共查询到20条相似文献,搜索用时 93 毫秒
1.
Summary To test whether gluconeogenesis is increased in non-insulin-dependent diabetic (NIDDM) patients we infused (post-absorptive
state) healthy subjects and NIDDM patients with [6,6-2H2]glucose (150 min) and [3-13C]lactate (6 h). Liver glutamine was sampled with phenylacetate and its labelling pattern determined (mass spectrometry) after
purification of the glutamine moiety of urinary phenylacetylglutamine. After correction for 13CO2 re-incorporation (control test with NaH13CO3 infusion) this pattern was used to calculate the dilution factor (F) in the hepatic oxaloacetate pool and fluxes through
liver Krebs cycle. NIDDM patients had increased lactate turnover rates (16.18 ± 0.92 vs 12.14 ± 0.60 μmol · kg−1· min−1, p < 0.01) and a moderate rise in glucose production (EGP) (15.39 ± 0.87 vs 12.52 ± 0.28 μmol · kg−1· min−1, p = 0.047). Uncorrected contributions of gluconeogenesis to EGP were 31 ± 3 % (control subjects) and 17 ± 2 % (NIDDM patients).
F was comparable (1.34 ± 0.02 and 1.39 ± 0.09, respectively) and the corrected percent and absolute contributions of gluconeogenesis
were not increased in NIDDM (25 ± 3 % and 3.8 ± 0.5 μmol · kg−1· min−1) compared to control subjects (41 ± 3 % and 5.1 ± 0.4 μmol · kg−1· min−1). The calculated pyruvate carboxylase over pyruvate dehydrogenase activity ratio was comparable (12.1 ± 2.6 vs 11.2 ± 1.4).
Lastly hepatic fatty oxidation, as estimated by the model, was not increased in NIDDM (1.8 ± 0.4 vs 1.6 ± 0.1 μmol · kg−1· min−1). In conclusion, in the patients studied we found no evidence of increased hepatic fatty oxidation, or, despite the increased
lactate turnover rate, an increased gluconeogenesis. [Diabetologia (1998) 41: 212–220]
Received: 4 July 1997 and in revised form: 16 September 1997 相似文献
2.
A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM 总被引:3,自引:0,他引:3
R. Harper C. N. Ennis A. P. Heaney B. Sheridan M. Gormley A. B. Atkinson G. D. Johnston P. M. Bell 《Diabetologia》1995,38(7):853-859
Summary In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular
choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse
metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic
insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two
12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences
between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect
on serum potassium, uric acid, fasting glucose and HbA1 c concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly
different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8 ± 2.9 vs
27.3 ± 3.5 μmol · kg− 1· min− 1, p < 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8 ± 3.6 vs 27.3 ± 3.5 μmol · kg− 1· min− 1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg
(11.7 ± 0.5 vs 10.2 ± 0.3 μmol · kg− 1· min− 1, p < 0.05) and suppressed to a lesser extent following insulin (4.0 ± 0.7 vs 2.0 ± 0.4 μmol · kg− 1· min− 1, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline
(11.7 ± 0.5 vs 10.6 ± 0.4 μmol · kg− 1· min− 1, p < 0.05) whereas bendrofluazide 1.25 mg did not (10.2 ± 0.3 vs 10.6 ± 0.4 μmol · kg− 1· min− 1, p = NS). At a dose of 1.25 mg bendrofluazide is as effective as conventional doses but has less adverse metabolic effects.
In contrast to conventional doses which worsen both hepatic and peripheral insulin resistance, low-dose bendrofluazide has
no effect on insulin action in non-insulin-dependent diabetic subjects. [Diabetologia (1995) 38: 853–859]
Received: 6 September 1994 and in revised form: 29 December 1994 相似文献
3.
