Insulin Sensitivity In Peripheral Tissues Research Articles

Dose-Response Relationship Between Lymph Insulin and Glucose Uptake Reveals Enhanced Insulin Sensitivity of Peripheral Tissues

To examine the role of transcapillary insulin transport to peripheral insulin sensitivity in vivo, we performed dose-response experiments in which both plasma and thoracic duct lymph insulin and glucose utilization (Rd) were measured in conscious dogs. Euglycemic clamps (n = 22) consisted of a 3-h activation period in which insulin was infused (rates: “physiological” 3.6, 5.4, 7.2 pmol · min−1 · kg−1; “pharmacological” 108 pmol · min−1 · kg−1), followed by a 3-h deactivation period. [14C]inulin was also infused as a diffusionary marker. Insulin sensitivity was estimated as the ED50. When based on plasma insulin, ED50 was 480 pM. However, when calculated from lymph (i.e., interstitial) insulin measurements, ED50 was 240 pM. Thus, interstitial insulin measurements reveal that insulin sensitivity of peripheral tissues is approximately twice that estimated from plasma insulin and is similar to sensitivity reported for suppression of hepatic glucose production. Furthermore, although [14C]inulin achieved equilibrium between plasma and lymph within 180 min, within the physiological range, steady state plasma insulin was higher than insulin in lymph (306 ± 18, 474 ± 42, and 780 ± 60 pM vs. 180 ± 18, 318 ± 12, and 504 ± 36 pM; P < 0.0001); plasma insulin achieved steady state faster than lymph insulin (6 ± 1, 6 ± 2, and 11 ± 3 min vs. 29 ± 4, 16 ± 6, and 44 ± 8 min; P < 0.01) and disappeared faster (5 ± 2, 7 ± 2, and 15 ± 6 min vs. 37 ± 8, 32 ± 4, and 43 ± 9 min; P < 0.01). The time course of lymph insulin at each dose was similar to that of Rd, and at each dose, unlike plasma insulin, lymph insulin was strongly correlated with Rd (r = 0.93 or better). At pharmacological hyperinsulinemia (plasma 35232 ± 5250 pM, lymph 27366 ± 4380 pM), Rd rose faster than lymph insulin and disappeared more slowly than insulin. Thus, lymph insulin data indicate that the periphery is more sensitive to insulin than previously realized from estimates based solely on plasma hormone. Furthermore, lymph insulin is proportional to Rd within the physiological but not pharmacological range of insulin, indicating that transcapillary insulin transport is rate limiting for insulin action in this range. Finally, based on in vivo lymph (i.e., interstitial) insulin measurements, peripheral tissue is almost twice as sensitive to insulin than previously realized.

The metabolic cardiovascular syndrome: syndrome X, Reaven's syndrome, insulin resistance syndrome, atherothrombogenic syndrome.

A short review of the metabolic cardiovascular risk syndrome (MCVS) is given. Traditionally, cardiovascular risk has been associated with three so-called "main" risk factors; hypercholesterolemia, hypertension, and smoking. In addition, the association between diabetes and cardiovascular disease has been known for many years in clinical medicine. Primarily, these risk factors have been regarded separately as independent factors, although epidemiological studies showed intercorrelations between them. However, it is now well accepted that relatively few at-risk individuals have only one risk factor, and in many cases a whole "symphony" of factors play together to create what we might call an individuals' risk profile. As an example, very often essential hypertension has been regarded as a disease in itself, which can be successfully treated just by lowering the blood pressure by drugs. When such a strategy obviously failed, the association of elevated blood pressure with dyslipoproteinemia and impaired glucose tolerance attracted more attention, particularly when it was realized that many antihypertensive drugs affected risk in MCVS in a possible negative way. The most important etiologic factor of MCVS is (besides genetics) an excessive caloric intake compared to what the individual spends in physical activity. In the clinical setting, the most important findings of MCVS are central obesity, dyslipoproteinemia with low high-density lipoprotein (HDL) cholesterol, hypertension, reduced insulin sensitivity in peripheral tissues, and increased thrombogenicity. The reduced insulin sensitivity leads to a compensatory increase in beta-cell insulin production, and thereby hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Temporal response of circulating metabolites and hormones during somatotropin treatment of growing pigs.

