defective glycolytic signaling proximal to mitochondrial oxidation (23, 24). If MODY3 patients have a similar ß-cell blindness to glucose, as observed in hnf-1 -/- mice, it might explain the present findings of a similarly poor effect of GIP and GLP-1 on insulin secretion, because the insulinotropic effect of both hormones is dependent on ß-cell glucose metabolism (20, 25). Another explanation for the impaired insulin response to the incretin hormones could be altered expression of genes involved in incretin hormone signaling in the ß-cells. Both mechanisms could explain the recent finding that theß-cell response to an oral glucose load is poor in subjects carrying mutations in the HNF-1 gene (26).
In conclusion, we have demonstrated that, in patients with diabetes mellitus secondary to CP, in lean type 2 diabetic patients, in patients with LADA, in patients with MODY3, and in newly diagnosed type 1 diabetic patients, the early-phase plasma insulin response to glucose is impaired but is significantly enhanced by both GLP-1 and GIP. In contrast, GIP is unable to improve the late-phase plasma insulin secretion, whereas GLP-1 enhances the late-phase plasma insulin response markedly. This defective response to GIP may contribute to the pathogenesis of diabetes mellitus; but because this defect is seen in all five groups of diabetic patients with completely different etiology, it is probably not a primary defect causing diabetes, but rather a defect that is secondary to the metabolic disturbances of diabetes. Further studies are needed to clarify this, e.g. studies with strict metabolic control of diabetic patients, who might regain the ß-cell responsiveness to GIP.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: AUC, Area under the curve; CP, chronic pancreatitis; FPG, fasting plasma glucose; GAD65, glutamic acid decarboxylase; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; ICA, islet cell autoantibodies; LADA, latent autoimmune diabetes in adults; MODY, maturity-onset diabetes of the young; NS, not statistically significant; PG, plasma glucose.
Received April 30, 2003.
Accepted June 24, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
gene: evidence for a hyperexcitability of pancreatic ß-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. Diabetes 46:726–730[Abstract]
-deficient mice. J Biol Chem 273:24457–24464 function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes 50:2472–2480This article has been cited by other articles:
 |
|
 |
|
  J. J Neumiller and R K. Campbell Liraglutide: A Once-Daily Incretin Mimetic for the Treatment of Type 2 Diabetes Mellitus Ann. Pharmacother., September 1, 2009; 43(9): 1433 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Chia, O. D. Carlson, W. Kim, Y.-K. Shin, C. P. Charles, H. S. Kim, D. L. Melvin, and J. M. Egan Exogenous Glucose-Dependent Insulinotropic Polypeptide Worsens Post prandial Hyperglycemia in T ype 2 Diabetes Diabetes, June 1, 2009; 58(6): 1342 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Kindel, Q. Yang, S. M. Yoder, and P. Tso Nutrient-driven incretin secretion into intestinal lymph is different between diabetic Goto-Kakizaki rats and Wistar rats Am J Physiol Gastrointest Liver Physiol, February 1, 2009; 296(2): G168 - G174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Vrbikova, M. Hill, B. Bendlova, T. Grimmichova, K. Dvorakova, K. Vondra, and G. Pacini Incretin levels in polycystic ovary syndrome Eur. J. Endocrinol., August 1, 2008; 159(2): 121 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Holst The Physiology of Glucagon-like Peptide 1 Physiol Rev, October 1, 2007; 87(4): 1409 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ghanaat-Pour, Z. Huang, M. Lehtihet, and A. Sjoholm Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats J. Mol. Endocrinol., August 1, 2007; 39(2): 135 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. K. Knop, T. Vilsboll, P. V. Hojberg, S. Larsen, S. Madsbad, A. Volund, J. J. Holst, and T. Krarup Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes, August 1, 2007; 56(8): 1951 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, M. F. A. Livak, M. Bernier, D. C. Muller, O. D. Carlson, D. Elahi, S. Maudsley, and J. M. Egan Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E538 - E547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Vilsboll and F. K Knop Review: DPP IV inhibitors - current evidence and future directions The British Journal of Diabetes & Vascular Disease, March 1, 2007; 7(2): 69 - 74. [Abstract] [PDF]
|
|
|
|
|
|
F. K. Knop, T. Vilsboll, S. Larsen, P. V. Hojberg, A. Volund, S. Madsbad, J. J. Holst, and T. Krarup Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E324 - E330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ryskjaer, C. F Deacon, R. D Carr, T. Krarup, S. Madsbad, J. Holst, and T. Vilsboll Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake Eur. J. Endocrinol., September 1, 2006; 155(3): 485 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Schou, K. Pilgaard, T. Vilsboll, C. B. Jensen, C. F. Deacon, J. J. Holst, A. Volund, S. Madsbad, and A. A. Vaag Normal Secretion and Action of the Gut Incretin Hormones Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide in Young Men with Low Birth Weight J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4912 - 4919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H Frid, M. Nilsson, J. J. Holst, and I. M. Bjorck Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects Am. J. Clinical Nutrition, July 1, 2005; 82(1): 69 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Meier, B. Gallwitz, B. Kask, C. F. Deacon, J. J. Holst, W. E. Schmidt, and M. A. Nauck Stimulation of Insulin Secretion by Intravenous Bolus Injection and Continuous Infusion of Gastric Inhibitory Polypeptide in Patients With Type 2 Diabetes and Healthy Control Subjects Diabetes, December 1, 2004; 53(suppl_3): S220 - S224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Holst and J. Gromada Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E199 - E206. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
