help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Basu, R.
Right arrow Articles by Rizza, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Basu, R.
Right arrow Articles by Rizza, R. A.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Diabetes
Hazardous Substances DB
*GLUCAGON
*GLUCOSE
*LACTIC ACID
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2314-2319
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Effect of Overnight Restoration of Euglycemia on Glucose Effectiveness in Type 2 Diabetes Mellitus1

Rita Basu, Ananda Basu, Michael Nielsen, Pankaj Shah and Robert A. Rizza

Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic (R.B., A.B., P.S., R.A.R.), Rochester, Minnesota 55905; Aarhus Kommunehospital (M.N.), Aarhus, Denmark

Address all correspondence and requests for reprints to: Dr. Robert A. Rizza, 200 First Street SW, 5–194 Joseph, Rochester, Minnesota 55905. E-mail: rizza.robert{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The ability of glucose to stimulate its own uptake and suppress its own release is impaired in type 2 diabetes. To determine whether glucose effectiveness is improved by short term euglycemia, 10 type 2 diabetic subjects were studied on 2 occasions. Insulin was infused throughout the night to maintain euglycemia (~5 mmol/L), or glucose was permitted to remain at ambient hyperglycemic levels (~10 mmol/L) until the following morning when euglycemia was achieved with a variable insulin infusion. A prandial glucose infusion (containing 35 g glucose) was started at 1000 h, and the variable insulin infusion was replaced by a constant infusion of insulin (0.25 mU/kg·min), somatostatin (60 ng/kg·min), glucagon (0.65 ng/kg·min), and GH (3 ng/kg·min) to maintain hormone concentrations at constant basal levels. Although nocturnal glucose concentrations were (by design) higher (P < 0.01) on the hyperglycemic than on the euglycemic study day (10.1 ± 0.2 vs. 5.4 ± 0.1 mmol/L), glucose concentrations did not differ either before (4.9 ± 0.1 vs. 4.9 ± 0.1 mmol/L) or during the prandial glucose infusion (peak, 11.1 ± 0.5 vs. 11.3 ± 0.5 mmol/L; incremental area, 1390 ± 254 vs. 1409 ± 196 mmol/L·6 h). Furthermore, glucose-induced stimulation of glucose disappearance (2068 ± 218 vs. 1957 ± 244 µmol/kg·6 h) and suppression of glucose production (-2253 ± 378 vs. -2124 ± 257 µmol/kg·6 h) did not differ. Thus, restoration of euglycemia by means of an overnight insulin infusion does not alter glucose effectiveness in people with type 2 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PLASMA glucose concentration is determined by the balance between rates of glucose appearance and disappearance, which, in turn, are regulated by the prevailing glucose and insulin concentrations (1, 2, 3, 4, 5, 6, 7). Type 2 diabetes is associated (8, 9, 10, 11, 12, 13, 14, 15) with defects in both insulin action and glucose effectiveness (defined as the ability of glucose to stimulate its own uptake and to suppress its own production). We and others have shown that a long term (i.e. weeks to months) improvement in glycemic control results in an increase in insulin action, presumably due to alleviation of so-called glucose toxicity (8, 16, 17, 18). More recently, we have demonstrated that short term (i.e. overnight) restoration of euglycemia results in an improvement in hepatic, but not extrahepatic, insulin action (19). This improvement could potentially account at least in part for the clinical observation that daytime glycemic control is greatly facilitated if glucose concentrations in the morning start out in the euglycemic range. However, as glucose effectiveness appears to be a major determinant of glucose concentration in individuals who have normal basal insulin concentrations but limited insulin secretory reserve (i.e. subjects with type 2 diabetes), enhanced daytime glycemic control could also occur if restoration of euglycemia also improved glucose effectiveness (15, 20, 21). Such a change could impact upon the design of clinical studies, as the glucose concentration at which glucose effectiveness is assessed frequently differs between groups and after various interventions.

