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1.
Aims/hypothesis We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli.
Methods We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein
diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed
at 40 weeks.
Results Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19±0.64 vs 6.45±0.67 g, p<0.001) and had fewer glomeruli (27,402±3,137 vs 34,203±6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=−0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770±541 vs 5,779±1,302 mm2, p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume
and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest
in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group
(2.40±0.693 ×10−3 mm2) than in the LPD control group (1.68±0.374 ×10−3 mm2, p<0.001) and in the NPD diabetic animals (1.71±0.291 ×10−3 mm2, p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals.
Conclusions/interpretation A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further
work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number
on the development of renal disease. 相似文献
2.
Giordano M Lucidi P Ciarambino T Gesuè L Castellino P Cioffi M Gresele P Paolisso G De Feo P 《Diabetologia》2008,51(1):21-28
Aims/hypothesis Diabetic nephropathy is associated with hypoalbuminaemia and hyperfibrinogenaemia. A low-protein diet has been recommended
in patients with diabetic nephropathy, but its effects on albumin and fibrinogen synthesis are unknown.
Methods We compared the effects of a normal (NPD; 1.38 ± 0.08 g kg−1 day−1) or low (LPD; 0.81 ± 0.04 g kg−1 day−1) -protein diet on endogenous leucine flux (ELF), albumin and fibrinogen synthesis (l-[5,5,5,-2H3]leucine infusion), and markers of inflammation in nine type 2 diabetic patients with macroalbuminuria. Six healthy participants
on NPD served as control participants.
Results In comparison with healthy participants, type 2 diabetic patients on an NPD had similar ELF, reduced serum albumin (38 ± 1.1
vs 42 ± 0.8 g/l; p < 0.05), similar fractional synthesis rates (FSR) and absolute synthesis rates (ASR) of albumin, and both increased plasma
fibrinogen concentration [10.7 ± 0.6 vs 7.2 ± 0.5 μmol/l (3.64 ± 0.22 vs 2.45 ± 0.18 g/l); p < 0.05] and fibrinogen ASR [11.03 ± 1.17 vs 6.0 ± 1.8 μmol 1.73 m−2 day−1 (3.7 ± 0.4 vs 1.9 ± 0.3 g 1.73 m−2 day−1); p < 0.01]. After LPD, type 2 diabetic patients had the following changes in comparison with NPD: reduced proteinuria (2.74 ± 0.4
vs 4.51 ± 0.8 g/day; p < 0.05), ELF (1.93 ± 0.08 vs 2.11 ± 0.08 μmol kg−1 min−1; p < 0.05) and total fibrinogen pool; increased serum albumin (42 ± 1 vs 38 ± 1 g/l; p < 0.01) and albumin ASR (14.1 ± 1 vs 9.9 ± 1 g 1.73 m−2 day−1; p < 0.05); and reduced plasma IL-6 levels, which were correlated with albumin ASR (r = −0.749; p < 0.05).
Conclusions/interpretation LPD in type 2 diabetic patients with diabetic nephropathy reduces low-grade inflammatory state, proteinuria, albuminuria,
whole-body proteolysis and ASR of fibrinogen, while increasing albumin FSR, ASR and serum concentration.
ISRCTN ID no: CCT-NAPN-16911 相似文献
3.
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
4.
H. Sackmann T. Tran-Van I. Tack H. Hanaire-Broutin J.-P. Tauber J.-L. Ader 《Diabetologia》1998,41(1):86-93
Summary The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM)
patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic
control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation
by amino acid infusion (4.5 mg · kg−1· min−1). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive
diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 ± 3 ml · min−1· 1.73 m−2) was higher whereas RFR (10 ± 4 ml · min−1· 1.73 m−2) was lower (p < 0.05) than in control subjects (113 ± 4 and 28 ± 2 ml · min−1· 1.73 m−2, respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR
and RFR (109 ± 7 and 24 ± 6 ml · min−1· 1.73 m−2, respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed
macroalbuminuria and hypertension, baseline GFR (78 ± 8 ml · min−1· 1.73 m−2) was lower than in control subjects (p < 0.05) and RFR (8 ± 4 ml · min−1· 1.73 m−2) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 ± 4 and 11 ± 4 mm Hg · l−1· min−1· 1.73 m−2, respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate
that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages
of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with
a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy
and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy. [Diabetologia (1998) 41: 86–93]
Received: 12 February 1997 and in final revised form: 28 August 1997 相似文献
5.
