Insulin binding to monocytes in trained athletes: changes in the resting state and after exercise.

Insulin binding to monocytes was examined in trained athletes (long distance runners) and in sedentary control subjects in the resting state and after 3 h of exercise at 40% of maximal aerobic power. At rest, specific binding of 125-I-insulin to monocytes was 69% higher in athletes than in sedentary controls and correlated with maximal aerobic power. The increase in insulin binding was primarily due to an increase in binding capacity. During acute exercise, insulin binding fell by 31% in athletes but rose by 35% in controls. The athletes had a smaller decline in plasma glucose and a lower respiratory exchange ratio during exercise than did controls. We conclude that physical training increases insulin binding to monocytes in the resting state but results in a fall in insulin binding during acute exercise. Changes in insulin binding in athletes thus may account for augmented insulin sensitivity at rest as well as a greater shift from carbohydrate to fat usage during exercise than is observed in untrained controls.

Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity.

UNLABELLED: We examined the mechanisms of enhanced insulin sensitivity in 9 male healthy athletes (age, 25 +/- 1 yr; maximal aerobic power [VO2max], 57.6 +/- 1.0 ml/kg per min) as compared with 10 sedentary control subjects (age, 28 +/- 2 yr; VO2max, 44.1 +/- 2.3 ml/kg per min). In the athletes, whole body glucose disposal (240-min insulin clamp) was 32% (P < 0.01) and nonoxidative glucose disposal (indirect calorimetry) was 62% higher (P < 0.01) than in the controls. Muscle glycogen content increased by 39% in the athletes (P < 0.05) but did not change in the controls during insulin clamp. VO2max correlated with whole body (r = 0.60, P < 0.01) and nonoxidative glucose disposal (r = 0.64, P < 0.001). In the athletes forearm blood flow was 64% greater (P < 0.05) than in the controls, whereas their muscle capillary density was normal. Basal blood flow was related to VO2max (r = 0.63, P < 0.05) and glucose disposal during insulin infusion (r = 0.65, P < 0.05). The forearm glucose uptake in the athletes was increased by 3.3-fold (P < 0.01) in the basal state and by 73% (P < 0.05) during insulin infusion. Muscle glucose transport protein (GLUT-4) concentration was 93% greater in the athletes than controls (P < 0.01) and it was related to VO2max (r = 0.61, P < 0.01) and to whole body glucose disposal (r = 0.60, P < 0.01). Muscle glycogen synthase activity was 33% greater in the athletes than in the controls (P < 0.05), and the basal glycogen synthase fractional activity was closely related to blood flow (r = 0.88, P < 0.001). IN CONCLUSION: (a) athletes are characterized by enhanced muscle blood flow and glucose uptake. (b) The cellular mechanisms of glucose uptake are increased GLUT-4 protein content, glycogen synthase activity, and glucose storage as glycogen. (c) A close correlation between glycogen synthase fractional activity and blood flow suggests that they are causally related in promoting glucose disposal.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Insulin action on heart and skeletal muscle glucose uptake in essential hypertension.

Essential hypertension is characterized by skeletal muscle insulin resistance but it is unknown whether insulin resistance also affects heart glucose uptake. We quantitated whole body (euglycemic insulin clamp) and heart and skeletal muscle (positron emission tomography and 18F-fluoro-2-deoxy-D-glucose) glucose uptake rates in 10 mild essential hypertensive (age 33 +/- 1 yr, body mass index 23.7 +/- 0.8 kg/m2, blood pressure 146 +/- 3/97 +/- 3 mmHg, VO2max 37 +/- 3 ml/kg per min) and 14 normal subjects (29 +/- 2 yr, 22.5 +/- 0.5 kg/m2, 118 +/- 4/69 +/- 3 mmHg, 43 +/- 2 ml/kg per min). Left ventricular mass was similar in the hypertensive (155 +/- 15 g) and the normotensive (164 +/- 13 g) subjects. In the hypertensives, both whole body (28 +/- 3 vs 44 +/- 3 mumol/kg per min, P < 0.01) and femoral (64 +/- 11 vs 94 +/- 8 mumol/kg muscle per min, P < 0.05) glucose uptake rates were decreased compared to the controls. In contrast, heart glucose uptake was 33% increased in the hypertensives (939 +/- 51 vs 707 +/- 46 mumol/kg muscle per min, P < 0.005), and correlated with systolic blood pressure (r = 0.66, P < 0.001) and the minute work index (r = 0.48, P < 0.05). We conclude that insulin-stimulated glucose uptake is decreased in skeletal muscle but increased in proportion to cardiac work in essential hypertension. The increase in heart glucose uptake in mild essential hypertensives with a normal left ventricular mass may reflect increased oxygen consumption and represent an early signal which precedes the development of left ventricular hypertrophy.