Temporal responses in the circulating concentrations of a number of intermediary metabolites and metabolic hormones were studied in chronically catheterized barrows (n = 4 per treatment) after either daily i.m. injection of porcine somatotropin (pST, 120 micrograms/kg of BW) or excipient. Blood sampling (every 1 or 2 h) began 24 h before the first injection (d 0) and continued until the end of d 2. Sampling was repeated on d 7 of treatment. Feed intake declined by d 3 in the pST-treated pigs and was 31% lower by d 7 of treatment (P less than .05). Blood glucose and plasma insulin concentrations began to increase about 3 h after the first pST injection, almost returning to preinjection levels before the next injection. By the end of d 2, circulating levels of glucose and insulin were higher in pST-treated pigs than in the controls. A temporal pattern of hyperglycemia and hyperinsulinemia was observed postinjection on each day of treatment. Although pST treatment did not chronically increase basal plasma concentrations of nonesterified fatty acids and glycerol, both metabolites exhibited transient postinjection elevations, the magnitudes of which were augmented by duration of treatment. Plasma urea nitrogen concentrations began to decrease within a few hours after the first pST injection and by d 7 were 70% (P less than .01) lower in the pST-treated pigs. A model is presented implicating pST-induced decreases in peripheral tissue insulin sensitivity and(or) responsiveness in the observed temporal responses in lipid and carbohydrate metabolism.

Phenylarsine oxide causes an insulin-dependent, GLUT4-specific degradation in rat adipocytes.

An incubation of rat adipocytes with phenylarsine oxide (PAO) and then with insulin caused an inhibition of 3-O-methylglucose equilibrium exchange flux and a parallel reduction in cellular GLUT4 content detected by Western blots. Both the transport inhibition and the GLUT4 reduction were saturable with an increasing concentration of PAO showing essentially an identical Ki value of 35 microM. Both effects were not observed in the absence of insulin or if cells were incubated with insulin first. The reduction was specific to GLUT4; the immunoreactivities of GLUT1, insulin receptor, and clathrin were not affected in these experiments. The GLUT4 reduction occurred only in intact cells and was not observed in homogenized cells or fractionated membranes. GLUT4 in both the microsomal storage pool and the plasma membrane pool were affected with no indication of insulin-induced recruitment impairment. GLUT4 reduction was not observed in the presence of chloroquine or at 18 degrees C suggesting involvement of the lysosomal pathway. Based on these results, we propose that there is a PAO-sensitive protein mechanism that controls an insulin-dependent GLUT4 degradation pathway in adipocytes. This protein mechanism and the GLUT4 degradation pathway may play an important role in determining the steady-state GLUT4 level in the insulin-sensitive peripheral tissues in normal and diseased states.

Peripheral and hepatic insulin sensitivity in healthy elderly human subjects

Insulin resistance has been reported in normal ageing but discrepancies between such studies may be related to compounding factors such as body composition and exercise patterns. We employed a two-step hyperinsulinaemic euglycaemic clamp to assess peripheral and hepatic tissue insulin sensitivity and glucose recycling in 13 elderly (E) and 14 young (Y) healthy subjects controlling for the above factors. There was no difference in basal hepatic glucose production (E: 2.36 +/- 0.06, Y: 2.47 +/- 0.1 mg kg-1 min-1; P = 0.4). At step 1 (insulin infusion 15 mU kg-1 h-1) glucose turnover was similar (E: 2.65 +/- 0.13, Y: 2.88 +/- 0.22 mg kg-1 min-1; P = 0.4) but hepatic glucose production was lower in the elderly group (0.20 +/- 0.16 vs 0.64 +/- 0.10 mg kg-1 min-1; P = 0.03). At step 2 (insulin infusion 50 mU kg-1 h-1) glucose turnover was similar (E: 7.60 +/- 0.24, Y: 8.05 +/- 0.34 mg kg-1 min-1; P = 0.3) and hepatic glucose production was equal but negative (E: -1.35 +/- 0.18, Y: -1.34 +/- 0.22 mg kg-1 min-1; P = 0.9). Glucose recycling did not differ between the groups at any stage. Similar serum insulin levels were achieved in both groups at each step. Decreased glucose tolerance was confirmed in E with a higher 2 h blood glucose after an OGTT (5.3 +/- 0.4 vs 4.1 +/- 0.3 mmol l-1; P = 0.03) but incremental insulin response was similar (E: 3236 +/- 289, Y: 3586 +/- 463 mU l-1 min-1; P = 0.5). We conclude that changes in hepatic tissue insulin sensitivity do not cause the deterioration in glucose tolerance observed with age. A small reduction in both peripheral tissue insulin sensitivity and late insulin secretion may be responsible.

