Combination of continuous subcutaneous infusion of insulin and octreotide in Type 1 diabetic patients.

The effect of 7 day continuous subcutaneous infusion of octreotide (200 microg day(-1)) was evaluated in seven insulin-pump treated Type 1 diabetic patients (age 43+/-1.5 year; BMI 25.1+/-0.7 kg m(-2); HbA(1c) 7.4+/-0.3%). A 24-h metabolic and hormonal profile, and a euglycaemic hyperinsulinaemic clamp (0.25, 0.5, 1.0 mg kg(-1) min(-1)), with [3H]glucose infusion and indirect calorimetry, were performed before and after a 7-day octreotide infusion. Mean 24-h plasma glucose was similar before and after octreotide (9.7+/-0.8 vs. 9.1+/-1.0 mmol l(-1)) but insulin requirement dropped by 45% (49+/-4 vs. 27+/-2 U day(-1); P<0.01). Both 24-h plasma hGH and glucagon were suppressed by octreotide (1.85+/-0.35 vs. 0.52+/-0.04 microg l(-1), and 117+/-23 vs. 102+/-14 ng l(-1), respectively). Glucose utilisation increased after octreotide (insulin 0.5 mU kg(-1) min(-1) clamp 3.09+/-0.23 vs. 4.19+/-0.19 mg kg(-1) min(-1); 1 mU kg(-1) min(-1) clamp 5.64+/-0.61 vs. 7.93+/-0.57 mg kg(-1) min(-1); both P<0.05) and endogenous glucose production was similarly suppressed. Glucose oxidation was not affected by octreotide, while the improvement in glucose storage (insulin 1.0 mU kg(-1) min(-1) clamp 3.89+/-0.60 vs. 5.64+/-0.67 mg kg(-1) min(-1), P<0.05) entirely accounted for the increase in glucose disposal. Endogenous glucose production was more effectively suppressed at the two lower insulin infusion rates (P>0.05). Energy expenditure declined after octreotide. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage, and reduces energy expenditure. These results support a role for counterregulatory hormones in the genesis of insulin resistance and the catabolic state of Type 1 diabetes.

Effects of metformin treatment on whole-body and splanchnic amino acid turnover in mild type 2 diabetes.

The effects of metformin therapy on whole body and splanchnic amino acid turnover are not known. Therefore, we have studied fasting and postprandial phenylalanine kinetics in type 2 diabetic subjects (non-insulin-dependent diabetes mellitus), previously treated with diet only, both before and after 4 weeks of either metformin (850 mg twice a day) (n = 11) or placebo administration (n = 6). Phenylalanine kinetic was evaluated by means of a multiple isotope technique: tritiated phenylalanine was infused i.v., whereas carbon-labeled phenylalanine was incorporated into a chemically-defined meal. Compared with placebo, metformin administration decreased both fasting (from 162 +/- 17 to 141 +/- 20 mg/dl) and postprandial (from 217 +/- 20 to 164 +/- 20 mg/dl) glucose concentrations (P < 0.05-P < 0.01). Fasting insulin concentrations were unaffected, but postmeal insulin tended to be lower (P < 0.06) after metformin. Compared with the pretreatment period, metformin administration did not change total phenylalanine rate of appearance (fasted state, 0.74 +/- 0.10 vs. 0.71 +/- 0.08 mumol/kg.min; fed state, 0.77 +/- 0.10 vs. 0.75 +/- 0.08 mumol/kg.min, respectively), dietary and endogenous phenylalanine rate of appearance, dietary phenylalanine oxidation, and splanchnic uptake, similar to what was observed in the placebo group. Our data indicate that, at least after a 4-week treatment, metformin does not affect fasting and postprandial protein turnover, as indicated by phenylalanine data, in subjects with mild non-insulin-dependent diabetes mellitus.

Fasting and postmeal phenylalanine metabolism in mild type 2 diabetes.

