Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin

In a prospective clinical trial, low-dose, continuous, IV infusion of insulin (dosage, 2.2 U/kg of body weight, q 24 h) was used to treat 21 dogs with diabetic ketoacidosis. Mean (+/- SD) blood glucose concentration at the onset of treatment was 550 +/- 150 mg/dl and after 6 hours, was 350 +/- 106 mg/dl, with a mean decline of 34 +/- 16 mg/dl/h. By 12 hours, mean blood glucose was 246 +/- 85 mg/dl, with a mean decline of 28 +/- 14 mg/dl/h during the second 6 hours of treatment. Mean duration of treatment required to reach a blood glucose concentration < or = 250 mg/dl was 10 +/- 4 hours, with a range of 4 to 24 hours. Ketonuria was observed for 26 +/- 14 hours (range, 6 to 72 hours). Hypoglycemia developed in 3 of 21 dogs during treatment, but responded to IV administration of a glucose solution and to a reduction in rate of insulin delivery. Potassium supplementation was required in 15 of 21 dogs. Mean bicarbonate concentration was 11.6 +/- 3.4 mEq/L before treatment and was 18.2 +/- 0.7 mEq/L after 24 hours. Fifteen of 21 dogs (71%) survived to be discharged. Mean duration of treatment with the insulin infusion was 50 +/- 30 hours (range, 7 to 124 hours). In this series of dogs, continuous, low-dose, IV infusion of insulin provided a gradual and consistent reduction in blood glucose concentration while ketoacidosis, electrolyte balance, and dehydration were corrected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in plasma insulin and growth hormone after intravenous glucagon in hepatic cirrhosis

Decreased increases in blood sugar by comparison with control subjects was noted in patients with cirrhosis of the liver after i.v. administration of 1 mg glucagon. Insulin secretion was similar to that observed in the controls. Basal GH values were higher in the liver patients, whereas after glucagon they displayed a gradual and progressive increase with a peak at 60'. No significant differences in GH pattern were noted in the two groups, however.     

Elevated growth hormone secretory rate in premature infants: deconvolution analysis of pulsatile growth hormone secretion in the neonate

Premature infants have higher circulating concentrations of growth hormone (GH) than term infants. Previous investigations of these differences have used sampling frequencies of every 30 min with subsequent application of pulse detection algorithms, such as the CLUSTER program, to assess serum GH pulse parameters. To determine differences in GH secretory rates or GH t1/2 values between premature and term infants, we have sampled 11 neonates at 15-min intervals. We performed deconvolution analysis of the resultant plasma GH values to estimate GH secretory and clearance parameters. Five premature infants (gestational age range 24-34 wk) and six term infants (gestational age range 38-42 wk) were sampled every 15 min for 6 h. All subjects had indwelling arterial catheters. GH was measured (in duplicate) by RIA using 10 microL of plasma. Premature infants had higher secretory burst amplitudes (2.2 +/- 0.13 micrograms/L/min versus 1.4 +/- 0.27 micrograms/L/min, p = 0.02), higher production rates (product of the total number of bursts and the mean mass of GH secreted per burst, 811 +/- 173 micrograms/L/6 h versus 283 +/- 77 micrograms/L/6 h, p = 0.03), and a higher mass of GH per secretory burst (106 +/- 25 micrograms/L versus 38 +/- 11 micrograms/L, p = 0.049) than term infants. The integrated plasma GH concentration exhibited a strong trend toward a higher value in the premature infants (18,100 +/- 800 micrograms/L versus 10,200 +/- 2,700 micrograms/L, p = 0.067).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin, glucagon, and somatostatin in normal physiology and diabetes mellitus

