Coefficient of beta-cell failure in patients with type 2 diabetes treated with pioglitazone or acarbose.

AIM: A new method of assessing the coefficient of failure of pancreatic beta-cells from any index of glycaemia has been proposed. This method of analysis has been used to assess data on HbA1c and fasting glucose concentrations from a randomised study comparing pioglitazone with acarbose. METHODS: Patients were treated for 26 weeks with either pioglitazone 45 mg once daily or acarbose 300 mg/day as 3 equal doses. Plasma HbA1c concentration was measured every two months and fasting glucose was measured monthly. The coefficient of failure was determined for each patient from the slope of the least squares regression line over time. RESULTS: The coefficient of failure from HbA1c was - 2.65 +/- 2.13 %/year with pioglitazone and - 1.25 +/- 3.11 %/year with acarbose, indicating improved beta-cell function in each case. The coefficient of failure was improved to a significantly greater extent with pioglitazone ( P < 0.001). Coefficient of failure from fasting blood glucose also showed a greater improvement with pioglitazone (- 53.1 +/- 95.0 mg/dl/year) than with acarbose (- 29.9 +/- 142.5 mg/dl/year; p = 0.049). CONCLUSION: The coefficient of failure showed a significantly greater improvement of beta-cell function with pioglitazone than with acarbose during 26 weeks of treatment.

Preprandial vs. postprandial insulin lispro-a comparative crossover trial in patients with Type 1 diabetes.

AIMS: Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. METHODS: Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. RESULTS: Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. CONCLUSIONS: Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.

Use of human GH in elderly patients with accidental hip fracture.

OBJECTIVE: To investigate whether early intervention with recombinant human growth hormone (hGH) after hip fracture improves functional recovery and long-term outcome. SUBJECTS AND METHODS: Functional recovery after hip fracture is often incomplete. The catabolic situation that develops after the hip fracture accident, and a state of malnutrition either pre-existing or developing after surgery, are main contributing factors for the poor clinical outcome. hGH has been used to promote anabolism in a variety of clinical catabolic situations. The study design was randomized, double-blind and placebo-controlled. A total of 111 patients older than 60 years with an accidental hip fracture (mean age 78.5+/-9.1 (s.d.) years) were randomized to receive either hGH (20 microg/kg per day) or placebo for a period of 6 weeks, starting within 24 h after the hip fracture accident. Thereafter patients were followed up for an additional period of 18 weeks. Efficacy was assessed by comparing the changes in the Barthel Index score of activities of daily living and in a patient's living situation between the hGH- and the placebo-treated subjects. RESULTS: Eighty-five (78.5%) patients completed the first 8 weeks of the study and 76 (68.5%) the entire study period of 24 weeks. When split according to age, a trend was found that for patients older than 75 years the changes in Barthel Index score from baseline were less in the hGH group than in the placebo group (-18.6+/-18 vs -28.1+/-26) at 6 weeks after surgery (P<0.075). There was an overall trend to a higher rate of return to the pre-fracture independent living situation in the hGH group than in the placebo group. Analysis by age revealed a significantly higher proportion of hGH- than placebo-treated patients returning to the pre-fracture living situation for subjects older than 75 years (93.8 vs 75.0%, P=0.034). hGH treatment increased IGF-I values to levels in the range of those of normal subjects of 50-60 years of age. CONCLUSIONS: A 6 week treatment with hGH (20 microg/kg per day) of otherwise healthy patients after an accidental hip fracture may be of benefit if given to subjects older than 75 years of age. The rate of return to the pre-fracture living situation in subjects of this age treated with hGH was significantly increased when compared with the placebo-treated group. The treatment intervention was well tolerated and no safety issues were recorded.

Acceptability and safety of a new 3.0 ml re-usable insulin pen (HumaPen) in clinical use.

