Dietary (n-3) polyunsaturated fatty acids improve adipocyte insulin action and glucose metabolism in insulin-resistant rats: relation to membrane fatty acids.

To study the effects of dietary fish oil on insulin-stimulated glucose metabolism in adipocytes of insulin-resistant rats (rats fed 50% sucrose and 30% fat), eighteen 5-wk-old Sprague-Dawley rats were fed, for 6 wk, a diet containing 30% fat as either fish oil (FO) or a mixture of vegetable and animal oils [control oils (CO)]. A third reference group was fed a standard diet (62% corn starch and 13% fat). At the end of the 6-wk period, the two experimental groups had comparable plasma glucose concentrations that were higher than that found in the reference group. FO feeding corrected the hyperinsulinemia of the experimental rats (P < 0.05) to reach values in the reference group. Plasma triacylglycerol (P < 0.01) and cholesterol (P < 0.001) concentrations were also lower in rats fed FO than in those fed CO. The body weights of FO-fed rats were similar to that of CO-fed rats, but epididymal adipose tissue weight was lower (P < 0.01). Adipocytes of FO-fed rats, compared with those of CO-fed rats, had high insulin-stimulated glucose transport (P < 0.05), oxidation (P < 0.001) and incorporation into total lipids (P < 0.05). The incorporation of (n-3) polyunsaturated fatty acids in adipocyte membrane phospholipids was higher in FO-fed rats than in those fed CO (P < 0.0001). Insulin action was positively correlated with the fatty acid unsaturation index in membrane phospholipids. Thus dietary fish oil has beneficial effects on insulinemia, plasma lipids and insulin-stimulated glucose metabolism in insulin-resistant slightly diabetic rats.

Low-fat (41%) butter consumption decreases total energy and lipid intake in diabetic patients under acute conditions.

Decreasing fat intake in subjects at risk of cardiovascular diseases and particularly diabetics is a major issue. To investigate whether low-fat (41%) butter (LFB) is of any benefit compared to regular butter (RB), 97 hospitalized diabetics (41 insulin-dependent) were studied on four consecutive days. Breakfast (bread, butter and drink) was served at 0830 hrs, on successive mornings. LFB and RB were presented ad libitum, on alternate days. Satiety was assessed at 10 and 12 h, using line rating scales. At 1230 hrs lunch was served, with large servings corresponding to 130% of the recommended lunch intake, so that carry-over effects from the breakfast manipulation could be measured. At breakfast, LFB was consumed in higher amounts, 27 vs. 21 g, F(1,96) = 33.24, p < 0.0001, than RB; however, the energy intake was significantly lower (by about -38%) on LFB days, F(1,96) = 158.3, p = 0.0001. Hunger at 10 h but not at 12 h was affected by breakfast conditions. Lunch intake was comparable following LFB and RB breakfasts. In conclusion, LFB utilization under acute conditions seems to benefit diabetics by reducing caloric and fat intake.

Low-fat (41%) butter use decreases butter lipid intake over 4-week trials in healthy persons.

All members of 18 families (n = 75; ages from 1 to 65 years) participated in a cross-over study of butter usage. Two types of butter were compared: regular (82%) fat) and low-fat (41%) butter. Butter was supplied to the families by the laboratory for use in raw (spread) form over two successive periods of 5 weeks (first week served as training). No other butter was allowed. The number of consumers (75) remained constant throughout the study. Over four consecutive weeks, the families consumed as much low-fat as regular butter (10.70 +/- 1 g versus 10.06 +/- 1.17 g per day per person). However, lipid intake from butter was significantly reduced during the low-fat butter period as compared to the regular butter period (4.39 +/- 0.41 g versus 8.25 +/- 0.96 g per day per person, p = 0.0005). Since previous studies showed that nutrient-specific compensatory intake is unlikely, it is suggested that use of low-fat butter can facilitate a reduction in fat intake over extended periods of time in healthy persons.

A new non-invasive method for treating insulin-reaction: intranasal lyophylized glucagon.