Koopmans SJ Jong MC Que I Dahlmans VE Pijl H Radder JK Frölich M Havekes LM 《Diabetologia》2001,44(4):437-443
Aims/hypothesis. Insulin resistance for glucose metabolism is associated with hyperlipidaemia and high blood pressure. In this study we investigated
the effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism
and mean arterial pressure in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APOC1). Previous studies have
shown that APOC1 transgenic mice develop hyperlipidaemia primarily because of an impaired hepatic uptake of very low density
lipoprotein (VLDL). Methods. Basal and hyperinsulinaemic (6 mU · kg–1· min–1), euglycaemic (7 mmol/l) clamps with 3-3H-glucose or 9,10-3H-palmitic acid infusions and in situ freeze clamped tissue collection were carried out. Results. The APOC1 mice showed increased basal plasma cholesterol, triglyceride, NEFA and decreased glucose concentrations compared
with wild-type mice (7.0 ± 1.2 vs 1.6 ± 0.1, 9.1 ± 2.3 vs 0.6 ± 0.1, 1.9 ± 0.2 vs 0.9 ± 0.1 and 7.0 ± 1.0 vs 10.0 ± 1.1 mmol/l,
respectively, p < 0.05). Basal whole body glucose clearance was increased twofold in APOC1 mice compared with wild-type mice (18 ± 2 vs 10
± 1 ml · kg–1· min–1, p < 0.05). Insulin-mediated whole body glucose uptake, glycolysis (generation of 3H2O) and glucose storage increased in APOC1 mice compared with wild-type mice (339 ± 28 vs 200 ± 11; 183 ± 39 vs 128 ± 17 and
156 ± 44 vs 72 ± 17 μmol · kg–1· min–1, p < 0.05, respectively), corresponding with a twofold to threefold increase in skeletal muscle glycogenesis and de novo lipogenesis
from 3-3H-glucose in skeletal muscle and adipose tissue (p < 0.05). Basal whole body NEFA clearance was decreased threefold in APOC1 mice compared with wild-type mice (98 ± 21 vs 314
± 88 ml · kg–1· min–1, p < 0.05). Insulin-mediated whole body NEFA uptake, NEFA oxidation (generation of 3H2O) and NEFA storage were lower in APOC1 mice than in wild-type mice (15 ± 3 vs 33 ± 6; 3 ± 2 vs 11 ± 4 and 12 ± 2 vs 22 ±
4 μmol · kg–1· min–1, p < 0.05) in the face of higher plasma NEFA concentrations (1.3 ± 0.3 vs 0.5 ± 0.1 mmol/l, p < 0.05), respectively. Mean arterial pressure and heart rate were similar in APOC1 vs wild-type mice (82 ± 4 vs 85 ± 3 mm
Hg and 459 ± 14 vs 484 ± 11 beats · min–1). Conclusions/interpretation. 1) Hyperlipidaemic APOC1 mice show reduced NEFA and increased glucose metabolism under both basal and insulin-mediated conditions,
suggesting an intrinsic defect in NEFA metabolism. Primary hyperlipidaemia alone in APOC1 mice does not lead to insulin resistance
for glucose metabolism and high blood pressure. [Diabetologia (2001) 44: 437–443]
Received: 14 September 2000 and in revised form: 23 November 2000 相似文献
4.
Summary There are important differences between the short- and long-term effects of adrenaline on determinants of glucose tolerance.
To assess this metabolic adaptation at tissue level, the present study examined the effect of acute and prolonged in vivo
elevation of adrenaline on glycogen metabolism and glycolysis in skeletal muscle. Adrenaline (50 ng · kg−1 · min−1) was infused for 2 h or 74 h and the results compared with 1 h 0.9% NaCl infusion in six trained dogs. Muscle glycogen content
was reduced by long-term adrenaline (161 ± 17 vs NaCl 250 ± 24 μmol/g dry weight;p < 0.05) but not short-term adrenaline (233 ± 21) indicating a sustained effect of adrenaline on glycogen metabolism. Acutely,
glycogen synthase I was reduced (short-term adrenaline 12 ± 6 vs NaC122 ± 7μmol glycosyl units · g−1 · min−1;p < 0.05) but returned to normal with prolonged adrenaline infusion (20 ± 5). In contrast, Km for glycogen phosphorylasea was not changed acutely (short-term adrenaline 31 ± 6 vs NaCl 27 ± 7 mmol/1 inorganic phosphate) but was reduced during long-term
infusion (19 ± 4;p < 0.05 vs short-term adrenaline). Thus, with short- and long-term adrenaline infusion, there were different enzyme changes,
although likely to promote glycogenolysis in both cases. In the glycolytic pathway the substrates glucose 6-phosphate and
fructose 6-phosphate did not change significantly and hexokinase was not inhibited. Acutely, phosphofructokinase had reduced
Vmax (short-term adrenaline 34 ± 6 vs NaCl 44 ± 5 U/g; p < 0.05) but was still above the maximal operating rate in vivo. With
prolonged adrenaline infusion, the Km for phosphofructokinase was reduced (long-term adrenaline 0.32 ± 0.03 vs NaCl 0.44 ± 0.07 mmol/l fructose 6-phosphate;p < 0.05). In this situation of relatively low glycolytic flux, the sustained glycogenolytic effect of prolonged adrenaline
infusion mediated by increased glycogen phosphorylase a ctivity occurs without a significant accumulation of hexose monophosphates
or impairment of glycolysis. 相似文献
5.