The effects of low-dose BAY-m-1099 (Miglitol) on serum lipids and liver enzyme activity of obese and obese-diabetic corpulent rats

1. Groups of lean, obese, and obese-non-insulin-dependent diabetic LA/N-cp and SHR/N-cp rats were administered the a-glucosidase inhibitor Miglitol (150 mg/kg diet, ad libitum) from 8 until 15 weeks of age. 2. Phenotype effects (obese > lean) were present for weight gain, adiposity, serum glycémic and lipid parameters, and for liver glucokinase, glucose-6-phosphate dehydrogenase, and malic enzyme activity. Miglitol treatment was associated with improvements in glucokinase and malic enzyme in both strains, and in improvements in glycémic parameters in obese rats. 3. These results are consistent with variable improvements in glycémic control and insulin action following low dose Miglitol treatment, and indicate that indirect effects of the drug on insulin sensitivity in peripheral tissues and on glucoregulatory enzymes may contribute to the glycémic improvements observed with this drug, while greater dosages or longer treatment may be required to observe comparable improvements in adiposity or plasma lipid profiles.

Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

Insulin sensitivity in alcoholics in a withdrawal state

Insulin sensitivity in non-diabetic alcoholics in a withdrawal state was investigated using a euglycaemic clamp technique on two occasions with an interval of 1 week. Insulin was infused at a rate of 40 mU m-2 min-1 (n = 9) and 20 mU m-2 min-1 (n = 9). Hepatic glucose production was estimated with tritiated glucose in six subjects. The fasting glucose level at the first examination, 5.1 +/- 0.2 mmol l-1, exceeded that found at the second examination, 4.7 +/- 0.1 mmol l-1 (P less than 0.05), although the C-peptide concentration was higher at the first examination (2.7 +/- 0.3 vs. 1.6 +/- 0.2 ng ml-1; P less than 0.001). Both glucose uptake (5.0 +/- 0.6 vs 6.2 +/- 0.7 mg kg-1 min-1; P less than 0.05) and tissue sensitivity (M/I; 0.08 +/- 0.02 vs. 0.1 +/- 0.02 mg kg-1 min-1/mU l-1; P less than 0.05) increased between the first and second euglycaemic clamp (40 mU m-2 min-1). At the low insulin infusion rate (20 mU m-2 min-1), the tissue sensitivity to insulin increased (0.09 +/- 0.01 vs. 0.13 +/- 0.02 mg kg-1 min-1/mU l-1; P less than 0.05). Hepatic glucose production did not change during the examination period (2.2 +/- 0.2 vs. 2.3 +/- 0.1 mg kg-1 min-1), neither was there a change in the suppression of hepatic glucose output during hyperinsulinaemia (40 mU m-2 min-1). Our findings indicate that, in non-diabetic alcoholics, insulin sensitivity in peripheral tissues is decreased during the early part of a withdrawal period.

Glyburide Increases Insulin Sensitivity and Responsiveness in Peripheral Tissues of the Rat as Determined by the Glucose Clamp Technique*

The effect of chronic glyburide treatment on insulin sensitivity and responsiveness in vivo in unanesthetized male Sprague-Dawley rats was determined by the hyperinsulinemic-euglycemic clamp technique. Normal animals were surgically prepared for the clamp procedure and then gavaged with glyburide, 2 mg/kg/day, or with normal saline for 6-18 days. Basal plasma glucose concentrations were significantly lower in glyburide-treated animals compared to controls, but basal plasma insulin concentrations were the same. Rates of glucose disposal, calculated before and during insulin infusions of 2 to 40 mU/kg.min with plasma glucose concentration clamped at 125 mg/dl, were significantly greater in the glyburide-treated rats compared to controls. Insulin dose-response curves demonstrate that glyburide treatment increased both insulin sensitivity and responsiveness. Basal hepatic glucose production, estimated by D-[3-3H]Glucose infusion, was significantly greater with glyburide treatment; however the sensitivity of the liver to suppression by insulin infusions of 2 and 4 mU/kg.min was unchanged. These data suggest that the decreased basal plasma glucose concentration observed in rats chronically treated with glyburide is the result of increased glucose disposal in peripheral tissues and not associated with an increase in plasma insulin concentrations or a decrease in hepatic glucose production.

