P. Tessari

Abnormal meal carbohydrate disposition in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy.

Postprandial hyperglycemia in insulin-deficient, insulin-dependent diabetic subjects may result from impaired suppression of endogenous glucose production and/or abnormal disposition of meal-derived glucose. To investigate the relative contributions of these processes and to determine whether 2 wk of near normoglycemia achieved by using intensive insulin therapy could restore the pattern of glucose disposal to normal, meal-related and endogenous rates of glucose appearance were measured isotopically after ingestion of a mixed meal that contained deuterated glucose in seven lean insulin-dependent and five lean nondiabetic subjects. Diabetic subjects were studied once when insulin deficient and again during intensive insulin therapy after 2 wk of near normoglycemia. Total glucose production was determined by using tritiated glucose and the contribution of meal-related glucose was determined by using the plasma enrichment of deuterated glucose. The elevated basal and peak postprandial plasma glucose concentrations (252 +/- 33 and 452 +/- 31 mg/dl) of diabetic subjects when insulin deficient were decreased by intensive insulin therapy to values (82 +/- 6 and 193 +/- 10 mg/dl, P less than 0.01) that approximated those of nondiabetic subjects (93 +/- 3 and 140 +/- 15 mg/dl, respectively). Total and endogenous rates of glucose appearance (3,091 +/- 523 and 1,814 +/- 474 mg/kg per 8 h) in the diabetic subjects were significantly (P less than 0.02) greater than those in non-diabetic subjects (1,718 +/- 34 and 620 +/- 98 mg/kg per 8 h, respectively), whereas meal-derived rates of glucose appearance did not differ. Intensive insulin therapy decreased (P less than 0.01) both total (1,581 +/- 98 mg/kg per 8 h) and endogenous (478 +/- 67 mg/kg per 8 h) glucose appearance to rates that approximated those observed in the nondiabetic subjects, but did not alter meal-related glucose appearance. Thus, excessive entry of glucose into the peripheral circulation in insulin-deficient diabetic patients after ingestion of a mixed meal resulted from a lack of appropriate suppression of endogenous glucose production rather than impairment of initial splanchnic glucose uptake. Intensive insulin therapy restored postprandial suppression of endogenous glucose production to rates observed in nondiabetic subjects.

Inverse relationship of leucine flux and oxidation to free fatty acid availability in vivo.

To determine the effect of fatty acid availability on leucine metabolism, 14-h fasted dogs were infused with either glycerol or triglyceride plus heparin, and 46-h fasted dogs were infused with either nicotinic acid or nicotinic acid plus triglyceride and heparin. Leucine metabolism was assessed using a simultaneous infusion of L-[4,5-3H]leucine and alpha-[1-14C]ketoisocaproate. Leucine, alpha-ketoisocaproate (KIC), and totalleucine carbon (leucine plus KIC) flux and oxidation rates were calculated at steady state. In 14-h fasted animals, infusion of triglyceride and heparin increased plasma free fatty acids (FFA) by 0.7 mM (P less than 0.01) and decreased leucine (P less than 0.01), total leucine carbon flux (P less than 0.02), and oxidation (P less than 0.05). The estimated rate of leucine utilization not accounted for by oxidation and KIC flux decreased, but the changes were not significant. During glycerol infusion, leucine and KIC flux and oxidation did not change. In 46-h fasted dogs, nicotinic acid decreased FFA by 1.0 mM (P less than 0.01) and increased (P less than 0.05) the rate of leucine and total leucine carbon flux, but did not affect KIC flux. Leucine oxidation increased (P less than 0.01) by nearly threefold, whereas nonoxidized leucine utilization decreased. Infusion of triglyceride plus heparin together with nicotinic acid blunted some of the responses observed with nicotinic acid alone. In that changes in oxidation under steady state condition reflect changes in net leucine balance, these data suggest that FFA availability may positively affect the sparing of at least one essential amino acid and may influence whole body protein metabolism.