Dr. A. M. Umpleby M. A. Boroujerdi P. M. Brown E. R. Carson P. H. Sönksen 《Diabetologia》1986,29(3):131-141
Summary Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic
patients after (1) 24 h insulin withdrawal, (2) conventional insulin therapy and (3) an overnight insulin infusion to maintain
normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 ± 17 μmol/1), production
rate (2.65 ± 0.29 p mol·min−1 kg−1) and oxidation rate (0.69 ± 0.10 μmol · min−1 · kg−1) were significantly greater (p < 0.001;p < 0.05;p < 0.005 respectively) than corresponding values in control subjects (127±6; 1.81 ± 0.12; 0.19 ± 0.02). Following conventional
insulin therapy, leucine concentration (162 ± 12 μmol/1) and oxidation rate (0.43 ± 0.05 μmol · min−1 · kg−1) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p<0.05;p<0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin
infusion, leucine oxidation rate was still greater than normal (0.34 ± 0.06 μmol · min−1 kg−1;p<0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production
rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment. 相似文献
6.
W. Pimenta N. Nurjhan P. -A. Jansson M. Stumvoll Dr. J. Gerich M. Korytkowski 《Diabetologia》1994,37(7):697-702
Summary To assess the relative contributions of gluconeogenesis and glycogenolysis to overall hepatic glucose output in postabsorptive normal humans and those of the indirect and direct pathways for glycogen synthesis, we studied six normal volunteers, who had been fasted for 16 h to reduce their hepatic glycogen stores, and then ingested glucose (250 g over 10 h) enriched with [6-3H] glucose to replenish and label their hepatic glycogen. After a 10-h overnight fast, release of the [6-3H] glucose into the circulation was traced with [2-3H] glucose to estimate breakdown of glycogen that had been formed via the direct pathway while gluconeogenesis was simultaneously estimated by incorporation of infused [14C] lactate into plasma glucose. We found that release of [6-3H] glucose into plasma (6.79±0.69 mol · kg–1 · min–1) accounted for 46±5% of hepatic glucose output (15.0±0.7 mol · kg–1· min–1) while glucose formed from lactate (2.71±0.28 mol · kg–1 · min–1) accounted for 19±2% of hepatic glucose output. Since these determinations underestimate direct pathway glycogenolysis and overall gluconeogenesis, a maximal estimate for the contribution of indirect pathway glycogenolysis to hepatic glucose output is obtained by subtracting the sum of direct pathway glycogenolysis and lactate gluconeogenesis from hepatic glucose output. This amounted to a maximum of 36±5 % of hepatic glucose output and 44±6% of overall glycogenolysis. Assuming that the relative proportions of direct and indirect pathway glycogen breakdown would reflect the relative contributions of these pathways to glycogen formation, we conclude that under our experimental conditions the direct pathway is the predominant route for glycogen formation in man and that in overnight fasted humans, hepatic glucose output is mainly the result of glycogenolysis. 相似文献
7.
