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Plasma glucagon and growth hormone concentrations were measured fasting and after oral glucose in 19 patients with portal vein block with extensive portal-systemic shunting but minimal liver cell damage, 11 cirrhotic patients and 12 matched control subjects. Portal vein block patients and controls had similar fasting glucose and glucagon levels (glucose 3.8 ±0.1 mmol/l vs control 3.4±0.1 mmol/l (mean±SEM); glucagon 57.5 ±9.1 pg/ml vs control 51.3±7.8 pg/ml). Cirrhotic patients were hyperglycaemic (cirrhosis 4.3±0.2 mmol/l vs control 3.4 ±0.1 mmol/l, p < 0.01) with significantly elevated glucagon levels (167.3±61.1 pg/ml vs control 51.3 ±7.8 pg/ml, p < 0.05), which suppressed towards control values after oral glucose. There was no correlation between fasting plasma glucagon levels and the degree of portal-systemic shunting in cirrhotic patients. There was a strong correlation between fasting plasma glucagon concentrations and aspartate transaminase levels (r = 0.68; p < 0.01) in cirrhotic and portal vein block patients. Significant elevations of growth hormone were seen only in cirrhotic patients. It is concluded that hyperglucagonaemia is a feature of hepatocellular damage rather than portalsystemic shunting but the relationship between elevated glucagon and growth hormone concentrations and carbohydrate intolerance in cirrhosis remains unclear. [ABSTRACT FROM AUTHOR]

Non-islet cell tumour hypoglycaemia (NICTH) is characterised by severe and recurrent fasting hypoglycaemia, and is usually caused by secretion of insulin-like growth factor-II (IGF-II) by the tumour. This induces secondary changes in the circulating levels of insulin, growth hormone (GH), and the IGF-binding proteins (IGFBPs), resulting in an increased insulin-like hypoglycaemic activity of IGF-II. A participating role of IGF-I is not established. We measured serum levels of free IGF-I and free IGF-II, total IGF-I, total IGF-II, big IGF-II and IGFBP-1, IGFBP-2 and IGFBP-3 in patients with NICTH before (n=14) and after surgical removal of the tumour (n=3). A control group (n=20) was included for comparison. In NICTH patients, free IGF-II was 20-fold increased (26.8+/-8.1 [mean+/-SEM] vs. 1.3+/-0.1 microg/l), and free IGF-I was four fold increased (2.8+/-0.4 vs. 0.7+/-0.1 microg/l), as compared to control subjects (p < 0.0001). In accordance with earlier observations levels of total IGF-I, total IGF-II, and IGFBP-3 were decreased, whereas IGFBP-1 and IGFBP-2 were increased in NICTH (all p-values < 0.05). The highly elevated levels of free IGF-I and free IGF-II most likely imply a considerable hypoglycaemic insulin-like activity, and may, by negative feedback explain the marked suppression of the GH/IGF-I axis observed in NICTH. Finally, free IGF-II seems to be a powerful biochemical marker in the diagnosis of NICTH.

Treatment of diabetic rats with octreotide can inhibit early diabetic renal hypertrophy. Octreotide administration for 6 months from the day of diabetes induction inhibits renal hypertrophy and diminishes increase in urinary albumin excretion. To investigate the effect of octreotide on manifest diabetic renal changes, octreotide treatment was given for 3 weeks after an untreated diabetic period of 3 or 6 months. In addition, following 6 months of diabetes, a group of diabetic rats was treated with insulin for 3 weeks. Renal and glomerular hypertrophy, and increased urinary albumin excretion were observed in diabetic rats compared to non-diabetic control rats from 3 months and throughout the study period. Octreotide treatment did not affect body weight, food intake, blood glucose or serum fructosamine levels. We observed no effect of octreotide treatment on renal and glomerular hypertrophy or urinary albumin excretion compared to placebo-treated diabetic rats. Insulin treatment for 3 weeks after 6 months of untreated diabetes normalized blood glucose and serum fructosamine levels, and furthermore renal hypertrophy was significantly diminished compared to the placebo-treated diabetic rats. However, insulin treatment had no effect on glomerular hypertrophy or urinary albumin excretion. In conclusion, octreotide treatment for 3 weeks following an untreated diabetic period of 3 or 6 months is unable to reduce the increased renal and glomerular volume or urinary albumin excretion. However, insulin treatment for 3 weeks with induction of euglycaemia diminishes the renal hypertrophy but has no effect on glomerular volume or urinary albumin excretion.

