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1.
Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations
before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with
normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic
clamp (99 ± 12 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high
insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased
in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed.
Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at
more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity,
dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity
is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943]
Received: 26 January 1999 and in revised form: 1 March 1999 相似文献
2.
Winzell MS Brand CL Wierup N Sidelmann UG Sundler F Nishimura E Ahrén B 《Diabetologia》2007,50(7):1453-1462
Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia
in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here,
we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice
on a high-fat diet (HFD).
Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days. Insulin
secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine.
Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets.
Results Fasting plasma glucose levels were reduced by GRA (6.0 ± 0.2 vs 7.4 ± 0.5 mmol/l; p = 0.017). The acute insulin response to intravenous glucose was augmented (1,300 ± 110 vs 790 ± 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 ± 160 vs 3,040 ± 420 pmol/l;
p = 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response
(129 ± 12 vs 36 ± 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass
was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after
GRA treatment (0.061 ± 0.007 vs 0.030 ± 0.004 pmol islet−1 h−1 at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation.
Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion,
suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes. 相似文献
3.
Ahrén B 《Diabetologia》2006,49(1):117-122
Aims/hypothesis The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions.
Materials and methods A total of 155 healthy women with NGT (aged 53–70 years) underwent a glucose-dependent arginine-stimulation test for evaluation
of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after
raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during
the three glucose levels (AGR1, AGR2, AGR3) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic–hyperinsulinaemic
clamp study for estimation of insulin sensitivity.
Results Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg−1 min−1/pmol insulin l−1. When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with
increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity
and AGR2 was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes
in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion.
Conclusions/interpretation The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of
glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes
during the development of insulin resistance. 相似文献
4.
Aims/hypothesis The aim of this study was to investigate whether intrahepatic and intramyocellular fat are related to insulin resistance in
these respective tissues or to the metabolic syndrome.
Methods Hepatic (insulin 1.8 pmol kg−1 min−1 combined with [3-3H]glucose) and muscle (insulin 6.0 pmol kg−1 min−1) insulin sensitivity were measured on separate occasions in 45 non-diabetic men (age 42 ± 1 years, BMI 26.2 ± 0.6 kg/m2) using the euglycaemic–hyperinsulinaemic clamp. Liver fat and intramyocellular lipid (IMCL) were measured by proton magnetic
resonance spectroscopy and body composition by magnetic resonance imaging. We also determined fasting serum insulin and adiponectin
concentrations, components of the metabolic syndrome and maximal oxygen consumption.
Results In participants with high [median 12.0% (interquartile range 5.7–18.5%)] vs low [2.0% (1.0–2.0%)] liver fat, fasting serum
triacylglycerols (1.6 ± 0.2 vs 1.0 ± 0.1 mmol/l, p = 0.002) and fasting serum insulin (55 ± 4 vs 32 ± 2 pmol/l, p < 0.0001) were increased and serum HDL-cholesterol (1.26 ± 0.1 vs 1.48 ± 0.1 mmol/l, p = 0.02) and fasting serum adiponectin (9.5 ± 1.2 vs 12.2 ± 1.2 μg/ml, p = 0.05) decreased. In participants with high [19.5% (16.0–26.0%)] vs low [5.0% (2.3–7.5%)] IMCL, these parameters were comparable.
Liver fat was higher in participants with [10.5% (3.0–18.0%)] than in those without [2.0% (1.5–6.0%), p = 0.010] the metabolic syndrome, even independently of obesity, while IMCL was comparable. Insulin suppression of glucose
rate of appearance and serum NEFA was significantly impaired in the high liver fat group.
Conclusions/interpretation Fat accumulation in the liver rather than in skeletal muscle is associated with features of the metabolic syndrome, i.e. increased
fasting serum triacylglycerols and decreased fasting serum HDL-cholesterol, as well as with hyperinsulinaemia and low adiponectin. 相似文献
5.