Structural basis of diabetic nephropathy in microalbuminuric NIDDM patients: a light microscopy study 总被引:1,自引:0,他引:1
Summary The objective of the study was to evaluate early structural changes occurring in patients with non-insulin-dependent diabetes
mellitus (NIDDM) and microalbuminuria by light microscopy. Basal renal biopsy was performed in patients who were subsequently
randomized to different antihypertensive treatments. Fourteen NIDDM patients aged 36–65 years (duration of diabetes 9 ± 7
years) with microalbuminuria (mean urinary albumin excretion 66 ± 49 μg/min) underwent percutaneous renal biopsy. Control
biopsies were obtained from five patients of similar age undergoing nephrectomy for renal neoplasia with normal renal function
and no history of renal disease. Control and diabetic biopsies were processed by light microscopy and stained with haematoxylin
and eosin, periodic acid Schiff, Masson's trichrome and silver methenamine. The percentage of globally sclerotic glomeruli
was evaluated. Glomerular volume was determined using perimeter analysis. A semiquantitative assessment (range 0 to 3 +) was
made of mesangial sclerosis, interstitial fibrosis, tubular atrophy, arteriosclerosis and arteriolar hyalinosis. Glomerular
volume was significantly increased in diabetic as compared to control glomeruli (3.2 ± 8 vs 1.8 ± 7, p < 0.01). Mesangial sclerosis (0.9 vs 0, p < 0.0001) and arteriolar hyalinosis (0.91 vs 0.2, p < 0.022) were significantly higher in diabetic compared to control subjects. No significant differences between diabetic
and control subjects were found in the percentage of globally sclerotic glomeruli or in the extent of interstitial fibrosis,
tubular atrophy and arteriosclerosis. Thus NIDDM patients with microalbuminuria show histological findings consistent with
diabetic nephropathy characterized by glomerular hypertrophy, mesangial sclerosis and arteriolar hyalinosis. However, the
renal histological changes are mild and appear less marked than in insulin-dependent diabetic patients. [Diabetologia (1996)
39: 1625–1628]. 相似文献
6.
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
7.
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
8.
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
9.
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
10.
Patterns of renal injury in NIDDM patients with microalbuminuria 总被引:11,自引:2,他引:11
P. Fioretto M. Mauer E. Brocco M. Velussi F. Frigato B. Muollo M. Sambataro C. Abaterusso B. Baggio G. Crepaldi R. Nosadini 《Diabetologia》1996,39(12):1569-1576
Summary Microalbuminuria predicts overt nephropathy in non-insulin-dependent diabetic (NIDDM) patients; however, the structural basis
for this functional abnormality is unknown. In this study we evaluated renal structure and function in a cohort of 34 unselected
microalbuminuric NIDDM patients (26 male/8 female, age: 58 ± 7 years, known diabetes duration: 11 ± 6 years, HbA1 c: 8.5 ± 1.6 %). Systemic hypertension was present in all but 3. Glomerular filtration rate (GFR) was 101 ± 27 ml · min–1· 1.73 m–2 and albumin excretion rate (AER) 44 (20–199) μg/min. Light microscopic slides were categorized as: C I) normal or near normal
renal structure; C II) changes “typical” of diabetic nephropathology in insulin-dependent diabetes (IDDM) (glomerular, tubulo-interstitial
and arteriolar changes occurring in parallel); C III) “atypical” patterns of injury, with absent or only mild diabetic glomerular
changes associated with disproportionately severe renal structural changes including: important tubulo-interstitial with or
without arteriolar hyalinosis with or without global glomerular sclerosis. Ten patients (29.4 %) were classified as C I, 10
as C II (29.4 %) and 14 as C III (41.2 %); none of these patients had any definable non-diabetic renal disease. GFR, AER and
blood pressure were similar in the three groups, while HbA1 c was higher in C II and C III than in C I patients. Diabetic retinopathy was present in all C II patients (background in 50
% and proliferative in 50 %). None of the patients in C I and C III had proliferative retinopathy, while background retinopathy
was observed in 50 % of C I and 57 % of C III patients. In summary, microalbuminuric NIDDM patients are structurally heterogeneous
with less than one third having “typical” diabetic nephropathology. The presence of both “typical” and “atypical” patterns
of renal pathology was associated with worse metabolic control, suggesting that hyperglycaemia may cause different patterns
of renal injury in older NIDDM compared to younger IDDM patients. [Diabetologia (1996) 39: 1569–1576] 相似文献
11.