The insulin-like growth factors, insulin-like growth factor I and insulin-like growth factor II are bound to six distinct classes of insulin-like growth factor binding proteins (IGFBPs) in the circulation and in extracellular fluids. Diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I suggestive of a renotropic function for insulin-like growth factor I. In order to examine a possible involvement of IGFBPs in initial diabetic kidney growth and in kidney insulin-like growth factor I accumulation, we studied rat kidney IGFBPs by ligand blotting during the first 4 days after induction of diabetes. Six distinct bands were identified in kidney and liver tissue with apparent molecular weight values of 38-47 (doublet), 34, 30, 24 and 20 kDa. The 38-47 kDa doublet band probably corresponds to the insulin-like growth factor binding subunit of IGFBP-3, the 24 kDa band to IGFBP-4 and the 30 kDa band to IGFBP-1 and/or IGFBP-2, as these IGFBPs in rats have similar molecular weight. In untreated diabetic rats a transient increase in the kidney 30 kDa band was demonstrable 24 h after induction of diabetes with a maximal rise (two-fold) after 48 h, followed by a decrease to baseline values after 4 days. In untreated diabetic rats the 38-47 kDa doublet band also increased (two-fold) in kidney during the first 2 days after induction of diabetes, followed by a subsequent decrease. Insulin-treatment prevented both the increase in the 30 kDa and in the 38-47 kDa bands.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I suggesting that insulin-like growth factor I may be implicated in diabetic kidney growth. The present study was undertaken to examine the effects of exogenous insulin-like growth factor I infusion on diabetic renal hypertrophy at a time when renal insulin-like growth factor I concentration had returned to normal and the initial steep kidney growth rate had diminished to a much slower rate. Groups of rats with diabetes duration of 5 days were infused s.c. for 4 subsequent days with equimolar concentrations of insulin-like growth factor I (36 nmol/day) or insulin (35 nmol/day). Insulin infusion lowered blood glucose to a normal level within 2 days and induced an average body-weight gain of 9.3 +/- 0.6 g/day. Insulin-like growth factor I infused diabetic rats maintained the original diabetic state with blood glucose levels comparable to those of 0.154 mol/l NaCl-infused diabetic rats, but had nevertheless an average body-weight gain of 6.8 +/- 1.0 g/day while untreated diabetic rats had a lower body-weight gain amounting to 3.3 +/- 0.8 g/day (p less than 0.01). The kidney weight at day 9 in untreated diabetic animals was about 25% greater than that of non-diabetic control animals, while in insulin-like growth factor I treated diabetic rats a further increase (p less than 0.05) was seen, amounting to 36% above control level. No increase was seen in the insulin-treated diabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)

We have measured specific binding of insulin-like growth factor I and growth hormone to renal plasma membranes from control, streptozotocin-diabetic, insulin-treated diabetic, uninephrectomised and combined diabetic-uninephrectomised male Wistar rats. Control, insulin-treated and uninephrectomised rats had similar body weights after 7 days (243 +/- 2 g), whereas diabetic and diabetic-uninephrectomised animals were significantly lighter (219 +/- 4 and 203 +/- 4 g, p less than 0.05). Blood glucose concentrations were similar in the diabetic and diabetic-uninephrectomised animals (around 26 mmol/l) but significantly lower in the insulin-treated group. Right kidney weight increased by 14% in the control, insulin-treated and sham-nephrectomised animals, by 33% in the diabetic group, 38% in thenephrectomised animals and 60% in the diabetic-nephrectomised group. The renal content of insulin-like growth factor I was similar and stable in the control, insulin-treated and sham-nephrectomised animals (208 +/- 14 ng/g wet weight) but rose to a peak of 669 +/- 35 ng/g in the diabetic group (p less than 0.001), 871 +/- 34 ng/g in the nephrectomised animals (p less than 0.001) and 1012 +/- 43 ng/g in the diabetic-uninephrectomised group (p less than 0.001). Maximum binding of insulin-like growth factor I fell on day 1 in the diabetic group (8.3 +/- 1.4 vs 5.2 +/- 0.71 x 10(-11) mol/l; p less than 0.01) but thereafter was identical to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

