1 Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps University, 35033 Marburg, Germany; 2 Novo Nordisk, 2880 Bagsvaerd, Denmark; and 3 Department of Gastroenterology, Ludwig-Maximilians University, 81377 Munich, Germany.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Impaired glucose tolerance (IGT) and
non-insulin-dependent diabetes mellitus (NIDDM) are associated with an
impaired ability of the -cell to sense and respond to small changes
in plasma glucose. The aim of this study was to establish whether acute hyperglycemia per se plays a role in inducing this defect in
-cell response. Seven healthy volunteers with no family history of NIDDM were
studied on two occasions during a 12-h oscillatory glucose infusion
with a periodicity of 144 min. Once, low-dose glucose was infused at a
mean rate of 6 mg · kg
1 · min
1 and
amplitude 33% above and below the mean rate, and, once, high-dose glucose was infused at 12 mg · kg
1 · min
1 and
amplitude 16% above and below the mean rate. Mean glucose levels were
significantly higher during the high-dose compared with the low-dose
glucose infusion [9.5 ± 0.8 vs. 6.8 ± 0.2 mM (P < 0.01)], resulting in increased mean insulin
secretion rates [ISRs; 469.1 ± 43.8 vs. 268.4 ± 29 pmol/min (P < 0.001)] and mean insulin levels
[213.6 ± 46 vs. 67.9 ± 10.9 pmol/l (P < 0.008)]. Spectral analysis evaluates the regularity of oscillations in glucose, insulin secretion, and insulin at a predetermined frequency. Spectral power for glucose, ISR, and insulin was reduced during the
high-dose glucose infusion [11.8 ± 1.4 to 7.0 ± 1.6 (P < 0.02), 7.6 ± 1.5 to 3.2 ± 0.5 (P < 0.04), and 10.5 ± 1.6 to 4.6 ± 0.7 (P < 0.01), respectively]. In conclusion, short-term
infusion of high-dose glucose to obtain glucose levels similar to those previously seen in IGT subjects results in reduced spectral power for
glucose, ISR, and insulin. The reduction in spectral power previously
observed for ISR in IGT or NIDDM subjects may be due partly to hyperglycemia.
insulin secretion; connecting peptide; oscillations; spectral power
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IMPAIRED GLUCOSE
TOLERANCE (IGT) is a relatively common condition defined by
plasma glucose concentration greater than 7.8 mM and less than 11.1 mM,
2 h after ingestion of a 75-g glucose load (standard oral glucose
tolerance test) (33). It is characterized by the presence
of insulin resistance (7) and early defects in -cell
function (1, 3, 18, 19). First-phase insulin secretory responses (ISR) to intravenous glucose are significantly reduced in relation to the degree of insulin resistance
(3), and there is an impaired ability of the
-cell to
sense and respond to small changes in plasma glucose concentrations
(3, 18). Hyperglycemic progression in IGT subjects has
been shown to be associated with a progressive decline in
-cell
function (32), and the restoration of normoglycemia in
non-insulin-dependent diabetes mellitus (NIDDM) subjects has been shown
to improve
-cell dysfunction (13).
Chronic hyperglycemia has been shown to have a deleterious effect on
both insulin secretion and insulin action, a concept termed "glucose
toxicity" (23, 34). The possible mechanisms whereby
hyperglycemia may induce defects in glucose-induced insulin secretion
include downregulation of several genes including GLUT2 and glucokinase
(4, 5, 12, 14, 26), and induction of mitochondrial defects
(16, 17). However, to date, very few data come from human
studies, because acute or chronic experimental hyperglycemia is
difficult to generate, and the nonavailability of pancreatic biopsies
is a major impediment that has resulted in limited molecular or
biochemical information about hyperglycemia-induced -cell defects in humans.