Regulation of Whole-Body Leucine Metabolism With Insulin During Mixed-Meal Absorption in Normal and Diabetic Humans

To determine the effects of insulin on dietary and endogenous leucine metabolism, five normal subjects, seven insulin-insufficient insulin-dependent (IDDM) diabetic patients, and five diabetic patients controlled with continuous subcutaneous insulin infusion (CSII) were studied before and for 8 h after ingestion of a chemically defined elemental test meal (10 cal/kg) containing crystalline amino acids. L-[1-14C]leucine was included in the meal to trace the entry and oxidation of the dietary leucine. Total (meal + endogenous) entry of leucine into the circulation was estimated with a constant infusion of [2H3]leucine. Postabsorptive and meal-related increases in the plasma leucine concentration were greater (P < .05) in the insulin-insufficient IDDM than in the normal subjects but returned to near-normal values with CSII. Baseline leucine flux was ∼40% greater in the insulin-insufficient IDDM than in normal subjects (2.17 ± 0.17 vs. 1.55 ± 0.15 μmol · kg−1 · min−1, respectively; .05 < P < .01) but were near normal during CSII treatment (1.85 ± 0.25 μmol · kg−1 · min−1). Furthermore, total leucine entry during meal absorption was greater in the insulin-insufficient IDDM (1.41 ± 0.10 mmol · kg−1.8 h−1) than in either normal (0.96 ± 0.08 mmol · kg−1 · 8 h−1, P < .01) or IDDM subjects during CSII treatment (1.09 ± 0.11 mmol · kg−1 · 8 h−1, P < .05). Fractional oxidation (∼40–50%) and entry of dietary leucine were similar in all three groups. The calculated rate of leucine entry from endogenous proteins over the 8 h of study in insulin-insufficient IDDM (1.04 ± 0.12 mmol · kg−1 · 8 h−1) was significantly greater than in normal subjects (0.64 ± 0.07 mmol · kg−1 · 8 h−, P < .01) or in IDDM subjects during CSII treatment (0.76 ± 0.10 mmol · kg−1 · 8 h−1, P < .05). However, during meal absorption, the calculated rate of leucine entry from endogenous protein was significantly suppressed below baseline only in the normal subjects. In summary, during absorption of a mixed meal, 1) one-third of the leucine entering the peripheral plasma space is derived from the diet in normal humans; 2) the rate of absorption and oxidation of dietary leucine in IDDM is normal regardless of adequacy of insulin therapy; and 3) postprandial hyperleucinemia in poorly controlled diabetic patients is at least partly the result of inadequate suppression of the entry rate of leucine from endogenous protein, suggesting persistence of excessive rates of proteolysis, which is at least partly corrected by intensified insulin treatment. Thus, insulin-mediated suppression of endogenous proteolysis is an integral part of protein anabolism during meal absorption.

Effects of a long-acting somatostatin analogue on postprandial hyperglycemia in insulin-dependent diabetes mellitus.

To determine whether an agent such as WY-41,747, a long-acting somatostatin analogue, could be useful as an adjunct to insulin in the treatment of diabetes mellitus, postprandial plasma glucose concentrations were determined in subjects with insulin-dependent diabetes rendered euglycemic with the Biostator insulin infusion device under four conditions: (1) subcutaneous minipump infusion of insulin alone (13 +/- 1 units) over 30 minutes beginning 30 minutes before ingestion of a meal using insulin doses determined by the Biostator; (2) the same conditions as 1 but beginning immediately before meal ingestion; (3) the same conditions as 1 but with less insulin (7 +/- 1 units) accompanied by the analogue (0.01-0.05 mg/kg); (4) the same conditions as 2 but with the analogue and less insulin (11 +/- 1 units). Administration of the somatostatin analogue increased the effectiveness of insulin in controlling postprandial hyperglycemia and permitted satisfactory postprandial glycemic control when the insulin infusion was initiated immediately before meal ingestion. Administration of the analogue suppressed postprandial plasma glucagon and triglyceride concentrations and delayed xylose absorption. These results suggest that subcutaneous administration of a long-acting somatostatin analogue such as WY-41,747 along with insulin may be clinically useful in the treatment of diabetes mellitus.

Effects of the disaccharidase inhibitor acarbose on meal and intravenous glucose tolerance in normal man

To determine whether the effects of the disaccharidase inhibitor Acarbose on glucose tolerance could be solely explained via an action on intestinal nutrient absorption, the effects of this agent and placebo (100 mg p.o.) on intravenous and postprandial glucose tolerance were compared in six normal subjects. Acarbose significantly diminished plasma glucose, insulin, and gastrointestinal inhibitory polypeptide responses following meal ingestion without affecting plasma glucagon and pancreatic polypeptide responses, but had no effect on plasma glucose and insulin responses following intravenous injection of glucose. These results suggest that the acute effects of Acarbose on glucose tolerance can be explained on the basis of its ability to alter intestinal nutrient absorption.