I. Lager

Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency.

In a double-blind, cross-over, placebo-controlled trial, the effect of 26 weeks of replacement therapy with recombinant human growth hormone (rhGH) on insulin sensitivity and glucose metabolism in nine patients with adult-onset growth hormone deficiency was studied with a euglycemic clamp. Glucose production and utilization were studied with D-(3-3H)-glucose infusions. Comparisons were made with placebo treatment for 6 and 26 weeks, respectively. GH therapy for 6 weeks increased fasting plasma concentrations of glucose and insulin. However, after 26 weeks of GH treatment, no significant changes in glucose or insulin concentrations were recorded. GH treatment induced a marked change in insulin action evident after 6 weeks of therapy as shown by lower glucose infusion rates (GIRs) during the clamp compared with placebo treatment (2.6 +/- 0.4 v 4.1 +/- 0.7 mg.kg-1.min-1). This change in insulin action was due to a decreased insulin effect on glucose utilization. After 26 weeks of GH therapy, there was no significant difference in GIRs. During placebo treatment, insulin sensitivity and insulin, glucose, and nonesterified fatty acid (NEFA) concentrations were unchanged compared with concentrations measured before the study. Thus GH replacement therapy induces a change in insulin action in GH-deficient individuals. Whether this change represents a decrease in insulin action (ie, insulin resistance) or a restoration of action to normal is presently unclear, since a healthy control group was not included in the study. During long-term treatment, the present study suggests that the change in insulin action can be reversed, probably secondarily to changes in body composition.

Characterization of the insulin-antagonistic effect of growth hormone in man.

SummaryThe insulin-antagonistic effect of growth hormone was characterized by infusing the hormone at three different infusion rates (6, 12 or 24 mU·kg−1·min−1) for one h in 11 healthy subjects. The insulin effect was measured with the euglycaemic clamp technique combined with D-(3-3H)-glucose infusion to evaluate glucose production and utilization. A control study with NaCl (154 mmol·l−1) infusion was also performed. The insulin levels during the clamps were similar in all studies (36±0.2 mU·l−1). Peak growth hormone levels were reached at 60 min (growth hormone 6mU·kg−1·h−1: 31±5; growth hormone 12 mU·kg−1·h−1: 52±4 and growth hormone 24 mU·kg−1·h−1: 102±8mU·l−1). The insulin-antagonistic effect of growth hormone started after ∼2 h, was maximal after 4–5 h (∼39% inhibition of glucose infusion rate between control and growth hormone 24 mU·kg−1·h−1) and lasted for 6–7 h after peak levels. The resistance was due to a less pronounced insulin effect both to inhibit glucose production and to stimulate glucose utilization. Growth hormone infusion of 12 mU·kg−1·h−1 induced a similar insulin-antagonistic effect as the higher infusion rate whereas 6 mU·kg−1·h−1 induced a smaller response with a duration of 1 h between 3–4 h after peak levels of growth hormone. The present study demonstrates that growth hormone levels similar to those frequently seen in Type 1 (insulin-dependent) diabetic patients during poor metabolic control or hypoglycaemia, have pronounced insulin-antagonistic effects. The effects starts after about 2–3 h, is maximal after 4–5 h and lasts for about 6–7 h. Both duration and inhibitory effect of growth hormone are related to the plasma levels, where a maximal effect is seen at about 50 mU·l−1 or higher.

Altered Recognition of Hypoglycaemic Symptoms in Type I Diabetes during Intensified Control with Continuous Subcutaneous Insulin Infusion

The effect of intensified metabolic control obtained with continuous subcutaneous insulin infusion (CSII) on the frequency and symptoms of hypoglycaemia was studied in type I diabetic patients. The reproducibility of the questionnaire used to evaluate the hypoglycaemic symptoms was verified in a control group receiving unchanged conventional insulin therapy for 2 months. Metabolic control was significantly improved during CSII (HbA1c 6.8 ± 0.4% versus 8.7 ± 0.7%, normal range up to 5.4%) in all patients while no change was seen in the control group. The results of frequent self glucose monitoring showed that the incidence of low glucose levels (below 3.5 mmol/l) increased about threefold in the CSII group. Awareness of hypoglycaemia was clearly changed during CSII with less pronounced adrenergic symptoms while no alterations were found in the group with unchanged metabolic control. These results emphasize the importance of regular self glucose monitoring during CSII and of informing the patients that their hypoglycaemic symptoms may change during intensified control.