Studies are reviewed in which the roles of insulin and glucagon in normal physiology and in diabetes are examined. In normal man, glucose ingestion is accompanied by a rise in insulin and fall in glucagon and is primarily disposed of in the liver, an organ sensitive to both hormones. However, infusions of glucagon in physiologic amounts indicate that insulin secretion rather than glucagon inhibition is the primary factor determining glucose disposal. Furthermore, minor elevations in blood glucose elicit increments in insulin concentration and inhibition of hepatic glucose output in the absence of changes in plasma glucagon. The primary physiologic role of glucagon is to prevent the hypoglycemia that would otherwise accompany noncarbohydrate (protein)-mediated insulin secretion. In diabetic as well as normal patients the stimulatory effect of glucagon on hepatic glucose production is evanescent. Increases in glucagon or changes in the I/G ratio can bring about deterioration in glucose tolerance or in diabetic control only so long as absolute insulin deficiency is present or pharmacologic elevations in glucagon are produced. After somatostatin administration, prolonged hypoinsulinemia in normal subjects is observed to result in fasting hyperglycemia in the absence of basal glucagon secretion. In diabetic patients the improvement in postprandial hyperglycemia produced by somatostatin can be accounted for by its inhibitory action on carbohydrate absorption in the gastrointestinal tract. It is concluded that insulin deficiency is the primary pathophysiologic disturbance in diabetes. While glocagon may worsen the consequences of insulin lack, it is neither sufficient nor necessary for the development of diabetes.     

Transient diabetes mellitus and peripheral insulin resistance following Tacrolimus intoxication in a child after renal transplantation

OBJECTIVE: Cord entanglement is a common complication of monoamniotic twins and it is associated with high perinatal mortality. Apart from preterm delivery, no treatment has previously been used to reduce the risks of this complication. We postulated that reducing amniotic fluid volume would stabilize fetal lie and reduce the risk of cord compression. STUDY DESIGN: Cord entanglement was documented in three cases of monoamniotic twins in the midtrimester. Sulindac was administered to the mother. Amniotic fluid index, fetal urine output, and umbilical artery and ductus arteriosus Doppler waveforms were investigated before and during treatment by use of real-time and pulsed Doppler techniques. RESULTS: Sulindac was associated with a dose-related reduction in amniotic fluid index and fetal urine production without alteration in fetal flow velocity waveforms. Fetal lie stabilized after commencement of treatment. All six twins were delivered with no complications. CONCLUSION: Medical amnioreduction with sulindac is a new management option in monoamniotic twins to reduce cord complications.     

Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis

Infantile cystinosis, a rare lysosomal storage disease of cystine, leads to Fanconi syndrome and end-stage renal failure. After renal transplantation, no recurrence of the disease occurs in the graft, but other organ involvement becomes evident later in life. Diabetes mellitus has been associated with cystinosis, but the mechanisms of impaired glucose tolerance have not yet been characterized. Here, we studied glucose tolerance, glucose constant decay (k-values), insulin and C-peptide by intravenous glucose tolerance test (IVGTT) in eight patients with infantile cystinosis (three with impaired GFR (CRF) and five after kidney transplantation (KTX)). For comparison, 15 age-matched children with CRF and 15 age-matched KTX patients were analysed. Both early and second insulin secretion phases were diminished in patients with infantile cystinosis, whereas in CRF, k-values were no different from control patients. After renal transplantation, k-values were significantly lower in cystinotic patients with a markedly reduced early insulin secretion phase. There was a significant negative correlation between k-values and age in patients with cystinosis. Repetitive IVGTTs in these patients demonstrated progressive but rather slow loss of first phase insulin secretion and C-peptide production, suggesting a slowly reducing secretion potential of the beta cell due to cystine storage. CONCLUSION: Unlike type I diabetes mellitus, glucose intolerance in patients with infantile cystinosis is characterized by a slow, progressive loss of insulin secretion and C-peptide production. For these patients, the data indicate a 50% risk of developing glucose intolerance by the age of 18 years. We recommend to perform intravenous glucose tolerance tests at 5-year intervals.     

Comparison of the blood levels of insulin and growth hormone in healthy adolescents, adolescents with excessive weight and with hereditary loading with regard to diabetes mellitus

Changes in insulin and growth hormone secretion were studied in 112 children and adolescents (50 healthy ones, 40 with excessive weight, and 22 with heredity aggravated by diabetes mellitus). Three types of these changes were distinguished in healthy adolescents: normoreactive, hyperreactive, and inert. The same type of growth hormone secretion changes corresponded to each type of insulin secretion changes. There was revealed a negative correlation between the insulin and growth hormone levels in the group of healthy adolescents. Dynamic relation was noted between the indices of the mentioned hormones in the course of the test: it was stronger during the ascending than during the descending phase of the test. Glucose load proved to change the correlation between the hormones level. In the group of healthy adolescents correlation between the insulin and the growth hormone levels was greater before carbohydrate load than after it. In case of excessive weight or heredity aggravated by diabetes mellitus glucose load disturbed the correlation between the hormones: when a negative correlation existed between the insulin and growth hormone levels before the load no correlation was revealed after in. This fact confirmed the role played by excessive carbohydrate consumption in the pathogenesis of diabetes mellitus.     