Aims/hypothesis The aim of this prospective trial was to compare the effect of different long-acting insulin preparations injected at bedtime
on glucose concentrations in patients with type 2 diabetes omitting breakfast and lunch the next day.
Methods Twenty patients (ten women) with type 2 diabetes who were on an intensified insulin therapy participated. Mean (±SD) age was
63 ± 10 years, diabetes duration 18 ± 9 years, BMI 32.5 ± 5 kg/m2, and HbA1c 7.3 ± 0.7%. Patients received neutral protamine Hagedorn (NPH) insulin, insulin detemir or insulin glargine for at least
2 months; doses were adjusted to achieve morning blood glucose levels of <7 mmol/l. At the end of the respective treatment
period, the long-acting insulin was injected at bedtime (at 22:45 hours) as usual but patients refrained from breakfast and
lunch the next day; glucose was measured by a continuous glucose monitoring system (CGMS).
Results
Comparable glucose target ranges were reached at midnight (5.8 to 6.1 mmol/l) and at 07:00 hours (6.7 to 6.9 mmol/l) with
all three insulin preparations, using mean doses of 29 ± 10 U (NPH insulin), 33 ± 13 U (insulin detemir), and 32 ± 12 U (insulin
glargine). Glucose levels between midnight and 07:00 hours were not significantly different for the three insulin preparations.
Symptomatic hypoglycaemia did not occur from 08:00 to 16:00 hours; glucose concentrations during this time were slightly lower
with NPH insulin than with insulin detemir (p = 0.012) and insulin glargine (p = 0.049).
Conclusions/interpretation Following bedtime injection of NPH insulin or of the analogues insulin detemir or insulin glargine, fasting glucose <7 mmol/l
was achieved in the morning, without subsequent hypoglycaemia when participants continued to fast during the day. 相似文献
6.
Højberg PV Zander M Vilsbøll T Knop FK Krarup T Vølund A Holst JJ Madsbad S 《Diabetologia》2008,51(4):632-640
Aims/hypothesis The ability of glucagon-like peptide-1 (GLP-1) to enhance beta cell responsiveness to i.v. glucose is impaired in patients
with type 2 diabetes mellitus compared with healthy individuals. We investigated whether 4 weeks of near normalisation of
blood glucose (BG) improves the potentiation of glucose-stimulated insulin secretion by GLP-1.
Methods Nine obese patients with type 2 diabetes and inadequate glycaemic control (HbA1c 8.0 ± 0.4%) were investigated before and after 4 weeks of near normalisation of BG using insulin treatment (mean diurnal
blood glucose 6.4 ± 0.3 mmol/l, HbA1c 6.6 ± 0.3%). Nine matched healthy participants were also studied. Beta cell function was investigated before and after insulin
treatment using stepwise glucose infusions and infusion of saline or GLP-1 (1.0 pmol kg−1 min−1), resulting in supraphysiological total GLP-1 concentrations of approximately 200 pmol/l. The responsiveness to glucose or
glucose+GLP-1 was expressed as the slope of the linear regression line relating insulin secretion rate (ISR) and plasma glucose
concentration (pmol kg−1 min−1 [mmol/l]−1).
Results In the diabetic participants, the slopes during glucose+saline infusion did not differ before and after insulin treatment
(0.33 ± 0.07 and 0.39 ± 0.04, respectively; p = NS). In contrast, near normalisation of blood glucose improved beta cell sensitivity to glucose during glucose+GLP-1 infusion
(1.27 ± 0.2 before vs 1.73 ± 0.31 after; p < 0.01). In the healthy participants, the slopes during the glucose+saline and glucose+GLP-1 infusions were 1.01 ± 0.14 and
4.79 ± 0.53, respectively.
Conclusions/interpretation A supraphysiological dose of GLP-1 enhances beta cell responses to glucose in patients with type 2 diabetes, and 4 weeks of
near normalisation of blood glucose further improves this effect.
ClinicalTrials.gov ID no.: NCT00612625 相似文献
7.