It has recently been demonstrated that immunoassayable kidney insulin-like growth factor I concentration increases 24-48 h after induction of diabetes, preceding the initial renal hypertrophy. To elucidate whether this increase is due to increased local production we studied rat kidney insulin-like growth factor I gene expression during the first four days after induction of streptozotocin diabetes. Eighteen hours after injection with streptozotocin the diabetic animals were divided into two groups, one of which was treated with insulin, and daily for four days animals from each group were taken out for investigation. After four days the wet kidney weight had increased from baseline by 20% (from 687 +/- 23 to 827 +/- 6 mg (mean +/- SEM), p less than 0.01) in the untreated diabetic group, while no significant increase occurred in the insulin-treated group (687 +/- 23 vs 732 +/- 21 mg, NS). Kidney insulin-like growth factor I increased rapidly from baseline, the rise amounting to 52% after 48 h (from 271 +/- 11 to 411 +/- 32 ng/g, p less than 0.01) with a decline to control level on day four in the untreated diabetic group. Kidney insulin-like growth factor I remained unchanged in the insulin-treated diabetic group. Insulin-like growth factor I mRNA was measured by solution-hybridization assay. No differences were found in kidney insulin-like growth factor I mRNA between the two diabetic groups over the study period, while in liver, insulin-like growth factor I mRNA tended to be lower on day four in diabetic rats when compared to insulin-treated rats (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

In a previous study we demonstrated that the kidney content of somatomedin C was maximal one to two days after uninephrectomy or induction of diabetes, and that insulin treatment prevented an increase in kidney somatomedin C as well as kidney growth in diabetic animals. In the present study we have examined the effect of a somatostatin analogue on kidney somatomedin C and initial renal growth in the two experimental situations. The kidney hypertrophy in untreated diabetic animals amounted to 23% four days after streptozotocin injection and followed an increase in kidney somatomedin C content of 60% reaching the maximum after 48 h. In young and old uninephrectomized rats kidney growth was 19% and 16% after four days. In young animals a prompt increase of 50% in kidney somatomedin C was seen as reaching the maximum after 24 h, while the somatomedin C content in kidneys from old animals was maximal after 48 h (increase of 58%) in good accordance with the slightly slower kidney growth. The new findings of the present study are that administration of a long-acting somatostatin analogue (Sandostatin) effectively prevented the obligatory increase in kidney somatomedin C content as well as kidney growth both in experimental diabetes and after uninephrectomy. It is noteworthy that Sandostatin administration did not alter the metabolic state in diabetic animals indicating that the inhibition of kidney hypertrophy could not be attributed to improved metabolic control. The results thus support the concept that somatomedin C is involved in initial diabetic and post-nephrectomy renal growth.

Twelve 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 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 X kg-1 X min-1 in the normal subjects) but was significantly decreased during subcutaneous insulin (1.04 +/- 0.09 mg X kg-1 X 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.

Kidney function and size were studied in seven well-controlled male Type 1 (insulin-dependent) diabetic patients before and after administration of highly purified human growth hormone for one week. Glomerular filtration rate, renal plasma flow (steady state infusion technique with urinary collections using 125I-iothalamate and 131I-hippuran), kidney size (ultrasonic scanning) and urinary excretion rates of albumin and beta-2-microglobulin were measured. Highly purified growth hormone was injected subcutaneously, 2 IU in the morning and 4 IU in the evening. The growth hormone dosage applied induced an elevation in plasma growth hormone concentration from the normal level seen in these very well controlled diabetics to levels within the range previously demonstrated in normally controlled Type 1 diabetic patients. During the week of growth hormone administration, glycaemic control was maintained unchanged by increasing the insulin dose by 79 +/- 9% (mean +/- SEM). Glomerular filtration rate increased from 122 +/- 3 to 131 +/- 3 ml/min X 1.73 m2 (p less than 0.05) and renal plasma flow increased from 535 +/- 10 to 569 +/- 22 ml/min x 1.73 m2 (p less than 0.05). Kidney size changed from 128 +/- 5 to 133 +/- 5 ml/1.73 m2 (NS). Urinary excretion rates of albumin and beta-2-microglobulin were unchanged. The present findings suggest that the growth hormone elevation typically found in Type 1 diabetic patients with reasonable clinical control, contributes to the enhanced glomerular filtration rate and renal plasma flow present in that disease.

