Simona Frontoni

Effects of Insulin on Cholesterol Synthesis in Type II Diabetes Patients

OBJECTIVE To evaluate the effects of intensive insulin therapy and subsequent optimized metabolic control on daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, and the acute effects of insulin on plasma MVA concentrations in type II diabetes. RESEARCH DESIGN AND METHODS Ten (five men and five postmenopausal women) nonobese, normolipidemic (total cholesterol < 6.2 mmol/l, triglycerides < 2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA1c > 10%, fasting plasma glucose > 11 mmol/l) and receiving sulfonylurea treatment were selected. The 24-h urinary MVA excretion and plasma lipid values were determined before and after intensive insulin therapy. The acute effects of insulin on plasma MVA concentrations were also evaluated during a 3-h euglycemic hyperinsulinemic clamp study. RESULTS Urinary MVA excretion rates (μmol/24h) were 1.82 ± 0.21 in control subjects and 2.49 ± 0.35 (P < 0.01 vs. control subjects) and 1.78 ± 0.28 in patients before and after intensive insulin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respectively, after blood glucose optimization. Acute insulin infusion during the euglycemic clamp studies reduced mean plasma MVA concentrations at 120 and 180 min by 29 and 38%, respectively (P < 0.01 for both vs. baseline). CONCLUSIONS Our study demonstrates that in nonobese, normolipidemic, type II diabetic patients under poor metabolic control, an increased cholesterol synthesis is normalized by insulin therapy. Hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of MVA, the immediate product of hydroxymethylglutaryl-CoA reductase activity and an index of whole-body cholesterol synthesis.

Carbohydrate metabolism in hypertension: influence of treatment.

Epidemiologic studies suggest a close association between hypertension, obesity, and diabetes. It has been demonstrated that essential hypertension, per se, is an insulin-resistant state. However, the pathogenesis of the association between insulin resistance and hypertension is poorly understood. Elevated plasma insulin levels may contribute to the development of hypertension through renal sodium reabsorption. the sympathetic nervous system, the transmembranous cation transport, the renin-angiotensin system, the cardiovascular reactivity, and the atrial natriuretic peptide. Diuretics. β-blockers. calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and α1-antagonists are first-choice drugs in the management of hypertension. Diuretics, except indapamide, impair insulin sensitivity and glucose tolerance. The same negative effects, exerted by β-blockers, are reduced employing those with selective activity. With few exceptions, calcium antagonists have no adverse influence on carbohydrate metabolism. ACE inhibitors and α1-antagonists do not influence or even improve glucose metabolism.

Regression of microalbuminuria in type II diabetic, hypertensive patients after long-term indapamide treatment

The influence of hypertension on the progression of persistent microalbuminuria in type II diabetes has not yet been clarified. We have studied the effects of 36 months of indapamide treatment (2.5 mg once daily) on blood pressure (BP), albumin excretion rate (AER), urinary immunoglobulin G4 (IgG4), and glomerular filtration rate (GFR) in 10 patients who were mildly hypertensive and had type II microalbuminuric diabetes (AER greater than 30 mg/24 hours and less than 300 mg/24 hours). BP, AER, and IgG4 significantly decreased after 6 months until the end of the study. Mean GFR was 94.4 +/- 7.5 ml/min/1.73 m2 in the baseline and did not change significantly throughout the course of the antihypertensive therapy. AER and IgG4 were directly related (r = 0.57; p less than 0.004), whereas BP did not relate to GFR, AER, or IgG4. The nephropathy index (45.5 +/- 4 in the baseline) significantly decreased at 12 months (38.7 +/- 2.1), 24 months (35.4 +/- 1.6), and 36 months (36.5 +/- 1.5) (at least p less than 0.01). Long-term indapamide treatment reduced BP and urinary protein loss without affecting GFR. These results indicate a potential role of this drug in the long-term renal protection of patients with type II diabetes, mild hypertension, and microalbuminuria.

New Parameters to Monitor the Progression of Diabetic Nephropathy

The possible differential elimination of the anionic IgG4 and of the other cationic IgG molecules whose pH differs but whose other characteristics are similar, has been hypothesized as a possibly useful parameter in monitoring preclinical diabetic nephropathy. An enzyme-linked immunosorbent assay method has been developed, based on a sandwich technique with subclass-specific antiimmunoglobulin monoclonal antibodies, which detects about 2 ng/mL IgG4. A sensitive radioimmunoassay method has been used to detect IgG. Normoalbuminuric, microalbuminuric, and macroalbuminuric patients, together with normal control subjects, were included in the cross-sectional study. Whereas IgG levels were elevated, as expected, in macroalbuminuric patients, it was interesting to note that IgG4, but not total IgG, levels were elevated in microalbuminuric patients. The IgG4/IgG ratio was increased almost to the same extent in microalbuminuric and macroalbuminuric patients. These findings are strongly in favor of the selective elimination of the acid medium-sized protein, IgG4, in incipient diabetic nephropathy. The measurement of immunoglobulin subclasses in the urine appears to be a promising parameter to characterize and subgroup diabetic patients with preclinical diabetic nephropathy.