Effects of body composition on insulin sensitivity.

We studied the effects of body composition and maximal aerobic power on insulin sensitivity in 23 normal-weight, healthy male subjects. Eight were weight lifters, eight were long-distance runners, and seven were untrained controls. In each subject, the percentage of body weight (BW) made up of muscle and fat tissue (% muscle and % fat, respectively), the maximal aerobic power (VO2max), and the tissue sensitivity to insulin were measured. The weight lifters were characterized by 35% higher % muscle as compared with the runners or controls (P less than 0.01). VO2max in the runners was 30-40% higher than in the weight lifters or controls (P less than 0.001). During the euglycemic clamp studies, similar steady-state plasma glucose and insulin levels were achieved in each group. When calculated per total BW, the rate of glucose metabolism (M) was virtually identical in the weight lifters (10.26 +/- 1.02 mg/kg BW/min) and the runners (10.03 +/- 0.86 mg/kg BW/min), and 4045% higher than in the controls (7.10 +/- 0.75 mg/kg BW/min, P less than 0.05). When calculated per muscle mass (Mm), only the runners had a higher than normal rate of glucose metabolism (P less than 0.02). M was directly proportional to% muscle (r = 0.54, P less than 0.01) and inversely related to % fat (r = -0.72, P less than 0.001). The multiple linear regression analysis revealed a highly significant multivariate correlation between M and the combined effect of % muscle, %fat, and VO2max (r = 0.78, P less than 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of interferon on glucose tolerance and insulin sensitivity.

Many viral infections induce interferon (IFN) production and cause insulin resistance. To examine the causal relationship between IFN and insulin resistance, we injected natural human leukocyte IFN-alpha (3 x 10(6) IU, i.m.) twice overnight in eight healthy subjects and determined oral (OGT) and intravenous (IVGT) glucose tolerance and sensitivity to insulin (287 nmol or 40 mU.m-2.min-1 euglycemic insulin clamp) the following morning. IFN caused mild influenzalike symptoms and induced a rise in circulating glucose, insulin, hydrocortisone (cortisol), growth hormone, and glucagon concentrations (P less than .05-.001). In the OGT test, the area under the glucose curve was 2.6-fold greater (P less than .02), and the disappearance rate of intravenously administered glucose was reduced by 28% (P less than .05) after IFN administration. The impairment in OGT and IVGT occurred despite augmented insulin response. Insulin-stimulated glucose disposal was reduced by 22% (P less than .005), and insulin clearance increased by 18% (P less than .02) after IFN administration. When the insulin-clamp study was repeated in patients with steady-state hyperinsulinemia that was 12% higher (P less than .005) after IFN, the glucose disposal rate was still reduced by 15% (P less than .01). These data indicate that IFN 1) stimulates counterregulatory hormone secretion, 2) impairs glucose tolerance and insulin sensitivity, and 3) stimulates insulin clearance. Thus, IFN may be involved in the development of insulin resistance during viral infections.

Hyperglycemia decreases glucose uptake in type I diabetes.

It has recently been postulated that hyperglycemia per se may contribute to insulin resistance in diabetes. To examine this possibility directly, we measured glucose uptake after 24 h of hyperglycemia (281 +/- 16 mg/dl) and normoglycemia (99 +/- 6 mg/dl) in 10 type I (insulin-dependent) diabetic patients (age 33 +/- 3 yr, relative body wt 102 +/- 3%) treated with continuous subcutaneous insulin infusion. Hyperglycemia was induced by an intravenous glucose infusion, whereas saline was administered during the control day. During both studies the patient received a similar diet and insulin dose. After hyper- and normoglycemia, a primed continuous infusion of insulin (40 mU X m-2 X min-1) was started, and plasma glucose was adjusted to and maintained at 142 +/- 2 and 140 +/- 2 mg/dl, respectively, during 60-160 min of insulin infusion. The rate of glucose uptake after hyperglycemia averaged 8.3 +/- 1.1 mg X kg-1 X min-1, which was lower than the rate after the normoglycemic period (10.1 +/- 1.2 mg X kg-1 X min-1, P less than .001). In conclusion, short-term hyperglycemia reduces glucose uptake in type I diabetic patients. Thus, part of the glucose or insulin resistance in these patients may be caused by hyperglycemia per se.