Somatostatin release from the isolated pancreas of 3 normal and 6 streptozotocin diabetic dogs has been measured in response to various stimuli to determine whether abnormalities in somatostatin release are present in the diabetic pancreas. Simultaneous measurement of glucagon secretion was also made. In the pancreas from normal dogs increases in perfusate glucose from 25 to 200 mg/100 ml induced a 2--3 fold increase in somatostatin release and a two thirds decrease in glucagon secretion. In contrast, in the diabetic pancreas glucose caused no change in the secretion of the two hormones. In the diabetic pancreas addition of insulin to the perfusate (25,000 microU/ml) for periods from 10 to 75 minutes aimed at restoring normal extracellular insulin levels in the islets failed to restore either somatostatin or glucagon secretion to normal. In contradistinction to the lack of effect of glucose, the somatostatin and glucagon responses to arginine (5 mmol/l), isoproterenol (2 ng/ml) and calcium (5 mmol/l) were normal in the diabetic pancreas. The data suggests the presence of a selective glucoreceptor abnormality of the D as well as of B and A cells in the streptozotocin diabetic dog.

The effect of calcium on somatostatin secretion was investigated in the isolated, perfused canine pancreas preparation and compared with those of acetylcholine, glucose, isoproterenol and arginine. Calcium (5 mmol/l) stimulated somatostatin release in a typical biphasic response pattern being about 5 times as potent as acetylcholine (1 mumol/l), arginine (5 mmol/l), and isoproterenol (2 ng/ml) while the release of insulin and glucagon in response to calcium and the other secretagogues were of the same magnitude. Somatostatin release increased progressively when perfusate calcium was increased step-wise from 0 through 1.25 and 2.5 to 5.0 mmol/l. Calcium stimulated the secretion of somatostatin in the absence of glucose. The stimulatory effect of calcium was, however, modulated by the glucose concentration being about twice as large at 200 mg/100 ml as at 25 mg/100 ml glucose in the perfusion medium.

Kidney growth after induction of experimental diabetes in rats was compared to compensatory renal growth in response to unilateral nephrectomy. After 4 days of diabetes, kidney weight had increased from 816 +/- 21 mg (SEM) to 940 +/- 42 mg (15%). In insulin-treated diabetic rats kidney weight was unchanged at the end of the study, namely 828 +/- 15 mg. In unilaterally nephrectomised rats kidney weight increased from 840 +/- 20 mg (SEM) to 1050 +/- 60 mg during 4 days (24%). We observed increased kidney content of somatomedin C in both diabetic and uninephrectomized rats. In untreated diabetic rats it was maximal after 48 h, with an increase of 77% (3469 +/- 312 ng/g (SEM) versus 1961 +/- 173 ng/g). After 4 days the somatomedin C content had returned to initial levels. In insulin-treated rats somatomedin C content did not increase during the observation period. The somatomedin C content of the remaining kidney after unilateral nephrectomy was maximal after 24 h with an increase of 58% (from 1340 +/- 203 ng/g (SEM) to 2122 +/- 214 ng/g). The somatomedin C content returned to normal at day 4. Serum somatomedin C declined insignificantly in diabetic animals during the experimental period, but a significant decrease (p less than 0.02) was found in uninephrectomized rats. This study demonstrates that kidney somatomedin C peaks during the first or second day after uninephrectomy or induction of diabetes, respectively, and that insulin treatment sufficient to prevent kidney growth abolishes the increase. These similar rapid initial hypertrophies/hyperplasies may thus be dependent on local somatomedin C formation.

