K. G. M. M. Alberti

Effects of growth hormone on insulin sensitivity and forearm metabolism in normal man

SummaryTo elucidate the short-term actions of growth hormone on insulin sensitivity and forearm metabolism, we have studied six normal male subjects receiving a 6-h hyperinsulinaemic euglycemic clamp with and without a concomitant 4-h growth hormone infusion. When infused, serum growth hormone rose to 25±4 mU/l and during administration of insulin serum insulin increased by 11±1 mU/l. During euglycemic clamp, administration of growth hormone decreased forearm glucose uptake after 180 min and onward (240 min 0.216±0.031 vs 0.530±0.090 mg/100 ml/min, p<0.05). Glucose infusion rate (240 min 2.83±0.24 vs 4.35±0.28 mg·kg−1· min#x2212;1, p<0.05) and glucose disposal rate (240 min 3.57±0.17 vs 4.00±0.15 mg·kg−1· min−1, p<0.05) also decreased. Growth hormone persistently increased hepatic glucose production after 120 min. After 210 min, all circulating lipid intermediates increased slightly. The decrease in forearm glucose uptake and glucose infusion rate and the increase in hepatic glucose production was observed before there was any detectable increase in circulating levels and forearm uptake of lipid intermediates. These data suggest that growth hormone induces insensitivity to insulin in liver, muscle and fat after 120, 180 and 210 min respectively. The early effects of growth hormone on glucose metabolism seems independent of changes in the rate of lipolysis.

The prognostic value of stress hyperglycaemia and previously unrecognized diabetes in acute stroke

In a prospective study of 86 patients with acute stroke, blood glucose and HbA1 were estimated within 72 h of onset. The prevalence of previously diagnosed diabetes mellitus was 8% whereas 28% could be assumed to have had unrecognized hyperglycaemia preceeding the acute event as identified by a stable HbA1 raised more that two SD above the mean reference value. Complete functional recovery of the limbs within 4 weeks of the stroke was confined to those patients with a normal admission blood glucose. None of the patients with a raised admission blood glucose regained full functional recovery within 4 weeks. Cumulative mortality at 4 weeks was significantly raised in patients with an elevated blood glucose value irrespective of their HbA1 values (p <0.05). The prevalence of unrecognized hyperglycaemia as a risk factor for acute stroke is greater than previously reported in the UK and admission blood glucose concentration is of greatest importance in predicting early mortality and morbidity.

Improved glucose tolerance four hours after taking guar with glucose

SummaryTo gain some insights about the possible cumulative metabolic effect after a high-fibre meal, 6 subjects took two 80 g oral glucose loads, 4 h apart. Addition of 22.3 g guar to the first load decreased the rise in blood glucose and insulin after the second (guar-free) load by 50% (p<0.002) and 31% (p< 0.02) respectively. This corresponded with decreased 3-hydroxybutyrate levels at the start of the glucose tolerance test after guar (by 20%, p<0.02). When no guar was added to the first glucose load, both 3-hydroxybutyrate and non-esterified fatty acids tended to rise before the second test. No significant effect was seen in the responses of the gut hormones, gastric inhibitory peptide and enteroglucagon. Spreading the intake of the first 80 g of glucose over the initial 4 h (2 subjects) similarly flattened the glycaemic but increased the insulin response. The effect of guar on carbohydrate and fat metabolism, therefore, lasts at least 4 h and may result in improved carbohydrate tolerance to subsequent guar-free meals.

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

SummaryThe effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol ≥5.5 mmol·l−1). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l−1 (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l−1 (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l−1 (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min−1·1.73 m−2, placebo: 97.1±6.7 vs 88.8±6.0 ml·min−1·1.73 m−2) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min−1, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min−1)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg−1·min−1 (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg−1·min−1 (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5 mg·kg−1·min−1 (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic Type 2 diabetic patients.