Using an oscillatory glucose infusion protocol, we previously
demonstrated that, in IGT subjects, there is an impaired ability of the
-cell to sense and respond to small changes in plasma glucose
compared with controls (3). However, during this protocol, mean plasma glucose levels were significantly higher in IGT subjects compared with controls (9.8 ± 0.6 mM vs. 8.3 ± 0.2 mM). To
establish whether short-term hyperglycemia plays a role in inducing
this
-cell defect, we attempted to mimic this degree of
hyperglycemia in normal subjects by infusing high-dose glucose in an
oscillatory manner. This enabled us to study the pattern of insulin
secretion in response to short-term hyperglycemia in normal subjects.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects
Studies were performed in seven healthy male Caucasian volunteers aged 24-35 yr (mean ± SE: 28 ± 1 yr). Subjects were within 10% of ideal body weight (body mass index 23.8 ± 0.7 kg/m2) and had normal fasting glucose (5.0 ± 0.1 mM) and insulin levels (24.1 ± 3.3 pmol/l). None of the participants had a personal or family history of diabetes. Subjects had no other medical illnesses and were not receiving any medications. All subjects were placed on a weight maintenance diet consisting ofExperimental Protocol
Each subject was studied on two occasions separated by intervals ofAdministration of Oscillatory Glucose Infusion
It has been previously demonstrated that the peripheral administration of glucose in an oscillatory pattern results in regular oscillations in plasma glucose (25). In normal subjects, theAssays
Plasma glucose levels were measured by the glucose oxidase technique (YSI, Schlag, Bergisch-Gladbach, Germany). The coefficient of variation of this method is <2%. Plasma insulin was measured by the Abbott IMx Microparticle Enzyme Immunoassay, which shows cross-reactivity with proinsulin of <0.005%. The average intra-assay coefficient of variation was 5%. Plasma C-peptide was measured using a commercially available radioimmunoassay kit (Biermann, Bad Nauheim, Germany) with an average intra-assay coefficient of variation of 4%.Data Analysis: Determination of ISRs
Standard kinetic parameters for C-peptide clearance adjusted for age, sex, and body surface area were utilized (28). These parameters were used to derive, in each 15-min interval between blood sampling, the ISR from the plasma C-peptide concentrations by deconvolution, as previously described (6, 21).Ultradian Oscillations in Insulin Secretion
Spectral analysis. Each individual ISR profile from the oscillatory glucose infusion protocol was submitted to spectral analysis to investigate whether the oscillations were entrainable as previously reported (25). Each spectrum was normalized on the assumption of the total variance of each series being 100% and is expressed as the normalized spectral power (SP). Each series was detrended with the first difference filter before spectral estimates were calculated using a Tukey window of 24 data points, as described by Jenkins and Watts (9).
Pulses of insulin secretion. Pulses of glucose and ISR were identified using Ultra, a computer program for pulse detection (27), with a threshold for pulse significance of twice the intra-assay coefficient of variation of the glucose assay, and of three times the intra-assay coefficient of variation of the C-peptide assay. Previous studies have shown that such a detection limit results in a false-positive rate <1% and thus minimizes the impact of any cumulative error resulting from deconvolution. For each significant pulse, the increment was defined as the difference between the level at the peak and the level at the preceding trough and was expressed in absolute concentration units (i.e., absolute increment). The relative amplitude of the pulses was calculated by dividing the absolute amplitude of each individual pulse by the value at the preceeding trough. Pulse amplitudes were based on medians rather than means because of the non-Gaussian nature of pulse distribution.
Statistical Analyses
All results are expressed as means ± SE. Data analysis was performed using the Statistical Analysis System (SAS version 6 Edition for Personal Computers, SAS Institute, Cary, NC). The significance of differences within individuals was determined using paired t-tests. Differences were considered to be significant if P < 0.05. ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Volume of Dextrose Infused
Mean volume of 20% dextrose infused during the low-dose infusion was 1,652.3 ± 61.5 ml compared with 3,306.3 ± 123.0 ml during the high-dose infusion (P < 0.0001).Mean 10-h Levels of Plasma Glucose, Insulin, and ISR
Mean glucose, ISR, and insulin levels were significantly higher during the high-dose compared with the low-dose glucose infusion study. Mean and individual values are shown in Table 1.