Two main methods are available for assessing insulin sensitivity with the hyperinsulinaemic euglycaemic clamp technique: one employs a glucose-controlled insulin infusion system (the Biostator) with automatic feedback control; the second depends on frequent glucose measurement and the use of an algorithm and a pocket calculator ('manual') to determine the glucose infusion rate. The amount of glucose infused is a measure of insulin sensitivity. The efficiency of the two methods was compared in nine normal subjects (seven lean, two obese). After an overnight fast subjects were infused with insulin at 50 mU X kg-1 X h-1 for 2 h; this rate was doubled during the first 10 min for the manual technique. Blood glucose averaged 4.7 +/- 0.1 and 4.8 +/- 0.1 mmol/l from 0 to 120 min for Biostator and manual techniques and did not deviate significantly from the desired level. Variability of the clamp was also similar over the same period (coefficient of variation 5.1 +/- 0.6% and 6.4 +/- 0.7%, Biostator and manual). Glucose infused to maintain steady state from 60 to 120 min was higher, however, with the manual than the Biostator method (5.7 +/- 0.6 versus 4.4 +/- 0.6 mg X kg-1 X min-1, p less than 0.01) even when the loading dose was omitted, although the two methods correlated closely (p less than 0.05). Glucose infusion rate varied more from minute to minute with the Biostator (coefficient of variation 28.8 +/- 3% versus 12.2 +/- 2.1%). Steady-state serum insulin levels (30-120 min) were the same during both methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma glucagon and growth hormone concentrations were measured fasting and after oral glucose in 19 patients with portal vein block with extensive portal-systemic shunting but minimal liver cell damage, 11 cirrhotic patients and 12 matched control subjects. Portal vein block patients and controls had similar fasting glucose and glucagon levels (glucose 3.8 +/- 0.1 mmol/l VS control 3.4 +/- 0.1 mmol/l (mean +/- SEM); glucagon 57.5 +/- 9.1 pg/ml VS control 51.3 +/- 7.8 pg/ml). Cirrhotic patients were hyperglycaemic (cirrhosis 4.3 +/- 0.2 mmol/l VS control 3.4 +/- 0.1 mmol/l, p < 0.01) with significantly elevated glucagon levels (167.3 +/- 61.1 pg/ml VS control 51.3 +/- 7.8 pg/ml, p < 0.05), which suppressed towards control values after oral glucose. There was no correlation between fasting plasma glucagon levels and the degree of portal-systemic shunting in cirrhotic patients. There was a strong correlation between fasting plasma glucagon concentrations and aspartate transaminase levels (r = 0.68; p < 0.01) in cirrhotic and portal vein block patients. Significant elevations of growth hormone were seen only in cirrhotic patients. It is concluded that hyperglucagonaemia is a feature of hepatocellular damage rather than portal-systemic shunting but the relationship between elevated glucagon and growth hormone concentrations and carbohydrate intolerance in cirrhosis remains unclear.

The concentration of biologically active insulin was measured by the isolated fat cell method in serum and urine from healthy subjects and compared with the concentration of immunoreactive insulin. In both urine and serum the values obtained by the two methods correlated closely; In addition, there was a close correlation between the concentration of biologically active and immunoreactive insulin in urine from maturity onset diabetics. Therefore, conclusions on the excretion in the urine and the urinary clearance of insulin, which are based on measurements of immunoreactive insulin, are also valid for biologically active insulin.

Alloxan diabetes was induced in rats by intraperitoneal injection or by injection into the vena cava. In 3 groups the renal vessels were clamped during, and for some minutes after, the injection. The histological appearance of the kidneys after 5, 10 and 15 months of diabetes was compared with findings in groups of untreated rats of the same age as well as in non-diabetic rats treated with insulin throughout comparable periods. The glomeruli of the alloxan diabetic rats showed changes similar but not quite identical to the human diabetic glomerulopathy. These changes were present only after diabetes of 10 months. The main difference is that the rats showed no actual nodules and that the PAS-positive hyalinosis of the arterioles, characteristic of human longterm diabetes, was absent. The glomerular changes are not age-conditioned, and the results do not suggest that the administration of insulin or direct alloxan damage played any role in inducing these lesions. Tubular damage (atrophy, dilatation) and interstitial fibrosis were most marked in rats which had not been protected against the high initial alloxan concentration in the blood by clamping the renal vessels.