No reduction in total hepatic glucose output by inhibition of gluconeogenesis with ethanol in NIDDM patients.

Increased gluconeogenesis has been suggested to account for all of the increase in basal glucose production in patients with non-insulin-dependent diabetes mellitus (NIDDM). We studied the effect of inhibition of gluconeogenesis with ethanol on total hepatic glucose output (HGO) in patients with NIDDM. Fourteen patients with NIDDM (mean +/- SE age 61 +/- 2 yr, fasting plasma glucose 11.4 +/- 0.8 mM; body mass index 27 +/- 1 kg/m2) were studied twice after an overnight fast, once during ethanol administration (blood ethanol approximately 12 mM) and once during saline administration. Total HGO rate was measured with [3H]glucose. Inhibition of gluconeogenesis by ethanol was followed qualitatively with [U-14C]lactate (n = 8) and [U-14C]glycerol (n = 6) as tracers. Ethanol inhibited gluconeogenesis from lactate by 71 +/- 5% (0.5 +/- 0.2 vs. 1.8 +/- 0.1 mumol glucose.kg-1.min-1, 240-300 min, P less than 0.001; ethanol vs. saline, P less than 0.001) and from glycerol by 65 +/- 6% (0.8 +/- 0.2 vs. 2.3 +/- 0.6 mumol glucose.kg.min-1, P less than 0.001). Total HGO rate remained unchanged and averaged 12.8 +/- 1.8 and 11.8 +/- 2.1 mumol.kg-1.min-1 in the saline and ethanol studies, respectively (NS). We concluded that inhibition of gluconeogenesis by ethanol does not decrease total HGO in patients with NIDDM. Our results suggest the existence of a regulatory mechanism in the liver that maintains constant total HGO despite inhibition of gluconeogenesis.

Intracellular enzymes of collagen biosynthesis in rat kidney in streptozotocin diabetes.

The activities of the four enzymes catalyzing intracellular post-translational modifications of the collagen polypeptide chains were assayed in the kidneys of rats with streptozotocin diabetes. When the changes in the four enzyme activities were expressed per milligram of protein in the 15,000 X g supernatant of the kidney homogenates, there were no changes in any of the enzyme activities at four weeks and only slight increases in the prolyl and lysyl hydroxylase activities at 12 weeks after the induction of diabetes. When the changes were expressed as total enzyme activities per two kidneys, again no changes were found in any enzyme activity at four weeks, but at 12 weeks significant increases were found in all four enzyme activities, namely prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase, and collagen glucosyltransferase. The data would be consistent with an increased collagen synthesis in diabetic kidneys, but they do not support the hypothesis that there might be specific changes in some of these enzyme activities or in the level of certain posttranslational modifications of the collagen polypeptide chains in this disease.

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.

Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients.

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.

No evidence of amyloidosis in type I diabetics treated with continuous subcutaneous insulin infusion.

A recent study has demonstrated secondary amyloidosis in dogs treated with continuous intravenous insulin infusion. Since elevated levels of serum amyloid A protein (SAA) and diminished amyloid fibril degrading activity (AFDA) are associated with amyloidosis, we measured SAA and AFDA in ten type I diabetics treated with continuous subcutaneous insulin infusion and in five conventionally treated patients. Only one pump- and one conventionally treated patient had detectable but low SAA levels, comparable with these seen in healthy controls. In patients with secondary amyloidosis the mean SAA level was 24-fold higher than in controls (P less than 0.001). Similarly, in both diabetic groups, AFDA was normal whereas it was reduced by 41% in patients with amyloidosis (P less than 0.001). Furthermore, no local amyloidosis was seen at the infusion site in any of the patients studied. Thus, our data fail to provide any evidence of secondary amyloidosis in patients treated for 3-40 mo with continuous subcutaneous insulin infusion.