Aims/hypothesis Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise
that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing
to insulin resistance.
Materials and methods The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1
(50 pmol min−1 kg−1 for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min−1 kg−1 for 2 h). Insulin clamps (10 or 15 mU min−1 kg−1) were performed after 30 min of saline infusion.
Results Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p < 0.05) and blood pressure by 20% (p < 0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1
with 10 mU min−1 kg−1 insulin caused a decrease in insulin clearance from 0.35 ± 0.6 to 0.19 ± 0.02 ml/min (p = 0.02), resulting in significantly higher plasma insulin levels (10 mU min−1 kg−1 insulin: 2,120 ± 190 pmol/l; endothelin-1 + 10 mU min−1 kg−1 insulin: 4,740 ± 910 pmol/l), equivalent to 15 mU min−1 kg−1 insulin alone (4,920 ± 190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary
recruitment and glucose uptake were blocked by endothelin-1.
Conclusions/interpretation Endothelin-1 blocks insulin’s haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle
glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin
resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery. 相似文献
8.
P. V. Højberg T. Vilsbøll R. Rabøl F. K. Knop M. Bache T. Krarup J. J. Holst S. Madsbad 《Diabetologia》2009,52(2):199-207
Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness
to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was
to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and
GLP-1 in patients with type 2 diabetes.
Methods Eight obese patients with type 2 diabetes with poor glycaemic control (HbA1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l)
using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l)
with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide
curve.
Results Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin
secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2
(nmol/l) × (110 min)−1 (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)−1 (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood
glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]−1).
Conclusions Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three
to four. No effect was found on beta cell responsiveness to glucose alone.
ClinicalTrials.gov ID no.: NCT 00612950
Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen. 相似文献
9.
Seghieri G Tesi F Anichini R De Bellis A Barsotti E Mari A Ferrannini E 《Diabetologia》2007,50(11):2234-2238
Aims/hypothesis Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function
and insulin action in women who maintain normal glucose tolerance (NGT) for a long time.
Methods Ninety-one women with NGT (aged 41 ± 8 years, mean±SD) were studied (by mathematical modelling of the C-peptide response to
an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT
(pNGT). In all women an OGTT had also been performed at 29 ± 3 weeks of the index pregnancy.
Results Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy,
parity, BMI (25.4 ± 3.9 vs 26.8 ± 6.4 kg/m2), and fasting (4.64 ± 0.56 vs 4.97 ± 0.46 mmol/l) and 2 h plasma glucose levels (5.91 ± 1.14 vs 5.91 ± 1.21 mmol/l). Nonetheless,
fasting (49 [29] vs 70 [45] pmol min−1 m−2, p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m−2, p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration–response function)
(95 [71] vs 115 [79] pmol min−1 m−2 (mmol/l)−1, p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs
398 [77] ml min−1 m−2). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359
[93] vs 417 [92] ml min−1 m−2, p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122]
pmol/mmol, p = 0.028) were reduced in women with pGDM.
Conclusions Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several
years after a GDM pregnancy. 相似文献
10.