A new re-usable insulin pen (the HumaPen) was tested in a multinational study in patients with Type 1 (45.1%) or Type 2 (54.9%) diabetes. Prior to study entry, patients used either syringes or a comparison pen. Patients changed to the HumaPen for all insulin injections during the 5-to 7-week study and a 12- to 13-week extension period. Acceptability of the HumaPen was assessed from a questionnaire completed at the end of the study by 72 previous syringe users and 209 previous pen users. HumaPen features considered easy/very easy by pre-study syringe users or pre-study pen users were correcting a mis-dialled dose (97.2%; 95.1%, respectively), reading the dose numbers (95.8%; 97.1%) and ease of learning (95.8%; 92.3%). Convenience, comfort and ease of use were stated to be better by a majority of pre-study syringe users and similar by pre-study pen users. At the end of the initial study, 73.6% of syringe users and 55.5% of previous pen users said they would continue to use the HumaPen, and 171 patients continued into the extension. As expected, the most common adverse event was hyperglycaemia but the majority were mild and none caused discontinuation from HumaPen use. The main reason for not continuing into the extension period, and for return of pens, was the injection force, which was subsequently reduced by modification of design and production prior to launch. The HumaPen therefore appeared well accepted and safe in this global study and a majority said they would recommend it to other patients.

Postprandial insulin lispro. A new therapeutic option for type 1 diabetic patients.

OBJECTIVE: For intensified insulin therapy of type 1 diabetes, bolus injection of regular human insulin 30-15 min before a meal is currently recommended. This randomized study is aimed to determine whether insulin lispro (LIS), a new insulin analog with a rapid onset of action, can provide comparable blood glucose (BG) control by injection after the meal. RESEARCH DESIGN AND METHODS: Eighteen type 1 diabetic subjects injected regular insulin (REG) at 40, 20, or 0 min before or LIS at 20 or 0 min before or 15 min after the start of a standardized test meal. BG excursions and area under the curve of BG excursions (AUC) at the six visits were compared by analysis of variance. Hypoglycemic events (BG < or = 2.78 mmol/l) were evaluated in relation to the achieved postprandial BG control. RESULTS: Mean AUC values were 2.00, 2.55, and 3.33 mmol.h.l-1 for REG given 40, 20, and 0 min before the test meal, respectively, and -2.19, -2.15, and 1.98 mmol.h.l-1 for LIS given 20 and 0 min before and 15 min after the start of the test meal, respectively. LIS injected 20 min (-20) or immediately (0) before the meal was significantly more effective in controlling postprandial BG excursion (P < 0.001) than any REG treatment. Postprandial injection of LIS (15) did not compromise postprandial BG control and resulted in less hypoglycemia. REG -40 and LIS -20 were associated with early hypoglycemia, but other hypoglycemic events were equally distributed among groups. CONCLUSIONS: The optimal time for bolus insulin injection was 20 min before the meal for REG and immediately before the meal for LIS. LIS injected immediately after a standard meal provided postprandial BG control at least as good as REG injected from 40 to 0 min before the meal. Postprandial injection of LIS is an attractive new therapeutic option.

The safety profile of GH replacement therapy in adults.