The main therapeutic indication for glucagon is the treatment of hypoglycaemia in insulin overdosed Type 1 (insulin-dependent) diabetic patients. We have previously shown that an intranasal spray of 7.5 mg glucagon with deoxycholic acid as surfactant was able to correct an i.v. insulin-induced hypoglycaemia in diabetic patients. However, bioavailability and stability needed to be improved before intranasal glucagon could be introduced into clinical practice. This has now been achieved with a freeze-dried mixture of glucagon (1 mg) and glycocholic acid (1 mg) as a surfactant. Kinetics and efficacy have been controlled by (1) comparing subcutaneous and intranasal glucagon in 12 healthy non-hypoglycaemic subjects; (2) testing intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by an i.v. bolus of insulin and (3) comparing subcutaneous and intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by adding extra subcutaneous regular insulin to their usual morning dosage. Our results show that 1 mg of intranasal glucagon is as effective as 1 mg of subcutaneous glucagon in terms of the rise in blood glucose. Differences in kinetics between the subcutaneous and the intranasal routes may be observed: intranasal glucagon initiates the blood glucose rise earlier than does the subcutaneous form but the effect of the latter is more sustained. Glycocholic acid appears to be a perfectly tolerated agent in acute conditions. The use of intranasal lyophylized glucagon, for the reversal of hypoglycaemia in Type 1 diabetes, seems to be a clinically relevant alternative to its parenteral equivalent and should now be ready to be introduced in the market.

The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solutin, or gel for the correction of insulin reactions.

Recommendations for the treatment of insulin reactions are based more on habit than data. We investigated the efficacy in correcting blood glucose levels and alleviating clinical symptoms of hypoglycemia of seven orally administered carbohydrates--glucose in solution, tablets, and gel; sucrose in solution and tablets; a hydrolized polysaccharide solution; and orange juice--each of which provided 15 g of carbohydrate. Forty-one type I diabetic patients recently treated with insulin agreed to submit to artificially induced hypoglycemia by an intravenous injection of insulin. Corrective therapy was given when patients experienced symptoms and asked for treatment. Mean blood glucose levels 10 minutes after ingestion were found to be similar whether correction was dispensed with the tablets and the solutions of glucose, those of sucrose, or the polysaccharide preparation. However, almost no increment was obtained at this time point with the gel or the fruit juice. Fifteen and 20 minutes after carbohydrate intake, blood glucose levels were higher with the tablet forms than with the solutions, although differences only became signifiant for sucrose. Glycemic responses were again consistently lower with the sucrose gel and the orange juice. Clinical symptoms were alleviated in 14.0 +/- 0.8 minutes (mean +/- SEM) with sucrose and glucose in solution or tablets. We conclude that in moderately severe hypoglycemia, ingestion of 15 g of carbohydrate in the form of glucose or sucrose tablets or as a solution provides an effective therapy; both sugars seem equivalent. Even if sucrose lumps are better recommended in terms of cost and availability, they may not be recommendable in terms of palatability. Glucose gel or orange juice cannot be recommended, at least in light of our experimental procedure and at the dosage used therein.

[Auto-immune hypoglycemic syndrome induced by pyritinol]. / Syndrome hypoglycémique auto-immun induit par le pyritinol.

The auto-immune hypoglycemic syndrome is characterized by the association of hypoglycemia (clinical and/or biological) and anti-insulin antibodies in patients who have never received exogenous insulin. Initially this syndrome was most often described in Japanese patients some of whom were treated with drugs containing a sulfydril group. We now recall the case of a female caucasian patient treated with Pyritinol for rhumatoid polyarthritis and who presented severe spontaneous hypoglycemia linked with the presence of anti-insulin antibodies in her serum. The level of her antibodies decreased abruptly on suspension of the drug. The recent and more developed characterization techniques of the different forms of circulating insulin and of their antibodies may help to differenciate an auto-immune hypoglycemia from hypoglycemia due to the secret auto-administration of bovine and porcine insuline, and permit us to suggest that an abnormality in the structure of the molecule of insulin might be a cause of this syndrome. However, the exact mechanism of hypoglycemia linked with the presence of anti-insulin auto-antibodies is not yet clear as is the predisposition of a drug with a sulfydril group to induce such an auto-immune phenomenon.

Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin-dependent diabetes.

Glucagon in solution with a surfactant (deoxycholic acid 1% w/v) was administered by intranasal spray to 6 healthy fasting subjects and 6 insulin-dependent diabetics with insulin-induced hypoglycaemia. In the normal subjects, intranasal glucagon increased plasma glucose levels, with a dose-response effect. In the diabetic patients, plasma glucose levels showed a mean increase of 100% above nadir values in approximately 26 min in response to 7.5 mg intranasal glucagon; hypoglycaemic symptoms were relieved within about 7 min. These results suggest that intranasal glucagon is effective and may represent an alternative to parenteral glucagon or glucose or to oral sugar as the first-line treatment of hypoglycaemic episodes in insulin-dependent diabetics.

In vitro and in vivo digestibility and metabolic effects of 3 wheat-flour products (white bread, french toast (rusk) and french toast bran-enriched) in normal subjects.

We devised to study the effects of two technological processings of industrial bread (degree of cooking and enrichment with bran) on in vitro digestibility and repercussions on carbohydrate metabolism in healthy subjects. 3 products were tested in vitro and in vivo: white bread (WB), french toast obtained from the same white bread (FT) and french toast enriched with bran (BFT). In vitro, the percentage of starch hydrolysed was significantly lower for the bran-enriched toast than for WB and FT (p less than 0.001). In vivo, the 3 products and an oral glucose load were given at 08.00 h, after an overnight fast, to 12 healthy volunteers (8 F; 4 M); (age = 24 +/- 1 years; BMI = 21.9 +/- 0.9; mean +/- SEM) on four consecutive days and in random order (latin squares 3 x 4). Each meal contained 35 g carbohydrate and 125 ml water and, for the wheat products, about 190 Kcal. The mean results of the glycemic indexes were: WB = 115 +/- 17%; FT = 99 +/- 21%; BFT = 87 +/- 21% (NS) with the corresponding insulin indexes at 81 +/- 8%, 79 +/- 9% and 90 +/- 8% respectively (NS). The mean plasma glucose and insulin values at 30 minutes did not differ between the three tested foods but were all significantly lower than that observed with glucose (p less than 0.01). Plasma glucose transiently descended below baseline values in all subjects for glucose and BFT. Neither the toasting process nor the presence of wheat bran had any major effect upon hyperglycemia and insulin secretion in the healthy subjects studied.

Plasma insulin and C-peptide levels during continuous subcutaneous insulin infusion.

A study was performed to estimate the absorption kinetics of insulin infused subcutaneously. Four insulin-dependent diabetic subjects had their insulin pumped through a subcutaneously implanted fine polyethylene catheter at a constant rate of 5.0 +/- 0.3 ml/h but at two different insulin concentrations: 218 mU/ml between meals, and 2400 mU/ml at the start of breakfast, lunch, and dinner (lasting 20, 30, and 30 min, respectively). The amount (40 U/day) and distribution of insulin delivered was identical in the four patients in order to facilitate comparison between the subjects. No attempt was made to normalize their blood glucose during the study period. A study of the kinetics of insulin absorption was made by assaying plasma insulin levels; lack of plasma anti-insulin antibodies was verified; plasma C-peptide levels were measured and were far below values observed in the fed state in nondiabetic patients. The mean maximum insulin level reached after switching from low to high concentration insulin was observed 87 +/- 2 min after breakfast, 117 +/- 22 min after lunch, and 125 +/- 20 min after dinner. Differences observed are not significant. These values are similar to those observed after subcutaneous injection of 40 U/ml Regular insulin as a single bolus. After switching from high to low concentration, plasma insulin levels did not return to their basal values before the third or fourth hour. Subcutaneous insulin infusion could be a safe and easy way of insulin administration in an open-loop system; however, this method does not seem to be suitable for a closed-loop system.