The present experiments were, therefore, undertaken to determine whether short term restoration of euglycemia by means of an overnight insulin infusion improves the ability of glucose to stimulate its own uptake and to suppress its own release in subjects with type 2 diabetes mellitus. To do so, we measured glucose effectiveness in diabetic individuals after either overnight hyperglycemia (i.e. glucose concentrations permitted to remain at ambient levels) or overnight euglycemia. On the hyperglycemic study day, the glucose concentration was acutely lowered the following morning by means of a variable insulin infusion so that glucose effectiveness was assessed in all subjects in the presence of comparable baseline glucose and insulin concentrations. We report that in contrast to its effects on insulin action (19), overnight restoration of euglycemia does not alter glucose effectiveness in subjects with type 2 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

After obtaining approval from the Mayo Institutional review board, 10 subjects (6 men and 4 women) with type 2 diabetes (age, 55 ± 3 yr; height, 1.7 ± 0.04 m; weight, 84.2 ± 2.7 kg; body mass index, 30.2 ± 2.6 kg/m2; lean body mass, 52.3 ± 2.6 kg) gave informed written consent to participate in the study. Glycosylated hemoglobin concentration (GlycAffin, Isolab, Akron, OH) averaged 9.1 ± 2.7% (normal range, 4–7%), and the fasting glucose concentration was 9.3 ± 0.7 mmol/L. The average duration of diabetes was 9 ± 2.5 yr. All subjects were in good health and had no evidence of significant diabetic complications. Seven of the 10 volunteers were treated with oral hypoglycemic agents, which were discontinued 3 weeks before the study.

Experimental design

Each subject was studied on two occasions separated by at least 1 week. The order of study was random. On each occasion subjects were admitted to the General Clinical Research Center at 1800 h the evening before the study. After the ingestion of a standard 10 Cal/kg meal (55% carbohydrates, 30% fat, and 15% protein), subjects remained fasting (with the exception of occasional sips of water) until the end of the study. After the meal, an 18-gauge cannula was inserted into each forearm. On one occasion, human insulin (0.1 U/mL Humulin R, Eli Lilly & Co., Indianapolis, IN) was infused in amounts sufficient to maintain euglycemia throughout the night (referred to as the euglycemic study day), whereas on the other occasion, saline was infused, thereby permitting glucose to remain at ambient levels (referred to as the hyperglycemic study day) until the following morning when a variable insulin infusion was started and adjusted so as to achieve euglycemia within 2–3 h. On both occasions, glucose concentrations were measured at 30- to 60-min intervals, and the results were used to adjust the insulin infusion rate. The morning variable insulin infusion was started at 0800 h in the first subject, at 0700 h in the next two subjects, and at 0600 h in the remaining seven subjects to insure there were at least 60 min of stable glucose and insulin concentrations before the start of the prandial glucose infusion at 1000 h (15). Hypoglycemia did not occur either during night or on the morning of the study in any subject.

At 0530 h, an 18-gauge cannula was inserted retrogradely into a dorsal hand vein. The hand was then placed in a heated box (~55 C) to obtain arterialized venous blood samples. A primed continuous infusion of [3-3H]glucose (12 µCi prime; 0.12 µCi/min continuous; New England Nuclear, Boston, MA) was started at 0700 h and continued until the end of the study at 1600 h. On both occasions, the variable insulin infusion was replaced at 1000 h by a constant infusion of insulin (0.25 mU/kg·min), somatostatin (60 ng/kg·min), glucagon (0.65 ng/kg·min), and GH (3 ng/kg·min). A prandial infusion of glucose (containing 35 g glucose) also was started at 1000 h as previously described (22). All infused glucose contained [3-3H]glucose in amounts equal to the calculated basal glucose specific activity. In addition, the rate of infusion of [3-3H]glucose was altered so as to approximate the anticipated pattern of fall in glucose production (-180 to 0 min, 100%; 0–15 min, 70%; 15–75 min, 30%; 75–120 min, 45%; 120–360 min, 50%). This resulted in a less than a 10% change in plasma [3-3H]glucose specific activity during the prandial glucose infusion. Arterialized venous blood samples and expired air were collected at regular intervals as previously described (23).