Glycosylated hemoglobin and fetal growth in normal, gestational and insulin dependent diabetes mellitus pregnancies

Aims of the study were: evaluation of HbA1c levels in the peripheral blood of pregnant women with insulin dependent diabetes, gestational diabetes, glucose intolerance, and healthy pregnant controls; implications of HbA1c concentration on detection and the control of women with impaired carbohydrate metabolism in pregnancy; comparison of HbA1c levels with appearance of miscarriages, and premature deliveries; comparison of weight gain during pregnancy to HbA1c levels; comparison of difference from ideal body weight with HbA1c in diabetic pregnant women; comparison of neonatal birth weight and HbA1c levels. 290 pregnant women were enrolled to the study. The highest value of HbA1c was in the group IDDM pregnant women (7.7% +/- 1.8%), and the lowest value of HbA1c was in the control group (4.1% +/- 0.5%). Statistically significant coefficients were found between HbA1c and weight gain during pregnancy, between weight deviation from ideal body weight and HbA1c (r = 0.54 and r = 0.48 respectively); and between newborns weight and HbA1c (r = 0.51). Well regulated glycemia and intensive pregnancy follow-up of diabetic women reduces stillbirths, neonatal complications and neonatal macrosomia incidence.     

Changes in plasma glucose, insulin, glucagon, catecholamine, and glycogen contents in tissues during development of alloxan diabetes mellitus in rats

Leishmanial antigens (LAg) were used as a vaccine against Leishmania donovani, the causative agent of visceral leishmaniasis. BALB/c mice, immunized intraperitoneally with 20 micrograms of the antigen in phosphate-buffered saline (PBS) or entrapped in liposomes, were infected intravenously with 2 x 10(7) L. donovani promastigotes. Mice immunized with PBS and empty liposomes showed similar levels of parasite burdens in the liver and spleen. Injection of the antigen alone or entrapped in liposomes, followed with infection, induced significant levels of protection against the disease. After 2 and 4 mo of infection, mice immunized with free antigen induced 7.4% and 50.7% reduction in the liver parasite burden, respectively, compared to control (PBS) mice. With antigen encapsulated in liposome, the liver parasite burden was further reduced by 30.4% and 73% at 2 and 4 mo by infection, respectively. Splenic parasite burden was very low at 2 mo of infection. At 4 mo, the parasite level was reduced by 54.2% with free antigen and 69.3% with antigen entrapped in liposomes. Whereas the protection induced by the free antigen is mainly cell mediated, stimulation of an antibody response together with a strong delayed-type hypersensitivity may be responsible for the better protection with liposomal antigen.     

Evaluation of growth hormone secretion during sleep and after L-dopa

Control of infectious atrophic rhinitis in swine breeding herds by culturing of 3 series of nasal swab specimens from each animal, with subsequent elimination of Bordetella bronchiseptica culture-positive animals, was evaluated. Thirteen of 17 (77%) B bronchiseptica-infected herds experiencing clinical atrophic rhinitis were feedic rhinitis were freed of clinical signs of the disease by the use of this nasal culturing procedure. In 15 of 23 (65%) B bronchiseptica-infected herds, pigs were cultured negative for this organism at 4 to 10 weeks of age.     

The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes

The type 1 copper in Pseudomonas aeruginosa azurin was studied by electron paramagnetic resonance (EPR) spectroscopy at low microwave frequencies. Partially resolved ligand hyperfine structure was observed in the perpendicular region of the spectra at both S-band (2.4 GHz) and L-band (1.1 GHz). A trial and error method, requiring several hundred simulations, has been used to simulate the low frequency EPR data and yield an optimum value of 30 MHz for ACUx, more than one half that previously reported. The fit between the simulated and experimental data is sensitive to changes in the Euler angles and, in particular, to the angle alpha which rotates the Cu A-tensor about the z-axis. Thus, the A- and g-tensors for copper in P. aeruginosa azurin do not appear to be coincident. A value for the Euler angle beta of at least 10 degrees does not disturb the fit between the simulated and experimental data. These studies demonstrate the advantage of evaluating EPR parameters from simulations at more than one frequency, especially at low frequencies where ligand superhyperfine structure may be resolved for type 1 copper.     