We have investigated postabsorptive and postprandial phenylalanine kinetics in non-obese type 2 diabetic patients [non-insulin-dependent diabetes mellitus (NIDDM)], using a double-isotope technique and the constant oral administration of a synthetic mixed meal. Fasting and postmeal glucose levels were increased (P < 0.01) in NIDDM (165 +/- 16 to 226 +/- 24 mg/dl), with respect to normal controls (85 +/- 3 to 102 +/- 6 mg/dl). Fasting insulin concentrations were comparable in NIDDM (13 +/- 2 microU/ml) and in normals (12 +/- 2 microU/ml), but after the meal it increased less (P < 0.07) in NIDDM vs. normals (to 36 +/- 5 vs. 56 +/- 12 microU/ml, respectively; P < 0.01 vs. basal for both). Postabsorptive phenylalanine rate of appearance (R(a)) in NIDDM (0.63 +/- 0.08 mumol.kg-1 x min-1) was comparable to that of controls (0.73 +/- 0.05 mumol.kg-1 x min-1, not significant). During the meal, total and endogenous phenylalanine R(a), splanchnic uptake, oxidation, and nonoxidative disposal of the ingested phenylalanine were also comparable in the two groups. These data indicate that fasting and postprandial kinetics of the essential amino acid phenylalanine are normal in NIDDM.

Retrospective analysis of daily glucose profile in type 1 diabetic patients with continuous subcutaneous insulin infusion (CSII).

A retrospective analysis of blood glucose control was performed in 17 type 1 diabetic patients who regularly monitored their blood glucose concentration by visual strips over a period of 3-83 months. Analysis was performed by a patient management software loaded on a personal computer. In this cohort of patients the average daily blood glucose reading was 1.6 +/- 0.3. Blood glucose readings were collected more frequently following meal ingestion (40.3%) than in the post-absorptive state (24.6%; P less than 0.05). Blood glucose concentration fluctuated from a basal level of 146 +/- 5 mg/dl to 167 +/- 4 mg/dl in the post-prandial phases with an average daily value of 156 +/- 2 mg/dl. Blood glucose values below 80 mg/dl were evenly distributed throughout the day, while hyperglycemia (greater than 300 mg/dl) occurred more commonly after meals (42%). Daily blood glucose was higher during weekends (164 +/- 5 mg/dl) than during weekdays (155 +/- 2 mg/dl; P less than 0.05). A weak correlation was found between the number of blood glucose readings/day and daily blood glucose level. These results suggest that long-term maintenance of satisfactory metabolic control is attainable in type 1 diabetic patients and that this is mainly dependent upon subject self awareness.

Leucine and phenylalanine kinetics during mixed meal ingestion: a multiple tracer approach.

To estimate whole body and splanchnic metabolism of dietary amino acids, phenylalanine and leucine kinetics were determined simultaneously in six normal volunteers before and during the constant administration of a complete mixed meal, employing multiple tracers of these amino acids. L-[5,5,5-2H]leucine and L-[2,6-3H]-phenylalanine were infused intravenously; L-[1-13C]leucine and L-[1-14C]phenylalanine were administered orally with the meal. During the meal, steady-state leucine concentration rose from 136 +/- 6 to 190 +/- 14 mumol/l (P less than 0.01), phenylalanine from 44 +/- 4 to 61 +/- 6 mumol/l (P less than 0.01), total leucine rate of appearance (Ra) from 1.29 +/- 0.03 to 1.77 +/- 0.07 (P less than 0.01, +37 +/- 3%), and phenylalanine Ra from 0.73 +/- 0.05 to 0.80 +/- 0.07 mumol.kg-1.min-1 (P less than 0.05, +8 +/- 3%). Splanchnic uptake of dietary phenylalanine was greater (P less than 0.001) than that of leucine (58 +/- 4 vs. 25 +/- 4%, respectively), 44 +/- 3% of circulating leucine derived from the diet vs. 20 +/- 2% of circulating phenylalanine (P less than 0.01). Endogenous leucine and phenylalanine Ra were significantly suppressed (P less than 0.05). In summary: 1) splanchnic uptake of dietary phenylalanine is onefold greater than that of leucine; 2) dietary contribution to systemic phenylalanine Ra is about half of that to leucine Ra; and 3) endogenous appearance of both leucine and phenylalanine after the meal is suppressed. In conclusion, splanchnic metabolism of dietary leucine and phenylalanine differs markedly and can be quantitated in vivo without catheterization.