Analytical techniques

Plasma samples were placed on ice, centrifuged at 4 C, separated, and stored at -20 C until assay. Glucose and lactate concentrations were measured using a glucose oxidase method (YSI, Inc., Yellow Springs, OH). Plasma insulin, cortisol, and GH were measured using a chemiluminescence assay with reagents obtained from Beckman Coulter, Inc. (Access Assay, Beckman Coulter, Inc., Chaska, MN). Plasma glucagon and C peptide were measured by RIA using reagents supplied by Linco Research, Inc.. Free fatty acid concentrations were measured using a colorimetric assay (Wako Pure Chemical Industries, Osaka, Japan). Body composition was measured using dual energy x-ray absorptiometry (DPX scanner, Hologic, Inc., Waltham, MA). Plasma glucose specific activity was measured using liquid scintillation counting.

Calculations

Glucose specific activity was smoothed using the method of Bradley et al. (24). Glucose appearance and disappearance were calculated using the equations of Steele (25). The volume of distribution of glucose was assumed to equal 200 mL/kg, and the pool correction factor was assumed to equal 0.65. Endogenous glucose production was determined by subtracting the glucose infusion rate from the tracer-determined rate of glucose appearance (1).

Statistical analysis

All data are expressed as the mean ± SEM. Rates of glucose turnover are expressed per kg lean body mass. Values during the 30 min before the start of the prandial glucose infusion (i.e. -30 to 0 min) were meaned and considered as the baseline. Statistical analysis was performed using Student’s two-tailed paired t test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Glucose and insulin concentration and insulin infusion rates (Figs. 1Go and 2Go)

Glucose concentrations were higher (P < 0.01) during the night on the hyperglycemic than on the euglycemic study days (10.1 ± 0.2 vs. 5.4 ± 0.1 mmol/L). After initiation of the variable insulin infusion on the morning of the hyperglycemic study day, plasma insulin concentrations increased, and plasma glucose concentrations began to fall. The variable insulin infusion was then tapered so that the insulin infusion rate from -60 min onward no longer differed on the hyperglycemic and euglycemic study days. This resulted in stable and comparable baseline glucose (4.9 ± 0.1 vs. 4.9 ± 0.1 mmol/L) and insulin concentrations (90 ± 24 vs. 72 ± 12 pmol/L) on the 2 study days.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Glucose concentrations observed on the hyperglycemic and euglycemic study days. A prandial glucose infusion was started at time zero.

 


View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Insulin infusion rates and insulin concentrations observed on the euglycemic and hyperglycemic study days. A prandial glucose infusion was started at time zero.

 
Initiation of the prandial glucose infusion at time zero resulted in a prompt increase in glucose concentration that peaked at about 120 min, followed by a fall toward baseline. The increase in glucose concentrations was virtually identical on the hyperglycemic and euglycemic study days whether measured as the peak glucose concentration (11.1 ± 0.5 vs. 11.3 ± 0.5 mmol/L) or as the area above basal (1390 ± 254 vs. 1409 ± 196 mmol/L·6 h). The plasma insulin concentration remained constant and equal during the prandial glucose infusion on both study days.

C Peptide and glucagon concentrations (Fig. 3Go)

C Peptide concentrations from 2300–0600 h were higher (P < 0.01) on the hyperglycemic than on the euglycemic study days (0.6 ± 0.1 vs. 0.4 ± 0.1 pmol/L). After initiation of the morning variable insulin infusion, C peptide concentrations on the hyperglycemic study day fell in parallel with the fall in glucose concentrations to values no longer different from those observed on the euglycemic study day. Somatostatin (starting at time zero along with the prandial glucose infusion) resulted in comparable suppression of C peptide on both occasions, indicating equivalent inhibition of endogenous insulin secretion. Plasma glucagon remained constant and equal on both study days. Cortisol and GH concentrations also did not differ on the 2 study days (data not shown).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 3. C Peptide and glucagon concentrations observed on either the hyperglycemic or euglycemic study days. A prandial glucose infusion was started at time zero.