Stingl H Krssák M Krebs M Bischof MG Nowotny P Fürnsinn C Shulman GI Waldhäusl W Roden M 《Diabetologia》2001,44(1):48-54
Aims/hypothesis. Non-esterified fatty acids and glycerol could stimulate gluconeogenesis and also contribute to regulating hepatic glycogen stores. We examined their effect on liver glycogen breakdown in humans.¶Methods. After an overnight fast healthy subjects participated in three protocols with lipid/heparin (plasma non-esterified fatty acids: 2.2 ± 0.1 mol/l; plasma glycerol: 0.5 ± 0.03 mol/l; n = 7), glycerol (0.4 ± 0.1 mol/l; 1.5 ± 0.2 mol/l; n = 5) and saline infusion (control; 0.5 ± 0.1 mol/l; 0.2 ± 0.02 mol/l; n = 7). Net rates of glycogen breakdown were calculated from the decrease of liver glycogen within 9 h using 13C nuclear magnetic resonance spectroscopy. Endogenous glucose production was measured with infusion of D-[6,6-2H2]glucose.¶Results. Endogenous glucose production decreased by about 25 % during lipid and saline infusion (p < 0.005) but not during glycerol infusion (p < 0.001 vs lipid, saline). An increase of plasma non-esterified fatty acids or glycerol reduced the net glycogen breakdown by about 84 % to 0.6 ± 0.3 μmol · kg–1· min–1 (p < 0.001 vs saline: 3.7 ± 0.5 μmol · kg–1· min–1) and by about 46 % to 2.0 ± 0.4 μmol · kg–1· min–1 (p < 0.01 vs saline and lipid), respectively. Rates of gluconeogenesis increased to 11.5 ± 0.8 μmol · kg–1· min–1 (p < 0.01) and 12.8 ± 1.0 μmol · kg–1· min–1 (p < 0.01 vs saline: 8.2 ± 0.7 μmol · l–1· min–1), respectively.¶Conclusion/interpretation: An increase of non-esterified fatty acid leads to a pronounced inhibition of net hepatic glycogen breakdown and increases gluconeogenesis whereas glucose production does not differ from the control condition. We suggest that this effect is not due to increased availability of glycerol alone but rather to lipid-dependent control of hepatic glycogen stores. [Diabetologia (2001) 44: 48–54] 相似文献
8.
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
9.
L. Li Y. Oshida M. Kusunoki K. Yamanouchi B.-L. Johansson J. Wahren Y. Sato 《Diabetologia》1999,42(8):958-964
Aims. To study the effects of physiological concentrations of rat proinsulin C peptide I and II, respectively, on whole body glucose
utilization in streptozotocin diabetic and healthy rats. Methods. A sequential insulin clamp procedure was used (insulin infusion rates 3.0 and 30.0 mU · kg–1· min–1) in awake animals. C-peptide infusion rates were 0.05 and 0.5 nmol · kg–1· min–1. Blood glucose was clamped at 7.7 ± 0.3 mmol/l in the diabetic rats and at 3.9 ± 0.1 mmol/l in the healthy rats. Results. In diabetic rats infused at lower rates of C peptide and insulin, glucose utilization increased by 79–90 % (p < 0.001) compared with diabetic animals infused with saline and insulin. Increasing the rate of C-peptide infusion tenfold
did not elicit a statistically significant further increase in glucose utilization. C peptide I and II exerted similar effects.
The metabolic clearance rate for glucose in the diabetic animals infused with C peptide was not different from that of the
healthy rats. During high-dose insulin infusion (30.0 mU · kg–1· min–1) glucose utilization increased considerably and no statistically significant C-peptide effects were observed. About 85 %
of the increase in glucose utilization induced by C peptide could be blocked by treatment with N-monomethyl-l-arginine. Conclusions/interpretation. Physiological concentrations of homologous C peptide stimulate whole body glucose utilization in diabetic but not in healthy
rats. C peptide I and II elicit similar effects. The influence of C peptide on glucose utilization may be mediated by nitric
oxide. [Diabetologia (1999) 42: 958–964]
Received: 8 January 1999 and in final revised form: 20 April 1999 相似文献
10.
