P. M. Piatti

Hypocaloric high-protein diet improves glucose oxidation and spares lean body mass: Comparison to hypocaloric high-carbohydrate diet

The aim of the study was to investigate the effects of two hypocaloric (800-kcal) diets on body weight reduction and composition, insulin sensitivity, and proteolysis in 25 normal glucose-tolerant obese women. The two diets had the following composition: 45% protein, 35% carbohydrate (CHO), and 20% fat (HP diet, 10 subjects), and 60% CHO, 20% protein, and 20% fat (HC diet, 15 subjects); both lasted 21 days. A euglycemic hyperinsulinemic (25 mU/kg/h) clamp lasting 150 minutes combined with indirect calorimetry was performed before and after the diet. Both diets induced a similar decrease in body weight and fat mass (FM), whereas fat-free mass (FFM) decreased only after the HC diet. 3-Methylhistidine (3-CH3-HIS) excretion was reduced by 48% after the HP diet and remained unchanged after the HC diet (P < .05). A significant correlation was found between the changes in FFM and in 3-CH3-HIS excretion after the diet (rs = .50, P < .02). Blood glucose remained unchanged, while insulin decreased in both diets. Free fatty acids (FFA) significantly increased only after the HC diet (P < .05). During the clamp period, glucose disposal and glucose oxidation significantly increased after the HP diet and significantly decreased after the HC diet. Opposite results were found when measuring lipid oxidation. In conclusion, our experience suggests that (1) a hypocaloric diet providing a high percentage of natural protein can improve insulin sensitivity; and (2) conversely, a hypocaloric high-polysaccharide-CHO diet decreases insulin sensitivity and is unable to spare muscle tissue.

Forearm insulin- and non-insulin-mediated glucose uptake and muscle metabolism in man: Role of free fatty acids and blood glucose levels

Muscle can utilize glucose by two different mechanisms, one non-insulin-mediated and the other insulin-mediated. The aim of this study was to investigate and to quantify the influence of high and low free fatty acids (FFA) levels on muscle non-insulin-mediated glucose uptake (MNIMGU) and muscle insulin-mediated glucose uptake (MIMGU) and on muscle metabolism during euglycemia and hyperglycemia. Six healthy volunteers were submitted, in a random order, to a 2-hour euglycemic clamp (EC) followed by a 2-hour hyperglycemic (11 mmol/L) clamp (HC) under five different conditions: (1) somatostatin infusion (SRIF, 500 micrograms/h); (2) SRIF infusion preceded by a nicotinic acid analogue (acipimox, 250 mg orally, (3) SRIF plus insulin infusion; (4) SRIF plus insulin plus intralipid infusion; and (5) SRIF plus insulin infusion plus acipimox. In the postabsorptive state MNIMGU represented 71% of the total muscle glucose uptake (MGU) and during the EC a sharp reduction of FFA levels increased the MNIMGU by 10% (P less than .05), and an acute increase in FFA levels decreased the MNIMGU by 26% (P less than .05). MIMGU was significantly increased by 103% after acipimox administration (P less than .05) and was decreased by 65% during intralipid infusion (P less than .05). During HC, MNIMGU was not significantly influenced by low or high FFA levels, and MIMGU was not affected by a sharp lowering of FFA levels, but was significantly decreased (85%) during intralipid infusion. There was no significant difference in the lactate, pyruvate, and alanine balance across the forearm during EC and HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an acute increase in plasma triglyceride levels on glucose metabolism in man

The aim of the study was to evaluate the effects of an acute increase in triglyceride levels induced by Intralipid (Kabivitrum, Stockholm, Sweden) infusion on forearm glucose uptake, glucose oxidative metabolism, and hepatic glucose production independent of circulating free fatty acid (FFA) levels in man. Six normal subjects underwent three different tests in random order. Each test consisted of a control period of 120 minutes followed by a euglycemic, hyperinsulinemic clamp lasting 120 minutes. In test 1, a high-dose intravenous Intralipid infusion was performed to increase triglyceride and FFA levels. In test 2, heparin (30 U/min) plus low-dose Intralipid infusions were performed to maintain triglyceride at normal levels and increase only FFA levels. Test 3 was performed as a control study. During the 120-minute control period, forearm glucose uptake and hepatic glucose production were not affected by increasing only FFA levels (test 2) or FFA and triglyceride levels (test 1) as compared with the control study. On the contrary, glucose oxidation was significantly decreased as compared with the control study during tests 1 and 2, without a further significant decrease during simultaneously increased FFA and triglyceride levels. Concomitantly, lipid oxidation was similar in tests 1 and 2, at values significantly greater than in test 3. During the euglycemic clamp, forearm glucose uptake and glucose oxidation were significantly lower during tests 1 and 2 than test 3. At variance with the control period, the increase of triglyceride levels during test 1 caused a significant 30% to 40% decrease of both parameters as compared with test 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an acute decrease in non-esterified fatty acid levels on muscle glucose utilization and forearm indirect calorimetry in lean NIDDM patients