 
Rates of glucose disappearance and production (Fig. 4Go)

Rates of glucose disappearance (15.9 ± 0.8 vs. 14.8 ± 0.8 µmol/kg·min) and glucose production (16.2 ± 1.4 vs. 14.3 ± 0.9 µmol/kg·min) during the 30 min before the start of the prandial glucose infusion did not differ on the hyperglycemic and euglycemic study days. The prandial glucose infusion resulted in a comparable increase in glucose disappearance (2068 ± 218 vs. 1957 ± 244 µmol/kg·6 h) and a comparable decrease in glucose production (-2253 ± 379 vs. -2124 ± 257 µmol/kg·6 h) on both the hyperglycemic and euglycemic study days.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 4. Rates of glucose disappearance and endogenous glucose production observed on either the hyperglycemic or euglycemic study days. A prandial glucose infusion was started at time zero.

 
Free fatty acid and lactate concentrations (Fig. 5Go)

Free fatty acid and lactate concentrations were comparable both before and during the prandial glucose infusion on both study days.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 5. Plasma free fatty acid and lactate concentrations observed on either the hyperglycemic or euglycemic study days. A prandial glucose infusion was started at time zero.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We and others have shown that glucose effectiveness, defined as the ability of glucose to stimulate its own uptake and to suppress its own release, is impaired in people with type 2 diabetes (11, 12, 13, 14, 15, 26, 27). The present studies indicate that short term normalization of glucose concentrations does not reverse this defect. This observation contrasts with the effects of short term normalization of glucose concentration on insulin action. Using the same experimental approach, we have previously demonstrated that nocturnal euglycemia produced by means of an overnight insulin infusion improves hepatic, but not extrahepatic, insulin action in a similar group of people with type 2 diabetes (19).

There is ample evidence that chronic hyperglycemia can impair insulin action (a phenomenon commonly referred to as glucose toxicity), and that this impairment can at least in part be reversed by an improvement in glycemic control (8, 16, 17, 18, 28, 29, 30). However, we are unaware of any previous studies examining whether chronic hyperglycemia also has the same deleterious effect on the ability of glucose to regulate its own metabolism. Lack of concordance between the effect of improved glycemic control on insulin action and glucose effectiveness is not particularly surprising, as insulin and glucose use different mechanisms to modulate glucose production and utilization (3, 29, 31, 32, 33, 34). Whereas hyperglycemia and hyperinsulinemia both acutely increase glucose uptake and translocation of GLUT4 transporters to the plasma membrane, the former does so via a calcium dependent pathway (i.e. it can be inhibited by dantrolene), whereas the latter does so via the phosphoinositol kinase pathway (i.e. it can be inhibited by wortmanin) (35). Similarly, whereas an increase in either glucose or insulin concentration can suppress net hepatic glucose production, hyperglycemia appears to do so in the presence of basal insulin concentrations primarily by inhibiting glycogen breakdown, whereas hyperinsulinemia in the presence of euglycemia appears to do so primarily by stimulating glycogen synthesis (31). The lack of improvement in glucose effectiveness observed in the present experiments implies that either chronic hyperglycemia does not alter the ability of glucose to modulate its own metabolism (i.e. glucose toxicity is limited to insulin action) and therefore cannot be reversed by lowering glucose concentration or that a longer period of euglycemia is necessary for an effect to be seen. In either case, in contrast to insulin action, where an enhanced ability of insulin to suppress glucose production may help explain the clinical observation that beginning the day with a normal glucose concentration is typically associated with better daytime glycemic control, an improvement in glucose effectiveness does not appear to be a factor.