Prospective studies of insulin sensitivity in normal women receiving oral contraceptive agents.

Seven normal premenopausal women were studied before (control) and after 3 and 6 months of oral contraceptive agent (OCA) administration (30 micrograms ethinyl estradiol plus 150 micrograms levonorgestrel). The plasma glucose responses during 75-g oral glucose tolerance tests were not altered by the OCA, but the 3- and 6-month plasma insulin responses significantly exceeded control values (P less than 0.05). On a separate morning a constant iv infusion of [3H]3-glucose was given throughout a 2-h basal period and during two successive 2-h euglycemic clamp procedures at iv insulin delivery rates of 10 and 40 mU/m2.min, respectively. Endogenous glucose production rates (milligrams per kg/min) were not altered after 3 or 6 months of OCA administration. Peripheral glucose utilization rates were expressed as M (milligrams per kg/min) or the ratio of M over the prevailing plasma insulin concentration (M/I). One or both parameters were significantly reduced below control values at both insulin infusion rates after 3 months (P less than 0.05), but returned toward control values after 6 months. Serum androgen concentrations were reduced or not altered by OCA administration. We conclude that insulin resistance induced by OCA administration is manifested by reduced peripheral tissue insulin sensitivity and may ameliorate with time. This effect does not relate consistently to total plasma insulin responses during oral glucose tolerance tests or to elevated serum androgen concentrations.

Peripheral tissue insulin sensitivity in healthy elderly subjects.

To determine whether the decline in glucose tolerance with age is related to changes in peripheral tissue insulin sensitivity, 11 healthy older (65-85 years) and 12 healthy younger (20-38 years) subjects, matched for physical activity and body mass index, were studied. The glucose-insulin infusion technique, in which glucose and insulin are infused at constant rates over 150 min, was used to assess peripheral tissue insulin sensitivity. The metabolic clearance rate (MCR) of glucose, which reflects peripheral tissue insulin sensitivity, is derived from the resulting steady-state blood glucose. Fasting blood glucose was similar in the two groups, but mean blood glucose 2 h after an oral glucose load was higher in the older group. MCR of glucose expressed per kilogram lean body mass was almost identical in both groups (13.3 +/- 1.3 vs. 13.5 +/- 1.3 ml/kg lean body mass/min, respectively). Evidence of decreased glucose tolerance with normal peripheral tissue insulin sensitivity suggests that changes in other factors may be more important than previously recognised.

Increased insulin sensitivity and responsiveness during lactation in rats.

In 12-day lactating rats blood glucose and plasma insulin were decreased by, respectively, 20 and 35% when compared with nonlactating rats, despite a 25% increase of their glucose turnover rate. Then, by using the euglycemic hyperinsulinemic clamp technique, dose-response curves for the effects of insulin on glucose production and utilization in lactating and nonlactating rats were performed. Glucose production rate was totally suppressed at 250 microU/ml of insulin in lactating rats and for plasma insulin concentrations higher than 500 microU/ml in nonlactating rats. Plasma insulin level inducing half-maximal inhibition of glucose production was decreased by 60% during lactation. The maximal effect of insulin on glucose utilization rate and glucose metabolic clearance rate was, respectively, increased 1.5- and 2.4-fold during lactation and was obtained for plasma insulin concentrations lower in lactating than in nonlactating rats (250 vs. 500 microU/ml). Insulin concentrations inducing half-maximal stimulation of glucose utilization and glucose metabolic clearance were decreased by 50% during lactation. In conclusion, this study has shown that insulin sensitivity and responsiveness of liver and peripheral tissues are improved at peak lactation in the rat.

Cold Exposure Reverses the Diabetogenic Effects of High-Fat Feeding

Long-term cafeteria feeding, cold exposure, and the combination of treatments increased energy intake in female Wistar rats by 25%, 113%, and 150%, respectively, in comparison with controls (P less than 0.01). Although cafeteria feeding at room temperature markedly increased the insulin response to an intravenous glucose tolerance test (IVGTT), glucose tolerance was deteriorated (P less than 0.01). In contrast, cold exposure significantly improved glucose tolerance in the presence of a reduced insulin response in Purina- and cafeteria-fed animals. Moreover, cold exposure also decreased body weight gain and increased brown adipose tissue mass, total cytochrome-oxidase activity, and cellularity by approximately 600-800%. The results suggest that cold exposure enhances insulin sensitivity of peripheral tissues, whereas hyperphagia on a high-fat, low-protein diet leads to insulin resistance. In addition, the results demonstrate that prolonged stimulation of energy expenditure by cold exposure not only reverses the diabetogenic effects of cafeteria feeding but also improves glucose tolerance. This phenomenon could result from a combination of two factors: (1) a cold-induced prevention of obesity; and (2) an enhanced disposal of circulating glucose into peripheral tissues, including brown adipose tissue.

