We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r ‫؍‬ 0.44, P ‫؍‬ 0.012) and negatively with podocyte number in proteinuric patients (r ‫؍‬ ؊0.48, P ‫؍‬ 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r ‫؍‬ ؊0.72, P ‫؍‬ 0.002). In conclusion, crosssectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain. Diabetes 51:3083-3089, 2002

In insulin-dependent diabetic (IDDM) patients survival is significantly affected by the development of nephropathy which leads to renal failure and increased cardiovascular mortality [1].Raised albumin excretion rate (AER) per se is strongly related to early cardiovascular morbidity and mortality both in insulin-dependent and non-insulin-dependent (NIDDM) diabetic patients [2,3]. Moreover IDDM patients with microalbuminuria, a Diabetologia (1997) Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 m g/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 m g/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1-107) vs 15.6 (0.2-98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K itt index: 3.7 (0.7-6.2) vs 4.8 (0.7-6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy.

Insulin resistance characterizes type 1 diabetes in patients with albuminuria. A PC-1 glycoprotein amino acid variant, K121Q, is associated with insulin resistance. We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15). Patients carrying the Q allele (n = 22; 20 with KQ and 2 with QQ genotypes) had a faster GFR decline than those patients with the KK genotype (n = 55) (median 7.2 vs. 3.7 m l · min -1 · year -1 ; range 0.16 to 16.6 vs. -3.8 to 16.0 m l · min -1 · year -1 ; P < 0.001). Significantly more patients carrying the Q allele belonged to the highest tertile of GFR decline (odds r a t i o = 5.7, 95% CI 4.1-7.2, P = 0.02). Levels of blood pressure, HbA 1 c , and albuminuria were comparable in the two genotype groups. Albuminuria (P = 0.001), mean blood pressure (P = 0.046), and PC-1 genotype (P = 0.036) independently correlated with GFR decline. Because all patients were receiving antihypertensive treatment, the faster GFR decline in the patients carrying the Q allele could be the result of reduced sensitivity to the renoprotective effect of antihypertensive t h e r a p y. PC-1 genotyping identifies type 1 diabetic patients with a faster progression of diabetic nephr o p a t h y. D i a b e t e s 4 9 :5 2 1-524, 2000 T he rate of progression of diabetic nephropathy (DN) varies greatly among individuals. Differences in environmental factors may explain part of this variability, but genetic factors, which are mostly unknown, also play an important role (1-6).Insulin resistance characterizes type 1 diabetes in patients with albuminuria and their nondiabetic first-degree relatives (7,8) and underlies many of the alterations of DN, including high blood pressure, lipid abnormalities, increased left ventricular mass, and a family history of hypertension and cardiovascular disease (9). These observations suggest that insulin resistance is likely to precede and play a role in the vascular damage of DN. As for DN, insulin resistance also recognizes genetic determinants (10). It is possible, therefore, that DN and/or its progression and insulin resistance share a common genetic background.The molecular mechanisms of insulin resistance are not completely understood (10,11). Recently, the role of specific inhibitors of insulin signaling has been described in human insulin resistance (10,11). These inhibitors include membrane glycoprotein PC-1 (12-16). We have recently reported an amino acid polymorphic variant of PC-1 glycoprotein, K121Q, which is strongly associated with insulin resistance (17). Because of the relationship between insulin resistance and DN, we have examined the impact of the PC-1 Q121 amino acid variant on the rate of DN progression.From January 1995 to April 1997, 77 type 1 diabetic patients with albuminuria attended the diabetes units of five participating centers (as descr...

Diabetic glomerulopathy develops in a subset only of patients with insulin-dependent diabetes (IDDM) and early, in its course, is characterized by cell hypertrophy and by excessive extracellular matrix production. These observations suggest that an alteration in the control of cell growth processes may contribute to its pathogenesis and be related to the susceptibility to kidney disease. We therefore investigated whether the development of diabetic nephropathy is associated with abnormalities of cell growth and morphology. Cultured skin fibroblasts from 14 IDDM patients with nephropathy (DN) were compared with those of 10 IDDM patients without nephropathy (D) and of 14 control non-diabetic subjects (C). Cell volume (in arbitrary units) and total protein content (microgram/10, 000 cells) were increased in serially passaged skin fibroblasts of IDDM patients with nephropathy (DN = 809.5 +/- 33.1 and 1.93 +/- 0.38 vs. D = 764.4 +/- 31.5 and 1.5 +/- 0.37, P = 0.005 and P = 0.03, respectively; vs. C = 756.2 +/- 36.3 and 1.5 +/- 0.38, P = 0.0006 and P = 0.03, respectively). These hypertrophic cells had a tendency to a slower duplication rate and exhibited a dissociation of the DNA and cytoplasmic cell-cycles, resulting in a higher proportion of tetraploid cells (DN = 25 +/- 15% vs. D = 6 +/- 4%, P = 0.005; and vs. C = 10 +/- 8%, P = 0.04). The frequency of terminally differentiated post-mitotic fibrocytes, cells specialized for extracellular matrix production, was higher in patients with nephropathy compared to that of patients without nephropathy and normal controls (DN = 34 +/- 14% vs. D = 21 +/- 10%, P = 0.02; and vs. C = 19 +/- 12%, P = 0.008). That early differentiation was a specific feature of cells derived from patients with diabetic nephropathy was confirmed by the study of cell life-span which demonstrated that these cells aged prematurely (log rank test, chi 2 = 10,012; P = 0.0067). We conclude that an acceleration of cell aging is a peculiar feature of diabetic kidney disease and may contribute to its pathological tissue changes.

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