[Show abstract][Hide abstract] ABSTRACT: Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients.
Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as <3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events.
In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM.
Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar.
[Show abstract][Hide abstract] ABSTRACT: Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes.
In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TWAM) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TWPM) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA1c 7·0-10·0%; body-mass index ≤45 kg/m(2)) were randomly allocated (1:1) without stratification by a central interactive response system to IDeg 3TW or IGlar OD. Both groups continued taking metformin with or without dipeptidyl peptidase-4 inhibitors. Insulin was titrated to achieve a prebreakfast self-monitored blood glucose (SMBG) concentration of between 3·9 and less than 5·0 mmol/L. The primary outcome was non-inferiority of IDeg 3TW compared with IGlar OD, as assessed by change in HbA1c from baseline to 26 weeks (non-inferiority limit of 0·4%) by ANOVA in an intent-to-treat analysis (full analysis set). These trials are registered with ClinicalTrials.gov, numbers NCT01068678 and NCT01076647.
We recruited 460 patients for the AM trial (IDeg 3TWAM, n=230; IGlar OD, n=230) and 467 patients for the PM trial (IDeg 3TWPM, n=233; IGlar OD, n=234). After 26 weeks, mean HbA decreased by 0·9% (IDeg 3TWAM) and 1·3% (IGlar OD) in the AM trial, and by 1·1% (IDeg 3TWPM) and 1·4% (IGlar OD) in the PM trial. Non-inferiority was not confirmed in either trial (estimated treatment difference [IDeg 3TWAM-IGlar OD] 0·34%, 95% CI 0·18-0·51; [IDeg 3TWPM-IGlar OD] 0·26%, 0·11-0·41). Across the two trials, rates of confirmed hypoglycaemia (SMBG <3·1 mmol/L or severe [needing assistance]) ranged from 1·0 to 1·6 episodes per patient-year and were similar for IDeg 3TWAM and IGlar OD (estimated rate ratio [ERR] 1·04, 95% CI 0·69-1·55), but higher for IDeg 3TWPM than for IGlar OD (ERR 1·58, 1·03-2·43). The rate of nocturnal confirmed hypoglycaemia was higher for IDeg 3TWAM than for IGlar OD (ERR 2·12, 1·08-4·16); we noted no significant difference between IDeg 3TWPM and IGlar OD (ERR 0·60, 0·21-1·69).
The inferior glycaemic control and increased risk of hypoglycaemia with IDeg 3TW compared with IGlar OD do not support a three-times-weekly dosing regimen.
The lancet. Diabetes & endocrinology. 10/2013; 1(2):123-31.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin.RESEARCH DESIGN AND METHODS
This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin-naïve and receiving oral antidiabetic drugs (OADs) (HbA(1c) = 7-11%) or previously on basal insulin ± OAD(s) (HbA(1c) = 7-10%). Participants were randomized to 1) once-daily IDeg in a prespecified dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA(1c) reduction after 26 weeks.RESULTSAfter 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex - IGlar OD]: 0.04% points [-0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups.CONCLUSIONS
The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To compare ultra-long acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).RESEARCH DESIGN AND METHODS
In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.RESULTSIn all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.CONCLUSION
Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.
[Show abstract][Hide abstract] ABSTRACT: The efficacy and safety of insulin degludec (degludec), a new-generation ultra-long-acting basal insulin, was compared with insulin glargine (glargine) in people with Type 1 diabetes mellitus in a 16-week, open-label, randomized trial. Health status, an important aspect of effective diabetes management, was also assessed.
Degludec (n = 59) or glargine (n = 59) were injected once daily, with insulin aspart at mealtimes. Health status assessment utilized the validated Short Form 36 Health Survey, version 2, which has two summary component scores for mental and physical well-being, each comprising four domains.
At study end, HbA(1c) reductions were comparable between groups, but confirmed nocturnal hypoglycaemia was significantly less frequent with degludec [relative rate 0.42 (95% CI 0.25-0.69)], and overall hypoglycaemia numerically less frequent [relative rate 0.72 (95% CI 0.52-1.00)]. After 16 weeks, a significant improvement in Short Form 36 Health Survey mental component score of +3.01 (95% CI 0.32-5.70) was obtained for degludec against glargine, attributable to significant differences in the social functioning [+8.04 (95% CI 1.89-14.18)] and mental health domains [+2.46 (95% CI 0.10-4.82)]. For mental component score, Cohen's effect size was 0.42, indicating a small-to-medium clinically meaningful difference. The physical component score [+0.66 (95% CI -2.30 to 3.62)] and remaining domains were not significantly different between degludec and glargine. ConCLUSIONS: In the context of comparable overall glycaemic control with glargine, degludec improved mental well-being as measured using the mental component score of the Short Form 36 Health Survey. The improvements in overall mental component score and the underlying social functioning and mental health domains with degludec compared with glargine may relate to the observed reduction in hypoglycaemic events.
