Frida Leonetti

Effectiveness of Laparoscopic Sleeve Gastrectomy (First Stage of Biliopancreatic Diversion with Duodenal Switch) on Co-Morbidities in Super-Obese High-Risk Patients

Background: We evaluated laparoscopic sleeve gastrectomy (LSG) on major co-morbidities (hypertension, type 2 diabetes / impaired glucose tolerance, obstructive sleep apnea syndrome (OSAS) and on American Society of Anesthesiologists (ASA) operative risk score in high-risk super-obese patients undergoing two-stage laparoscopic biliopancreatic diversion with duodenal switch (LBPD-DS). Methods: 41 super-obese high-risk patients (mean BMI 57.3±6.5 kg/m2, age 44.6±9.7 years) were entered into a prospective study (BMI ≥60, or BMI ≥50 with at least two severe co-morbidities, no Prader-Willi syndrome, no conversion, minimum follow-up 12 months). 9 patients had BMI ≥60. 17 patients (41.4%) had OSAS on C-PAP therapy. In 10 patients, at least one intragastric balloon had been positioned and 4 had undergone laparoscopic adjustable gastric banding, all with unsatisfactory results. At surgery, 41.5% were classified ASA 4 and 58.5% as ASA 3 (mean ASA score 3.4±0.5). Patients underwent evaluation every 3 months postoperatively and were restaged at 12 months and/or before the second step. Results: 60% of major co-morbidities were cured and 24% improved. Average BMI after 6 and 12 months was 44.5±8.1 and 40.8±8.5 respectively (mean follow-up 22.2±7.1 months). After 12 months, 57.8% of the patients were co-morbidity-free and 31.5% had only one major co-morbid condition. At restaging, 20% of patients were still classified as ASA score 4 (OSAS on C-PAP therapy). 3 patients showed BMI <30 and were co-morbidity-free 12 months after LSG. Conclusions: LSG represents a safe and effective procedure to achieve marked weight loss as well as significant reduction of major obesity-related co-morbidities. The procedure reduced the operative risk (ASA score) in super-obese patients undergoing two-stage LBPD-DS.

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

SummaryTwo study protocols to examine the effects of chronic (72–96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol·kg−1·min−1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20–40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p<0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25–39% (p<0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.

Relationship of thyroid function with body mass index, leptin, insulin sensitivity and adiponectin in euthyroid obese women

Background   A possible relationship between thyroid hormones and adipose tissue metabolism in humans has been suggested.

Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent

Context:The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m−2 also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia.Objective:To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.Participants and methods:The study was carried out in 678 obese Italians (mean BMI=41 kg m−2) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests.Main outcome measures:Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.Results:Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P=2.2 × 10−5 and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (>40 U l−1) compared with 25% of 148I allele homozygotes (P=0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes.Conclusion:Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.

Association of the human adiponectin gene and insulin resistance.

Adiponectin is an adipocyte-secreted protein that modulates insulin sensitivity and whose low circulating concentration is associated with insulin resistance. In the present study, we analysed the association between two single-nucleotide polymorphisms (SNPs) in the adiponectin gene and insulin resistance in 253 nondiabetic subjects. In addition, we investigated whether this association is modulated by body mass index (BMI) levels. The SNPs +45T>G and +276G>T in the human adiponectin gene were detected in real-time PCR with LightCycler. No association was found with the +45T>G SNP. The +276G>T SNP was associated with higher BMI (P<0.01), plasma insulin (P<0.02) and HOMAIR (P<0.02). To analyse the possible interaction between BMI and the adiponectin gene on insulin resistance, the study group was divided into two subgroups, according to the BMI below or above the median of 26.2 kg/m2. In both subgroups, subjects carrying the +276G>T SNP had higher HOMAIR; however, the difference was highly significant among leaner (P<0.001), but not among heavier individuals, indicating that BMI status and the adiponectin gene interact in modulating insulin resistance. Among individuals with BMI <26.2 kg/m2, the relative risk of insulin resistance was 9.7 (CI: 1.32–87.7, P<0.035). In a subgroup of 67 subjects, carriers of the +276G>T SNP had significantly (P<0.05) lower mean serum adiponectin levels (25.7 ng/ml) compared to noncarriers (37.0 ng/ml), suggesting a possible influence of the +276G>T SNP on adiponectin levels. In summary, we observed an association between the +276G>T SNP in the adiponectin gene and insulin resistance. In particular, among leaner individuals, the adiponectin gene appears to determine an increased risk to develop insulin resistance.

Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus

Evidence suggests an association between low serum 25‐hydroxy‐vitamin D3 [25(OH)D3] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated. We evaluated the hepatic expression of VDR along with that of vitamin D 25‐hydroxylases in patients with nonalcoholic steatohepatitis (NASH) or chronic hepatitis C (CHC) and its relationship with hepatic histological features and serum 25(OH)D3 levels. We evaluated 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy for clinical purposes and 20 subjects without liver disease. Serum 25(OH)D3 was measured via colorimetric assay. Expression of VDR, CYP2R1, and CYP27A1 was evaluated via immunohistochemistry in hepatocytes, cholangiocytes, and liver inflammatory cells. Parenchymal and inflammatory cells from liver biopsies of patients with NASH and CHC expressed VDR, CYP2R1, and CYP27A1. In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (P < 0.02), lobular inflammation (P < 0.01), and nonalcoholic fatty liver disease score (P < 0.03). Moreover, expression of CYP2R1 in hepatocytes correlated strongly with VDR positivity on liver inflammatory cells. In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas portal inflammation was significantly higher in patients with VDR‐negative inflammatory cells (P < 0.009) and low VDR expression in hepatocytes (P < 0.03). Conclusion: VDR is widely expressed in the liver and inflammatory cells of chronic liver disease patients and its expression is negatively associated with the severity of liver histology in both NASH and CHC patients. These data suggest that vitamin D/VDR system may play a role in the progression of metabolic and viral chronic liver damage. (HEPATOLOGY 2012;56:2180–2187)

Quality of life and treatment satisfaction in adults with Type 1 diabetes: a comparison between continuous subcutaneous insulin infusion and multiple daily injections.

Aims  The aim of this case–control study was to compare quality of life (QoL) and treatment satisfaction in adults with Type 1 diabetes (T1DM) treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI).

Glucose homeostasis in acromegaly: effects of long‐acting somatostatin analogues treatment

objective  Acromegaly is a syndrome with a high risk of impaired glucose tolerance (IGT) and diabetes mellitus (DM). Somatostatin analogues, which are used for medical treatment of acromegaly, may exert different hormonal effects on glucose homeostasis. Twenty‐four active acromegalic patients were studied in order to determine the long‐term effects of octreotide‐LAR and SR‐lanreotide on insulin sensitivity and carbohydrate metabolism.

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-3H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 μmol/kg · min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 μmol/kg · min), and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 μmol/kg · min) glucose disposal was lower during all three steps (p < 0.05–0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 μmol/kg · min) only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8 ± 1.7 μmol/kg · min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 μmol/kg · min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ± 1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 μmol/kg · min; p < 0.05–0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687–697]

In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia.

SummaryWe tested the hypothesis that glucosamine, a putative activator of glucose toxicity in vitro through acceleration of the hexosamine pathway, may determine in vivo the two key features of glucose toxicity in diabetes, namely, peripheral insulin resistance and decreased insulin secretion. Two groups of awake rats were studied either with intraarterial administration of glucosamine (5 Μmol·kg−1· min−1) or saline. Insulin secretion was determined after arginine, glucose (hyperglycaemic clamp), and arginine/glucose infusions, while insulin-mediated glucose metabolism was assessed by the euglycaemic hyperinsulinaemic clamp in combination with [3-3H]-glucose infusion. Glucosamine had no effects on arginine-induced insulin secretion both at euglycaemia and hyperglycaemia, but significantly (40–50%) impaired glucose-induced insulin secretion (both first and second phases). During euglycaemic hyperinsulinaemic clamp studies, glucosamine decreased glucose uptake by ∼30%, affecting glycolysis (estimated from 3H2O rate of appearance) and muscle glycogen synthesis (calculated from accumulation of [3H]-glucosyl units in muscle glycogen) to a similar extent. Muscle glucose 6-phosphate concentration was markedly reduced in the glucosamine-infused rats, suggesting an impairment in glucose transport/phosphorylation. Therefore, an increase in hexosamine metabolism in vivo: 1) inhibits glucose-induced insulin secretion, and 2) reduces insulin stimulation of both glycolysis and glycogen synthesis, thereby mimicking in normal rats the major alterations due to glucose toxicity in diabetes.