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The metabolic response to exercise in insulin-dependent diabetic (IDD) man was assessed during continuous insulin infusion using the subcutaneous (CSII), intravenous (CIVII), and intraperitoneal (CIPII) routes. During the basal period, plasma glucose levels were higher with CIPII (153 +/- 17 mg/dl) than with CSII (117 +/- 13 mg/dl) or CIVII (118 +/- 17 mg/dl). Basal free insulin concentrations were similar for CSII (12.3 +/- 10 microU/ml) and CIVII (12.4 +/- 1.4 MicroU/ml) but lower in CIPII (8.5 +/- 1.0 microU/ml, P less than 0.05). Exercise on a stationary bicycle at 75 W for 60 min produced a decline of plasma glucose in each protocol that was significantly only during CIVII (55 +/- 11 mg/dl, P less than 0.01). Insulin levels remained unchanged throughout the study period in all protocols. In normals, insulin values decreased during exercise and remained below basal levels through the recovery period (P less than 0.05), while plasma glucose remained unchanged. Plasma glucagon and epinephrine levels were similar in all protocols and remained unchanged with exercise, while plasma norepinephrine tended to be higher than normal in all diabetic subjects. Significant differences between normal and diabetic subjects (P less than 0.05) were observed for blood ketone bodies, while blood lactate, glycerol, and plasma FFA were similar. Normalization of intermediary metabolites occurred only with CIVII. Continuous insulin infusion provides near-normal glycemic and metabolic control before, during and following exercise in IDD man. However, to produce normal blood concentrations of intermediary metabolites during exercise, the insulin infusion rate may be excessive in terms of its hypoglycemic effect. CSII appears to be a safe, accessible, and adequate method for treating diabetic man during exercise.

The roles of basal insulin, glucagon, and free fatty acids in the regulation of ketogenesis were studied in three-day-fasted anesthetized dogs. Four protocols were employed: (1) infusion of somatostatin, resulting in combined insulin and glucagon deficiency, (2) somatostatin and intraportal glucagon replacement (1 ng./kg./min.) to produce insulin deficiency, (3) somatostatin combined with intraportal insulin replacement (350 μU./kg./min.) to produce glucagon deficiency, and (4) saline controls. Simultaneous blood sampling from the femoral artery and portal and hepatic veins allowed determination of hepatic uptake or production of free fatty acids, glycerol, ketone bodies, and glucose. When combined deficiency of insulin and glucagon was produced, no significant effect on hepatic ketone production was noted (108 ± 6 per cent of mean basal), whereas the induction of selective Insulin deficiency (basal glucagon level maintained) resulted in a rise of net hepatic ketone production (185 ± 24 per cent of mean basal, P < 0.01). Isolated glucagon lack (basal insulin maintained) did not alter net hepatic ketone production. To assess the effect of increased substrate supply on ketogenesis, all experiments included a period of acute elevation of free fatty adds (FFA), produced by infusion of Intralipld and heparin. FFA elevation in saline controls caused only a moderate stimulation of ketone production (149 ± 16 per cent of mean basal, P < 0.01) despite a threefold increase in FFA uptake. However, the combination of elevation of FFA and selective insulin deficiency (glucagon maintained) resulted in a greatly increased hepatic ketone production (357 ± 58 per cent of mean basal, P < 0.01 vs. controls), which was also significantly higher than during combined insulin and glucagon deficiency (P < 0.05). Lipolysis, as indicated by arterial glycerol levels, as well as hepatic FFA uptake was not affected by acute suppression of pancreatic hormone levels. The study demonstrated that basal insulin plays an important role in repressing ketogenesis and that basal amounts of glucagon, while ineffective in the presence of insulin, exert a stimulatory effect on ketogenesis when insulin is deficient. Glucagon's stimulatory effect on ketogenesis was due to an effect in the liver rather than to an increase in lipolysis or in hepatic FFA uptake. Increasing FFA supply per se was associated with only limited stimulation of ketogenesis, whereas the combination of insulin deficiency, basal concentrations of glucagon, and increased FFA load produced a synergistic augmentation of hepatic ketone production.

Somatostatin has recently been used as a tool to investigate the roles of insulin and glucagon in the regulation of glucose metabolism in vivo. The alterations in glucose uptake and production that somatostatin causes have been attributed to the modifications it induces in pancreatic hormone levels rather than to effects of the peptide per se, although the direct effects of the latter on glucose turnover have not been clearly assessed. The aim of the present study therefore was to determine whether or not somatostatin directly affects either the rate of glucose uptake by fat and muscle or the rate of glucose production by the liver. Glucose uptake by the perfused rat hindquarter (skeletal muscle) was unaltered by somatostatin (10-1,000 ng./ml.) whether or not the process was stimulated by insulin (250 μU./ml.). Basal and insulin-(5-40 / μU./ml.)-stimulated glucose oxidation (uptake) by isolated rat adipocytes was also unaffected by somatostatin (5-500 ng./ml.). In addition, the peptide had no effect on basal or glucagon-(10−l0–10−9 M)-stimulated glucose output by isolated rat liver cells. Somatostatin also failed to modify the actions of these sub-maximally effective levels of glucagon on either the intracellular level of cAMP or the activity of cAMP-dependent protein kinase. The present studies support the hypothesis that the acute changes in the level and turnover of glucose induced by somatostatin are attributable to its effect on the endocrine system rather than to its direct effects on glucose metabolism.

The major effects of insulin on glucose, fatty acid and amino acid metabolism and on ion flux are initiated by the interaction of insulin with certain unidentified components of the cell membrane. These early events in the action of insulin were studied further with purified plasma membranes prepared from rat epididymal adipose cells. The binding of 125I-labeled insulin to fat cell plasma membranes gives results quantitatively similar to those reported previously with unlabeled insulin. In addition, intact fat cells, plasma membranes from fat cells and a soluble extract from the plasma membranes contain a highly active insulin degrading system. Both the capacity of the plasma membranes to bind insulin and the insulin degrading activity of the membrane extract can be inhibited by the addition of unlabeled insulin to the incubation medium even though albumin is present in excess. The degraded products have not been fully identified but are soluble in 10 per cent trichloroacetic acid, nonreactive with anti-insulin guinea pig serum, nonadsorbable to a 125I adsorbing resin and, therefore, probably represent fragments of the insulin molecule. When isolated fat cells are treated with trypsin they become insulin unresponsive. Plasma membranes derived from such cells have a reduced capacity to bind insulin, and the insulin degrading system of the membranes or in the soluble extract from the membranes is inactive. This suggests that both the insulin receptor and the insulin degrading system are located on the external surface of the plasma membranes of the fat cells. It is postulated that an insulin degrading system of the plasma membrane may be one of the physiological mechanisms by which the response of fat cells to insulin is terminated.