OBJECTIVE: The benefits of GH replacement in GH-deficient adult patients are becoming accepted but the safety profile continues to be defined. The GH deficiency in adults may have arisen i either childhood or during adult life and these two groups differ with regard to history of disease. The aid of the present report was to study differences in safety profile between these two groups during long-term replacement therapy with recombinant human GH (hGH). Possible factors which placed a patient at risk of experiencing an adverse event were also examined. PATIENTS AND DESIGN: GH-deficient adult patients were randomized into two study protocols, differing only in age of onset of the GH deficiency syndrome. There were 98 patients with adult-onset and 67 patients with childhood-onset GH deficiency. Each study consisted of a 6-month double-blind placebo-controlled phase followed by an open-label hGH treatment phase. Glucose tolerance, incidence of treatment-emergent adverse events and relationship to IGF status were studied throughout the 36 months of treatment. RESULTS: Human growth hormone-related adverse events were reported less commonly in childhood-onset patients compared with adult-onset patients. Adult-onset patients who continued into the open-label therapy phase reported an increased incidence of arthralgia, myalgia and paraesthesia. There were significant increases in fasting glucose with hGH therapy but values remained within the normal range. Hypertension was reported in 7.7% of adult-onset patients at 18 months of hGH, which was within the expected prevalence for the number of patients, but was not reported for any childhood-onset patients. Only in adult-onset patients were sufficient adverse events reported to enable analysis of risk factors. Patients reporting hGH-related adverse events were significantly heavier and, therefore, received more hGH. There was a significantly greater increase in IGF-I and IGFBP-3 in the first month in patients who experienced hGH-related adverse events compared with those who did not. CONCLUSION: The risks of replacement therapy with hGH in GH-deficient adults varied with pathogenesis of disease; hGH-related adverse events occurred more frequently in patients with adult-onset compared with those childhood-onset GH deficiency. In the adult-onset patients there was an increased risk of adverse events in heavier patients and those who had the greatest increases in IGF-I and IGFBP-3 at 1 month of therapy.

Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.

The onset of adult GH deficiency may be during either adulthood (AO) or childhood (CO), but potential differences have not previously been examined. In this study the baseline and GH therapy (12.5 micrograms/kg per day) data from CO (n = 74; mean age 29 yr) and AO (n = 99; mean age 44 yr) GH-deficient adult patients have been compared. The first 6 months comprised randomized, double-blind treatment with GH or placebo, then all patients were GH-treated for a further 12 months. At baseline the height, body weight, body mass index, lean body mass, and waist/hip ratio of AO patients were significantly (P < 0.001) greater than in CO patients. Serum insulin-like growth factor-I (IGF-I) levels were below normal but were lower in CO than AO patients (P < 0.001), and the correlation with IGF binding protein-3 was stronger in CO than in AO patients. Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients. Both groups had significant psychosocial distress, but the deviation from normality was greater in AO patients. Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group. Wais/hip ratio was decreased by long-term therapy in AO but not CO patients. Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy. IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups. Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy, whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease. Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients. GH-induced side effects were mainly reported by AO patients; very few CO patients reported treatment-emergent adverse events. These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome. This is consistent with the existence of two entities, developmental (CO) and metabolic (AO), and the different functions of GH at different periods of life.

Influence of dietary protein, energy and corticosteroids on protein turnover, proteoglycan sulphation and growth of long bone and skeletal muscle in the rat.

1. We report here the extent to which changes in protein turnover contribute to the previously described inhibition of growth of rat tibial length and skeletal muscle mass in response to protein deficiency [1], energy restriction and corticosterone treatment [2]. Measurements of 35S uptake in vivo also enabled the qualitative pattern of changes in proteoglycan synthesis in bone and muscle to be established. 2. Protein deficiency was examined by ad libitum feeding of 20%, 7%, 3.5% and 0.5% protein diets with measurements at 1, 3 and 7 days (all diets), and 14 and 21 days (0.5% protein). In bone this induced delayed inhibition of tibial growth with parallel inhibition of protein synthesis, as measured by the phenylalanine flooding dose method. This was mediated by reductions in both ribosomal capacity (RNA/protein ratio) and activity (protein synthesis/RNA) in the 0.5% protein group. The pattern of inhibition of proteoglycan sulphation, measured as 35S uptake 60 min after injection of a tracer dose of labelled sulphate, was similar to that of protein synthesis. 3. In muscle there was an intermediate graded inhibition of protein synthesis by protein deficiency, mediated by reductions in both ribosomal capacity and activity in the 0.5% protein group, which preceded growth inhibition in the 7% and 3.5% groups, and which was progressive with time. Transient increases in proteolysis contributed to the growth inhibition is some groups, but the rate fell eventually in the 0.5% group. The pattern of response of proteoglycan sulphation differed from protein synthesis with a delayed inhibition, but with subsequent marked reduction. 4. Energy restriction was induced by diets fed for 4 or 8 days at 75%, 50% and 25% ad libitum intakes with protein intakes held constant, and corticosterone treatment involved a dose of 10 mg day-1 100-1 g (subcutaneous) with ad libitum feeding. In bone this induced a pattern of length growth inhibition which was dissociated from inhibition of protein synthesis in the moderately restricted (75% and 50%) groups. Only in the 25% group and in the 8 day corticosterone group was protein synthesis inhibited, through reductions in ribosomal capacity and activity. 35S uptake was also dissociated from growth inhibition, with reduced 35S uptake observed only after corticosterone treatment or 8 days of the 50% or 25% diets. 5. In muscle the energy restriction and corticosterone treatment induced parallel inhibitions of growth and protein synthesis, mediated by similar graded reductions in the RNA/protein ratios and in the 25% group in the KRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Dietary energy, glucocorticoids and the regulation of long bone and muscle growth in the rat.

