Giuseppe Benedetti

Reversibility of insulin resistance in obese diabetic patients: role of plasma lipids

Summary The aim of the present study was to measure whole body glucose uptake (M) and oxidation rate by euglycaemic hyperinsulinaemic clamp and indirect calorimetry in 7 morbidly obese subjects (BMI > 40 kg/m2) at three time points: before bilio-pancreatic diversion (BPD) surgery (Ob); 3 months after surgery (POI); and after reaching stable body weight, at least 2 years after surgery (POII). A group of 7 control subjects (C), matched groupwise for sex, age and BMI with POII patients, was also studied. The M value at POI was significantly higher than at Ob (49.12 ± 8.57 vs 18.14 ± 8.57 μmol · kg−1· min−1). No statistical difference was observed between the POII and C groups. Similarly, glucose oxidation rate was significantly increased at POI with respect to Ob (24.2 ± 7.23 vs 9.42 ± 3.91 μmol · kg−1· min−1) and was not significantly different between POII and C. Basal levels of non-esterified fatty acids (NEFA) decreased significantly both from Ob to POI and from POI to POII (1517.1 ± 223.9 vs 1039.6 ± 283.4 vs 616.0 ± 77.6 μmol · l−1). The same applied to basal plasma triglycerides (2.07 ± 0.77 vs 1.36 ± 0.49 vs 0.80 ± 0.19 g · l−1). Weight decreased mainly in the late postoperative period (POI to POII 124.28 ± 11.22 to 69.71 ± 11.78, 83 % of total decrement), rather than in the early postoperative period (Ob to POI 135.25 ± 14.99 to 124.28 ± 11.22 kg, 17 % of total decrement). We also report the clinical case of a young woman of normal weight, who underwent BPD for chylomicronaemia (secondary to familial lipoprotein lipase deficiency), whose M value, plasma insulin and blood glucose levels were normalized upon normalization of serum NEFA and triglyceride levels as determined by the therapeutic lipid malabsorption. In conclusion, in obese diabetic patients lipid malabsorption induced by BPD causes a definite enhancement of insulin sensitivity and glucose tolerance. This improvement in metabolism is noticeable before the surgery has major effects on body weight. These observations suggest that lowered plasma lipids, rather than weight loss per se, are the cause of the reversibility of insulin resistance. [Diabetologia (1997) 40: 599–605]

L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients

OBJECTIVE Aim of the present study is to evaluate the effects of L-carnitine on insulin-mediated glucose uptake and oxidation in type II diabetic patients and compare the results with those in healthy controls. DESIGN Fifteen type II diabetic patients and 20 healthy volunteers underwent a short-term (2 hours) euglycemic hyperinsulinemic clamp with simultaneous constant infusion of L-carnitine (0.28 micromole/kg bw/minute) or saline solution. Respiratory gas exchange was measured by an open-circuit ventilated hood system. Plasma glucose, insulin, non-esterified fatty acids (NEFA) and lactate levels were analyzed. Nitrogen urinary excretion was calculated to evaluate protein oxidation. RESULTS Whole body glucose uptake was significantly (p<0.001) higher with L-carnitine than with saline solution in the two groups investigated (48.66+/-4.73 without carnitine and 52.75+/-5.19 micromoles/kg(ffm)/minute with carnitine in healthy controls, and 35.90+/-5.00 vs. 38.90+/-5.16 micromoles/kg(ffm)/minute in diabetic patients). Glucose oxidation significantly increased only in the diabetic group (17.61+/-3.33 vs. 16.45+/-2.95 micromoles/kg(ffm)/minute, p<0.001). On the contrary, glucose storage increased in both groups (controls: 26.36+/-3.25 vs. 22.79+/-3.46 micromoles/kg(ffm)/minute, p<0.001; diabetics: 21.28+/-3.18 vs. 19.66+/-3.04 micromoles/kg(ffm)/minute, p<0.001). In type II diabetic patients, plasma lactate significantly decreased during L-carnitine infusion compared to saline, going from the basal period to the end-clamp period (0.028+/-0.0191 without carnitine and 0.0759+/-0.0329 with carnitine, p<0.0003). CONCLUSIONS L-carnitine constant infusion improves insulin sensitivity in insulin resistant diabetic patients; a significant effect on whole body insulin-mediated glucose uptake is also observed in normal subjects. In diabetics, glucose, taken up by the tissues, appears to be promptly utilized as fuel since glucose oxidation is increased during L-carnitine administration. The significantly reduced plasma levels of lactate suggest that this effect might be exerted through the activation of pyruvate dehydrogenase, whose activity is depressed in the insulin resistant status.