SummaryThe aim of the study was to evaluate an acute decrease in NEFA levels during an oral glucose tolerance test and its effects on glucose tolerance, muscle glucose uptake and muscle indirect calorimetry in ten lean non-insulin-dependent diabetic subjects. Two 75-g oral glucose tolerance tests were performed in random order. Placebo or 250 mg acipimox (to inhibit lipolysis) were administered orally 2 h before the start of the oral glucose tolerance test. Two hours after acipimox administration (time 0), non-esterified fatty acid, glycerol and 3-hydroxybutyrate levels decreased by 84, 68 and 77% respectively, compared to basal levels. Concomitantly, muscle lipid oxidation and non-oxidative glycolysis also decreased significantly. After placebo administration, non-esterified fatty acids, glycerol and 3-hydroxybutyrate and lipid oxidation increased by 29, 28, 106 and 33%, respectively (NS vs basal levels; p<0.001 vs acipimox). There was a negative rate of net glucose storage (interpreted as glycogenolysis) during post-absorptive conditions and at time 0 after administration of both drugs. After oral glucose tolerance test, the incremental areas of blood glucose and insulin were significantly decreased by 18 and 19% after acipimox compared to placebo. In addition, the ratio between the incremental area of forearm muscle glucose uptake and the insulin levels was significantly increased by 45% during acipimox compared to placebo administration. Glucose oxidation and non-oxidative glycolysis were significantly higher while lipid oxidation was significantly lower after acipimox than after placebo. In conclusion, our study found that in lean non-insulin-dependent diabetic subjects, an acute decrease in non-esterified fatty acid levels improves glucose tolerance, muscle glucose uptake, glucose oxidation and non-oxidative glycolysis, but is unable to normalize glucose storage.

The continuous low dose insulin and glucose infusion test: a simplified and accurate method for the evaluation of insulin sensitivity and insulin secretion in population studies

In this study we investigated a simple nonlabor-intensive method to evaluate insulin sensitivity and beta-cell function which is suitable for application in population studies. The method is a refinement of the modified Harano test and consists of a continuous low dose insulin (25 mU/kg.h) and glucose (4 mg/kg.min) infusion test (LDIGIT) lasting 150 min. Insulin sensitivity was evaluated as the MCR of glucose divided by the steady state serum insulin level achieved at the end of the test. Insulin secretion was expressed as the incremental area for C-peptide concentration during the first 15 min of the test. We compared the indices of insulin sensitivity and insulin secretion yielded by LDIGIT with those derived from the euglycemic clamp and the hyperglycemic clamp, respectively. Fifty-four subjects underwent a LDIGIT (33 with normal glucose tolerance and 21 with impaired glucose tolerance); of the 54, 19 were submitted to a euglycemic clamp, 18 to a hyperglycemic clamp, and 10 to a modified Harano test (insulin infusion, 50 mU/kg.h; glucose infusion, 6 mg/kg.min). LDIGIT overcame the drawbacks associated with the modified Harano test because it resulted in more stable final glucose levels and prevented the occurrence of hypoglycemic episodes. No significant differences were found between the insulin sensitivity index (ISI) of the LDIGIT and that of the euglycemic clamp for each group of subjects. Moreover, there was a strong correlation between the ISI determined by LDIGIT and the ISI determined by clamp (r = 0.90; P < 0.0001), and the best regression line was not different from the identity line, suggesting that the two indices are equivalent. The index of insulin secretion provided by LDIGIT correlated well with that of the hyperglycemic clamp (r = 0.82; P < 0.001) and was significantly higher in overweight subjects than in normal weight subjects. In conclusion, LDIGIT is a simple and accurate method to assess insulin sensitivity and secretion. It can be useful in population studies and in situations when more complex techniques are not feasible.