D. P. Rooney R. D. G. Neely O. Beatty N. P. Bell B. Sheridan A. B. Atkinson E. R. Trimble P. M. Bell 《Diabetologia》1993,36(2):106-112
Summary It has been suggested that increased glucose/glucose 6-phosphate substrate cycling impairs net hepatic glucose uptake in Type 2 (non-insulin-dependent) diabetes mellitus and contributes to hyperglycaemia. To investigate glucose/glucose 6-phosphate cycle activity and insulin action in Type 2 diabetes we studied eight patients and eight healthy control subjects, using the euglycaemic glucose clamp and isotope dilution techniques with purified [2-3H]- and [6-3H] glucose tracers, in the post-absorptive state and eight patients and five healthy control subjects during consecutive insulin infusions at rates of 0.4 and 2.0 mU·kg–1·min–1. [2-3H]glucose and [6-3H]glucose radioactivity in plasma samples were determined using selective enzymatic detritiation, allowing calculation of glucose turnover rates for each isotope, the difference being glucose/glucose 6-phosphate cycling. Endogenous glucose production ([6-3H]glucose) was greater in diabetic than control subjects in the post-absorptive state (15.6±1.5 vs 11.3±0.4 mol·kg–1·min–1, p<0.05) and during the 0.4 mU insulin infusion (10.1±1.3 vs 5.2±0.3 mol·kg–1·min–1, p<0.01) indicating hepatic insulin resistance. Glucose/glucose 6-phosphate cycling was significantly greater in diabetic than in control subjects in the post-absorptive state (2.6±0.4 vs 1.6±0.2 mol·kg–1·min–1, p<0.05) but not during the 0.4 mU insulin infusion (2.0±0.4 vs 2.0±0.3 mol·kg–1·min–1). During the 2.0 mU insulin infusion endogenous glucose production was suppressed to a similar degree in both groups (2.6±0.5 vs 3.4±0.7 mol · kg–1·min–1) but glucose disappearance was lower in the diabetic subjects (30.8±2.0 vs 52.4±4.6 mol·kg–1·min–1, p<0.01). During the 2.0 mU insulin infusion glucose/glucose 6-phosphate cycling was greater in the diabetic subjects (3.8±0.7 vs 0.8±0.6 mol·kg–1·min–1, p<0.05). In conclusion, both hepatic and peripheral insulin action are impaired in Type 2 diabetes. Increased glucose/glucose 6-phosphate cycling is seen in the post-absorptive state and also during marked hyperinsulinaemia, when insulin resistance is predominantly due to reduced peripheral tissue glucose uptake. 相似文献
11.
Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM 总被引:2,自引:0,他引:2
T. Utriainen T. Takala M. Luotolahti T. Rönnemaa H. Laine U. Ruotsalainen M. Haaparanta P. Nuutila H. Yki-Järvinen 《Diabetologia》1998,41(5):555-559
Summary Skeletal muscle insulin resistance and coronary heart disease (CHD) often precede non-insulin-dependent diabetes mellitus
(NIDDM). A recent study showed the myocardium of patients with CHD to be insulin resistant, independent of blood flow. We
determined whether myocardial insulin resistance is a feature of NIDDM patients with no CHD. Skeletal muscle and myocardial
glucose uptake were determined in 10 patients with NIDDM and 9 age- and weight-matched normal men of similar age and body
mass index men using [18F]-2-fluoro-2-deoxy-d-glucose and positron emission tomography under normoglycaemic hyperinsulinaemic conditions. Whole body glucose uptake, as
determined by the euglycaemic clamp technique, was significantly lower in the patients with NIDDM (35 ± 3 μmol/kg body weight
· min) than the normal subjects (45 ± 3 μmol/kg body weight · min, p < 0.02). Insulin-stimulated femoral muscle glucose uptake was significantly lower in the patients with NIDDM (71 ± 6 μmol/kg
muscle · min) than in the normal subjects (96 ± 5 μmol/kg muscle · min, p < 0.01). Whole body glucose uptake was correlated with femoral muscle glucose uptake in the entire group (r = 0.76, p < 0.001), in patients with NIDDM and in normal subjects. Rates of insulin-stimulated myocardial glucose uptake were comparable
between the patients with NIDDM (814 ± 76 μmol/kg muscle · min) and the normal subjects (731 ± 63 μmol/kg muscle · min, p > 0.4). Whole body or femoral muscle, and myocardial glucose uptake were not correlated in all subjects, patients with NIDDM
or normal subjects. We conclude that insulin resistance of the myocardium is not a feature of uncomplicated NIDDM. [Diabetologia
(1998) 41: 555-559]
Received: 8 August 1997 and in revised form: 6 December 1997 相似文献
12.