Differential mechanisms of glucose and palmitate in augmentation of insulin secretion in mouse pancreatic islets 总被引:2,自引:1,他引:2
Aims/hypothesis. To assess the possible importance of saturated fatty acids in glucose amplification of K+
ATP channel-independent insulin secretion. Methods. Insulin release from perifused pancreatic islets of NMRI mice was determined by radioimmunoassay. Results. In the presence of K+ (20 mmol/l) and diazoxide (250 μmol/l), which stimulates Ca2+ influx and opens K+
ATP channels, palmitate (165 μmol/l total; 1.2 μmol/l free) increased insulin secretion at 3.3, 10 and 16.7 mmol/l glucose while
glucose (10; 16.7 mmol/l) did not increase insulin secretion. In the presence of K+ (60 mmol/l) and diazoxide (250 μmol/l), glucose (10; 16.7 mmol/l) stimulation of K+
ATP channel-independent insulin secretion increased, whereas the effectiveness of palmitate (165 μmol/l total; 1.2 μmol/l free)
on insulin secretion at both 3.3, 10 or 16.7 mmol/l glucose was reduced. Palmitate thereby mimicked the stimulatory pattern
of the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (0.16 μmol/l), which also failed to increase insulin
secretion at maximum depolarising concentrations of K+ (60 mmol/l). Furthermore, the protein kinase C inhibitor calphostin C (1 μmol/l), led to a complete suppression of the effects
of both palmitate (165 μmol/l total; 1.2 μmol/l free) and myristate (165 μmol/l total; 2.4 μmol/l free) stimulation of glucose
(16.7 mmol/l)-induced insulin secretion. Calphostin C (1 μmol/l), however, failed to affect insulin secretion induced by glucose
(16.7 mmol/l). Conclusion/interpretation. These data suggest that glucose could increase insulin secretion independently of saturated fatty acids like palmitate and
myristate, which amplify glucose-induced insulin secretion by activation of protein kinase C. [Diabetologia (2001) 44: 738–746]
Received: 30 October 2001 and in revised form: 31 January 2001 相似文献
11.
Summary To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics
were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (KG) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic
(16.7 mmol/l) hyperinsulinaemic (60 pmol · min−1· kg−1) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simultaneous sampling of arterial blood and hindlimb lymph. Alloxan induced fasting hyperglycaemia
(12.9 ± 2.3 vs 5.7 ± 0.2 mmol/l; p = 0.018 vs pre-treatment) and variable insulinopenia (62 ± 14 vs 107 ± 19 pmol/l; p = 0.079). The acute insulin response, however, was suppressed by alloxan (integrated insulin from 0–10 min: 155 ± 113 vs
2745 ± 541 pmol · l−1· 10 min−1; p = 0.0027), resulting in pronounced glucose intolerance (KG: 0.99 ± 0.19 vs 3.14 ± 0.38 min−1; p = 0.0002 vs dogs treated with saline). During clamps, steady state arterial insulin was higher in dogs treated with alloxan
(688 ± 60 vs 502 ± 38 pmol/l; p = 0.023) due to a 25 % reduction in insulin clearance (p = 0.045). Lymph insulin concentrations were also raised (361 ± 15 vs 266 ± 27 pmol/l; p = 0.023), such that the lymph to arterial ratio was unchanged by alloxan (0.539 ± 0.022 vs 0.533 ± 0.033; p = 0.87). Despite higher lymph insulin, glucose uptake (Rd) was significantly diminished after injection of alloxan (45.4 ± 2.5 vs 64.3 ± 6.5 μmol · min−1· kg−1; p = 0.042). This was reflected in resistance of target tissues to the lymph insulin signal (ΔRd/Δlymph insulin: 3.389 ± 1.093 vs 11.635 ± 2.057 · 10−6· l · min−1· kg–1· pmol−1· l−1; p = 0.012) which correlated strongly with the KG (r = 0.86; p = 0.0001). In conclusion, alloxan induces insulinopenic diabetes, with glucose intolerance and insulin resistance at the
target tissue level. Alloxan treatment, however, does not alter lymph insulin kinetics, indicating that insulin resistance
of Type 1 (insulin-dependent) diabetes mellitus reflects direct impairment at the cellular level. [Diabetologia (1998) 41:
1327–1336]
Received: 3 November 1997 and in final revised form: 2 June 1998 相似文献
12.