|
Number and Amplitude of Oscillations
The number of glucose pulses was similar during low- vs. high-dose glucose infusion [5.0 ± 0.7 vs. 5.2 ± 0.5 (P = 0.1)], as was the number of pulses of ISR [4.3 ± 0.4 vs. 4.2 ± 0.2 (P = 0.5)]. The mean absolute amplitude of the glucose pulses did not differ, being 2.44 ± 0.3 during the low-dose glucose infusion and 2.35 ± 0.3 during the high-dose infusion (P = 0.4). The median absolute amplitude of the pulses of ISR was also not significantly different during low- and high-dose glucose infusion [192.4 ± 24.7 vs. 252.8 ± 48.7 (P = 0.3)]. The mean relative amplitude of the glucose pulses was significantly lower during the high-dose infusion, 0.29 ± 0.02, compared with 0.47 ± 0.06 during the low-dose infusion (P < 0.01).Relationship Between Glucose and ISR During Low- and High-Dose Glucose Infusion
In normal subjects during a low-dose glucose infusion, each pulse of glucose is tightly coupled to a pulse of ISR (25). This is clearly seen from the data from three representative subjects shown in Fig. 1, A, C, and E. During high-dose glucose infusion, there is a reduction in the tight coupling between glucose and ISR (Fig. 1, B, D, and F). To determine whether insulin secretion is entrained by glucose in individual subjects, the temporal profiles of glucose, insulin secretion, and insulin were analyzed by spectral analysis. This method evaluates the regularity of insulin secretory oscillations at a predetermined frequency. Peaks in plasma glucose spectra occurred at 144 min, corresponding to the period of exogenous glucose infusion. There was a reduction in mean SP for glucose during high-dose glucose infusion from 11.8 ± 1.4 to 7.0 ± 1.6 (P < 0.02). This was associated with a reduction in mean SP for ISR from 7.6 ± 1.5 to 3.2 ± 0.5 (P < 0.04) and for insulin from 10.5 ± 1.6 to 4.6 ± 0.7 (P < 0.01) during high-dose glucose infusion. Individual normalized SP values are shown in Fig. 2. The drop in SP for glucose from the low- to high-dose glucose infusion study did not correlate with the drop in SP for ISR (P < 0.8) or insulin (P < 0.7).
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Under both basal and stimulated conditions, normal insulin secretion is oscillatory, with periods in the 80- to 150-min range (20). These ultradian oscillations are of importance in the maintenance of normal glucose homeostasis (24). Many of these pulses in insulin and C-peptide are synchronous with pulses of a similar period in glucose, raising the possibility that these oscillations are a product of the insulin-glucose feedback mechanism. In this study, ultradian oscillations in insulin secretion were evaluated during short-term low-dose and high-dose oscillatory glucose infusions with an oscillatory period of 144 min. The study was designed to determine, under short-term experimental conditions, whether the periodicity of the ultradian oscillations could be entrained to the frequency of the exogenous glucose stimulus. If a nonlinear, self-oscillating system is perturbed exogenously with a periodic stimulus, different types of oscillatory behaviors may emerge, one of which is entrainment. When entrainment occurs, the oscillation of the system reacts to the exogenous stimulus by adjusting its period to that stimulus. In fact, consistent with previous studies (25), when low-dose glucose is administered in an oscillatory pattern in this study, entrainment of the glucose and ISR profiles occurs. In contrast, in this study, short-term oscillatory high-dose glucose infusion resulted in entrainment of neither glucose nor ISR.
The lack of entrainment of glucose during acute high-dose glucose
infusion (yielding plasma glucose concentrations of 9.5 mM, similar to
those previously seen in IGT subjects) in nonobese, insulin-sensitive
subjects may be due to a combination of defective insulin secretion and
altered peripheral glucose utilization in the presence of acute
hyperglycemia (30, 34). If peripheral glucose uptake is
not entrained during acute hyperglycemia, this will feed back to the
-cell. The abnormal insulin secretory pattern to higher glucose
levels will also affect peripheral glucose utilization to a larger
degree in insulin-sensitive subjects (22) compared with
insulin-resistant subjects. In our previous studies, subjects with
classic NIDDM and IGT demonstrated a lack of entrainment of ISR;
however, entrainment of glucose profiles was seen in these two groups
(3, 18). However, in insulin-sensitive subjects with
glucokinase mutations, there was also a lack of entrainment of glucose
in addition to ISR, with mean plasma glucose concentrations of 13.1 mM
(2).