Diabetic Medicine 12/2011; 29(6):716-20. · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs.
In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18–75 years with type 2 diabetes and glycosylated haemoglobin (HbA(1C)) of 7·0–11·0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer-generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA(1C) after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884.
Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA(1C) levels were much the same across treatment groups, at 7·3% (SD 1·1), 7·4% (1·0), 7·5% (1·1), and 7·2% (0·9), respectively. Estimated mean HbA(1C) treatment differences from insulin degludec by comparison with insulin glargine were 0·08% (95% CI –0·23 to 0·40) for the three dose per week schedule, 0·17% (–0·15 to 0·48) for group A, and 0·28% (–0·04 to 0·59) for group B. Few participants had hypoglycaemia and the number of adverse events was much the same across groups, with no apparent treatment-specific pattern.
Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile.
The Lancet 03/2011; 377(9769):924-31. · 39.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to demonstrate differential effects of growth hormone (GH) on food intake in lean and obese rats and to investigate whether an anticipated anorectic response in obese rats might be associated with increased lipid oxidation and altered hypothalamic neuropeptide levels. GH (4 mg/kg/day) was administered during 5-21 days to non-obese and obese rats. Whereas GH stimulated food intake in the non-obese rats, the obese animals responded with a significantly (p<0.05) suppressed food intake for 4-5 days. On day 4, the obese rats injected with GH and those injected with vehicle consumed 9.2 ± 0.66 g and 12.7 ± 1.05 g, respectively. The suppression of food intake was associated with significantly (p<0.05) increased lipid oxidation. A similar, but statistically not verified, trend was seen in pair-fed rats not exposed to GH. However, while these animals appeared to economize their energy expenditure, the GH-exposed animals did not, thus creating a significant (p<0.05) difference between these two groups. The increased lipid oxidation and energy expenditure observed in the rats exposed to GH were associated with significantly (p<0.05) decreased levels of hypothalamic galanin (111 ± 33.2 pmol/g vs. those of the pair-fed controls: 228.5 ± 49.4 pmol/g). This difference was, however, not sustained. Thus, on day 21 both hypothalamic galanin and the food intake in the GH group were back to normal. Hypothalamic NPY remained unchanged by GH at all times. In conclusion, the present study suggests that increased lipid oxidation and decreased hypothalamic galanin are components in the mechanism by which GH inhibits food intake in an obese phenotype.
[Show abstract][Hide abstract] ABSTRACT: Introduction
L’insuline Degludec (IDeg) est un nouvel analogue de l’insuline qui forme des multi-hexamères solubles après injection sous-cutanée (SC), ce qui confère ainsi une durée d’action ultra longue.
Matériels et méthodes
Essai ouvert de phase 2, Treat to Target, de 16 semaines, randomisé en groupes parallèles, portant sur l’efficacité et l’innocuité de l’IDeg administrée le soir une fois par jour (1x/j), ou 3 fois par semaine (3S) chez des patients diabétiques de type 2, naïfs en insuline et non contrôlés par les antidiabétiques oraux (objectif de glycémie à jeun à 0,72 – 1,08 g/l).
Les patients (54,2 ans, HbA1c 8,7 %, GAJ 1,84 g/l, IMC 29,5 kg/m2) ont reçu l’IDeg 1x/j (n = 60), 3S (n = 62), ou de l’insuline Glargine 1x/j (IGlar, n = 62) plus metformine. Après 16 semaines de traitement, l’HbA1c était comparable en termes de diminution (IDeg 1x/j – 1,3 % ; IDeg 3S – 1,5 %, IGlar – 1,5 %) et de valeur obtenue (7,4 % ; 7,3 % et 7,2 %). La GAJ moyenne était aussi comparable en valeur obtenue (1,13 g/l, 1,16 g/l, et 1,15 g/l) et en réduction moyenne (− 0,65 g/l ; − 0,75 g/l et − 0,61 g/l). La dose d’insuline était similaire (3,1 U/kg/sem = 0,45 U/kg/jour, 3,4 U/kg/sem = 0,49 U/kg/jour et 3,3 U/kg/sem = 0,48 U/kg/jour). Le taux d’hypoglycémie confirmée était faible et semblait plus bas avec IDeg 1x/j qu’avec IDeg 3S et IGlar (0,6, 2,3 et 1,1 év/pt-année ; NS pour les deux). La proportion de sujets présentant des événements indésirables était voisine dans les 3 groupes (47 %, 50 % et 66 %).