Early posthypoglycemic insulin resistance in man is mainly an effect of beta-adrenergic stimulation.

The insulin effect following hypoglycemia was studied with the euglycemic clamp technique in seven healthy subjects. Following an initial euglycemic clamp hypoglycemia was induced and after glucose recovery a second clamp was performed. Glucose production (Ra) and utilization (Rd) were studied with [3-3H]glucose. Each subject was studied four times; during infusion of placebo, propranolol, somatostatin, and a control study where hypoglycemia was prevented. Hypoglycemia induced an insulin resistance with a lower steady state glucose infusion rate following the hypoglycemia during placebo as compared to the control study (2.5 +/- 0.5 and 4.8 +/- 1.0 mg/kg min, respectively, P less than 0.05). The insulin resistance was due to an attenuated insulin effect on both inhibition of Ra (impaired by 37%) and stimulation of Rd (impaired by 61%). The insulin-antagonistic effect was completely prevented by propranolol but only partly by somatostatin. Thus, early posthypoglycemic insulin resistance (2.5-3.5 h after hypoglycemia) is a sustained effect mainly due to beta-adrenergic stimulation.

Combined effect of growth hormone and cortisol on late posthypoglycemic insulin resistance in humans

The occurrence and mechanisms for late (6.5- to 7.5-h) posthypoglycemic insulin resistance were studied with the euglycemic clamp in 19 healthy subjects. Comparisons were made with a control study with the same insulin infusion rate but where hypoglycemia was prevented by glucose infusion. Glucose production and utilization were studied with D-[3-3H] glucose infusions. Hypoglycemia induced marked insulin resistance shown by lower glucose infusion rates compared with the control study 3.1 ± 0.3 vs. 6.0 ± 0.7 mg · kg−1 · min−1 P < .001). This late posthypoglycemic insulin resistance was mainly due to a decreased insulin effect on glucose utilization. Infusion of propranolol did not prevent insulin resistance, whereas somatostatin partially prevented its appearance. Somatostatin plus metyrapone completely normalized posthypoglycemic insulin resistance. A positive correlation (r = .72, P < .001) was found between initial insulin sensitivity and percent reduction of the insulin effect after hypoglycemia. Thus, hypoglycemia is followed by prolonged (6- to 8-h) insulin resistance. In contrast to early-phase (2- to 3-h) resistance, long-term resistance is not due to β-adrenergic stimulation but to the combined effect of growth hormone and cortisol. This resistance is also more pronounced in subjects with initially high insulin sensitivity.

Insulin resistance in Type 1 (insulin-dependent) diabetes following hypoglycaemia — evidence for the importance of β-adrenergic stimulation

SummaryThe insulin effect, evaluated with the euglycaemic clamp technique, was studied before and after hypoglycaemia in 7 patients with Type 1 (insulin-dependent) diabetes. Following an initial 2 h clamp (clamp I) hypoglycaemia was induced and 2 h later a second clamp (clamp II), identical to the former, was performed. Each subject was studied twice; during infusion with saline (placebo) or propranolol. Glucose production and disposal were studied with the 3(3H)glucose technique. During placebo infusion, hypoglycaemia elicited an insulin resistance leading to approx. 50% reduction in the steady state glucose infusion rate during clamp II as compared to clamp I (clamp I 2.58±0.32, clamp II 1.26±0.08 mg·kg−1·min−1, p<0.02). The insulin resistance was prevented by infusing propranolol (clamp I 2.29±0.29, clamp II 2.85±0.56 mg·kg−1·min−1). The posthypoglycaemic insulin resistance was due to a less pronounced insulin effect on both glucose production (clamp I 0.29±0.21, clamp II 0.86±0.19 mg·kg−1·min−1, p<0.05) and glucose utilisation (clamp I 2.84±0.26, clamp II 2.13±0.23 mg·kg−1·min−1, p<0.05). The insulin resistance on both glucose production and utilisation was prevented by propranolol. Thus, the present study demonstrates that hypoglycaemia elicits a prolonged insulin resistance which is due to a less pronounced effect of insulin to both inhibit splanchnic glucose production and to stimulate peripheral glucose utilisation. The insulin resistance is due to β-adrenergic stimulation and can be prevented by propranolol.