Stingl H Chandramouli V Schumann WC Brehm A Nowotny P Waldhäusl W Landau BR Roden M 《Diabetologia》2006,49(2):360-368
Aims/hypothesis Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer
techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic
glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways.
Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the
direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling
to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect
pathways and 100.
Materials and methods The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested
2H2O (5 ml/kg body water) and were infused with [5-3H]glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution
of the indirect pathway was calculated from the ratio of 2H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the 3H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h.
Results Glucose infusion rates increased (p<0.01) to ∼50 μmol kg−1 min−1. Plasma insulin and the insulin : glucagon ratio rose ∼3.6- and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2–4 h, 54±6%; 4–6 h, 59±5%; 6–8 h, 63±4%)
and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2–4 h) to 4±3% (4–6 h) and 1±3% (6–8 h).
Conclusions/interpretation This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs
most in the early hours after glucose loading subsequent to a fast. 相似文献
13.
S. Del Prato M. Matsuda D. C. Simonson L. C. Groop P. Sheehan F. Leonetti R. C. Bonadonna R. A. DeFronzo 《Diabetologia》1997,40(6):687-697
Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent
(IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a
sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin
plus replacing doses of basal insulin and glucagon, 3-3H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic
step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 μmol/kg · min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 μmol/kg · min),
and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 μmol/kg · min) glucose disposal was lower during all three steps (p < 0.05–0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in
all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 μmol/kg · min)
only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8
± 1.7 μmol/kg · min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau
(IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 μmol/kg · min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ±
1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 μmol/kg · min; p < 0.05–0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative
glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose
disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts
for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia
to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of
glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687–697]
Received: 20 August 1996 and in revised form: 5 March 1997 相似文献
14.
Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria 总被引:1,自引:0,他引:1
Dr. S. Nielsen O. Schmitz N. Møller N. Pøksen I. C. Klausen K. G. M. M. Alberti C. E. Mogensen 《Diabetologia》1993,36(10):1079-1086
Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated
in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol
≥5.5 mmol·l−1). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l−1 (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l−1 (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l−1 (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min−1·1.73 m−2, placebo: 97.1±6.7 vs 88.8±6.0 ml·min−1·1.73 m−2) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min−1, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min−1)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks
in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal
was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg−1·min−1 (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg−1·min−1 (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the
suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5
mg·kg−1·min−1 (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary
albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic
Type 2 diabetic patients. 相似文献
15.
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
16.
Aims/hypothesis Disturbances in substrate source metabolism and, more particularly, in fatty acid metabolism, play an important role in the
aetiology and progression of type 2 diabetes. However, data on substrate source utilisation in type 2 diabetes are inconclusive.
Methods [U-13C]palmitate and [6,6-2H2]glucose tracers were used to assess plasma NEFA and glucose oxidation rates and to estimate the use of muscle- and/or lipoprotein-derived
triacylglycerol and muscle glycogen. Subjects were ten male patients who had a long-term (7 ± 1 years) diagnosis of type 2
diabetes and were overweight, and ten matched healthy, male control subjects. Muscle biopsy samples were collected before
and after exercise to assess muscle fibre type-specific intramyocellular lipid and glycogen content.
Results At rest and during exercise, the diabetes patients had greater values than the controls for palmitate rate of appearance (Ra)
(rest, 2.46 ± 0.18 and 1.85 ± 0.20 respectively; exercise, 3.71 ± 0.36 and 2.84 ± 0.20 μmol kg−1 min−1) and rate of disappearance (Rd) (rest, 2.45 ± 0.18 and 1.83 ± 0.20; exercise, 3.64 ± 0.35 and 2.80 ± 0.20 μmol kg−1 min−1 respectively). This was accompanied by significantly higher fat oxidation rates at rest and during recovery in the diabetes
patients (rest, 0.11 ± 0.01 in diabetes patients and 0.09 ± 0.01 in controls; recovery, 0.13 ± 0.01 and 0.11 ± 0.01 g/min
respectively), despite significantly greater plasma glucose Ra, Rd and circulating plasma glucose concentrations. Furthermore,
exercise significantly lowered plasma glucose concentrations in the diabetes patients, as a result of increased blood glucose
disposal.