1. The influence of dietary energy restriction and corticosterone on long bone and muscle growth, and their interrelationships, was studied in rats fed a range of restricted amounts of diets containing increasing concentrations of protein, thus maintaining constant protein intakes. Tibial length and epiphyseal cartilage width were measured radiographically. 2. In experiment 1, tibial length and gastrocnemius muscle growth were examined in ad libitum fed rats and during 4 days of severe energy restriction (25% ad libitum intake), starvation and ad libitum feeding with corticosterone treatment (10 mg/100 g), a mediator of the response to energy restriction. Weight loss occurred in all groups. Tibial growth continued in the 25% and starvation groups albeit at reduced rates with the inhibition of starvation > 25% group (P < 0.05), but was arrested after 2 days of corticosterone treatment. 3. Muscle growth inhibition was proportional to tibial growth inhibition of the 25% group, insofar as the muscle/bone ratio (W/L), was maintained. This inter-relationship between muscle and bone growth previously reported for ad libitum high-protein-fed rats, is likely to reflect the anabolic influence of bone on muscle via passive muscle stretching induced by length growth. For both starvation and corticosterone groups the muscle/bone ratio fell (P < 0.05 compared with the ad libitum group), suggesting that muscle growth inhibition included an additional direct catabolic influence of starvation and corticosterone treatment. 4. In experiment 2, measurements of bone, muscle and liver growth were made in rats fed 75%, or 50% and 25% ad libitum intakes with corticosterone treatment for 8 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of porcine insulin-like growth factor I and growth hormone receptor mRNA expression by energy status.

Regulation of insulin-like growth factor I (IGF-I) and growth hormone (GH) receptor mRNA in liver and muscle by energy status was assessed in 2-mo-old pigs by altering thermoregulatory demand and energy intake over a 5-wk period to produce a range of plasma IGF-I concentrations from 3.5 +/- 0.7 to 28.9 +/- 6.2 nmol/l. These values were related directly to growth rates (0.06 +/- 0.02 to 0.44 +/- 0.01 kg/day) and total hepatic IGF-I mRNA levels. Increased growth rates were accompanied by an increase in hepatic class 1 and class 2 IGF-I mRNA levels and an increase in the ratio of class 2 to class 1 IGF-I mRNA in liver, suggesting a distinct role for class 2 expression in the endocrine growth response. High levels of class 1 transcripts and a virtual absence of class 2 transcripts characterized all muscle tissues examined, and there was no correlation with plasma IGF-I levels. This suggests that growth promotion in response to increased energy status is regulated via endocrine hepatic IGF-I rather than via a paracrine response. The levels of GH receptor mRNA were positively correlated with overall growth rate (P < 0.005) in liver and negatively correlated (P < 0.05) in muscle, indicating distinct tissue-specific effects of energy status.

Interactions between growth hormone and nutrition in hypophysectomised rats: skeletal muscle myosin heavy chain mRNA levels.