Body composition and energy expenditure after weight loss following bariatric surgery

Objectives: To assess the effectiveness of biliopancreatic diversion (BPD) in the treatment of morbid obesity and to evaluate how the procedure affects body weight. Subjects: Fourteen morbidly obese subjects studied before and 30 months after BPD and fifteen healthy volunteers matched for age, sex and height (controls). Methods: Comparison of the following parameters were made in the study groups before surgery and 30 months after BPD and with those of the controls group: fat mass, fat-free mass, non-protein substrate oxidation, basal metabolic rate, plasma glucose, insulin and free fatty acid concentrations. Results: Obese subjects lost 60.38±10.71 kg of weight during 18 months following surgery and then remained stable for another 12 months, when this study was performed. Weight loss was substantially due to a loss of fat mass (FM: 60.13±13.01 kg before and 19.02±8.61 kg after BPD; p<0.001). FM were not statistically different between post-obese subjects and controls; however, post-obese patients retained significantly more fat free mass (FFM) than controls. Subsequently, basal metabolic rates of post-obese subjects were higher than those of the control group (p<0.05). Fasting non-protein respiratory quotient (npRQ) was significantly lower before BPD than 30 months after the surgery (0.798±0.04 vs. 0.90±0.048, p<0.001), suggesting that, while obese, patients oxidized more lipids than carbohydrates. Moreover, fasting and two-hour plasma glucose and insulin concentrations decreased significantly after BPD to values comparable to those of the control group. Conclusion: Weight loss in obese patients after BPD is mainly due to lipid malabsorption, but increased energy expenditure associated with retaining a high FFM in physically active post-obese subjects may also play a role, enabling them to maintain long-term reduced body weights.

Normalization of Insulin Sensitivity in the Obese Patient after Stable Weight Reduction with Bilio-Pancreatic Diversion

Insulin resistance is a common feature in obese patients. To evaluate the modifications in insulin sensitivity after a bariatric operation such as Bilio-pancreatic diversion (BPD), three groups of subjects (14 normal controls (N); seven eX-obese patients (X) with at least 2 years at weight-stable conditions after BPD surgery; and eight morbidly obese patients (O)) were studied with intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The ratio of the area under the curve (AUC) for glucose over that of insulin was used as a measure of insulin sensitivity. All the following tests were conducted as Bonferroni-corrected pairwise t-tests, in case overall ANOVA was significant. No significant difference was found between N and X subjects, while obese patients showed a reduced AUCg/AUCi ratio with respect to the normal controls (O vs N: 0.01164 ± 0.00039 vs 0.02392 ± 0.0039, p < 0.05). IVGTT, AUCs: significant differences were found in each case: N vs X: 0.0591 ± 0.0075 vs 0.1402 ± 0.0399, p < 0.05; N vs O: 0.0591 ± 0.0075 vs 0.0223 ± 0.0031, p < 0.01; X vs O: 0.1402 ± 0.0399 vs 0.0223 ± 0.0031, p < 0.05. IVGTT-derived data were also analyzed using the minimal model of glucose kinetics; with this method, glucose effectiveness was significantly different between normal subject and obese subjects (0.0248 ± 0.00288 vs 0.00905 ± 0.00135 per min, p < 0.001). The insulin sensitivity index was not significantly different between normal and ex-obese subjects, while both of these groups were significantly different from obese patients (N vs O: 12.04 × 10−5 ± 2.61 × 10−5 vs 3.29 × 10−5 ± 0.61 × 10−5, p < 0.066; X vs O: 16.42 × 10−5 ± 4.23 × 10−5 vs 3.29 × 10−5 ± 0.61 × 10−5 per min per pM, p < 0.02). In conclusion, the present study indicates that, after a body weight reduction operation capable of almost re-establishing ideal body weight like BPD, obese individuals with a family history of obesity show a normalization of insulin response to glucose load.