Summary In order to evaluate the role of portal insulin in the modulation of hepatic glucose production (HGP), measurements of plasma
glucose and insulin concentrations and both HGP and peripheral glucose disappearance rates were made following an infusion
of a dose of tolbutamide (0.74 mg · m−2· min−1) in healthy volunteers that does not result in an increase in peripheral vein insulin concentrations or metabolic clearance
rate of glucose. The results showed that the infusion of such a dose of tolbutamide was associated with a significant and
rapid decline in both HGP (from 9.0 ± 0.5 to 7.7 ± 0.5 μmol · kg−1· min−1 or Δ = − 13.8 ± 4.5 %; p < 0.001 compared to saline) and plasma glucose concentration (from 5.1 ± 0.2 to 4.4 ± 0.1 mmol/l or Δ = − 13.0 ± 2.1 %; p < 0.01 compared to saline). Since neither HGP nor fasting glucose fell when tolbutamide-stimulated insulin secretion was
inhibited by the concurrent administration of somatostatin, it indicated that tolbutamide by itself, does not directly inhibit
HGP. Finally, HGP fell by 26.3 ± 6.0 % at 10 min after a dose of tolbutamide that elevated both peripheral and portal insulin
concentrations, at a time when HGP had barely increased (Δ = + 6.9 ± 5.3 %). The difference in the magnitude of the two responses
was statistically significant (p < 0.03), providing further support for the view that insulin can directly inhibit HGP, independent of any change in flow
of substrates from periphery to liver. [Diabetologia (1997) 40: 1300–1306]
Received: 8 April 1997 and in revised form: 20 June 1997 相似文献
13.
Glucose-dependent arginine stimulation test for characterization of islet function: studies on reproducibility and priming effect of arginine 总被引:11,自引:3,他引:11
Summary Quantitative determination of insulin secretion is of importance both clinically and in research. The optimal method has
not been established, although several different methods have been used. We determined the reproducibility of islet function
parameters obtained by the glucose-dependent arginine stimulation test, and also studied the priming effect of arginine on
subsequent acute insulin responses. The test measures the acute insulin (AIR) and glucagon (AGR) responses to i. v. arginine
(5 g injected over 45 s) at fasting glucose and glucose concentrations clamped at 14 and above 25 mmol/l, as well as the glucose
potentiation of insulin secretion (slopeAIR) and the glucose inhibition of glucagon secretion (slopeAGR). When the test was performed twice in seven healthy women (mean ± SD age 58.7 ± 0.5 years, BMI 27.6 ± 5.5 kg/m2), the AIRs to arginine had a within-subject coefficient of variation (CV) of 18.6 % at fasting glucose, 18.7 % at 14 mmol/l
glucose and 16.3 % at above 25 mmol/l glucose. The CVs for AGR were 11.6, 14.9 and 8.9 %, respectively. The CV of the slopeAIR was 24 % and of the slopeAGR 17.2 %. The arginine priming study was performed in six healthy women (age 63.7 ± 0.3 years, BMI 28.0 ± 6.9 kg/m2). Saline or arginine (5 g) was injected at fasting glucose, followed by arginine (5 g) at 14 mmol/l glucose. There was no difference between the acute insulin or glucagon responses to arginine at 14 mmol/l glucose
in the two conditions, suggesting that there is no priming effect of arginine on the subsequent acute insulin or glucagon
responses. Therefore, this method is a good tool to determine insulin secretion as, apart from its good reproducibility, it
also provides several important parameters of islet function. [Diabetologia (1998) 41: 772–777]
Received: 4 December 1997 and in final revised form: 13 February 1998 相似文献
14.
Aims/hypothesis The association between increased (visceral) fat mass, insulin resistance and type 2 diabetes mellitus is well known. Yet,
it is unclear whether the mere increase in intra-abdominal fat mass, or rather functional alterations in fat tissue in obesity
contribute to the development of insulin resistance in obese patients. Here we attempted to isolate the metabolic effect of
increased fat mass by fat tissue transplantation.
Methods Epididymal fat pads were removed from male C57Bl6/J mice and transplanted intraperitoneally into male littermates (recipients),
increasing the combined perigonadal fat mass by 50% (p < 0.005). At 4 and 8 weeks post-transplantation, glucose and insulin tolerance tests were performed, and insulin, NEFA and
adipokines measured.