The aim of this study was to examine the role of growth hormone (GH) in regulating muscle phenotype and to determine how this is modulated by altered nutrition. Total RNA was extracted from gastrocnemius muscles of hypophysectomised rats treated with saline, GH or GH but fed a restricted intake. Type 1, 2A, 2B, embryonic and neonatal myosin heavy chain mRNA levels were estimated by slot blot hybridization. Hypophysectomy reduced the concentrations of types 1, 2A and embryonic mRNAs and dramatically elevated types 2B and neonatal compared to control levels, but this was time-dependent. All MHC mRNA levels were partially restored to control levels in the GH-treated rats except for type 1; the level of this transcript was only elevated by GH in the restricted intake group. Restricted food intake modulated the effects of GH administration for all other MHC mRNA concentrations.

Interactions between growth hormone and nutrition in hypophysectomized rats: body composition and production of insulin-like growth factor-I.

Hypophysectomy of adult rats results in a loss of body growth which can be reversed by treatment with GH. The increased growth caused by administration of GH is accompanied by an increase in food consumption. The effects of GH and interactions with nutrition were investigated by treating hypophysectomized rats with GH and either providing unrestricted food or preventing the increased food consumption by pair-feeding with the same intake as that of the hypophysectomized animals. Over the 7-day experimental period, the GH-treated animals grew significantly when food was available ad libitum but did not gain body weight when an increase in food intake was prevented. However, there was a significant interaction between GH and nutrition on body composition; GH significantly decreased body fat and increased the protein: fat ratio only in the animals with the restricted intake. Gastrocnemius muscle weight was increased by GH regardless of food intake, but heart weight did not increase and liver weight was actually decreased by GH treatment when food intake was restricted. Serum concentrations of insulin and insulin-like growth factor-I (IGF-I) were increased by GH in the rats with food available ad libitum but not in the pair-fed rats. However, the liver concentration of IGF-I and its mRNA were increased by GH although the increase in IGF-I mRNA was modulated by the restricted food intake. The decreased weight of the liver in the pair-fed GH-treated rats, despite the increase in IGF-I mRNA, suggests that IGF-I does not influence liver growth. In the gastrocnemius muscle, however, GH increased IGF-I mRNA concentration similarly in both rats with food available ad libitum and in pair-fed rats. Decreased nutrition therefore modulated the action of GH but emphasized its nutrient partitioning effect, thus increasing the anabolic drive towards skeletal muscle growth; this appeared to be mediated by the local production of IGF-I within the muscle.

Potentiation of insulin-like growth factor-I (IGF-I) activity by an antibody: supportive evidence for enhancement of IGF-I bioavailability in vivo by IGF binding proteins.

The effects of ovine polyclonal antibodies raised against human recombinant IGF-I were investigated in GH-deficient rodents in vivo both in the presence and absence of exogenous IGF-I. Dwarf mice (negligible endogenous serum IGF-I) treated with anti-IGF-I serum which had been pre-incubated with IGF-I exhibited a significantly greater rate of daily weight gain than did mice treated with the same dose of IGF-I alone (P < 0.001) or even a 2.5-fold higher dose (P < 0.001). Similar increases in whole body weight gain were observed in dwarf rats, with a concomitant increase in dissected muscle weight. Serum IGF-I concentrations were greater in all animals treated with the complex of anti-IGF-I antibodies and IGF-I than in those administered only IGF-I. Size exclusion chromatography of dwarf rat serum indicated the presence of high mol wt material (> 160 kDa) capable of binding 125I-IGF-I in the anti-IGF-I treated rats. We suggest that this particular polyclonal antibody is behaving in a similar manner to an enhancing IGF binding protein, maintaining a reservoir of bioactive IGF-I. Since the antibody has a slightly lower affinity (2 x 10(8) liters/M) than that of the type 1 receptor, these data provide tentative indirect evidence to support the hypothesis that the recently discovered mechanisms which apparently decrease the affinities of several IGFBPs may indeed result in increased IGF-I bioavailability.