Conclusion This study demonstrates that substrate source utilisation in long-term-diagnosed type 2 diabetes patients, in whom compensatory
hyperinsulinaemia is no longer present, shifts towards an increase in whole-body fat oxidation rate and is accompanied by
disturbances in fat and carbohydrate handling. 相似文献
17.
Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone 总被引:12,自引:0,他引:12
Summary Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is
nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus
improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks,
fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind,
cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial
administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses
(clamp); vasoconstrictor responses to N
G-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo)
of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared
with leans (whole-body glucose uptake: 26.8 ± 3.0 vs. 53.9 ± 4.3 μmol · kg–1· min–1, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9 ± 3.3 μmol · kg–1· min–1, p = 0.028), and forearm glucose uptake (from 1.09 ± 0.54 to 2.31 ± 0.69 μmol · dL–1· min–1, p = 0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean
66.5 ± 23.0 %, vs. 10.1 ± 11.3 % in obese, p = 0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did
not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion,
in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin.
Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses.
These data do not support an association between insulin resistance and endothelial function. [Diabetologia (1998) 41: 569–576]
Received: 19 September 1997 and in revised form: 22 December 1997 相似文献
18.
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
19.
Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects 总被引:1,自引:0,他引:1
T. Utriainen S. Mäkimattila A. Virkamäki R. Bergholm H. Yki-Järvinen 《Diabetologia》1996,39(12):1477-1482
Summary Insulin increases limb blood flow in a time- and dose-dependent manner. This effect can be blocked by inhibiting nitric oxide
synthesis. These data raise the possibility that insulin resistance is associated with endothelial dysfunction. To examine
whether endothelial function and insulin sensitivity are interrelated we quantitated in vivo insulin-stimulated rates of whole
body and forearm glucose uptake at a physiological insulin concentration (euglycaemic hyperinsulinaemic clamp, 1 mU · kg–1· min–1 insulin infusion for 2 h) and on another occasion, in vivo endothelial function (blood flow response to intrabrachial infusions
of sodium nitroprusside, acetylcholine, and N-monomethyl-l-arginine) in 30 normal male subjects. Subjects were divided into an insulin-resistant (IR) and an insulin-sensitive (IS)
group based on the median rate of whole body glucose uptake (31 ± 2 vs 48 ± 1 μmol · kg–1· min–1, p < 0.001). The IR and IS groups were matched for age, but the IR group had a slightly higher body mass index, percentage of
body fat and blood pressure compared to the IS group. The IR group also had diminished insulin-stimulated glucose extraction
(p < 0.05) compared to the IS group, while basal and insulin-stimulated forearm blood flow rates were identical. There was no
difference between the IR and IS groups in the forearm blood flow response to endothelium-dependent (acetylcholine and N-monomethyl-l-arginine) or -independent (sodium nitroprusside) vasoactive drugs. In conclusion, the ability of insulin to stimulate glucose
uptake at physiological insulin concentrations and endothelium-dependent vasodilatation are distinct phenomena and do not
necessarily coexist. [Diabetologia (1996) 39: 1477–1482]
Received: 31 May 1996 and in revised form: 10 July 1996 相似文献
20.
Insulin resistance and coronary artery disease 总被引:5,自引:0,他引:5
Summary The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients
with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance.
We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched
control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU · m−2· min−1) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control
subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 ± 6 vs 42 ± 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 ± 54 vs 348 ± 42 pmol · l−1· min−1, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 ± 3.9 vs 38.3 ± 4.4
μmol · kg fat free mass (FFM)−1· min−1, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal
(8.9 ± 2.8 vs 20.0 ± 3.3 μmol · kg FFM−1· min−1, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused
a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized
by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster
of disorders that comprise the insulin resistance syndrome or ’syndrome X'. [Diabetologia (1996) 39: 1345–1350]
Received: 6 February 1996 and in revised form: 29 May 1996 相似文献