Anionic versus cationic immunoglobulin clearance in normal subjects : a novel approach to the evaluation of charge permselectivity

The excretion of proteins differing in charge (the different immunoglobulin subclasses) and/or size (albumin, immunoglobulins) were investigated in normal subjects in a number of physiological conditions aiming at the evaluation of renal charge permselectivity. In 101 randomly selected normal subjects the urinary excretion rates of albumin, IgG4 (anionic proteins) and of total IgG (mostly cationic) were evaluated in basal conditions; the protein/creatinine urinary ratio and protein clearances were assessed in part of them. In addition, the intra- and interday variations of protein excretion were evaluated. Protein clearances were measured in a sample group after standardized physical exercise, after an amino acid load, and in orthostatism. Albumin, IgG4 and IgG were assayed using sensitive methods developed in our laboratories. The excretion rate values of albumin, IgG4 and total IgG (median, interquartile range) were 4.36 micrograms/min, (2.58-6.59), 4.25 ng/min (2.6-7.6), and 1.47 micrograms/min (0.85-2.44), respectively. The clearances of the three proteins (mean +/- SD) were 0.13 +/- 0.07, 0.017 +/- 0.012 and 0.14 +/- 0.08 ml/min x 10(-3), respectively. The IgG4/IgG ratio averaged 0.1 and was always below 0.25. Protein excretion rates showed a noticeable variation during the day and from day to day. Physical exercise, the change of posture and the amino acid load significantly increased proteinuria but did not significantly modify the anionic/cationic immunoglobulin ratio. Thus, the anionic/cationic immunoglobulin ratio of about one tenth, substantially stable during dynamic tests, in normal subjects may be considered an index of physiological renal protein charge permselectivity.

The selective elimination of anionic immunoglobulins as a parameter of kidney damage in diabetes and diabetic pregnancy

IgG1 and IgG4 have similar molecular weights but differ in pH (about 9 and 4.6, respectively). Their different rates of excretion in the urine of diabetic patients may indicate an impairment of charge selectivity in the kidney filter. Working on this hypothesis, a sensitive new ELISA for the detection of urinary IgG4 has been developed. This method can detect less than 1 ng/ml of this immunoglobulin; total IgG was detected by a RIA method developed by our laboratory. Twenty-eight Type I diabetic patients with or without clinical nephropathy were included in a cross-sectional study. An additional seven diabetic patients were followed over time, and eight diabetic pregnant women were studied during the different trimesters of pregnancy. Whereas both IgG4 and total IgG values were increased in clinically nephropathic patients, levels of IgG4, but not IgG1-3, were enhanced in patients without clinical nephropathy. In the latter group as well, IgG4-positive patients were microalbuminuric; all but one of the remaining patients were IgG4 and albumin negative. There was no significant variation in IgG4 values with time on repeated samples. The increased glomerular filtration rate in diabetic pregnancy did not significantly modify the levels of IgG4 in the urine. These results are in accordance with a selective excretion of this medium to large sized anionic protein (IgG4) in incipient (or stage III) diabetic nephropathy. Urinary IgG4 could be an additional useful marker when studying diabetic patients with early and pre-clinical stages of diabetic nephropathy.

Position Statement on the management of continuous subcutaneous insulin infusion (CSII): The Italian Lazio experience

This document has been developed by a group of Italian diabetologists with extensive experience in continuous subcutaneous insulin infusion (CSII) therapy to provide indications for the clinical management of CSII in diabetic patients (both type 1 and type 2) based on delivery mode operating in Italy. Although the potential benefits of pump therapy in achieving glycemic goals is now accepted, such results cannot be obtained without specific knowledge and skills being conveyed to patients during ad hoc educational training. To ensure that these new technologies reach their full effectiveness, as demonstrated theoretically and clinically, a careful assessment of the overall therapeutic and educational process is required, in both qualitative and quantitative terms. Therefore, to ensure the cost‐effectiveness of insulin pump therapy and to justify reimbursement of therapy costs by the National Health System in Italy, in this article we present a model for diabetes and healthcare centers to follow that provides for different levels of expertise in the field of CSII therapy. This model will guarantee the provision of excellent care during insulin pump therapies, thus representing the basis for a successful outcome and expansion of this form of insulin treatment in patients with diabetes while also keeping costs under control.