Martin Press

Importance of Raised Growth Hormone Levels in Mediating the Metabolic Derangements of Diabetes

To evaluate the importance of the raised levels of growth hormone that characterize poor diabetic control, we gave growth hormone for 21 to 45 hours in the form of hourly 100-micrograms pulses to 14 diabetics being treated by insulin pump. Insulin-pump settings and meals were kept constant. Mean 24-hour levels of growth hormone (+/- S.E.M.) rose from 8 +/- 1 to 16 +/- 2 ng per milliliter--values identical to those observed in 12 other patients with poorly controlled diabetes (17 +/- 3 ng per milliliter). Plasma glucose concentrations doubled within 8 to 10 hours and remained elevated until growth hormone was discontinued (fasting glucose level rose from 86 +/- 11 to 204 +/- 17 mg per deciliter at 18 hours and to 240 +/- 20 mg per deciliter at 42 hours). The hyperglycemia was due mainly to a marked stimulation of hepatic glucose production that occurred without changes in levels of free insulin or glucagon. Levels of circulating free fatty acids, ketones, and branched-chain amino acids were also increased. The moderate elevations in growth hormone levels that occur in poorly controlled diabetes can themselves reproduce the whole spectrum of abnormal metabolic fuel concentrations that are associated with poor diabetic control, despite optimized insulin treatment. Thus, hypersecretion of growth hormone may be the cause as much as the consequence of poor diabetic control.

Correction of essential fatty-acid deficiency in man by the cutaneous application of sunflower-seed oil.

Abstract The syndrome of essential fatty-acid (E.F.A.) deficiency is being increasingly recognised as a complication of long-term fat-free parenteral nutrition. In three patients who developed E.F.A. deficiency spontaneously after major intestinal resections the deficiency in the serum was corrected by the cutaneous application of sunflower-seed oil, a rich source of the essential fat linoleic acid. The results suggest that even if percutaneous absorption of the oil is complete, the daily requirement for linoleic acid in adult man may be only 2-3 mg. per kg. per day, which is much less than previous estimates.

Pituitary Response to Growth Hormone–releasing Factor in Diabetes: Failure of Glucose-mediated Suppression

To evaluate the mechanism underlying raised growth hormone levels in diabetes, we compared the response to growth hormone–releasing factor (GRF) in type I diabetic and healthy control subjects. In 12 poorly controlled diabetic subjects (fasting plasma glucose 276 ± 27 mg/dl) basal serum growth hormone levels were elevated by 200–300% (P < 0.02), yet the incremental increase in growth hormone after GRF injection was no greater than in control subjects. Furthermore, five additional diabetic subjects with normal growth hormone levels after long-term insulin pump treatment also showed an identical response to GRF. Thus, raised basal growth hormone levels in diabetes and the fall that follows intensive insulin treatment may reflect changes in hypothalamic regulation of, rather than in pituitary responsiveness to, GRF. However, when five normal subjects were restudied during glucose infusion, even quite modest hyperglycemie (plasma glucose ∼150 mg/dl) caused marked suppression of the response to GRF (P < 0.005). Thus, the “normal” response to GRF in poorly controlled diabetes is actually inappropriate. Failure of the pituitary to suppress in response to hyperglycemie in diabetes implies a second abnormality that may further aggravate disordered growth hormone secretion.

Effect of growth hormone treatment on hyperinsulinemia associated with turner syndrome

To determine whether the insulin resistance in patients with Turner syndrome, which may be exaggerated by treatment with human growth hormone, leads to excessive insulin secretion, we applied the hyperglycemic glucose-clamp technique to produce a standard hyperglycemic stimulus (6.9 mmol/L, or 125 mg/dl, greater than fasting plasma glucose level for 120 minutes) in seven patients with Turner syndrome and in seven healthy children. These studies were repeated in the patients after 6 to 12 months of therapy with growth hormone. Fasting plasma levels of insulin were comparable in control subjects and patients before therapy but increased significantly in the patients after 6 to 12 months of treatment with growth hormone. Despite identical glucose increments in the two groups during the glucose-clamp procedure, both first- and second-phase insulin responses were significantly greater in the patients than in the control subjects. Moreover, the hyperinsulinemic responses to glucose were markedly exaggerated in the patients after their treatment with growth hormone, reaching values (first phase 474 +/- 100 pmol and second phase 826 +/- 100 pmol; p less than 0.02 vs pretreatment values) that were almost threefold greater than those in control subjects (p less than 0.001). Nevertheless, the rate of insulin-stimulated glucose metabolism during the last 60 minutes of the clamp procedure was similar in all three groups of studies. Glycosylated hemoglobin, total cholesterol level, and blood pressure remained normal in patients after therapy with growth hormone. We conclude that glucose-stimulated insulin response is increased in patients with Turner syndrome and that these alterations are further exaggerated by treatment with growth hormone. These hyperinsulinemic responses appear to compensate for reductions in insulin sensitivity.