Results Circulating levels of NEFA, adiponectin and leptin were not significantly different between transplanted and sham-operated
control mice, while results of the postprandial insulin tolerance test were similar between the two groups. In contrast, under
fasting conditions, the mere increase in intra-abdominal fat mass resulted in decreased plasma glucose levels (6.9 ± 0.4 vs
8.1 ± 0.3 mmol/l, p = 0.03) and a ∼20% lower AUC in the glucose tolerance test (p = 0.02) in transplanted mice. Homeostasis model assessment of insulin resistance (HOMA-IR) was 4.1 ± 0.4 in transplanted
mice (vs 6.2 ± 0.7 in sham-operated controls) (p = 0.02), suggesting improved insulin sensitivity. Linear regression modelling revealed that while total body weight positively
correlated, as expected, with HOMA-IR (β: 0.728, p = 0.006), higher transplanted fat mass correlated with lower HOMA-IR (β: −0.505, p = 0.031).
Conclusions/interpretation Increasing intra-abdominal fat mass by transplantation of fat from normal mice improved, rather than impaired, fasting glucose
tolerance and insulin sensitivity, achieving an effect opposite to the expected metabolic consequence of increased visceral
fat in obesity. 相似文献
15.
Aims/hypothesis In addition to the improvement in insulin sensitivity, it has been shown that thiazolidinediones modulate beta cell function
and insulin clearance in type 2 diabetic subjects. However, interactions between all these actions, and confounding factors
due to co-morbidities and co-treatments in diabetic individuals, complicate the identification of specific effects. The aim
of this pilot study was to investigate the potential acute effects of rosiglitazone on beta cell function and insulin sensitivity
by the hyperglycaemic clamp technique in healthy volunteers.
Subjects and methods Twelve healthy men were included in a randomised, double-blind crossover study. Rosiglitazone (8 mg) or placebo was given
orally 45 min before the hyperglycaemic clamp (10 mmol/l for 2 h).
Results The second phase of the insulin response was significantly decreased by rosiglitazone: 13,066 ± 1,531 vs 16,316 ± 2,813 pmol
l−1 110 min in controls (p < 0.05), without change in the first phase. Serum C-peptide was not modified. Rosiglitazone treatment significantly increased
insulin clearance (molar ratio of the C-peptide to insulin AUCs: 12.80 ± 1.34 vs 11.38 ± .33, p < 0.05) and the insulin sensitivity index (12.0 ± 1.5 vs 8.5 ± 1.1 μmol m−2 min−1 pmol−1l, p < 0.01).
Conclusions/interpretation The present results show that a single dose of rosiglitazone rapidly increases insulin clearance and insulin sensitivity index
in healthy volunteers, with no direct effect on insulin secretion. The precise mechanisms mediating these actions remain to
be determined. ClinicalTrials.gov ID no.: NCT00285142 相似文献
16.
Nauck MA Duran S Kim D Johns D Northrup J Festa A Brodows R Trautmann M 《Diabetologia》2007,50(2):259-267
Aims/hypothesis The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin
mimetic) with that of biphasic insulin aspart.
Materials and methods Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment.
Results Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA1c change: exenatide −1.04 ± 0.07%, biphasic insulin aspart −0.89 ± 0.06%; difference −0.15 [95% CI −0.32 to 0.01]%). Exenatide-treated
patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference −5.4 (95%
CI −5.9 to −5.0) kg]. Both treatments reduced fasting serum glucose (exenatide −1.8 ± 0.2 mmol/l, p < 0.001; biphasic insulin aspart −1.7 ± 0.2 mmol/l, p < 0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic
insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide.
Conclusions/interpretation Exenatide treatment resulted in HbA1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative
for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk
of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction
may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide
have yet to be defined.
Electronic supplementary material A list of the site investigators is available as electronic supplementary material in the online version of this article at
and is accessible to authorised users. 相似文献
17.
