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, HbA1c: 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) micrograms/ 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 HbA1c 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.

Cystatin C may be considered as an alternative and more accurate serum marker than serum creatinine or the Cockcroft and Gault estimated GFR in discriminating type 2 diabetic patients with reduced GFR from those with normal GFR.

Renal and hormonal responses were studied in a group of healthy individuals fed, in random order, for three weeks, a vegetable protein diet (N = 10), an animal protein diet (N = 10), or an animal protein diet supplemented with fiber (N = 7), all containing the same amount of total protein (chronic study). In seven additional subjects the acute renal, metabolic and hormonal response to ingestion of a meat or soya load of equivalent total protein content was investigated (acute study). In the chronic study GRF, RPF and fractional clearance of albumin and IgG were significantly higher on the animal than the vegetable protein diets (GFR: 121 +/- 4 vs. 111 +/- 4 ml/min/1.73 m2, P less than 0.001; RPF: 634 +/- 29 vs. 559 +/- 26 ml/min/1.73 m2, P less than 0.001; theta alb: 19.5 +/- 3.1 vs. 10.2 +/- 1.6 x 10(-7), P less than 0.01; theta IgG: 11.6 +/- 3.1 vs. 7.5 +/- 1.7 x 10(-7), P less than 0.05). Renal vascular resistance was lower on the animal than vegetable protein diet (82 +/- 5 vs. 97 +/- 5 mmHg/min/liter; P less than 0.001). Fiber supplementation to APD did not have any effect on the renal variables measured which were indistinguishable from APD. In the acute study, GFR and RPF both rose significantly by approximately 16% (P less than 0.005) and approximately 14% (P less than 0.05), respectively, after the meat load, while RVR fell by approximately 12% (P less than 0.05). There were no significant changes in these parameters following the soya load.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity in renal structure has been described in t y p e 2 diabetic patients with both microalbuminuria and proteinuria; in fact, only a subset of type 2 diabetic patients have the typical diabetic glomerulopathy. Howe v e r, it is currently unknown whether abnormalities in albumin excretion rate (AER) have a different renal prognostic value depending on the underlying renal structure. Aims of this study were: 1) to study the course of renal function in type 2 diabetic patients with altered AER; 2) to evaluate the relationship between the course of glomerular filtration rate (GFR) and renal structure; and 3) to evaluate the relationship between the course of GFR and baseline AER levels, metabolic control, and blood pressure levels during a follow-up period of 4 years. A total of 108 type 2 diabetic patients, 74 with microalbuminuria (MA) and 34 with proteinuria (P), were recruited into a prospective study that encompassed: 1) a baseline kidney biopsy with morphometric measurements of glomerular parameters; 2) intensified antihypertensive treatment for an average 4-year period (blood pressure target < 1 4 0 / 9 0 mmHg); and 3) determinations of GFR at baseline and every 6 months. Mean (± SD) GFR significantly decreased from baseline in both MA (-1.3 ± 9.4 [95% CI -3.51 to +0.86], P < 0.05) and P (-3.0 ± 13.0 m l · min -1 · 1.73 m -2 per year [-7.71 to +1.61], P < 0.01). However, the changes in GFR were quite heterogeneous. Thus, on the basis of percent GFR change per year from baseline ( %GFR), both MA and P patients were defined as progressors or nonprogressors when they were below or above the median, respectively. Baseline parameters of glomerular structure had a strong influence on the course of GFR. Indeed, the odds ratios of being progressors significantly increased across the quartiles of baseline glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(mes/glom)], being 2.71 and 2.85 higher, respectively, in the fourth quartile than in the first quartile (P < 0.01 for both). Conv e r s e l y, nonprogressors outnumbered progressors in the first quartile of GBM width (odds ratio: 2.14, P < 0.05) and in the first quartile of Vv(mes/glom) (odds ratio: 2.28, P < 0.01). Baseline albumin excretion rate (AER) did not influence %GFR; in fact, the number of progressors did not increase across quartiles of baseline AER among either MA or P. Similarly, mean blood pressure levels during follow-up (and intensified antihypertensive therapy) did not affect the course of GFR: the number of progressors and nonprogressors did not change across quartiles of mean blood pressure. In contrast, HbA 1 c during follow-up had an impact on % G F R : the odds ratio for being a progressor increased across quartiles of HbA 1 c , particularly for the highest quartile ( H b A 1 c >9.0%). In conclusion, the course of renal function is heterogeneous in type 2 diabetic patients with microalbuminuria or proteinuria. In fact, a subset of patients has a rapid decline in GFR over a 4-year followup period; these patient...