L’IDeg utilisée 3 fois par semaine ou une fois par jour était bien tolérée et fournissait un contrôle glycémique similaire à l’IGlar.
[Show abstract][Hide abstract] ABSTRACT: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.
In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.
In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.
Diabetes care 01/2011; 34(3):661-5. · 7.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight-reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study, the effect on weight loss was studied in diet-induced obese rats after 3 days and 3 weeks of exposure to rimonabant, respectively. Induction of lipolysis was examined following acute administration and following 3 weeks of repeated dosing. Rimonabant-treated rats lost significantly more weight than their food-restricted controls. This effect was most pronounced in the beginning of the treatment period. No increase in lipolytic activity was found after 3 weeks of repeated dosing as measured by microdialysis in adipose tissue whereas acute administration of 10mg/kg produced a significant increase in microdialysate levels of glycerol illustrating an acute stimulation of lipolysis. No equivalent increase in glycerol was, however, observed in vitro following incubation of isolated rat adipocytes with rimonabant. This finding excludes a direct lipolytic action of rimonabant on tissue level. Instead, administration of 10mg/kg produced a significant increase in noradrenaline excretion in diet-induced obese rats, suggesting an increase in sympathoadrenal activity. In conclusion, the present study suggests an acute lipolytic effect of rimonabant mediated through activation of the sympathoadrenal system.
European journal of pharmacology 11/2010; 646(1-3):38-45. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microdialysis is a technique that allows continuous sampling of compounds from the interstitial fluid of different tissues with minimal influence on surrounding tissues and/or whole body function. In the present study, the feasibility of using microdialysis as a technique to sample free fatty acids (FFA) was investigated both in vitro and in vivo, by use of a high molecular weight (MW) cut-off membrane (3 MDa) and a push-pull system to avoid loss of perfusion fluid through the dialysis membrane. The relative recovery was examined in vitro for three different concentrations of radiolabelled oleic acid-BSA solutions (oleic acid:BSA molar ratio 1:1) and for various temperatures and flow rates. The recovery of oleic acid was found to be dependent on the concentration of analyte in the medium surrounding the membrane (17.3%, 29.0% and 30.6% for 50, 100 and 200 microM oleic acid-BSA solutions, respectively). Addition of 0.25% BSA to the perfusion fluid resulted, however, in a concentration-independent recovery of 31.4%, 28.1% and 28.1% for the 50, 100 and 200 microM solutions, respectively. The capability of the method to measure FFA together with glycerol was investigated in vivo in visceral adipose tissue of rats, before and after lipolytic treatment with the beta3-adrenergic agent, BRL37344. BRL37344 caused an increase in both dialysate FFA and glycerol, although the increase was markedly higher for glycerol, amounting to 24.5% and 329.2% increase from baseline, respectively. Subsequent in vitro test of probe performance revealed a decrease in the dialysing properties with regard to FFA, but not glycerol. This suggests that clogging of the membrane pores after 110 min prevented the measurement of the full FFA response in vivo.
Journal of Pharmaceutical and Biomedical Analysis 05/2007; 43(5):1751-6. · 2.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The obesity epidemic calls for complementary treatment possibilities in addition to lifestyle changes. One of the important regulators of lipid homeostasis is growth hormone (GH). Clinical trials have tested if GH can reduce obesity in humans. The mechanisms underlying the response to GH administration have also been investigated in animal models of human obesity. A literature search yielded 19 randomized placebo-controlled clinical studies and several animal studies investigating chronic GH treatment of obesity. Significant effects were found in some of the larger trials. One clinical trial showed significantly increased weight loss due to GH treatment, and in seven trials, a significant reduction of fat mass was found. The improvements observed were modest, but even minor improvements have been shown to be beneficial, especially if the reduction in fat mass includes visceral adipose tissue, as was reported in three of six trials. In principle, animal data support the clinical observations although the reduction of fat mass was more dramatic than observed in humans. The mechanisms resulting in lipid mobilization most likely include adipose tissue lipo-protein lipase (LPL) inhibition and antagonization of the anti-lipolytic activity of insulin. By feeding a restricted amount of a high fat diet to GH exposed rats hyper-insulinemia was avoided, loss of body fat was accelerated and metabolic markers were improved. Provision of a diet suitable for the metabolic conditions during GH treatment shows promise for improving metabolic control and can perhaps increase the efficacy and/or widen the therapeutic window of GH.
Metabolic syndrome and related disorders 02/2006; 4(1):57-69.
[Show abstract][Hide abstract] ABSTRACT: Growth Hormone (GH) promotes loss of body fat and causes insulin resistance. It is debated whether reduction of body fat mass during long term growth hormone (GH) administration improves carbohydrate metabolism. To answer this question we assessed carbohydrate handling and tissue specific function of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) during prolonged GH treatment of obese rats.