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
12.
Glomerular hyperfiltration in microalbuminuric NIDDM patients 总被引:3,自引:0,他引:3
P. Vedel J. Obel F. S. Nielsen L. E. Bang T. L. Svendsen O. B. Pedersen H.-H. Parving 《Diabetologia》1996,39(12):1584-1589
Summary Glomerular hyperfiltration and microalbuminuria are both regarded as risk factors for the development of diabetic nephropathy
in insulin-dependent diabetic patients. Information on glomerular hyperfiltration is scarse in microalbuminuric non-insulin-dependent
diabetic (NIDDM) patients. Therefore, we performed a cross-sectional study of glomerular filtration rate (single i. v. bolus
injection of 51Cr-EDTA, plasma clearance for 4 h) in 158 microalbuminuric NIDDM patients compared to 39 normoalbuminuric NIDDM patients and
20 non-diabetic control subjects. The groups were well-matched with regard to sex, age and body mass index. The uncorrected
(ml/min) and the adjusted (ml · min–1· 1.73 m–2) glomerular filtration rate were both clearly elevated in the microalbuminuric patients: 139 ± 29 and 117 ± 24 as compared
to 115 ± 19 and 99 ± 15; 111 ± 23 and 98 ± 21 in normoalbuminuric NIDDM patients and control subjects, respectively (p < 0.001). The glomerular filtration rate (ml · min–1· 1.73 m–2) in NIDDM patients who had never received antihypertensive treatment was also clearly elevated in the microalbuminuric patients
(n = 96): 119 ± 22 as compared to 100 ± 14 and 98 ± 21 in normoalbuminuric NIDDM patients (n = 27) and control subjects (n = 20), respectively (p < 0.001). Glomerular hyperfiltration (elevation above mean glomerular filtration rate plus 2 SD in normoalbuminuric NIDDM
patients) was demonstrated in 37 (95 % confidence interval 30–45)% of the microalbuminuric patients. Multiple regression analysis
revealed that HbA1 c, 24-h urinary sodium excretion, age and known duration of diabetes were correlated with glomerular filtration rate in microalbuminuric
NIDDM patients (r
2 = 0.21, p < 0.01). Our cross-sectional study indicates that NIDDM patients at high risk of developing diabetic nephropathy are also
characterized by an additional putative risk factor for progression, glomerular hyperfiltration. [Diabetologia (1996) 39:
1584–1589] 相似文献
13.