In this study, the absolute amplitude of the glucose oscillations did not differ between the two studies, as this was controlled by the exogenous glucose infusion. However, the relative amplitude of the glucose oscillations was significantly lower during the high-dose glucose infusion. This could potentially influence our results. This reduction in spectral power for glucose seen during the high-dose glucose infusion may also play a role in the reduction in the observed regularity of insulin secretion. However, it is not the whole explanation, because the drop in spectral power for glucose during the high-dose glucose infusion study did not correlate with the drop in spectral power for ISR.
The role of glucotoxicity in humans remains controversial. Flax et al.
(8) demonstrated in subjects with normal glucose tolerance
that, in response to 2 days of basal hyperglycemia (6.0 mM), both basal
and stimulated -cell responses to glucose were enhanced. We have
shown that a 42-h period of hyperglycemia, 6.9 mM in normal
glucose-tolerant subjects and 7.5 mM in IGT subjects, primes the
insulin-secretory response to a subsequent glucose stimulus
(3), whereas this priming effect was lost in subjects with
NIDDM (12.7 mM). Several in vitro and in vivo studies have previously
demonstrated that insulin-secretory responses are increased by exposure
to glucose (15, 29, 31). Even in subjects with glucokinase
mutations with severely reduced ISRs, a 42-h period of hyperglycemia
(9.7 mM) resulted in a subsequent 45% increase in ISR at each 1 mM
glucose interval (2). Despite preservation of the priming
effect of glucose, the entrainment of glucose was lost during an
exogenous oscillatory glucose infusion, suggesting that different
mechanisms are involved in controlling these two processes.
Exposure to high doses of glucose for prolonged periods, however, may
actually induce defects in insulin secretion (12, 13) and
insulin action. There is considerable evidence that prolonged exposure
of the -cell to high glucose may induce defects in insulin secretion
in patients with classical NIDDM that are improved by interventions
that lower the plasma glucose concentrations (11). An
important study in adults with variable fasting glucose levels
indicated that glucose-induced insulin secretion is abolished once a
level of 115 mg/dl is achieved, and some impairment may occur at lower
levels such as 100 mg/dl (1). Studies in various rodent
models have also shown that deranged insulin secretion can be found
with elevations of glucose levels that are difficult to distinguish
from normal (12).
-Cells exposed to hyperglycemia have
been shown to have differential expression of many transporters and
enzymes including GLUT2, glucokinase, mitochondrial glycerol phosphate
dehydrogenase, pyruvate carboxylase, lactate dehydrogenase, hexokinase,
glucose-6-phosphatase, and transcription factors (pancreatic duodenal
homeobox protein-1, hepatocyte nuclear factors, Nkx6.1, Pax6)
(10, 14, 26, 35).
In conclusion, this study demonstrates that an acute high-dose oscillatory glucose infusion yielding short-term hyperglycemia (9.5 mM) in healthy volunteers results in reduced entrainment of glucose and ISR. This finding suggests that hyperglycemia may be partially responsible for the reduction in entrainment in ISR in IGT subjects.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Sabine Jennemann and Elke Birkenstock for excellent technical support.
![]() |
FOOTNOTES |
---|
This study was supported by the Deutsche Forschungsgemeinschaft, Grant Ar 149/1-2.
Address for reprint requests and other correspondence: M. M. Byrne, Institute of Reproductive Medicine, Univ. of Münster, Domagkstrasse 11, 48129 Munster, Germany (E-mail: byrne{at}uni-muenster.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00427.2001
Received 24 September 2001; accepted in final form 4 December 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Brunzell, JD,
Robertson RP,
Lerner RL,
Hazzard WR,
Ensinck JW,
Bierman EL,
and
Porte D, Jr.
Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests.
J Clin Endocrinol Metab
42:
222-229,
1976[Abstract].
2.
Byrne, MM,
Sturis J,
Clement K,
Vionnet N,
Pueyo ME,
Stoffel M,
Takeda J,
Passa P,
Cohen D,
Bell GI,
Velho G,
Froguel P,
and
Polonsky KS.
Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.
J Clin Invest
93:
1120-1130,
1994[ISI][Medline].
3.
Byrne, MM,
Sturis J,
Sobel RJ,
and
Polonsky KS.
Elevated plasma glucose 2 h postchallenge predicts defects in -cell function.
Am J Physiol Endocrinol Metab
270:
E572-E579,
1996
4.
Chen, C,
Hosokawa H,
Bumbalo LM,
and
Leahy JL.
Regulatory effects of glucose on the catalytic activity and cellular content of glucokinase in the pancreatic beta-cell. Study using cultured rat islets.
J Clin Invest
94:
1616-1620,
1994[ISI][Medline].
5.
Chen, L,
Alam T,
Johnson JH,
Hughes S,
Newgard CB,
and
Unger RH.
Regulation of -cell glucose transporter gene expression.
Proc Natl Acad Sci USA
87:
4088-4092,
1990[Abstract].
6.
Eaton, RP,
Allen RC,
Schade DS,
Erickson KM,
and
Standefer J.
Prehepatic insulin production in man: peripheral analysis using connecting peptide behavior.
J Clin Endocrinol Metab
51:
520-528,
1980[Abstract].
7.
Eriksson, J,
Franssila-Kallunki A,
Ekstrand A,
Saloranta C,
Widén E,
Schalin C,
and
Groop L.
Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus.
N Engl J Med
321:
337-343,
1989[Abstract].
8.
Flax, H,
Matthews DR,
Levy JC,
Coppack SW,
and
Turner RC.
No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man.
Diabetologia
34:
570-575,
1991[ISI][Medline].
9.
Jenkins, GM,
and
Watts DG.
Spectral Aanalysis and Its Applications. San Francisco: Holden Day, 1968.
10.
Jonas, J-C,
Sharma A,
Hasenkamp W,
Ilkova H,
Patane G,
Laybutt R,
Bonner-Weir S,
and
Weir GC.
Chronic hyperglycemia triggers loss of pancreatic -cell differentiation in an animal model of diabetes.
J Biol Chem
274:
14112-14121,
1999
11.
Kosaka, K,
Kuzuya T,
Akanuma Y,
and
Hagura R.
Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment.
Diabetologia
18:
23-28,
1980[ISI][Medline].
12.
Leahy, JL,
Bonner-Weir S,
and
Weir GC.
-Cell dysfunction induced by chronic hyperglycemia: current ideas on mechanism of impaired glucose-induced insulin secretion.
Diabetes Care
15:
442-455,
1992[Abstract].
13.
Leahy, JL,
Cooper HE,
Deal DA,
and
Weir GC.
Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion.
J Clin Invest
77:
908-915,
1986[ISI][Medline].
14.
Leibowitz, G,
Yuli M,
Donath MY,
Nesher R,
Melloul D,
Cerasi E,
Gross DJ,
and
Kaiser N.
Beta-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes.
Diabetes
50:
S113-S117,
2001
15.
Liang, Y,
Najafi H,
Smith RM,
Zimmerman EC,
Magnuson MA,
Tal M,
and
Matschinsky FM.
Concordant glucose induction of glucokinase, glucose usage, and glucose-stimulated insulin release in pancreatic islets maintained in organ culture.
Diabetes
41:
792-806,
1992[Abstract].
16.
MacDonald, MJ,
Efendic S,
and
Östenson CG.
Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat.
Diabetes
45:
886-890,
1996[Abstract].
17.
MacDonald, MJ,
Tang J,
and
Polonsky KS.
Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats.
Diabetes
45:
1626-1630,
1996[Abstract].
18.
O'Meara, NM,
Sturis J,
Van Cauter E,
and
Polonsky KS.
Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus.
J Clin Invest
92:
262-271,
1993[ISI][Medline].
19.
O'Rahilly, S,
Turner RC,
and
Matthews DR.
Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes.
N Engl J Med
318:
1225-1230,
1988[Abstract].
20.
Polonsky, KS,
Given BD,
and
Van Cauter E.
Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.
J Clin Invest
81:
442-448,
1988[ISI][Medline].
21.
Polonsky, KS,
Licinio-Paixao J,
Given BD,
Pugh W,
Rue P,
Galloway J,
Karrison T,
and
Frank B.
Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.
J Clin Invest
77:
98-105,
1986[ISI][Medline].
22.
Prager, R,
Wallace P,
and
Olefsky JM.
In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects.
J Clin Invest
78:
472-481,
1986[ISI][Medline].
23.
Rossetti, L,
Giaccari A,
and
DeFronzo RA.
Glucose toxicity.
Diabetes Care
13:
610-629,
1990[Abstract].
24.
Sturis, J,
Scheen AJ,
Leproult R,
Polonsky KS,
and
Van Cauter E.
24-Hour glucose profiles during continuous or oscillatory insulin infusion. Demonstration of the functional significance of ultradian insulin oscillations.
J Clin Invest
95:
1464-1471,
1995[ISI][Medline].
25.
Sturis, J,
Van Cauter E,
Blackman JD,
and
Polonsky KS.
Entrainment of pulsatile insulin secretion by oscillatory glucose infusion.
J Clin Invest
87:
439-445,
1991[ISI][Medline].
26.
Tokuyama, Y,
Sturis J,
Depaoli AM,
Takeda J,
Stoffel M,
Tang J,
Sun X,
Polonsky KS,
and
Bell GI.
Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat.
Diabetes
44:
1447-1457,
1995[Abstract].
27.
Van Cauter, E.
Estimating false-positive and false-negative errors in analyses of hormone pulsatility.
Am J Physiol Endocrinol Metab
254:
E786-E794,
1988
28.
Van Cauter, E,
Mestrez F,
Sturis J,
and
Polonsky KS.
Estimation of insulin secretion rates from C-peptide levels: comparison of individual and standard kinetic parameters for C-peptide clearance.
Diabetes
41:
368-377,
1992[Abstract].
29.
Van Haeften, TW,
Voetberg GA,
Gerich JE,
and
van der Veen EA.
Dose-response characteristics for arginine-stimulated insulin secretion in man and influence of hyperglycemia.
J Clin Endocrinol Metab
69:
1059-1064,
1989[Abstract].
30.
Vuorinen-Markkola, H,
Koivisto VA,
and
Yki-Järvinen H.
Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type 1 diabetic patients.
Diabetes
41:
571-580,
1992[Abstract].
31.
Ward, WK,
Halter JB,
Beard JC,
and
Porte D.
Adaptation of B and A cell function during prolonged glucose infusion in human subjects.
Am J Physiol Endocrinol Metab
246:
E405-E411,
1984
32.
Weyer, C,
Bogardus C,
Mott DM,
and
Pratley RE.
The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.
J Clin Invest
104:
787-794,
1999
33.
World Health Organization.
Diabetes Mellitus: Report of a WHO Study Group. Geneva: WHO, 1985, vol. 727, p. 9-17. (WHO Tech Rep Ser).
34.
Yki-Järvinen, H,
Helve E,
and
Koivisto VA.
Hyperglycemia decreases glucose uptake in type 1 diabetes.
Diabetes
36:
892-896,
1987[Abstract].
35.
Zangen, DH,
Bonner-Weir S,
Lee CH,
Latimer JB,
Miller CP,
Habener JF,
and
Weir GC.
Reduced insulin, GLUT2, and IDX-1 in -cells after partial pancreatectomy.
Diabetes
46:
258-264,
1997[Abstract].