Influence of a 60-hour fast on insulin-mediated splanchnic and peripheral glucose metabolism in humans.

A brief period of starvation (2-3) depletes the hepatic glycogen stores but results in only a limited reduction of the muscle glycogen depots. In this situation insulin resistance contributes to the glucose intolerance, but it is not known which tissue or tissues are responsible for the decreased insulin sensitivity. The present study was therefore undertaken to examine the influence of a 60-h fast on insulin sensitivity in splanchnic and peripheral tissues in normal humans. Euglycemic (95 mg/dl) 1-mU insulin and hyperglycemic (215-225 mg/dl) glucose clamp studies were conducted for 2 h in overnight (12 h) and prolonged (60 h) fasted nonobese subjects. Splanchnic exchange of glucose and gluconeogenic precursors was measured using the hepatic vein catheter technique. During the euglycemic clamp, insulin infusion resulted in similar steady state insulin levels in 60-h and 12-h fasted subjects (73 +/- 7 vs. 74 +/- 5 microU/ml). Total glucose disposal was reduced by 45% after 60 h of fasting (4.0 +/- 0.3 vs. 7.6 +/- 1.1 mg/kg per min, P less than 0.05) and the splanchnic glucose balance reverted from a net release in the basal state (12 h fast, -1.7 +/- 0.2, and 60-h fast, -0.9 +/- 0.1 mg/kg per min, P less than 0.01) to a net uptake during the clamps that was similar after 60 h and 12 h of fasting (0.6 +/- 0.1 vs. 0.6 +/- 0.2 mg/kg per min). During the hyperglycemic clamp, insulin levels rose rapidly in all subjects. In the 12-h fasted group this rise was followed by a further gradual one, reaching significantly higher values than in 60-h fasted subjects during the second hour (67 +/- 15 vs. 25 +/- 2 microU/ml, P less than 0.05). Total glucose disposal was lower, though not significantly so, after the 60-h fast (2.6 +/- 0.4 vs. 5.4 +/- 1.3 mg/kg per min, 0.05 less than P less than 0.10), and as with the euglycemic clamp, the splanchnic glucose balance was altered from a basal net release to a net uptake during the clamp (1.3 +/- 0.2 vs. 1.1 +/- 0.2 mg/kg per min). After an overnight fast, splanchnic lactate uptake fell and the arterial lactate concentration rose in response to both hyperglycemia and hyperinsulinemia, whereas these variables were unchanged in the 60-h fasted subjects during both types of clamp studies.

The effect of growth hormone on splanchnic glucose and substrate metabolism following oral glucose loading in healthy man.

Elevated plasma concentrations of growth hormone impair glucose tolerance and insulin sensitivity of peripheral tissues. To study the effect of short-term exposure to growth hormone concentrations elevated into the upper physiologic range (7-10 ng/ml) on splanchnic carbohydrate metabolism, both splanchnic glucose output (SGO) and substrate exchange after ingestion of a 75-g glucose load were determined by means of the liver vein catheter technique in six healthy volunteers after growth hormone administration. Growth hormone was infused at a rate of 2 micrograms/kg X h starting 120 min before and continuing for 150 min following the glucose load. Control studies without growth hormone administration were performed in seven subjects. SGO was 104 +/- 10 (SEM) mg/min in the postabsorptive state and increased to 43.4 +/- 2.2 g during the 150-min period following glucose ingestion. Growth hormone infusion did not alter basal SGO (130 +/- 14 mg/min), nor the splanchnic exchange of lactate, pyruvate, and free fatty acids, whereas basal production of beta-OH-butyrate was increased twofold; following glucose ingestion a higher proportion of the given glucose load escaped the splanchnic bed after growth hormone exposure (66.9 +/- 6.8 g/150 min; P less than 0.005). The insulin production rate (basal 14 +/- 2 mU/min; following oral glucose 7.0 +/- 0.8 U/150 min) as calculated from C-peptide release from the splanchnic area was unaltered by growth hormone exposure in the basal state (14 +/- 3 mU/min), but augmented after glucose ingestion (14.8 +/- 1.5 U/150 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of cold exposure and starvation on glucose tolerance and insulin response.