Pituitary Response to Growth Hormone–Releasing Hormone in IDDM: Abnormal Responses to Insulin and Hyperglycemia

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone–releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 μg/kg i.v. GRF 1–40 was administered to nine poorly controlled IDDM subjects (HbA1 > 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (∼ 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 ± 90 pM) and hyperglycemia (16.5 ± 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 ± 11 vs. 20 ± 4 μg/L without insulin infusion, P < 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 ± 7 μg/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 ± 84 pM) and hyperglycemia (16.41 ± 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.

Effect of insulin on growth hormone-induced metabolic derangements in diabetes

To investigate the mechanism of growth hormone-induced hyperglycemia in diabetes, two studies were done in insulin-dependent diabetic patients receiving intensive insulin therapy with the insulin pump. First, the metabolic response to a standard breakfast following a subcutaneous insulin bolus was examined before and after 20 hourly boluses of intravenous growth hormone in eight patients. Despite unchanged insulin therapy, growth hormone administration produced a marked rise in fasting glucose concentrations (197 +/- 21 v 96 +/- 11 mg/dL), as well as increases in fasting levels of free fatty acids and branched chain amino acids. Nevertheless, postprandial blood glucose increments were only slightly greater after growth hormone (36 +/- 14 v 20 +/- 12 mgdL). Moreover, the increased levels of other insulin-sensitive fuels induced by growth hormone fell to normal following the meal. In a second study, six patients received a low-dose insulin clamp (designed to reproduce the mean postprandial concentrations of glucose and insulin observed in the meal study) before and after growth hormone administration. Despite endogenous glucose overproduction after growth hormone, modest elevations in free insulin (40 to 50 microU/mL) were sufficient to suppress glucose production to an extent comparable to the control day (from 2.8 +/- 0.2 to 0.6 +/- 0.3 mg/kg min after growth hormone v 1.6 +/- 0.1 to 0.4 +/- 0.2 mg/kg min on the control day). However, the normal stimulation of glucose uptake by insulin was abolished by growth hormone. We conclude that in diabetic patients growth hormone-stimulated hepatic glucose overproduction (and the increases in other insulin-sensitive fuels) can be relatively easily overcome with extra insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Deranged α-Adrenergic Regulation of Growth Hormone Secretion in Poorly Controlled Diabetes: Reversal of the Exaggerated Response to Clonidine after Continuous Subcutaneous Insulin Infusion

ABSTRACT: Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed in poorly controlled, insulin-dependent diabetes. Since the alpha adrenergic system plays an important role in hypothalamic regulation of GH secretion, we tested the hypothesis that altered central adrenergic activity contributes to the increased GH concentrations in diabetes. Clonidine, an α-adrenergic agonist, was administered to nine poorly controlled, young diabetic patients (age 12–19 yr) before and after 1 wk of continuous subcutaneous insulin infusion pump therapy. As expected, continuous subcutaneous insulin infusion lowered mean 24-h plasma glucose (from 203 ± 21 to 112 ± 7 mg/dl,p < 0.01) and GH (from 17.7 ± 2.1 to 9.2 ±1.2 ng/ml, p < 0.01) to values observed in normal controls. In the diabetic patients during conventional treatment, both the peak plasma GH level postclon-idine (48.3 ± 8.7 ng/ml) and the incremental area under the GH response curve (3.23 ± 0.58 mgmin/ml) were significantly increased above normal control values (25.2 ± 2.1 ng/ml, p < 0.05 and 1.63 ± 0.11 mgmin/ml, p ± 0.0025, respectively). In contrast, the GH response to clonidine was indistinguishable from normal after only 1 wk of intensified insulin treatment. Our findings support the contention that metabolic control of diabetes influences hypothalamic regulation of GH secretion and suggests that such alterations are related, at least in part, to changes in central α-adrenergic activity.