Body fat % estimated by DEXA scanning, plasma IGF-I, glucose and insulin were studied in 17 months old dietary induced obese rats treated for 4, 21 or 41 days (GH: 4 mg/kg/d or saline total n=90). Adipose tissue, muscle and liver samples were obtained after 21 days and expression and tyrosine phosphorylation of IR and IRS-1 proteins and the degree of IRS-1-Janus Kinase-2 (JAK2) interaction were analyzed by immunoprecipitation and immunoblotting.
Forty-one days GH treatment caused the body fat to decline significantly to 20+/-3% (Mean+/-SEM), whereas it remained steady on 51+/-4% in the pair fed group. Insulin levels in response to OGTT were significantly elevated throughout the experiment. IR amount was elevated in adipose tissue but decreased in liver after GH treatment while IR phosphorylation was increased in muscle only. IRS-1 amount was elevated in adipose tissue and muscle while IRS-1 phosphorylation was increased only in liver. The association of IRS-1 with JAK-2 was increased in liver and muscle.
An extensive reduction of fat mass did not improved signs of insulin resistance in GH treated old obese rats. The molecular events associated with GH treatment included tissue specific changes in the function of IR and IRS-1 suggesting the liver to be the primary site of insulin resistance. Furthermore, the association of IRS-1with JAK-2 in the course of GH signaling could present a mechanism for GH to directly induce insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Lipid storage and breakdown is mainly controlled by lipoprotein lipase and hormone-sensitive lipase. The aim of this work was to elucidate whether growth hormone mediated loss of adipose tissue involves a concerted action on tissue lipases, and to what degree such events are modulated by dietary regimen. Twelve-month-old rats fed first a high-fat diet or a low-fat diet for 14 weeks were injected with saline or growth hormone (4 mg/kg/d) for four days or three weeks in different combinations with either high- or low-fat diets. In adipose tissue, growth hormone generally inhibited lipoprotein lipase and also attenuated the inhibiting effect of insulin on hormone-sensitive lipase activity. Growth hormone treatment combined with restricted high-fat feeding reduced the activity of both lipases in adipose tissue and stimulated hormone-sensitive lipase in muscle. Generally, plasma levels of free fatty acids, glycerol and cholesterol were reduced by growth hormone, and in combination with restricted high-fat feeding, triglyceride levels improved too. We conclude that growth hormone inhibits lipid storage in adipose tissue by reducing both lipoprotein lipase activity and insulin's inhibitory action on hormone-sensitive lipase. We also propose that growth hormone's effects on tissue lipases and blood lipids are modulated by dietary regimen.
Hormone and Metabolic Research 05/2003; 35(4):243-50. · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This work was performed to elucidate whether growth hormone (GH)-mediated loss of adipose tissue and responses in plasma insulin and leptin are modulated by diet composition. 12-month-old rats were first fed a high-fat (HF) diet or a low-fat (LF) diet for 14 weeks. After that, GH or saline was administered to rat groups that were maintained on either HF or LF diets or that were switched from the HF to the LF diet. All 6 groups had free access to food. One additional saline group was pair-fed with the GH group that was switched from the HF to the LF diet. The caloric consumption of this latter group was also translated to yet another GH group receiving restricted amounts of the HF diet. GH was given in a total dose of 4 mg/kg/d for three weeks. After sacrifice, blood was collected and tissues were excised. In groups injected with saline, the weight of excised adipose tissue was 60 +/- 4.7, 41 +/- 3.8 and 50 +/- 4.5 g in animals that continued with the HF diet, LF diet, or that were switched from HF to LF, respectively. Corresponding figures after GH treatment were significantly (p < 0.05) decreased to 38 +/- 2.7, 30 +/- 2.3, and 31 +/- 2.7 g, respectively. Pair-feeding had no effect, whereas only 26 +/- 3.0 g of adipose tissue was retrieved in rats fed restricted amounts of HF diet while receiving GH. In this group, plasma insulin and leptin were also significantly (p < 0.05) depressed compared with other GH groups, especially to the group fed the unrestricted HF diet (203 +/- 35 vs. 1345 +/- 160 pmol/l and 9.3 +/- 1.2 vs. 31 +/- 4.4 micro g/l). In conclusion, this study shows that GH mediates breakdown of adipose tissue under a variety of dietary conditions, and that induction of hyperinsulinemia can be prevented if GH treatment is combined with restricted feeding of a diet which is relatively low in carbohydrates and rich in fat. This will also promote a fall of plasma leptin.
Hormone and Metabolic Research 04/2003; 35(4):236-42. · 2.15 Impact Factor