Differential actions of growth hormone and insulin-like growth factor-I on tissue protein metabolism in dwarf mice.

The actions and interactions of exogenous insulin-like growth factor-I (IGF-I) and bovine GH (bGH) on protein metabolism were investigated in vivo using Snell dwarf mice. Mice were administered a daily dose of 1.5 or 20 micrograms bGH in the presence or absence of 20 micrograms IGF-I. IGF-I and GH stimulated significant increases in whole body weight gain. Serum IGF-I concentrations increased dramatically in mice administered IGF-I, but more modestly in GH-treated mice. However, greater increases in tissue IGF-I content were observed for GH- than for IGF-treated mice, implying that GH exerted its anabolic actions by local IGF-I synthesis. Skeletal muscle (combined gastrocnemius plus plantaris) weight was significantly increased in GH-treated mice and tended to increase in IGF-treated mice. Muscle protein synthesis was stimulated by about 50% in mice treated with IGF-I alone and the lower dose of GH and by over 100% in the group treated with 20 micrograms/day GH compared with that in saline-treated mice; further additive increases in synthesis rates were observed for mice administered both IGF-I and GH. In all cases, this stimulation was due to both increased RNA content and efficiency of protein synthesis, expressed as grams of protein synthesized per g RNA/day. Liver weight and protein synthetic rate were increased by as much as 25% and 34%, respectively, in GH-treated mice, but IGF-I inhibited hepatic protein metabolism, tending to decrease synthesis rates and inducing a decrease in the efficiency of protein synthesis. Thus, IGF-I and GH have specific and differential effects on tissue protein metabolism in this model.

Growth hormone control of tissue protein metabolism in dwarf mice: enhancement by a monoclonal antibody.

Monoclonal antibody (MAb) to GH has been shown to increase the anabolic response induced by the hormone in individual tissues of dwarf mice. Dwarf mice were treated with GH at a low and a high dose (2.5 and 50 mU/day respectively), with and without complexing to an MAb. Treatment was for 7 and 14 days, at which times protein synthesis rates in skeletal muscle, liver and heart were determined from incorporation of labelled phenylalanine following injection of a flooding dose. The MAb potentiated the actions of GH and produced increases in the rates of protein synthesis in each of the tissues to a significantly greater extent than did GH alone. The increase in protein synthesis rate induced by MAb appears to be mechanistically distinct from that observed by increasing the dose of GH. In skeletal muscle and liver there was a dose-response to the GH alone in terms of the RNA concentration, i.e. the capacity for protein synthesis, whereas in each tissue examined the MAb caused very little further response in the RNA concentration. The MAb-induced enhancement of protein synthesis rate was almost entirely due to an increase in the RNA activity, i.e. the efficiency of the synthesizing system. Complexing GH to a particular MAb, or to antisera of restricted epitope specificity, has previously been shown to enhance the in-vivo effects of GH on whole body protein content; the mechanism for this enhancement has not been adequately determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of insulin-like growth factor 1 gene expression in skeletal muscle.

Insulin-like growth factor 1 (IGF-1) is implicated in the growth processes of many tissues in the adult animal. This hormone can act in an endocrine manner or can be produced in the specific tissues in response to growth promoting stimuli to act in an autocrine/paracrine manner. We have examined, in the rat, changes in serum concentrations of IGF-1 and muscle IGF-1 mRNA levels in several studies in which muscle growth has been significantly altered. In the first study we examined the interactions of growth hormone (GH) and under-nutrition upon muscle growth. We observed that when GH was administered to hypophysectomised rats the anabolic effect of this hormone was independent of dietary intake. In a similar manner muscle IGF-1 mRNA levels were also elevated by GH but unaffected by food intake. In contrast serum IGF-1 levels were markedly reduced by under-nutrition. These data suggested that the anabolic action of GH on muscle could be mediated through the autocrine/paracrine action of the IGF-1 hormone. Similarly we observed in other studies that muscle hypertrophic stimuli of work-overload and passive stretch are associated with significantly increased muscle IGF-1 mRNA levels. In contrast insulin dramatically affected muscle protein synthesis rates but had no measurable effect upon muscle IGF-1 mRNA levels, which suggests that the anabolic action of this hormone is not mediated through the autocrine/paracrine action of IGF-1. These studies suggest that IGF-1 may mediate growth in muscle in response to variety of stimuli by autocrine/paracrine action or in response to certain stimuli possibly by endocrine action.

