In Type 2 diabetic patients, who are poorly controlled despite high-dose s.c. insulin treatment, a period of 2 weeks of euglycaemia achieved by i.v. insulin reverses hyperglycaemia-induced insulin resistance and substantially improves metabolic control. Subsequent CSII treatment, using insulin analogues, appears to maintain improved metabolic control for at least 1 year. This approach is promising but needs further evaluation.

Results from a population-based survey O ur objective was to evaluate the diagnostic proficiency of the World Health Organization (WHO) and the National Cholesterol Education Program (NCEP)-III definitions (1,2) for the metabolic syndrome in a Mexican nationwide, population-based survey. Details of the sampling procedures have been previously described (3). The population was composed of 2,158 men and women aged 20 -69 years sampled after a 9-to 12-h fasting period. For the WHO criteria, insulin resistance was diagnosed if a nondiabetic case had fasting insulin concentrations Ն126 pmol/l (21 U/ml) (Ͼ75th percentile in Mexican adults). The ageadjusted prevalence was 13.61% for the WHO criteria (n ϭ 268) and 26.6% for the NCEP-III definition (n ϭ 574). After excluding patients with diabetes, the prevalence was 9.2 and 21.4%, respectively. The agreement between the definitions was assessed in 1,969 subjects; 189 cases were eliminated due to the lack of a urine sample.The number of abnormal cases was lower using the WHO criteria. Only 237 of the 545 subjects (43.4%) who fulfilled the NCEP criteria were diagnosed as affected using the WHO definition. Just 16 of 253 cases (6.3%) detected by the WHO definition did not fulfill the NCEP definition. The agreement between the criteria was moderate ( ϭ 0.507). On the other hand, the subjects diagnosed using the WHO recommendations had a worse profile than the cases detected by the NCEP-III definition only-they had a higher BMI and higher non-HDL cholesterol, triglyceride, and glucose concentrations. The demonstration of insulin resistance among the nondiabetic population caused the lack of agreement in 202 of the 242 cases that fulfilled the NCEP definition but failed the WHO criteria. Other reasons for disparity were the higher thresholds used by the WHO criteria; these differences explained the lack of agreement in 66 of the 152 cases with diabetes.In conclusion, the prevalence of the metabolic syndrome is influenced by the selection of the diagnostic criteria. The WHO criteria identified a lower number of cases than the NCEP-III definition. These differences were explained mainly by the inclusion of abnormally high insulin concentrations as a diagnostic criterion. However, the presence of insulin resistance may help to identify patients more severely affected (4). We had previously assessed the effect of complete blockade of the renin-angiotensin system (RAS) in patients with advanced diabetic nephropathy (type 2 diabetes) and severe proteinuria (2). To do so, we studied 10 patients on prior treatment with ACE inhibitors at recommended doses, to which 50 mg/day of Losartan was added. CARLOS A. AGUILAR-SALINASAfter 3 months of the combined therapy, urinary protein excretion decreased from a mean of 6.9 (95% CI 4.3-9.6) to 5.8 g/24 h (3-8.6) (P ϭ 0.025) and, with the exception of two patients, was reduced in all cases. The proteinuria/ urinary creatinine ratio also decreased from 7.6 (4.2-11.05) to 6.0 g/g (3.2-8.7) (P ϭ 0.02). In one patient in which proteinuria did not ...

Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 +/- 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during the clamp from 12.7 +/- 5.6 to 22.4 +/- 8.8 micro mol/kg.min (P < 0.0005) and a decrease in insulin requirement from 1.7 +/- 0.9 to 1.1 +/- 0.6 U/kg.d (P < 0.005), whereas metabolic control improved. Surprisingly, both UDP-GlcNAc, from 8.81 +/- 1.21 to 12.31 +/- 2.52 nmol/g tissue (P < 0.005), and UDP-GalNAc concentrations, from 4.49 +/- 0.85 to 5.89 +/- 1.55 nmol/g tissue (P < 0.05) increased. Isoelectric focusing patterns of serum transferrin and excretion of glycosaminoglycans were similar before and after euglycemia. In conclusion, after amelioration of hyperglycemia- induced insulin resistance, UDP-hexosamines increased in skeletal muscle of patients with type 2 DM. These results do not support the hypothesis that accumulation of products of the hexosamine pathway plays a major role in hyperglycemia-induced insulin resistance.

Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r = -0.992; p < 0.0001 for UDP-GlcNAc and r = -0.996; p < 0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 microM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30-40% above baseline values. This led us to conclude that despite exposure of adipocytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.