It is well established that cortisol excess causes insulin resistance in man, but the mechanisms responsible for this insulin resistance are poorly understood. We studied five women with Cushing's syndrome with impaired oral glucose tolerance tests and seven normal subjects, plotting the shape of the insulin-induced disposal dose-response curve obtained by means of the euglycemic clamp procedure during four different plasma insulin plateaus at four infusion rates of 21, 73, 760, and 1200 mU/M2 . min. Glucose disposal (M = mg/M2 . min) was calculated as glucose amount infused to maintain euglycemia. In Cushing's syndrome the dose-response curve was shifted to the right in comparison with normal subjects, with a significantly lower M (337 +/- 35 vs. 657 +/- 76 P less than 0.01) during the highest insulin infusion rate [maximal glucose disposal (MGD)] without any significant difference in the levels of insulin half-maximally effective in the stimulation of glucose utilization. Neither erythrocyte nor monocyte maximum insulin receptor binding were different between the two populations. Four Cushing's syndrome patients were studied again after surgical treatment. A marked improvement of MGD was observed without any significant change in insulin-binding capacity. These results, particularly the marked decrease in MGD, a typical feature of postreceptor defects, indicate that cortisol-induced insulin resistance in man is due to an impairment of peripheral insulin action located beyond the hormone-receptor binding step.

In contrast to "weightless" radioactive tracers, stable isotope tracers have nonnegligible mass and are naturally present in the system, and the measured variable is a ratio of two isotopic species. These features do not allow stable isotopic tracer data analysis using straightforward analogy with radioactive tracer approaches, even though this practice is common. In this study, we present kinetic variables, models, and measurements for the analysis and interpretation of stable isotope tracer data. Assumptions and mathematical techniques for modeling the data when perturbation is both nonnegligible and negligible are discussed. Emphasis is placed on the rich information content of the dynamic portion of a stable isotope tracer curve and on the role of compartmental and noncompartmental modeling approaches for its interpretation. A presumed and commonly used analogy between the radioactive specific activity and stable isotopic enrichment is shown to be incorrect. We show that the proper analogue of specific activity is the tracer-to-tracee molar ratio. This variable is not a directly measurable one, but a formula is derived that allows its computation from the data. A method for reconstructing the time course in blood of the concentration component due to endogenous synthesis is presented. This allows measurement of the extent of the perturbation in the case where a nonweightless tracer is used. Special attention is given to data analysis originating from a multiple tracer experiment, a configuration necessary for studying more complex systems, e.g., the kinetics of interacting substrates.

The minimal model is widely used to evaluate insulin action on glucose disappearance from frequently sampled intravenous glucose tolerance tests (FSIGT). The common protocols are a regular (rFSIGT, single injection of 0.3 g/kg of glucose) and an insulin-modified test (mFSIGT, with an additional insulin administration at 20 min). This study compared the insulin sensitivity index (SI) and glucose effectiveness (SG) obtained in the same individual (16 normal subjects) with the two tests. SI was 7.11 ± 0.80 10−4 ⋅ min−1 ⋅ μU−1 ⋅ ml in rFSIGT and 6.96 ± 0.83 in mFSIGT ( P = 0.656), regression r = 0.92, P < 0.0001; SG was 0.0260 ± 0.0028 min−1 and 0.0357 ± 0.0052, respectively, statistically different ( P = 0.013) but still with a good regression ( r = 0.66, P = 0.0051). SG and insulin amount during the early period correlated ( r = 0.6, P = 0.015 in rFSIGT and r = 0.76, P = 0.0006 in mFSIGT). In summary, both FSIGTs with minimal model analysis provide the same SI, which is a very robust index. SG was different by 28% due probably to the relationship between SG and the amount of circulating insulin. In studies comparing groups, the simpler rFSIGT can still be used with the advantage of accounting for endogenous insulin, thus offering the possibility of direct inferences on the β-cell activity.

To determine the effects of physiological and pharmacological insulin concentrations on leucine-carbon kinetics in vivo, eight postabsorptive normal volunteers were infused with L-[4,5-3H]leucine and alpha-[1-14C]ketoisocaproate (KIC). Insulin concentrations were sequentially raised from 8 +/- 1 to 43 +/- 6 and 101 +/- 14 and to 1,487 +/- 190 microU/ml, while maintaining euglycemia with adequate glucose infusions. At the end of each 140-min insulin-infusion period, steady-state estimates of leucine and KIC rates of appearance (Ra), KIC (approximately leucine-carbon) oxidation, nonoxidized leucine-carbon flux [an index of leucine incorporation into protein (Leu----P)], and leucine and KIC interconversion rates were obtained. After the three insulin infusions, leucine Ra decreased by a maximum of approximately 20%. KIC Ra decreased by a maximum of approximately 50%. The sum of leucine plus KIC Ra in the basal state was 2.59 +/- 0.24 mumol X kg-1 X min-1 and decreased by approximately 30% at the maximal insulin concentrations. KIC oxidation decreased by a maximum of approximately 65%. Leu----P did not increase after hyperinsulinemia. Interconversion rates were promptly and markedly suppressed by 50-70%. Leucine clearance increased by approximately 120%. We conclude that euglycemic hyperinsulinemia, at physiological and pharmacological concentrations, decreased leucine and KIC concentrations, leucine-carbon turnover and oxidation, and leucine and KIC interconversions in a dose-dependent manner in vivo.