A. Mari 《Diabetologia》1998,41(9):1029-1039
Summary A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance
test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose
bolus containing [6,6-2H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of
tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose
clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance
(Clb), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Clb/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration
and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity
(PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found
to be insulin resistant (BSI: 2.3 ± 0.6 vs 0.76 ± 0.18 ml · min–1· m–2· pmol/l–1, p < 0.02; ISI: 0.40 ± 0.06 vs 0.13 ± 0.05 ml · min–1· m–2· pmol/l–1, p < 0.02; Cl600: 333 ± 47 vs 137 ± 26 ml · min–1· m–2, p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 ± 169 vs 606 ± 123 μmol · min–1· m–2, NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 ± 15 vs 12 ± 7 pmol · min–1· m–2· mmol/l–1, p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity
in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using
a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion,
agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.
[Diabetologia (1998) 41: 1029–1039]
Received: 17 September 1997 and in final revised form: 28 April 1998 相似文献
18.
Sulphonylurea therapy doubles B-cell response to glucose in Type 2 diabetic patients 总被引:1,自引:0,他引:1
Summary The effect of sulphonylurea therapy for 3 weeks on glucose-stimulated insulin secretion and insulin resistance was studied in Type 2 diabetic patients. The fasting plasma insulin and C-peptide concentrations on diet alone were compared with each subject's fasting concentrations on sulphonylurea treatment at a lower fasting plasma glucose and at the original diet-alone glycaemic level obtained by the hyperglycaemic clamp technique. At this isoglycaemic level (mean 11 mmol/l), plasma insulin levels increased from 6.9 mU/l on diet alone to 12.1 mU/l on sulphonylurea treatment (p<0.01). The subjects were also studied by the hyperglycaemic clamp technique at mean glycaemic levels of 13 mmol/l before and after sulphonylurea treatment; the incremental insulin response was similarly enhanced from 7.6±3.5 to 13.7±6.9 mU/l (p<0.02) respectively. Sulphonylureas appear to reduce glycaemia by enhancing B-cell function two-fold. In the patients studied this was from approximately 21% to 37% of a normal response. Insulin resistance assessed by the same hyperglycaemic clamps as endogenous plasma insulin concentrations divided by glucose infusion rates was unchanged by sulphonylurea therapy (mean 4.37 compared to 4.40 mU. 1–1·mg–1·kg·min on diet alone). 相似文献
19.
Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients 总被引:5,自引:0,他引:5
Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance
is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of
beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests
with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent
diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1
± 0.9 kg/m2). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0]
vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin
sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04
10–4 min–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ±
0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the
control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before
and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6
± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l–1· min–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4
· min–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent
development of high 2-h post-dex OGTT plasma glucose levels (R
2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in
those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These
subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state.
[Diabetologia (1997) 40: 1439–1448]
Received: 20 January 1997 and in final revised form: 17 July 1997 相似文献
20.
Aims/hypothesis To aim of the study was to investigate the effect of bilio-pancreatic diversion (BPD) on type 2 diabetes in patients with
BMI <35 kg/m2.
Methods OGTTs were performed and anthropometric data were compared between five diabetes patients (BMI 27–33 kg/m2) following BPD and seven diabetes patients after a low-energy diet. Insulin secretion was computed by C-peptide deconvolution.
A euglycaemic–hyperinsulinaemic clamp was performed only in the BPD group and the M value measured.
Results One month after BPD, fasting and 2 h post-OGTT glycaemia decreased from 15.22 ± 3.22 to 6.22 ± 0.51 mmol/l (p = 0.043), while insulin sensitivity increased significantly. No significant changes were observed in the low-energy diet group.
Insulin secretion did not differ significantly after either intervention. Diabetes amelioration (change in HbA1c level) was observed up to 18 months after BPD without pharmacological therapy.
Conclusions/interpretation BPD can achieve adequate control of type 2 diabetes also in patients with BMI <35 kg/m2. The rapid postoperative remission of diabetes is primarily related to an improvement in insulin sensitivity. 相似文献