Effect of prolonged hyperglycemia on growth hormone levels and insulin sensitivity in insulin-dependent diabetes mellitus

The aim of the present study was to characterize the effect of a hyperglycemic period (44 hours) on the levels of insulin-antagonistic hormones and insulin sensitivity in seven subjects with well-controlled insulin-dependent diabetes mellitus (IDDM). Hyperglycemia (approximately 15 mmol.L-1) was induced by a glucose infusion while the degree of insulinization was similar to that of the period with near normoglycemia (approximately 6.9 mmol.L-1). Insulin sensitivity was measured with hyperinsulinemic euglycemic clamps performed 4 hours before and after the periods of normoglycemia (control) and hyperglycemia. D-[3-3H]glucose was infused in the second clamp in each study to evaluate glucose production and utilization. Since growth hormone (GH) levels frequently are elevated during poor diabetic control, diurnal GH secretion was measured in blood samples continuously drawn for 24 hours during the euglycemic and hyperglycemic periods. Levels of epinephrine, norepinephrine, cortisol, and nonesterified free fatty acids (NEFA) were similar during the control and hyperglycemic periods and during the clamps. GH levels were also similar, but an abnormal diurnal secretion pattern was present with increased numbers of daytime peaks. Hyperglycemia did not reduce GH secretion in IDDM. Hyperglycemia for 44 hours induced insulin resistance (32% reduction of glucose infusion rate, P < .02). In the control study, a 21% reduction (P = .064, NS) of the glucose disposal rate (Rd) was seen, suggesting that the hospitalization period per se may also reduce insulin sensitivity. In conclusion, a period of hyperglycemia leads to insulin resistance in IDDM patients. This insulin resistance cannot be attributable to increased levels of insulin-antagonistic hormones, although an abnormal secretion pattern for GH was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of Glucose Control for the Recovery from Hypoglycemia in Insulin-dependent Diabetics

To evaluate whether the delayed glucose compensation after hypoglycemia in insulin-dependent diabetics was associated with their elevated blood glucose levels, five diabetic patients were studied before and after a period of intensified metabolic control. The glucose recovery rate was found to be improved after better diabetic control. This influence seems to be better reflected by the mean diurnal level rather than the glucose level immediately before hypoglycemia. The improvement occurred despite the same or lower levels of the important glucocompensatory hormones. These results show the importance of antecedent metabolic control for glucose compensation after hypoglycemia.

Postprandial Hyperglycaemia Following a Morning Hypoglycaemia in Type 1 Diabetes Mellitus

The occurrence of hyperglycaemia following a morning hypoglycaemic episode was studied in nine patients with Type 1 diabetes. Each patient was studied twice, once following induced hypoglycaemia and once in a control study when hypoglycaemia was prevented by glucose infusion. After the initial hypoglycaemic/control period the patients were maintained on their regular insulin regimens and were given standard meals. Hypoglycaemia induced postprandial hyperglycaemia (3.1 ± 0.8 mmol I−1 above control) which lasted for about 8 h. Maximal growth hormone levels were seen 40 min after glucose nadir (control 7.8 ± 3.2, hypoglycaemia 74.0 ± 12.3 mU I−1) and the magnitude of the hyperglycaemia was related to the growth hormone levels following the hypoglycaemia (r = 0.80, p < 0.01).

Insulin Resistance in Fat Cells From Insulin-Treated Type I Diabetic Individuals

Fat biopsies from the lower abdominal wall were obtained from 13 insulin-treated type I diabetic subjects and from 12 age-, weight-, and sex-matched control subjects. Insulin binding and the antilipolytic effect of insulin were studied. Insulin binding was significantly reduced in the diabetic subjects (34% reduction at tracer binding, P < 0.05) due to a decreased number of binding sites. In agreement with this, the dose-response curve for the antilipolytic effect of insulin was shifted to the right in the diabetic subjects. Furthermore, the maximal antilipolytic effect of insulin was also reduced (64%, P < 0.05). Thus, fat cells from conventionally treated type I diabetic individuals are resistant to insulin. This resistance is due to a combination of a decreased number of insulin binding sites and an unspecified intracellular (postreceptor) defect involving the antilipolytic effect of insulin. These findings are in accord with recent in vivo studies showing that type I diabetic patients are also resistant to the stimulating effect of insulin on glucose disposal.