Proving no difference is impossible. The best that can be done is to minimize experimental variability so that a difference, if present, could be detected with confidence. Toward this end, the same subjects were studied on both occasions so as to avoid intersubject variation. A standard meal was ingested on both occasions on the evening before the study. All subjects received exactly the same basal insulin infusion rate to insure that insulin concentrations during the prandial glucose infusion were the same on the 2 days. This resulted in a virtually identical increase in glucose concentration above basal on the hyperglycemic and euglycemic study days. Perhaps more importantly, the increment above basal was higher in six and lower in four subjects on the hyperglycemic than on the euglycemic study days, strongly arguing against the possibility that a meaningful difference would be detected by studying a larger number of subjects.

The present experiments only examined the effects of a short term improvement in glycemic control on glucose effectiveness. On the euglycemic study day, the variable insulin infusion was adjusted so as to achieve normoglycemia by approximately 2300 h, whereas on the hyperglycemic study day, the variable insulin infusion was not started until 0600–0800 h on the following morning resulting in a 7- to 9-h difference in glycemic control. The time of initiation of the morning variable insulin infusion was moved from 0800 to 0700 h after the first study and to 0600 h after the second two studies to insure that the lack of difference observed in those experiments between the hyperglycemic and euglycemic study days was not due to any residual effects of the morning variable insulin infusion or to a subtle instability of the baseline glucose concentrations. Both of these possibilities seem unlikely, as the results were virtually identical in the next seven patients when the variable insulin infusion was started at 0600 h, permitting earlier achievement of stable basal glucose and insulin concentrations. The comparable free fatty acid concentrations on the two occasions further argues against different degrees of insulinization on the hyperglycemic and euglycemic study days, as lipolysis is exquisitely sensitive to small differences in insulin concentration (36). Nevertheless, we cannot totally exclude the possibility that the acute increase in insulin on the morning of the hyperglycemic study day had an impact (either positive or negative) on glucose effectiveness measured later that same morning.

It remains possible that glucose effectiveness would eventually improve after a longer period of normoglycemia. However, the present pattern of glycemic control would probably reflect the difference between that observed in an individual who received an injection of intermediate or long acting insulin at supper vs. that observed in an individual whose glucose concentrations were permitted to remain elevated throughout the night (37). Glucose concentrations were lowered on the morning of the hyperglycemic study day so that they would be same as those on the euglycemic study day at the time of initiation of the prandial glucose infusion. If this were not done, the protocol not only would have assessed the effects of a difference in antecedent glycemic control, but also the effects of a difference in ambient glucose concentration at the time of measurement of glucose effectiveness. As a number of investigators have shown that glucose clearance falls as glucose concentrations rise (38, 39, 40), interpretation of putative differences (or lack of differences) in glucose effectiveness measured in the presence of differing ambient glucose concentrations would be problematic.

A potential limitation of the present study is the fact that approximately 2 h were required to lower the glucose concentrations on the morning of the hyperglycemic study day. Furthermore, insulin was used to lower glucose. We used this approach because we have previously demonstrated (19) that a gradual lowering of glucose over 2 h does not alter counterregulatory hormone concentrations (i.e. epinephrine, norepinephrine, GH, and glucagon), which in themselves could alter glucose effectiveness. We cannot exclude the possibility that any adverse effect of chronic hyperglycemia on glucose effectiveness was fully reversed during this time. Ideally, glucose concentrations would have been instantly lowered by a means that did not require insulin and did not evoke a counterregulatory response. This, of course, is not possible in humans.