THE EFFECT OF VASOPRESSIN INFUSION ON GLUCOSE METABOLISM IN MAN

Studies on intact animals and isolated rat hepatocytes have shown that arginine vasopression (AVP) stimulates glycogen phosphorylase to break down gly‐cogen and raise plasma glucose concentrations. Since no similar work has been performed on healthy human adults, the effect of moderate (25 pmol/min) and high (75 pmol/min) dose AVP infusion on plasma glucose, intermediary metabolites, glucose kinetics, and circulating glucagon and insulin concentrations was investigated. After AVP infusion, plasma glucose rose from 4±9 ± 0±1 to a peak of 5±70±2 mmol/1 (P<0<001), but no changes in blood lactate, pyruvate, alanine, glycerol or 3‐hydroxybutyrate concentrations were observed. The glucose rise was accounted for entirely by an increase in the rate of appearance of glucose from 11±9 ± 0±43 to 13±38 · 0±63 μmol/kg/min (P < 0·001). Infusion of AVP also increased plasma glucagon concentrations from 38 ± 8 to 79 ± 20 pg/1 (P < 0·01). The hyperglycaemic effect of AVP may be mediated solely by stimulation of glucagon release, but we cannot exclude direct stimulation of glycogen phosphorylase activity.

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NORMAL MAN

Long‐acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201–995, 50 μg, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201–995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201–995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201–995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3‐hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side‐effects. SMS 201–995, 50 μg, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.

Metabolic effects of acute and prolonged growth hormone excess in normal and insulin-deficient man

SummaryThe metabolic effects of acute (4 h) and prolonged (24 h) growth hormone excess at pathophysiological concentrations were studied by growth hormone administration to normal subjects with and without somatostatin induced insulin deficiency. Acute growth hormone excess produced mild hyperinsulinaemia, but blood glucose concentrations were unaltered whereas chronic growth hormone excess caused a small (0.5 mmol/l) but significant rise in overnight-fasting blood glucose concentration together with a similar rise in fasting insulin levels (Mean ± SEM 9 ± 1 v 4 ± 1 mU/l, p<0.01). When insulin secretion was suppressed by somatostatin, a hyperglycaemic effect of acute growth hormone excess was unmasked, and the hyperglycaemic effect of chronic growth hormone excess was exaggerated. Acute growth hormone administration without somatostatin had a mild ketogenic action despite stimulated insulin secretion but no change in plasma non-esterified fatty acid or blood glycerol levels was observed. Somatostatin magnified the ketogenic effect of acute growth hormone excess, and unmasked a lipolytic action. Prolonged growth hormone excess had a lipolytic action that was increased by somatostatin, although the ketogenic effect of growth hormone was only seen during somatostatin induced insulin deficiency. The acute hyperglycaemic, lipolytic and ketogenic actions of growth hormone in normal subjects are limited by a compensatory rise in insulin secretion although with chronic exposure hyperglycaemic and lipolytic effects are seen. In insulin-deficient states, however, elevated growth hormone levels could be important in promoting hyperglycaemia and hyperketonaemia.

The Metabolic and Hormonal Response to Acute Normoglycaemia in Type 1 (Insulin-Dependent) Diabetes: Studies with a Glucose Controlled Insulin Infusion System (Artificial Endocrine Pancreas)