The relationship between concentration of growth hormone in serum and microangiopathy in patients with diabetes mellitus

OBJECTIVE: To study the relationship between growth hormone (GH) and microangiopathy in patients with diabetes mellitus in order to elucidate pathogenesis on microangiopathy in diabetics. METHODS: GH and insulin (INS) were detected by rdioimmunoassay, and blood sugar (BS) was detected by oxydase method. RESULTS: 138 NIDDM diabetics were examined. The concentration of serum GH in diabetics without microangiopathy (2.3 +/- 1.2 micrograms/L) was higher than in normal people (1.0 +/- 1.2 micrograms/L) and GH in diabetics with microangiopathy (5.74 +/- 1.94 micrograms/L) was higher than in diabetics without microangiopathy. The differences were significant (P < 0.01). As the history of diabetes went on, the level of GH in serum increased, and the incidence of microangiopathy increased too. The correlation of GH in serum with BS was parallel. The correlation of GH in serum with INS was not apparent. 27 ID-DM diabetics were examined, their level of GH in serum (6.8 +/- 3.4 micrograms/L) was higher than that of NIDDM diabetics (4.6 +/- 1.8 micrograms/L). They were all patients with microangiopathy. CONCLUSION: The rise of GH in serum may be an important pathogeny that causes microangiopathy in diabetics.     

Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects

To determine if both phases of glucagon secretion are excessive in diabetes, arginine was admimistered intravenously as pulses and as infusions to normal subjects, insulin-dependent diabetics, and noninsulin-requiring diabetics. The acute phase of glucagon secretion, in response to arginine pulses at four different doses (submaximal to maximal alpha-cell stimulating), was indistinguishable in terms of timing, peak levels attained, and total increments comparing controls and diabetics. During the first half of the arginine infusion (500 mg/kg over 30 min) the glucagon rise in controls and diabetics was similar (P greater than 0.1), whereas during the last half of the infusion excessive glucagon levels were seen in the diabetics. No difference in the glucagon responses to arginine administered as either a pulse or an infusion was observed between the two types of diabetics. The acute phase responses of insulin to intravenous, maximal stimulating doses of glucose (20 g) and arginine (2.5 g) were measured in five insulin-independent diabetics. Although the acute insulin response to arginine was normal, there was marked attentuation of the early beta-cell response upon stimulation by glucose. From these results we conclude that although in diabetes excessive glucagon levels are observed with chronic arginine stimulation, the acute phase of glucagon secretion in response to arginine is normal. In addition, the beta-cell in noninsulin-requiring diabetics, although acutely hyporesponsive to glucose, remains normally responsive to another stimulus, arginine.     

The role of growth hormone, somatostatin and glucagon in hepatic resection

BACKGROUND/AIMS: The aim of this study was to clarify the roles of growth hormone, somatostatin, and glucagon in vital reactions against surgical stress as well as in hepatic regeneration. METHODOLOGY: Eleven consecutive patients, who underwent hepatic resection, were included in this study. Changes in intrinsic hormones, specifically growth hormone, somatostatin, and glucagon, were investigated. Furthermore, a comparison was made between major (more than 2 segments) and minor (less than 1 segment) hepatectomies. RESULTS: Growth hormone was observed to increase four-fold during hepatectomy and thereafter remained at relatively high levels. Somatostatin reached its lowest level on postoperative day 1 and then returned to near the preoperative level on postoperative day 7, while glucagon gradually increased and reached a peak around postoperative day 3. The concentrations of both somatostatin and glucagon in the portal vein were higher than those in the peripheral vein. No significant differences between major and minor hepatectomies were found throughout the perioperative course. CONCLUSIONS: Growth hormone is considered to be a sensitive parameter in terms of surgical stress and can also act as a trigger as well as a promoter of hepatic regeneration, while a dissociation between somatostatin and glucagon in the early postoperative period indicates the promotion of hepatic regeneration. Furthermore, portal blood, which contains higher concentrations of these substances, plays an important role in regulating hepatic regeneration. However, the absence of a correlation between the extent of the hepatectomy and these parameters suggests that some other, as yet unidentified mechanism, may also be related to the regulation of hepatic regeneration.