Effects of insulin and amino acid infusion on leucine and phenylalanine kinetics in type 1 diabetes.

To evaluate the anabolic effects of hyperinsulinemia and hyperaminoacidemia on amino acid (and protein) metabolism in type 1 (insulin-dependent) diabetes mellitus (IDDM), we studied leucine and phenylalanine kinetics in nine IDDM and seven control subjects, both at basal euglycemic conditions and during a euglycemic hyperinsulinemic clamp (approximately 60-80 microU/ml of plasma free insulin), combined with an intravenous infusion of amino acids (AA), which doubled plasma concentrations of most AA. In the basal state, euglycemia was maintained in IDDM subjects at the expense of a peripheral free insulin level (16 +/- 2 microU/ml) greater (P less than 0.05) than controls (9 +/- 1 microU/ml). Despite that, leucine rate of appearance (Ra), alpha-ketoisocaproate oxidation (approximating leucine-carbon oxidation), and nonoxidative leucine disposal, were greater (P less than 0.05) in IDDM than in control subjects. Phenylalanine Ra was slightly but not significantly greater in IDDM vs. control subjects. During the clamp, at comparable plasma free insulin and amino acid concentrations, oxidation was similar in the two groups, endogenous leucine and phenylalanine Ra remained significantly greater (P less than 0.05) in IDDM than in normal subjects, and leucine disposal tended also to be greater in IDDM subjects. Thus, in IDDM subjects maintained at euglycemia, endogenous Ra of essential amino acid(s) (index of endogenous proteolysis) is increased, both in the postabsorptive state and after hyperinsulinemia combined with hyperaminoacidemia, while leucine utilization for protein synthesis is not impaired.

No effects of high-fiber diets on metabolic control and insulin-sensitivity in type 1 diabetic subjects.

The metabolic effects of a three-month treatment with a high-fiber diet (15 grams of guar-gum added to a standard diet) were investigated in seven type 1 diabetic subjects, with a moderately poor metabolic control. HbA1c levels, daily insulin requirement, cholesterol, triglyceride, amino acid and intermediate metabolite concentrations were evaluated before and following the high fiber diet, both in the postabsorptive state at euglycemia and during a euglycemic, hyperinsulinemic, hyperaminoacidemic clamp. Insulin-mediated glucose utilization, an index of insulin-sensitivity, was also measured during the clamp. Following the diet, no differences in HbA1c levels (7.6 +/- 0.7%----7.3 +/- 0.6%), daily insulin requirement (50 +/- 5----51 +/- 3 U/d), triglyceride, amino acid and intermediary metabolite concentrations in the basal, euglycemic state, were observed. Only cholesterol concentrations decreased significantly (from 165 +/- 12 to 142 +/- 12 mg/dl, P less than 0.01) after the diet. During the clamp, the concentrations of all measured substrates were comparable before and after high fiber treatment. Insulin-mediated glucose disposal was also unchanged by guar-gum treatment. Patients' body weights were not modified by the diet. In conclusion, our study shows that a high fiber diet, obtained with the addition of 15 grams of guar-gum to a standard diet, is of no benefit to IDDM either as regards the metabolic control or insulin sensitivity. Only cholesterol levels were decreased. Therefore, the costs and benefits of these diets in the treatment of IDDM should be reconsidered.