Summary The increased mortality of patients with diabetic nephropathy is mainly due to cardiovascular disease and end stage renal
failure. Left ventricular hypertrophy is an independent risk factor for myocardial ischaemia and sudden death. The aim of
our cross-sectional study was to evaluate left ventricular structure and function in Type I (insulin-dependent) diabetic patients
with diabetic nephropathy. M-mode and Doppler echocardiography were done on 105 Type I diabetic patients with diabetic nephropathy
[61 men, age (means ± SD) 44 ± 9 years, and albuminuria [median(range)] 567(10–8188) mg/24 h, serum creatinine 109 (53–558)
μmol/l], and 140 Type I diabetic patients with persistent normoalbuminuria [79 men, 47 ± 10 years, urinary albumin excretion
rate 8 (0–30) mg/24 h, and serum creatinine 81 (55–121) μmol/l]. Patients with and without nephropathy were comparable with
respect to sex, body mass index, and duration of diabetes. Arterial blood pressure was slightly higher in patients with nephropathy:
140/79 ± 17/9 mm Hg vs 134/78 ± 15/8 mm Hg, p < 0.01, and the majority of proteinuric patients received antihypertensive drugs, 84 vs 17 %, respectively, p < 0.001. Left ventricular mass index was increased in the nephropathic group (means ± SD) 100.6 ± 23.9 g/m2 compared with the normoalbuminuric group 91.4 ± 21.9 g/m2, p = 0.002. Left ventricular hypertrophy was found more often in patients with nephropathy 23 (14–31)% compared with patients
with normoalbuminuria 9 (5–14)%, p < 0.005. Diastolic function, assessed by the ratio between the peak diastolic velocity and the peak atrial systolic velocity
(E/A ratio) and isovolumic relaxation time, was reduced in patients with vs without nephropathy: 1.17 ± 0.29 vs 1.34 ± 0.32,
and 81.7 ± 16.5 vs 74.6 ± 14.5, p < 0.001 and p = 0.002, respectively. Systolic function was about the same and normal in both groups. Our study suggests that an increase
in left ventricular mass index and a decrease in diastolic function occurs early in the course of diabetic nephropathy. [Diabetologia
(1999) 42: 76–80]
Received: 16 April 1998 and in final revised form: 5 August 1998 相似文献
14.
J. Ek S. A. Urhammer T. I. A. Sørensen T. Andersen J. Auwerx O. Pedersen 《Diabetologia》1999,42(7):892-895
Aims/hypothesis. The objectives of the present investigation were to examine: 1) whether a Pro115Gln variant in the peroxisome proliferator-activated receptor-γ2 (PPAR-
γ
2) is associated with juvenile-onset obesity among Danish Caucasianmen and 2) whether the relation of a Pro12Ala polymorphism in PPAR-
γ
2 with BMI and long-term weight regulation differ between lean and obese subjects within the same cohort. Methods. The Pro115Gln and Pro112Ala variants were examined using PCR and RFLP in a group of 752 subjects with a Body Mass Index (BMI) of 31.0 kg/m2 or more and in 869 non-obese control subjects. Results. We did not find Pro115Gln in any of the 1621 male subjects we examined. Among the males with juvenile-onset obesity, the allelic frequency of the Pro12Ala polymorphism was 14 % (95 % confidence interval: 12–16 %) compared with 16 % (14–17 %) among the non-obese control subjects
(NS). Heterozygosity of the codon 12 variant was not associated with differences in BMI or changes in body weight regulation during follow up in lean or obese
subjects. In the group of obese subjects, 21 homozygous Ala12Ala carriers had, however, a higher BMI (38.9 ± 5.4 kg/m2 (means ± SD) vs 35.5 ± 5.5 kg/m2, p = 0.008) and a higher weight gain (0.27 ± 0.24 kg · m–2· year–1 vs 0.10 ± 0.24 kg · m–2· year–1, p = 0.004), compared with wild-type carriers. Moreover, within the control group of 869 men the 14 homozygous carriers of the
variant had a lower BMI (24.4 ± 2.7 kg/m2 vs 26.2 ± 3.7 kg/m2, p = 0.005) and a slower increase in BMI (0.11 ± 0.11 kg · m–2· year–1 vs 0.17 ± 0.11 kg · m–2· year–1, p = 0.002) compared with wild-type carriers. Conclusion/interpretation. The codon 12 variant of PPAR-
γ
2 is not intrinsically associated with juvenile obesity. The variant may in its homozygous form interact, however, with various
combinations of genetic and environmental factors in lean and obese subjects to cause divergent modulating effects on BMI
and long-term body weight control. [Diabetologia (1999) 42: 892–895]
Received: 22 December 1998 and in revised form: 3 March 1999 相似文献
15.