Action and interaction of growth hormone and the beta-agonist, clenbuterol, on growth, body composition and protein turnover in dwarf mice.

The responses of dwarf mice to dietary administration of clenbuterol (3 mg/kg diet), daily injections of growth hormone (15 micrograms/mouse per d) or both treatments combined were investigated and their actions, and any interactions, on whole-body growth, composition and protein metabolism, and muscle, liver and heart growth and protein metabolism, were studied at days 0, 4 and 8 of treatment. Growth hormone, with or without clenbuterol, induced an increase in body-weight growth and tail length growth; clenbuterol alone did not affect body-weight or tail length. Both growth hormone and clenbuterol reduced the percentage of whole-body fat and increased the protein:fat ratio. They also increased protein synthesis rates of whole body and muscle, although the magnitude of the increase was greater in response to growth hormone than to clenbuterol. Clenbuterol specifically induced growth of muscle, with a decrease in liver protein content, whereas growth hormone exhibited more general anabolic effects on tissue protein. Previous reports have suggested that effects of clenbuterol on skeletal muscle are mediated, at least in part, via decreased rates of protein degradation; we could find little evidence of any decrease in whole-body or tissue protein degradation and anabolic effects were largely due to increases in protein synthesis rates. However, small increases in muscle protein degradation rate were observed in response to growth hormone. Growth hormone induced a progressive increase in serum insulin-like growth factor-1 concentration, whereas there was no change with clenbuterol administration. Anabolic effects on whole-body and skeletal muscle protein metabolism, therefore, appear to be initially via independent mechanisms but are finally mediated by a common response (increased protein synthesis) in dwarf mice.

Responses to protein deficiency of plasma and tissue insulin-like growth factor-I levels and proteoglycan synthesis rates in rat skeletal muscle and bone.

The relative biological importance of plasma levels of insulin-like growth factors (IGFs) is uncertain since the IGFs may act through endocrine mechanisms involving circulating IGFs secreted by the liver, or by autocrine/paracrine mechanisms with IGF production in or close to their target cells. We report here studies in rats designed to examine this problem with an investigation of the changes in plasma and tissue concentrations of IGF-I in relation to the inhibition of bone and muscle growth and proteoglycan synthesis, a putative IGF-I-sensitive process, by protein deficiency. Over a 3-week period in young well-fed growing rats, there were marked increases in plasma IGF-I, whereas in the protein-deficient animals in which growth was inhibited concentrations fell markedly. In bone, concentrations of IGF-I were initially 20% of plasma, did not increase with age and were minimally influenced by protein deficiency. In skeletal muscle, concentrations of IGF-I were initially 3% of plasma, did not increase with age, but did fall with protein deficiency. In bone, the inhibition of proteoglycan synthesis by the protein deficiency was not correlated with changes in tissue IGF-I concentrations and was poorly correlated with changes in plasma hormone concentrations, although in the latter case an exponential relationship could be fitted to the data from the initial control and subsequent protein-deficient animals. In muscle, the changes in proteoglycan synthesis were significantly linearly correlated with changes in tissue IGF-I compared with an exponential relationship with plasma concentrations from the initial control and subsequent protein-deficient animals.(ABSTRACT TRUNCATED AT 250 WORDS)