Antonino Scarfone

Insulin Clearance in Obesity

Insulin uptake and degradation is a complex and not yet completely understood process involving not only insulin sensitive tissues. The most important degradative system is insulin degrading enzyme which is a highly conserved metalloendopeptidase requiring Zn++ for its proteolytic action, although protein disulfide isomerase and cathepsin D are also involved in insulin metabolism. The liver and the kidney are the principal sites for insulin clearance. In obese subjects with hyperinsulinemia and high levels of free fatty acids, insulin hepatic clearance is impaired, while the glomerular filtration rate, renal plasma flow and albumin excretion are increased, suggesting a state of renal vasodilatation leading to an abnormally transmitted arterial pressure to the glomerular capillaries through a dilated afferent arteriole. Insulin can be cleared also by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes which contain insulin receptors and internalization and regulation mechanism for insulin metabolism.

Sex hormone-binding globulin levels and cardiovascular risk factors in morbidly obese subjects before and after weight reduction induced by diet or malabsorptive surgery

One of the main goals of weight reduction in morbidly obese subjects is its benefit on coronary heart disease (CHD) risk. A cross-sectional study was designed to randomly assign 79 morbidly obese subjects (27 men and 52 women; age: 30-45 years) either to a diet protocol (20 kcal per kg fat-free mass (FFM); 55% carbohydrates, 30% fat, and 15% proteins) or to malabsorptive surgery (biliopancreatic diversion). Fatness parameters, measured by dual-energy X-ray absorptiometry, lipid profile, insulin, leptin, sex steroid hormones and sex hormone-binding globulin (SHBG) levels were compared at baseline and 1 year after the beginning of the study. The data showed that plasma SHBG levels, but not testosterone levels, correlated negatively to fasting insulin levels and positively to HDL-cholesterol in both men and women. Total leptin levels were significantly lower (P<0.0001) in post-BPD subjects of both sexes compared to dietary treated obese subjects. The logarithm of plasma leptin correlated significantly and positively with insulin but negatively with SHBG.A step-down regression analysis showed that FFM and SHBG, but not insulin levels, were the most powerful independent variables for predicting HDL-cholesterol levels in morbidly obese patients. The negative relationship between SHBG levels and CHD risk appears to be mediated by a concomitant variation in body fatness. Finally, in obese patients, SHBG levels seem to be an indicator of total adiposity rather than an index of an altered insulin/glucose homeostasis.

The ingestion of saturated fatty acid triacylglycerols acutely affects insulin secretion and insulin sensitivity in human subjects

To assess the effects of acute dietary saturated fat intake on glucose-induced insulin secretion rate (ISR), measured by the C-peptide deconvolution method, and on insulin clearance and sensitivity, five obese and five normal-weight women (controls) were studied after either a 100 g oral butter load or a 100 ml water load. At 120 min after the oral load a hyperglycaemic clamp was performed over 180 min. A dramatic increase of ISR occurred after butter compared with the water challenge in the controls (1305.6 (SE 124.1) v. 616.1 (SE 52.5) pmol/min; P<0.01) and to a lesser degree in the obese subjects (1975.0 (SE 44.1) v. 1417.5 (se 56.0) pmol/min; P<0.05). Insulin sensitivity was impaired after butter (0.60 x 10(-2) (SE 0.11 x 10(-2)) v. 2.26 x 10(-2) (SE 0.32 x 10(-2)) ml/min per kg FFM per (pmol/l); P<0.01) in the controls but not in the obese group. Insulin clearance during the clamp was reduced after butter compared with after the water load only in the controls (0.89 (SE 0.22) v. 1.70 (SE 0.15) litres/min; P<0.01). The data are consistent with the hypothesis that acute excess lipid availability may lead to a compensatory elevation in glucose-induced insulin secretion as a result of the decline in insulin sensitivity and a reduced insulin clearance.

Low-serum high-density lipoprotein-cholesterol concentration as a sign of celiac disease

TO THE EDITOR: The prevalence of celiac disease (CD) has been reported to be on the rise in both Europe and the United States (1, 2), and an early detection of the disease represents a key factor in the prevention of malignant and nonmalignant complications (3). It has now become evident that CD can be diagnosed not only as the classic malabsorption syndrome, but also as subclinical or silent forms, characterized by few and aspecific or even absent symptoms (3, 4). An alteration in lipid metabolism can easily occur in disorders of the small bowel mucosa, essentially as a consequence of lipid malabsorption and decreased intake (5); in addition, apolipoprotein (Apo)-AI, which constitutes the main portion of high-density lipoprotein-cholesterol (HDL-C) particles is produced at the small bowel level. Therefore, we decided to evaluate the prevalence of CD among patients with low serum HDL-C concentration. Out of the whole patient population referred to the Division of Metabolic Diseases of the Catholic University in Rome from June 1996 to October 1999, consisting of 2189 subjects, 68 patients with serum HDL-C concentration below 1.0 mmol were consecutively enrolled in the study. All patients underwent clinical and biochemical examination and the presence of gastrointestinal symptoms was carefully investigated. All subjects were on a free diet, containing at least 300 mg of cholesterol daily. Exclusion criteria were secondary causes of intestinal atrophy, endocrine disorders, consumption of drugs able to influence data collection, pregnancy, more than 10 cigarettes smoked daily, and inadequate alcohol consumption ( . 20 g/day in women and . 35 g/day in men). None of the patients reported a family history of CD or dyslipidemia. After a 12-h overnight fast, a blood sample was drawn, immediately centrifuged, and stored at 280°C until analysis. Antibodies to gliadin (AGA) were assessed by a microenzyme-linked immunosorbent assay technique and antiendomysium antibodies (EMA) were detected using an indirect immunofluorescence technique. Total cholesterol and triglycerides (TG) were assayed by an enzymatic colorimetric method (Boehringer Mannheim, Mannheim, Germany). HDL-C was enzimatically measured after precipitation of very low– and low-density lipoproteins with heparin-magnesium and plasma Apo-AI concentration was measured by an immunoturbidimetric assay (Boehringer Mannheim, Mannheim, Germany) (6). None of the patients had IgA deficiency. AGA IgG and IgA and EMA IgA were positive in eight patients (12%; three males and five females, aged 34.9 6 3.6 yr) and, after having obtained the patients’ informed consent, all of them underwent an endoscopic and bioptic examination, which revealed a subtotal (n 5 6) or total (n5 2) villous atrophy. Table 1 reports the biochemical values of the eight subjects who were diagnosed as CD patients. Two male patients were overweight (body mass indeces 5 26.7 and 25.6 kg/ m), while the others were normal weighing. Four patients had meteorism and reported occasional abdominal pain, two patients had blood iron concentration below the normal range and one patient had low blood folate concentration. None of the patients had diarrhea. Four of these patients were reexamined after 1-yr treatment with a GFD and biopsy-proven recovery of the intestinal mucosa. Their serum HDL-C and Apo-AI levels were within the normal range (respectively 1.32 6 0.10 mmol and 3.576 0.41 mmol/L). The other subjects will be studied at the 12-month follow-up period. The mechanism at the basis of low HDL-C concentration in the bloodstream of untreated CD patients may be 2-fold.