Athletes with IDDM exhibit impaired metabolic control and increased lipid utilization with no increase in insulin sensitivity.

Physical exercise is traditionally recommended to diabetic patients as part of their treatment. Although healthy athletes exhibit enhanced skeletal muscle insulin sensitivity, the metabolic effects of vigorous training in patients with insulin-dependent diabetes mellitus (IDDM) are not known. This study was designed to examine the effects of competitive sports on fuel homeostasis and insulin sensitivity in athletes with IDDM. We studied 11 athletes and 12 matched sedentary men with IDDM. In each subject, we measured glycemic control, insulin-stimulated glucose uptake in the whole body and forearm, rates of glucose and lipid oxidation, and muscle glycogen, glycogen synthase, and glucose transport protein (GLUT4) concentrations. The athletes had higher VO2max (52 +/- 1 vs. 42 +/- 1 ml.kg-1.min-1, P < 0.001) and HbA1c levels (8.4 +/- 0.4 vs. 7.2 +/- 0.2%, P < 0.05) than sedentary patients, but took smaller insulin doses (41 +/- 3 vs. 53 +/- 3 U/day, P < 0.05). The insulin-stimulated rates of whole-body and forearm glucose uptake and glucose oxidation were similar in the two groups, whereas both energy expenditure and lipid oxidation were increased in the athletes. Lipid oxidation correlated inversely with glycogen synthase activity. The mean glucose arterialized venous blood-deep venous blood (A-V) difference during the insulin infusion (60-240 min) correlated with the whole-body glucose disposal throughout the insulin infusion (after 60 min, r > 0.73, P < 0.001 for all 30-min periods). This association is accounted for by the relationship between glucose A-V difference and nonoxidative glucose disposal. Muscle glycogen and GLUT4 protein contents were not different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis and prevention of the dawn phenomenon in diabetic patients treated with CSII.

The mechanism of the dawn phenomenon was studied in 12 C-peptide-negative type I diabetic patients (age 30 +/- 2 yr) treated with continuous subcutaneous insulin infusion. During constant basal infusion, nocturnal glycemia remained constant until 4 a.m., but began to rise thereafter in 10/12 patients, with the mean rise from 4.6 +/- 0.4 mmol/L to 6.1 +/- 0.7 mmol/L (P less than 0.01) by 8 a.m. In these patients the rate of glucose production (Ra, 2.14 +/- 0.04 mg/kg/min, 3-H3-glucose infusion) exceeded the rate of utilization (Rd, 1.89 +/- 0.03 mg/kg/min, P less than 0.02). When the patients were restudied after the infusion rate was increased by 49 +/- 7%, Ra fell to 1.75 +/- 0.03 mg/kg/min (P less than 0.01) and the dawn phenomenon was abolished. However, both Ra and Rd remained higher in the diabetic subjects (P less than 0.05) than in eight healthy control subjects, in whom Ra (1.66 +/- 0.02 mg/kg/min) was equal to Rd with glycemia remaining unchanged. Peripheral free insulin levels in the diabetic patients were similar during constant (12.3 +/- 0.5 mU/L) and increased infusion rate (11.3 +/- 0.4 mU/L), and higher than those of the control subjects (5.2 +/- 0.2 mU/L, P less than 0.05). A diurnal rise in serum cortisol levels occurred 1 h earlier in the diabetic than in the control subjects, and Ra was directly proportional to serum cortisol concentration (r = 0.61, P less than 0.01). Serum growth hormone levels were also slightly higher in the diabetic than the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group.

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

Plasma acylation stimulating protein concentration and subcutaneous adipose tissue C3 mRNA expression in nondiabetic and type 2 diabetic men.