RISK OF HYPOGLYCAEMIA WITH ALTERNATE-DAY GROWTH HORMONE INJECTIONS

Fasting hypoglycaemia developed in three growth hormone deficient children after the start of treatment with synthetic growth hormone. The effects, which occurred 36-60 h after each injection, may have been due to insulin-like effects of endogenous somatomedins after waning of insulin antagonism induced by growth hormone. Daily growth hormone injections may be necessary to maintain normal plasma glucose levels in young children.

LACK OF METABOLIC EFFECT OF GROWTH HORMONE (GH) 36 HOURS AFTER INJECTION

Since GH is only given three times a week we studied whether metabolic effects were still apparent 36h after a shot. Six GH deficient boys aged 13-17 received a stepwise euglycemic insulin clamp (8, then 40 mU/m2.min for 90 mins each) combined with 2H-glucose infusion to independently measure hepatic and peripheral insulin sensitivity. Children were studied before and after 7-19 weeks of GH treatment (0.05 mg/kg IM qod) which increased growth rate from 4.6±0.9 to 8.9±1.4 cm/yr (p<0.02). At the time of the second study, 36h after the last shot, GH levels had returned to baseline (2.0±0.5 vs 1.7±0.3 ng/ml) while somatomedin C was still markedly elevated (1.29±0.25 vs 0.29±0.06 U/ml, p<0.01). There was no difference in fasting plasma glucose (79.7±3.4 vs 75.9±1.8 mg/dl) or insulin (7.4±2.0 vs 6.0±1.4 mU/l, although basal glucose turnover was slightly higher (2.48±0.28 vs 2.11±0.27 mg/kg.min, p<0.05). However, hepatic glucose production suppressed to the same extent during the low dose clamp (71 vs 85%), and insulin stimulated glucose uptake during the high dose clamp actually tended to be higher after GH treatment (9.4±1.9 vs 7.9±0.9 mg/kg.min). In contrast, in three children studied 12h after a GH shot, insulin sensitivity was decreased. Thus, 36h after GH, no adverse effects on carbohydrate metabolism were detectable, and some children were actually more insulin sensitive, possibly as a result of insulin-like effects of somatomedins.

DOES A DEFECT IN INSULIN LIKE GROWTH FACTOR-I (IGF-I) GENERATION EXIST IN INSULIN DEPENDENT DIABETES (IDDM)?

Elevated, normal and low IGF-I values have been reported in IDDM. To clarify the influence of blood glucose (BG) control on IGF-I in the young diabetic, we studied 19 IDDM (16±lyrs) before and after one week of intensified Rx. During conventional Rx, IGF-I levels were markedly reduced in comparison to age-matched healthy controls (198±20 vs. 448±34 ng/ml, p<0.001) and were negatively correlated with glycosylated Hb values (r=-0.55, p<0.02). Insulin infusion pump Rx, which lowered mean 24hr BG from 233±16 to 110±5 mg/dl, induced a rise in IGF-I (198±20 to 252±34 ng/ml, p<0.005) despite a 30% fall in mean 24hr growth hormone (GH) levels, (p<0.05). To evaluate this apparent defect in IGF-I generation, we administered exogenous GH (0.1U/kg IM × 4 days) to 8 prepubertal IDDM (11.4±0.3yrs) maintained on their usual Rx, and to 7 age-matched healthy controls. Despite a significant rise in BG from 176±21 to 276±22 mg/dl(p<0.001), exogenous GH resulted in a marked increase in IGF-I (from 63±11 to 146±27 ng/mg, p<0.02) indistinguishable from that observed in non-diabetic children (58±7 to 112±24 ng/ml).Conclusions: (1) Poorly controlled IDDM is associated with reduced IGF-I levels which can be restored by improved metabolic control. (2) This defect can be overcome by exogenous GH even in the face of poor metabolic control. (3) Low IGF-I values in IDDM in the presence of high GH levels may be due to reduced biological activity of endogenous GH.