Glucose effectiveness was only assessed in the presence of a basal insulin concentration. We chose this insulin concentration because it corresponds to the level at which glucose effectiveness is measured with the so-called minimal model (41). Furthermore, it is also the insulin concentration at which we and other have shown glucose effectiveness to be impaired in subjects with type 2 diabetes mellitus (11, 12, 13, 14, 15, 26, 27). As we (15, 26) as well as other investigators (11, 12, 13, 14, 27) have consistently shown that glucose effectiveness in the presence of basal insulin concentrations is impaired in subjects with type 2 diabetes, we did not include a nondiabetic control group studied at individually determined basal insulin concentrations. Therefore, it is possible that glucose effectiveness was not impaired in all of the diabetic volunteers. In addition, as we did not measure insulin action in these subjects, we do not know whether they were also insulin resistant. However, neither of these limitations detracts from our conclusion that glucose effectiveness in people with type 2 diabetes after overnight hyperglycemia does not differ from that observed after overnight euglycemia. Insulin was infused into the peripheral rather than the portal venous system. Although the importance of portal vs. peripheral insulin infusion continues to be debated (42, 43), this is unlikely to be an issue in the present studies, as somatostatin resulted in inhibition of endogenous insulin secretion, thereby insuring that all subjects had comparable portal and peripheral insulin concentrations on the hyperglycemic and euglycemic study days. This approach also resulted in comparable portal glucagon concentrations on the 2 study days.

Thus, in summary, short term restoration of euglycemia by means of an overnight insulin infusion does not alter glucose effectiveness. Further studies will be required to determine whether a longer term improvement in glycemic control and/or whether treatment with modalities other than insulin improve glucose effectiveness in subjects with type 2 diabetes mellitus.


   Acknowledgments
 
We thank T. Madson and C. Etter for their technical assistance, M. Davis for assistance in preparing the manuscript, and the staff of the Clinical Research Center for their help in performing the studies.


   Footnotes
 
1 This work was supported by USPHS Grants DK-29953, RR-00585, and DK-50456; the Mayo Foundation; and research grants (to M.N.) provided by the Danish Research Council, Aarhus University Hospital, and University of Aarhus (Aarhus, Denmark). Back

Received January 7, 1999.

Revised April 1, 1999.