Increased resting lipid oxidation in Crohn's disease

Resting energy expenditure (REE) was measured by indirect calorimetry and body composition was assessed by both direct (bioimpedance) and indirect (anthropometry) methods in 20 hospitalized patients with biopsy-proven ileal Crohns disease and in a group of 16 healthy volunteers matched for sex, age, and height with the patient group. The Crohns disease activity index was below 120 in all patients studied. who were treated with a low dose of corticosteroids (0.2–0.3 mg/kg body wt of prednisone). The average weight of Crohns patients was signficantly lower than that of controls (55.70 vs 70.50 kg,P<0.001) due to both lower fat mass (9.97 vs 18.30 kg,P<0.001) and lower lean body mass (45.72 vs 52.20 kg,P<0.02). The average REE was significantly higher in the control group (1785.42±7.503 vs 1559.1±48.39 kcal/day,P<0.001). However, these differences disappeared when REE was normalized by lean body mass (LBM) (34.49±2.56 vs 34.704±3.75 kcal/kg LBMP=NS). The nonprotein respiratory quotient was significantly lower in the patient group (0.823±0.031 vs 0.882±0.012.P<0.025), indicating an increased lipid oxidation. This increased lipid oxidation might explain the reduced fat stores found in the group of Crohns patients, suggesting also that a sufficiently lipid-rich diet could be useful in their nutritional management.

Vitamin B12 and folic acid plasma levels after ileocecal and ileal neobladder reconstruction

OBJECTIVES To compare the plasma levels of vitamin B12 and folic acid following resection of ileocecal or ileal segments used for orthotopic bladder substitution. METHODS Hemoglobin, hematocrit, and plasma levels of vitamin B12 and folic acid were measured in 34 patients with ileocecourethrostomy (ICUS) and in 16 patients with ileal reservoir (IR), with a mean follow-up of 59.8 +/- 41.9 months. The results were compared with regard to both the type of operation and the length of time since surgery. RESULTS The level of folic acid was normal in all patients. The mean level of vitamin B12 in the ICUS group was 413.67 +/- 160.45 ng/mL compared to 257.63 +/- 121.36 for the IR group. This difference was statistically significant. In the IR group, 18.75% of the patients had a level of vitamin B12 below normal. CONCLUSIONS There is a tendency for vitamin B12 levels to fall in patients in whom the ileum is used. Resection of the ileocecal segment including the junction does not alter the level of vitamin B12.

Acid-base and electrolyte balance in urinary intestinal orthotopic reservoir: ileocecal neobladder compared with ileal neobladder

OBJECTIVES To compare acid-base and electrolyte balance in ileocecal and ileal neobladders. METHODS Acid-base and electrolyte balance were studied in 45 patients with an ileocecourethrostomy and 18 patients with an ileal reservoir. The mean follow-up was 51 months. Results were compared with regard to both the type of operation and the time since surgery. RESULTS No significant differences were found with regard to either the type of operation or the length of follow-up. A preserved renal function is important in maintaining a healthy status. CONCLUSIONS The use of 35 to 40 cm of ileum or 10 cm of cecum with the ileocecal junction seems to be safe even after a long follow-up. The length rather than the kind of bowel used for bladder replacement appears to be important in safeguarding hydroelectrolyte and acid-base homeostasis. This is particularly true in the presence of preserved renal function.

A Surgical Option for Familial Chylomicronemia Associated with Insulin-Resistant Diabetes Mellitus

Background: The goal of the present work is to present an effective surgical approach for the treatment of a medically-resisitant form of hyperlipidemia. Methods: Two siblings with familial lipoprotein-lipase deficiency and subsequent hyperchylomicronemia, widespread skin xanthomas and severe insulin-resistant diabetes mellitus came to our observation after several unsuccessful attempts at medical treatment. In order to lower plasma lipids through lipid malabsorption, a modified bilio-pancreatic diversion operation was employed. The rationale in deciding to use this surgical approach was based also on the likely hypothesis that diabetes, in these subjects, was secondary to high circulating and tissue levels of lipids. Insulin sensitivity in the two treated subjects, as well as in 24 healthy volunteers constituting the control group, was assessed by euglycemic hyperinsulinemic clamp and indirect calorimetry, obtaining total end-clamp glucose uptake (M) and end-clamp glucose oxidation (ECGO) rates. Results: Within 3 weeks of surgery, plasma triglycerides and cholesterol levels had decreased from 4500 and 500 mg/dl (with dietary restrictions) to lower than 450 and 150 mg/dl (on a free, lipid-rich diet) respectively. Fasting plasma glucose levels had decreased from above 300 (under daily repeated subcutaneous injections of insulin) to 80-100 mg/dl (without administration of insulin or oral hypoglycemic agents). Body weight and fat free mass were maintained in both subjects after surgery. In both patients, before surgery M and ECGO were significantly lower than in normal subjects, while after surgery they were not significantly different from normal subjects, confirming the positive metabolic effect of the operation. Conclusion: The surgical option used in these patients may represent an interesting and effective new possibility for treatment of those severe cases of hyperlipemia leading otherwise to metabolic complications and a low quality of life.