A sensitive and reliable method for assaying true human insulin without interaction with human proinsulin-like molecules.

In the present study our interests focused on the evaluation of a high capacity assay (MEIA) which allows true insulin determinations in the absence of cross-reactivity with proinsulin-like molecules. This method was compared to a commercially available radioimmunoassay (RIA) for insulin determination. As the latter gives insulin levels which represent a mixture of insulin and proinsulin-like molecules, the proinsulin-like molecules were quantitated by subtracting the true insulin levels measured using MEIA from the total insulin levels obtained using RIA. These methods were applied for the analysis of blood samples drawn in 63 normal subjects, 16 obese subjects, 3 patients submitted to islet transplantation and 4 patients with insulinoma. The MEIA was precise, fully automated and time-saving, making its application on a routine basis particularly attractive. MEIA and RIA were equally able to correctly quantify human insulin molecules. On the contrary, the antibody present in the true insulin assay did not interact with proinsulin-like molecules, which were recognized even in the presence of increasing insulin levels. In normal subjects, the true and total insulin levels in the fasting state and at the time peak after glucose-or arginine-induced endogenous insulin release were well correlated atr=0.88 and 0.89, respectively. Interestingly, total insulin values were overestimated by 10%–16% as compared with true insulin levels, which represent proinsulin values superimposable on previously reported data. Proinsulin-like molecules made up 50% of the total insulin in obese and transplanted patients, and about 70% in patients with insulinoma. In conclusion, the present study describes a precise, sensitive, fully automated and time-saving method for true insulin determination which is competitive with previously published methods. By subtracting the immunoreactivity measured in the insulin RIA and the insulin MEIA, we obtained the proinsulin-like molecule levels in the range previously reported for normal and obese subjects and patients with insulinoma, and provided a new insight into islet-transplanted patients.

Hypoglycaemia and Lactic Acidosis in a MALT Non Hodgkin's Lymphoma

Hypoglycaemia associated with lactic acidosis is a rare complication of lymphomas; only four cases have been previously reported. Recent studies provide evidence of direct consumption of glucose by the tumour cells, leading to lactic acidosis. We report the case of a 64-year-old patient with a gastric diffuse large B cell non-Hodgkins lymphoma transformed from an indolent mucosa associated lymphoid tissue (MALT) lymphoma, admitted to our department for acute renal failure due to a tumour lysis syndrome. After recovery from renal failure, she developed severe hypoglycaemia and lactic acidosis refractory to therapy. She died after the onset of shock and coma.

Hyperinsulinemia Decreases Second-Phase But Not First-Phase Arginine-Induced Insulin Release in Humans

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU · kg−1 · min−1) and a high-dose (1.20 mU · kg−1 · min−1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means ± SE) 60.0 ± 2.4, 165.6 ± 1.8, and 455.4 ± 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 ± 10.1, 73.7 ± 12.8, and 73.4 ± 10.3 pmol/kg, whereas second phase was 266.1 ± 46.0, 143.1 ± 33.5, and 133.0 ± 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively. We conclude that second-phase, but not first-phase, arginine-induced insulin release is modulated by the pre-stimulus insulin levels. In addition, the inhibitory effect exerted by insulin on second-phase insulin response to arginine appears to be maximized at insulin levels only four times basal.

Effect of the withdrawal of phenformin on glycaemic control and on lactate production during exercise in non-insulin dependent diabetics

SummaryTo evaluate the metabolic effects of phenformin in non-insulin-dependent diabetics, 9 patients who had been treated for a long time with associations of sulphonyl-ureas and phenformin were submitted to exercise on a cycloergometer before and 7 days after the withdrawal of phenformin. Greater lactate production and lactate/pyruvate ratio during exercise without phenformin were observed in 8 of the 9 subjects, concomitant with worsened glycaemic control. The reverse was observed in 1 subject. In the 8 subjects, lactate and the lactate/pyruvate ratio approximated to the values observed in 8 well-controlled diabetics during phenformin treatment and to those observed in 9 poorly-controlled subjects after the withdrawal of phenformin. It is suggested that phenformin facilitates glucose utilization in non-insulin-dependent diabetics provided that it lowers their glycaemic profiles.