The metabolic interactions of cold exposure, cold acclimation, and starvation on glucose tolerance and plasma insulin levels were studied in precannulated, unrestrained, and unanesthetized rats. Cold exposure (48 h at 5 degrees C) significantly reduced the insulin response to intravenous glucose injection (P less than 0.01) while improving glucose tolerance (P less than 0.01). Starvation (48 h at 25 degrees C) also reduced the insulin response (P less than 0.01) but did not significantly alter glucose tolerance. "Accelerated starvation" induced by starving rats for 48 h at 5 degrees C dramatically reduced both basal and glucose-stimulated insulin levels while even improving glucose tolerance, resulting in a 15-fold reduction in the insulinogenic index. Cold acclimation (3 wk at 5 degrees C) induced essentially the same alterations as cold exposure. Approximately reversed changes were observed when cold-acclimated rats were returned to a warm environment for 15-18 h. Results from these studies indicate that 1) cold exposure and starvation, but not cold acclimation, act synergistically in decreasing the sensitivity and/or the capacity of pancreatic islets for secreting insulin in response to glucose stimulation; 2) glucose tolerance and possibly insulin sensitivity of peripheral tissues are enhanced by cold exposure and starvation, although glucose tolerance is improved by cold exposure only, not by starvation; 3) an improved glucose tolerance with barely detectable plasma insulin levels was obtained in cold-starved rats under normal physiological conditions.

Glucose Disposal in Low-Birth-Weight Infants During Steady-State Hyperglycemia: Effects of Exogenous Insulin Administration

The effects of exogenous insulin administration on glucose disposal during steady-state hyperglycemia were evaluated in eight well, low-birth-weight (LBW) infants (mean birth weight 1,090 gm; mean gestation 29 weeks) at age 5 to 14 days. The study was performed on two consecutive days. On the first day, at midpoint during a four-hour constant glucose infusion (14 mg/kg/min), a placebo was given. The following day, insulin (10 mU/kg/min) replaced the placebo. Serum insulin level increased significantly during steady-state hyperglycemia on both days. In contrast to placebo, the administration of exogenous insulin resulted in normoglycemia. It is speculated that the hyperglycemia during glucose infusion in well LBW infants is the result of persistent endogenous hepatic glucose production and/or decreased peripheral glucose utilization, both of which could be due to ineffective mediation of insulin on the liver or other insulin-sensitive peripheral tissues. The prompt reduction in serum glucose level which occurs as a result of the administration of exogenous insulin further suggests that in LBW infants a higher insulin level is necessary to achieve the appropriate control of glucose homeostasis. During this study, no osmotic diuresis was observed since the quantity of urinary glucose did not constitute an osmolar load.

Insulin sensitivity of forearm tissues in prediabetic man.

In genetic prediabetic subjects (the glucose tolerant offspring of two diabetic parents or the identical twin of a known diabetic) serum insulin concentrations after glucose administration are subnormal. Maintenance of glucose tolerance in this setting is apparently paradoxical, suggesting increased tissue insulin sensitivity. Accordingly, forearm tissue insulin sensitivity in nine genetic prediabetic males was compared with that of seven males without familial diabetes. Diabetes was excluded in all subjects by preliminary oral glucose tolerance testing. On the preliminary 3 h oral glucose tolerance test (OGTT) the sum of increments in blood glucose above fasting was greater in prediabetic than in control subjects. Conversely, the sum of increments in serum insulin was subnormal for the first 2 h. The insulin index (the sum of increments in insulin divided by the sum of increments in glucose) was significantly lower in prediabetics throughout the test. High physiologic levels of insulin were produced in the forearm by intrabrachial arterial insulin infusion (100 muU/kg per min for 26 min). Balances of glucose and amino acids across forearm muscle became more positive, as did balances of glucose and free fatty acids across adipose tissue plus skin. There were no differences in response between prediabetic and normal subjects.Hence, the insulin sensitivity of peripheral tissues is normal in genetic prediabetes. Increased tissue insulin sensitivity is not essential to explain coexisting euglycemia and insulinopenia in prediabetes because blood glucose values on the OGTT are, in fact, elevated although still within the range considered normal.