The metabolic effect of dodecanedioic acid infusion in non-insulin-dependent diabetic patients

Dodecanedioic acid (C12) is an even-numbered dicarboxylic acid (DA). Dicarboxylic acids are water-soluble substances with a metabolic pathway intermediate to those of lipids and carbohydrates. Previous studies showed that contrary to other DAs, very low amounts of C12 are lost with urine. The effects of 46.6 mmol of C12 intravenous infusion for 195 min on blood glucose levels were investigated in five patients with non-insulin-dependent diabetes mellitus (NIDDM), with a good metabolic compensation, and in five healthy volunteers matched for gender, age, and body mass index. Blood samples were taken every 15 min for a period of 360 min to measure glucose, insulin, C-peptide, ketone bodies, and free fatty acid (FFA) levels, and 24-h urine samples were collected to measure C12 and urea excretion. Plasma and urinary C12 concentrations were determined by high-pressure liquid chromatography (HPLC). Indirect calorimetry was continuously performed both basally and during the study period. The average 24-h urinary excretion of C12 was 6.5% versus 6.7% of the administered dose, respectively, in NIDDM patients and in healthy controls. The area under the curve (AUC) values of plasma C12 were 279.9 +/- 42.7 mumol in NIDDM patients and 219.7 +/- 14.0 mumol in controls (P = ns). Plasma glucose levels significantly decreased in NIDDM patients during C12 infusion (from 7.8 +/- 0.6 to 5.4 +/- 0.8 mM at the end of the study period, P < 0.05). Lactate plasma concentration decreased in NIDDM patients from 3.5 +/- 0.2 to 1.5 +/- 0.1 mM (P < 0.001), whereas blood pyruvate increased at the end of the experimental session from 26.0 +/- 11.6 to 99.5 +/- 14.9 microM (P < 0.01). Free fatty acids decreased in diabetic patients from the beginning until the end of C12 infusion, although this difference did not reach statistical significance. No significant increase was found between basal and final values in VO2 consumption and in the values of nonprotein respiratory quotient in both groups of subjects examined. The experimental data indicate that C12 infusion decreases plasma glucose levels in NIDDM patients to normal range without influencing plasma insulin levels. The balance between pyruvate and lactate was affected by C12 infusion only in diabetics patients. C12 might represent a fuel substrate immediately available for tissue energy requirements, especially in conditions such as diabetes mellitus in which glucose metabolism is impaired.

Comparison between dodecanedioic acid and long-chain triglycerides as an energy source in liquid formula diets

BACKGROUND Dicarboxylic acids (DA) are water-soluble substances with high-energy density proposed as an alternative lipid substrate for nutrition purposes. The aim of the present study was to investigate the interaction between glucose and DA or long-chain triglyceride (LCT) metabolism after oral administration. METHODS Two test meals containing either dodecanedioic acid (C12, the 12-atom DA) or LCT, together with glucose and amino acids, were each administered to five healthy volunteers. Tracer amounts of 14C-dodecanedioic acid were added to the C12 meal to recover expired traced CO2 and estimate the minimum rate of C12 oxidation. Glucose, insulin, and C12 plasma levels were measured for 360 minutes after the test meal. Indirect calorimetry was performed for the duration of the study. RESULTS LCTs proved ineffective in promoting their own oxidation after oral administration. On the contrary, C12 was promptly oxidized, a minimum of 21.9%+/-8.3% of the administered amount giving rise to the recovered expired CO2. This difference in metabolic fate was reflected in a sparing effect on glucose: suprabasal respiratory quotient and suprabasal carbohydrate oxidation were significantly (p < .05) lower under C12 administration than under LCT administration, with a difference of 0.024+/-0.015 in respiratory quotient (RQ) and a difference of 0.791+/-0.197 kJ/min in carbohydrate oxidation. In particular, carbohydrate oxidation increased by 54% over basal with LCT but only by 28% with C12 administration. RQ increased over basal by 5.8% with LCT but only by 3.0% with C12 administration. CONCLUSIONS These results show a fundamental metabolic difference between conventional lipids and DAs, which is the basis for a possible role of DAs in clinical nutrition. The fate of spared glucose is likely to be storage in glycogen form when dodecanedioic acid is made available as an energy source.