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
16.
Summary Abnormalities of renal autoregulation with glomerular hyperfiltration and raised intraglomerular pressure have been suggested
as important factors in the initiation and development of diabetic nephropathy. Angiotensin converting enzyme (ACE) inhibition
appears to have a specific reno-protective role in diabetic nephropathy, possibly by reducing intraglomerular pressure. The
acute effects of ACE inhibition on renal haemodynamics in normotensive, non-insulin-dependent diabetes mellitus (NIDDM) have
not been previously reported. We measured simultaneous glomerular filtration rate (GFR) and renal plasma flow (RPF) in 29
(4 female) subjects, mean age 52 years (range 27–70), using 51Cr EDTA and 125I Hippuran. Clearances were corrected to 1.73 m–2. All patients were normotensive (blood pressure < 75th centile for age and sex), newly diagnosed ( < 30 days), taking no antihypertensive or hypoglycaemic medication. Subjects
were randomly allocated (double blind) to receive the ACE inhibitor trandolapril 4 mg day–1 (H) (hypotensive dose), trandolapril 0.5 mg day–1 (L) (non-hypotensive dose) or placebo (P) for 10 days after which renal haemodynamics were remeasured. For all subjects baseline
GFR, RPF and filtration fraction (FF) were 97 ± 21 ml min–1 mean ± SD, 439 ± 120 ml min–1 and 22.3 ± 2.9 % respectively. Glomerular hyperfiltration (GFR > 120 ml min–1) was only demonstrated in 3 subjects (10.3 %). In group H mean arterial pressure (103 ± 8 vs 93 ± 9 mmHg, p < 0.001) and FF (23.8 ± 2.3 vs 20.0 ± 4.0 %, p = 0.03) fell while RPF increased (376 ± 111 vs 426 ± 60 ml min–1, p = 0.02), there was no significant change in GFR. No significant change in mean arterial pressure, GFR, RPF or FF occurred
in groups P and L. These studies suggest that in newly diagnosed normotensive NIDDM subjects normal renal autoregulation occurs
and glomerular hyperfiltration is uncommon. [Diabetologia (1998) 41: 206–211]
Received: 2 July 1997 and in revised form: 16 September 1997 相似文献
17.
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
18.
Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes 总被引:1,自引:0,他引:1
Reed MJ Meszaros K Entes LJ Claypool MD Pinkett JG Brignetti D Luo J Khandwala A Reaven GM 《Diabetologia》1999,42(1):102-106
Summary Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans
in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated
from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20 % fat (by weight) diet for 2 weeks prior
to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16–33 mmol/l) were treated with
vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol
treatment lowered glucose concentrations an average of 35 % compared with vehicle (14.2 ± 1.1 vs 21.7 ± 1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8 ± 0.9 mmol/l), without any change in insulin concentration. Masoprocol
treatment also lowered triglyceride concentrations 80 % compared with vehicle (1.0 ± 0.1 vs 4.8 ± 0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6 ± 0.3 mmol/l). Non-esterified fatty acid and glycerol
concentration were decreased by approximately 65 % by masoprocol compared with vehicle, a reduction approximately twice as
great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats
with glucose (0.22 mmol · kg · min–1) and insulin (30 pmol · kg · min–1) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30 % in masoprocol-treated
animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary
adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 μmol/l) had higher basal and insulin-stimulated
glucose clearance than did adipocytes treated with vehicle (p < 0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats,
presumably as a result of its ability to both increase glucose disposal and decrease lipolysis. [Diabetologia (1999) 42: 102–106]
Received: 3 April 1998 and in final revised form: 21 August 1998 相似文献
19.
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
20.
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