We studied the effect of an oral fat load on plasma acylation stimulating protein (ASP) concentrations in 9 lean healthy (age 59+/-2 years, body mass index [BMI] 23.2+/-0.4 kg/m(2); both mean+/-SEM), 9 obese nondiabetic (58+/-2 years, BMI 29.4+/-0.5 kg/m(2)), and 12 type 2 diabetic (60+/-2 years, BMI 29.6+/-1.0 kg/m(2)) men. Because ASP is a cleavage product of complement protein C3 (C3adesArg) and its secretion is regulated by insulin, we also examined the subcutaneous adipose tissue expression of C3 mRNA before and after a 240-minute euglycemic hyperinsulinemic clamp in a subgroup of these men. Plasma ASP concentration and adipose tissue C3 mRNA expression were higher in the obese groups than in the lean men. Plasma ASP concentration did not change significantly after the fat load. Fasting plasma ASP concentration and C3 mRNA expression were correlated negatively with insulin sensitivity and positively with the magnitude of postprandial lipemia in nondiabetic but not in type 2 diabetic men. The expression of C3 mRNA was not regulated by insulin. These data suggest that ASP is associated with whole-body glucose and lipid metabolism in nondiabetic individuals, whereas metabolic disturbances in diabetes may overcome the regulatory role of ASP in lipid and glucose metabolism.

Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group.

BACKGROUND: Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested. OBJECTIVES: To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM. METHODS: A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal. RESULTS: Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups. CONCLUSIONS: Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM.

Insulin therapy in type II diabetes.

Administration of exogenous insulin can ameliorate metabolic abnormalities in type II diabetes: It compensates for reduced endogenous insulin secretion, reduces excessive hepatic glucose production, and stimulates glucose uptake, enhancing both glucose oxidation and storage in the muscle tissue. In addition, insulin therapy has anti-atherogenic effects on serum lipid profile. The main concerns of insulin therapy are weight gain, hyperinsulinemia, hypoglycemia, and possibly sodium and fluid retention. Although studies in vitro and in experimental animals suggest that hyperinsulinemia may accelerate atherosclerosis, these data are not substantiated in patients with type II diabetes. Insulin therapy in type II diabetes patients can be used either temporarily when insulin requirements are increased (e.g., surgery, infection, pregnancy), or in the long-term when endogenous insulin secretion is vanishing or hyperglycemia does not respond to other therapy. Whether insulin should be used as a primary therapy in addition to diet and exercise in some patients has not been examined. The decision regarding the beginning of insulin therapy and targets should be established individually, taking into account factors such as age, other diseases, or life expectancy. Various regimens can be used, including evening insulin alone or in combination with oral agents, multiple injections, use of premixed insulins (short-plus intermediate-acting insulin in various combinations). Continuous subcutaneous insulin infusion also has been used. Comparative data between the regimens are scant, but a few studies suggest that no major differences occur between the regimens, with regard to glycemic control or hypoglycemic complications. In the future, insulin therapy in type II diabetes may become more common, particularly among patients with the autoimmune type of the disease.

Fructose as a dietary sweetener in diabetes mellitus.

Human beings, including those with diabetes, have a desire for sweetness in the diet that cannot be ignored. The Food and Drug Administration ban of cyclamates and possible ban of saccharin have raised the question of alternative sweeteners for diabetic persons. Considerable interest has been focused on fructose, and both basic and clinical research has delineated its metabolic effects. This paper reviews the characteristics of fructose, as well as its physiology and metabolism in both normal and diabetic man. Findings seems to indicate that, in controlled diabetes, chronic or limited consumption of fructose at moderate doses has no adverse effects on the levels of blood glucose, cholesterol, or tryglycerides.

Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients.

We studied the combined effect of cool (10 degrees C) and warm (30 degrees C) ambient temperatures and physical exercise on insulin absorption and postprandial glycemia. Nine type I (insulin-dependent) diabetic patients were injected subcutaneously with their usual morning dose of short- and intermediate-acting human insulin and were given breakfast. Warm temperature was associated with 3- to 5-fold higher insulin absorption (P less than .01) and significantly lower blood glucose concentration (P less than .001) than cool temperature regardless of exercise. Exercise was associated with 28% (P less than .01) and 22% (P less than .05) increases in plasma insulin and maximally 5.7 mM (P less than .025) and 7.1 mM (P less than .01) lower blood glucose at cool and warm temperatures, respectively. Warm temperature and exercise had an additive effect in stimulating insulin absorption and in lowering blood glucose concentrations. However, there was no evidence of synergism between higher temperature and exercise in increasing free-insulin concentrations or decreasing blood glucose concentrations. To avoid postprandial hyperglycemia at cool temperature or hypoglycemia after exercise at warm temperature, appropriate adjustments in diet and insulin dose, or both, should be made.