Accepted April 7, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Rizza RA, Mandarino LJ, Gerich JE. 1981 Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 240:E630–E639.
  2. Kolterman OG, Gray RS, Griffin J, et al. 1981 Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 68:957–969.
  3. Rossetti L, Giaccari A, Barzilai N, Howard K, Sebel G, Hu M. 1993 Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. J Clin Invest. 92:1126–11134.
  4. Ader M, Ni T-C, Bergman RN. 1997 Glucose effectiveness assessed under dynamic and steady state conditions. J Clin Invest. 99:1187–1199.[Medline]
  5. DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J. 1983 Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes. 32:35–45.[Medline]
  6. Yki-Jarvinen H, Young AA, Lamkin C, Foley JE. 1987 Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 79:1713–1719.
  7. Hansen IL, Cryer PE, Rizza RA. 1985 Comparison of insulin-mediated and glucose-mediated glucose disposal in patients with insulin-dependent diabetes mellitus and in nondiabetic subjects. Diabetes. 34:751–755.[Abstract]
  8. Firth RG, Bell PM, Rizza RA. 1986 Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 314:1280–1286.[Abstract]
  9. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. 1984 Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. 74:1238–1246.
  10. DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. 1985 Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (Type II) diabetes mellitus. J Clin Invest. 76:149–155.
  11. Kruszynska YT, Harry DS, Bergman RN, McIntyre N. 1993 Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients. Diabetologia. 36:121–128.[CrossRef][Medline]
  12. Wajchenberg BL, Santomauro ATMG, Porrelli RN. 1993 Effect of a sulfonylurea (gliclazide) treatment on insulin sensitivity and glucose-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Res Clin Pract. 20:147–154.[CrossRef][Medline]
  13. Del Prato S, Matsuda M, Simonson DC, et al. 1997 Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 40:687–697.[CrossRef][Medline]
  14. Taniguchi A, Nakai Y, Fukushima M, et al. 1992 Pathogenic factors responsible for glucose intolerance in patients with NIDDM. Diabetes. 41:1540–1546.[Abstract]
  15. Basu A, Caumo A, Bettini F, Gelisio A, Alzaid A, Cobelli C. 1997 Impaired basal glucose effectiveness in NIDDM. Contribution of defects in glucose disappearance and production, measured using an optimized minimal model independent protocol. Diabetes. 46:421–432.[Abstract]
  16. Simonson DC, Ferrannini E, Bevilacqua S, et al. 1984 Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes. 33:838–845.[Abstract]
  17. Scarlett JA, Kolterman OG, Ciaraldi TP, Kao M, Olefsky JM. 1983 Insulin treatment reverses the postreceptor defect in adipocyte 3-O-methylglucose transport in type II diabetes mellitus. J Clin Endocrinol Metab. 56:1195–1201.[Abstract]
  18. Foley JE, Kashiwagi A, Verso MA, Reaven G, Andrews J. 1983 Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. J Clin Invest. 72:1901–1909.
  19. Wise SD, Nielsen MF, Cryer PE, Rizza RA. 1998 Overnight normalization of glucose concentrations improves hepatic but not extrahepatic insulin action in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 83:2461–2469.[Abstract/Free Full Text]
  20. Kahn SE, Prigeon RL, McCulloch DK, et al. 1994 The contribution of insulin-dependent, and insulin-independent glucose uptake to intraveneous glucose tolerance in healthy human subjects. Diabetes. 43:587–592.[Abstract]
  21. Ader M, Pacini G, Yang YJ, Bergman RN. 1985 Importance of glucose per se to intravenous glucose tolerance. Comparison of the minimal-model prediction with direct measurements. Diabetes. 34:1092–1103.[Abstract]
  22. Alzaid AA, Dinneen SF, Turk DJ, Caumo A, Cobelli C, Rizza RA. 1994 Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans. J Clin Invest. 94:2341–2348.
  23. McMahon M, Marsh HM, Rizza RA. 1989 Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM. Diabetes. 38:291–303.[Abstract]
  24. Bradley DC, Steil GM, Bergman RN. 1993 Quantitation of measurement error with optimal segments: basis for adaptive time course smoothing. Am J Physiol. 264:E902–E911.
  25. Steele R, Wall JS, De Bodo RC, Altszuler N, Kiang SP, Bjerknes C. 1956 Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 187:15–24.[Abstract/Free Full Text]
  26. Nielsen MF, Basu R, Wise S, Caumo A, Cobelli C, Rizza RA. 1998 Normal glucose induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake. Diabetes. 47:1735–1747.[Abstract]
  27. Mevorach M, Giacca A, Aharon Y, Hawkins M, Shamoon H, Rossetti L. 1998 Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus. J Clin Invest. 102:744–753.[Medline]
  28. Butler PC, Caumo A, Zerman A, O’Brien PC, Cobelli C, Rizza RA. 1993 Methods for assessment of the rate of onset and offset of insulin action during nonsteady state in humans. Am J Physiol. 264:E548–E569.
  29. Postic C, Leturque A, Rencurel F, et al. 1993 The effects of hyperinsulinemia and hyperglycemia on GLUT4 and hexokinase II mRNA and and protein in rat skeletal muscle and adipose tissue. Diabetes. 42:922–929.[Abstract]
  30. Yki-Jarvinen H, Helve E, Koivisto VA. 1987 Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes. 36:892–896.[Abstract]
  31. Petersen KF, Laurent D, Rothman DL, Cline GW, Shulman GI. 1998 Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest. 101:1203–1209.[Medline]
  32. Lavoie L, Dimitrakoudis D, Marette A, et al. 1993 Opposite effects of hyperglycemia and insulin deficiency on liver glycogen synthase phosphatase activity in the diabetic rat. Diabetes. 42:363–366.[Abstract]
  33. Halimi S, Assimacopoulos-Jeannet F, Terrattaz J, Jeanrenaud B. 1987 Differential effect of steady-state hyperinsulinaemia and hyperglycaemia on hepatic glycogenolysis and glycolysis in rats. Diabetologia. 30:268–272.[CrossRef][Medline]
  34. Galante P, Mosthaf L, Kellerer M, et al. 1995 Acute hyperglycemia provides an insulin-independent inducer for GLUT4 translocation in C2C12 myotubes and rat skeletal muscle. Diabetes. 44:646–651.[Abstract]
  35. Nolte LA, Rincon J, Odegaard, et al. 1995 Hyperglycemia activates glucose transport in rat skeletal muscle via a Ca2+dependent mechanism. Diabetes. 44:1345–1348.[Abstract]
  36. Jensen MD, Caruso M, Heiling V, Miles JM. 1989 Insulin regulation of lipolysis in nondiabetic and IDDM subjects. Diabetes. 38:1595–1601.[Abstract]
  37. Taskinen M-R, Sane T, Helve E, Karonen S-L, Nikkilä EA, Yki-Jarvinen H. 1989 Bedtime insulin for suppression of overnight free-fatty acid, blood glucose, and glucose production in NIDDM. Diabetes. 38:580–588.[Abstract]
  38. Cherrington AD, Williams PE, Harris MS. 1978 Relationship between the plasma glucose level and glucose uptake in the conscious dog. Metabolism. 27:787–791.[CrossRef][Medline]
  39. Verdonk CA, Rizza RA, Gerich JE. 1981 Effects of plasma glucose concentration on glucose utilization and glucose clearance in normal man. Diabetes. 30:535–537.[Abstract]
  40. Best JD, Taborsky Jr GJ, Halter JB, Porte Jr D. 1981 Glucose disposal is not proportional to plasma glucose level in man. Diabetes. 30:847–850.[Abstract]
  41. Bergman RN, Ider YZ, Bowden CR, Cobelli C. 1979 Quantitative estimation of insulin sensitivity. Am J Physiol. 236:E667–E677.
  42. Kubota M, Yamasaki Y, Sekiya M, et al. 1996 Portal insulin delivery is superior to peripheral delivery in handling of portally delivered glucose. Metabolism. 45:150–154.[CrossRef][Medline]
  43. Pagliassotti MJ, Holste LC, Moore MC, Neal DW, Cherrington AD. 1996 Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. J Clin Invest. 97:81–91.[Medline]