SummaryTwelve insulin deficient Type 1 (insulin-dependent) diabetic subjects were studied over an 11 1/2 h period during both subcutaneous insulin therapy and closed loop insulin delivery, using a glucose controlled insulin infusion system (Biostator) programmed to maintain normoglycaemia. Results were compared with those from 21 age and weight-matched normal subjects. Using the Biostator, normoglycaemia was achieved in all diabetic subjects within 3.5 h and normal profiles maintained thereafter. Blood metabolite and hormone values were evaluated during the subsequent 8 h normoglycaemic period. Subcutaneous therapy resulted in abnormal glucose levels throughout the study period (mean 8 h value 8.3±0.7 compared with 5.6±0.3 mmol/l on feedback control and 5.5.±0.1 mmol/l in normal subjects). The mean value of lactate and pyruvate over the final 8 h period was 25% higher in diabetic patients than in normal subjects with no difference between the two insulin treatments (blood lactate: 0.94±0.04 on subcutaneous insulin, 0.91±0.04 on feedback control and 0.74±0.03 mmol/l in control subjects). The pre-prandial peaks of blood glycerol and plasma non-esterified fatty acids were significantly decreased or absent during both feedback control and subcutaneous therapy in comparison with the normal subjects, whereas after the midday and evening meals, total ketone body levels were significantly higher in the diabetic patients. Peripheral serum free insulin levels were two-to fourfold greater in the diabetic than in the normal subjects. There were no significant differences between levels in diabetic patients receiving subcutaneous insulin or on the Biostator. Glucose turnover (1600–1800 h) was normal on feedback control (1.41±0.20 versus 1.55±0.18 mg · kg-1 · min-1 in the normal subjects) but was significantly decreased during subcutaneous insulin (1.04±0.09 mg · kg-1 · min-1). There was, in addition, a decrease in glucose recycling during both subcutaneous insulin therapy and feedback control in the diabetic subjects. These data suggest that although fine control of glucose metabolism both in terms of circulating concentrations and rates of production can be achieved by feedback-control, insulin infusion by the peripheral route is associated with significant metabolic abnormalities, at least in the short term. Longer term studies and examination of portal insulin delivery seem warranted.

Metabolic and hormonal responses to exogenous hyperthermia in man.

To study whether hyperthermia reproduces hormonal and metabolic responses seen in stress states such as mild infections, six normal male subjects underwent (i) a 3‐h hot bath and (ii) a 3‐h thermoneutral control period. During the hot bath body temperature rose by 1.2 ± 0.03°C (mean ± SEM) and significant peaks of circulating growth hormone (56 ± 9 vs 7 ± 4 mu/l), adrenaline (310 ± 34 vs 152 ± 39 pmol/l), glucagon (19.2 ± 4.3 vs 11.8 ± 2.3 pmol/l) and cortisol were recorded together with slight hyperinsulinaemia (6.5 ± 1.3 vs 5.3 ± 1.0 mU/l, P > 0.05). Hyperthermia was also accompanied by significant increases in circulating levels of free fatty acids (0.93 ± 0.1 vs 0.46 ± 0.1 mmol/l), 3‐hydroxybutyrate (196 ± 67 is 50 ± 18 μmol/l), glycerol (102 ± 10 vs 48 ± 5 μmol/l) and lactate. Blood alanine decreased and blood glucose remained constant. When an intravenous glucose tolerance test was performed during the last hour of hyperthermia signs of impaired first phase and enhanced second phase insulin responses were recorded. Calculated values for glucose disappearance also deteriorated (1.34 ± 0.19 vs 2.04 ± 0.50 %/min, P > 0.05). We conclude that hyperthermia mimics most major metabolic and hormonal changes observed during mild infection and could provide a model to study these conditions.

Safety of continuous subcutaneous insulin infusion: Metabolic deterioration and glycaemic autoregulation after deliberate cessation of infusion

SummaryTo assess the rate of metabolic deterioration and potential risks of failure of continuous subcutaneous insulin infusion during basal insulin delivery, we deliberately stopped infusion in nine insulin dependent diabetics. Plasma glucose, blood 3-hydroxybutyrate and plasma free insulin were measured for 9 h whilst the patients remained supine and fasting. Mean plasma glucose remained unchanged at normal fasting levels for the first hour, then rose to plateau at about 10 mmol/l until the end of the experiment. The final plateau level of glucose varied from patient to patient; two C-peptide secreting diabetics plateaued at low glucose levels. In contrast, blood 3-hydroxybutyrate rose progressively, without plateauing. Plasma free insulin concentrations fell during the withdrawal period and there was a highly significant negative correlation between free insulin and 3-hydroxybutyrate. No patient was more than mildly unwell after 9 h of insulin deprivation. We conclude that under these experimental conditions there is glycaemic autoregulation and that ketones may sometimes be a more appropriate monitor of insulin deficiency or loss of diabetic control than is glucose. Accidental failure of continuous subcutaneous insulin infusion and interruption of basal delivery in resting and fasting diabetics will probably not cause dangerous metabolic or clinical deterioration.