This article has been cited by other articles:


Home page
 DiabetesHome page
P. Kishore, J. Tonelli, S. Koppaka, C. Fratila, A. Bose, D.-E. Lee, K. Reddy, and M. Hawkins
Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes
Diabetes, June 1, 2006; 55(6): 1761 - 1768.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. Hawkins, J. Tonelli, P. Kishore, D. Stein, E. Ragucci, A. Gitig, and K. Reddy
Contribution of Elevated Free Fatty Acid Levels to the Lack of Glucose Effectiveness in Type 2 Diabetes
Diabetes, November 1, 2003; 52(11): 2748 - 2758.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. Hawkins, I. Gabriely, R. Wozniak, K. Reddy, L. Rossetti, and H. Shamoon
Glycemic Control Determines Hepatic and Peripheral Glucose Effectiveness in Type 2 Diabetic Subjects
Diabetes, July 1, 2002; 51(7): 2179 - 2189.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
C. J. Greenbaum, R. L. Prigeon, and D. A. D'Alessio
Impaired {beta}-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose
Diabetes, April 1, 2002; 51(4): 951 - 957.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. Hawkins, I. Gabriely, R. Wozniak, C. Vilcu, H. Shamoon, and L. Rossetti
Fructose Improves the Ability of Hyperglycemia Per Se to Regulate Glucose Production in Type 2 Diabetes
Diabetes, March 1, 2002; 51(3): 606 - 614.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Basu, R.
Right arrow Articles by Rizza, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Basu, R.
Right arrow Articles by Rizza, R. A.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Diabetes
Hazardous Substances DB
*GLUCAGON
*GLUCOSE
*LACTIC ACID

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