Insulin dose-response studies in severely insulin-resistant type 2 diabetes--evidence for effectiveness of very high insulin doses.

AIM: To combat diabetic complications strict glycaemic control is desirable in type 2 diabetes, but some patients are severely insulin resistant and it is not known whether high doses of insulin are effective. This study was designed to determine the acute dose-response effects of insulin in patients with type 2 diabetes and severe insulin resistance. METHODS: We included eight insulin-resistant (mean insulin dose: 186 IU/day; body mass index: 35) subjects with type 2 diabetes in a single-blinded, randomized crossover study. Each subject was studied on two occasions. On each occasion, subjects underwent two 3-h hyperinsulinaemic euglycaemic clamps. The subjects were randomized to two low-dose insulin infusions (0.5 and 1.5 mU/kg/min in random order) on one occasion and to two high-dose insulin infusions (3.0 and 5.0 mU/kg/min in random order) on another occasion. RESULTS: On all occasions, steady-state glucose infusion rates (SSGIRs) were accomplished and we observed a clear dose-response relationship with GIR values of 0.4 ± 0.2 (s.e.), 2.6 ± 0.6, 3.7 ± 0.8 and 4.9 ± 0.9 mg/kg/min during the 0.5, 1.5, 3.0 and 5.0 mU/kg/min insulin infusions, respectively (p < 0.001). Likewise, there was a dose-dependent suppression of endogenous glucose production (EGP) (p < 0.009), plasma free fatty acids (FFAs) (p < 0.001) and plasma glucagon (p = 0.001). CONCLUSIONS: Our results show that the insulin dose response in terms of GIR and EGP is preserved for insulin doses corresponding to >800 IU/day, suggesting effectiveness of very high insulin doses in severely insulin-resistant subjects.

Influence of growth hormone on glucose-induced glucose uptake in normal men as assessed by the hyperglycemic clamp technique.

To determine whether physiological increments in circulating GH concentrations influence glucose-induced glucose uptake (GIGU), two-step sequential hyperglycemic clamp (plasma glucose, 6 and 14 mmol/L) studies were performed in six normal subjects with and without GH infusion (40 ng/kg.min). The latter resulted in serum GH levels of 15 +/- 1 (+/- SE) microgram/L. Infusion of somatostatin (250 micrograms/h during step 1 and 750 micrograms/h during step 2) together with a replacement dose of insulin (1.1 pmol/kg.min) resulted in serum insulin levels comparable to basal levels in both studies. The GIGU ([3-3H]glucose), assessed as the difference between steps 2 and 1 glucose utilization during the final 60 min of each step (150 min) was markedly impaired during GH infusion (with GH, 1.1 +/- 0.2 mg/kg.min; without GH, 3.1 +/- 0.3 mg/kg.min; P less than 0.001). Moreover, the percent increase in glucose uptake was considerably reduced during hypersomatotropinemia (with GH, 44 +/- 9%; without GH, 97 +/- 11%; P less than 0.01). In the GH infusion as well as control studies, endogenous glucose production (EGP) was similar at the two levels of glycemia, whereas GH infusion approximately doubled EGP [2.3 +/- 0.2 vs. 1.1 +/- 0.3 mg/kg.min and 2.0 +/- 0.4 vs. 1.1 +/- 0.4 mg/kg.min (step 1 and 2, respectively)]. We conclude that moderate hypersomatotropinemia for several hours is characterized by impaired GIGU as well as augmented EGP.

Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus.

Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.

Autonomic function in parkinsonian patients relates to duration of disease.

Autonomic functions were studied after withdrawal of all medication in parkinsonian out-patients with short and long duration of disease and in age-matched healthy control subjects. Vagal heart control and noradrenergic response to standing were impaired and related to duration of symptoms of idiopathic parkinsonism. Cholinergic function of pupil motility was unchanged. The cholinergic dysfunction of heart rate variation, therefore, could be due to a specific loss of dopaminergic neurons in the vagal motor nucleus.

Amylin receptor agonists: a novel pharmacological approach in the management of insulin-treated diabetes mellitus.

Amylin is a peptide hormone which is co-secreted with insulin from the pancreatic beta-cell. Type 1 diabetic individuals and some Type 2 diabetic individuals are characterised by amylin deficiency. Animal experiments have revealed several actions of amylin on intermediary metabolism, of these some have been demonstrated to be of potential physiological relevance in humans. In particular amylin appears to have important actions in controlling prandial glucose homeostasis. The peptide hormone inhibits postprandial glucagon secretion and delays gastric emptying thereby modifying postprandial hyperglycaemia in diabetic individuals which presumably adds to overall glycaemic control without a concomitant increase in the number of severe hypoglycaemic episodes. Moreover, amylin acts as a satiety agent. Amylin replacement may therefore improve glycaemic control in diabetes mellitus. However, human amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibres, which makes it unsuitable for pharmacological use. A stable analogue, pramlintide, with actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide has therefore been developed. The efficacy and safety of pramlintide administration to diabetic individuals have been tested in a large number of clinical trials. It is the aim of this review to describe possible (patho)physiological actions of amylin as demonstrated in animal and human models, to discuss the background for potential amylin (analogue) replacement in diabetes mellitus and to review results from clinical trials with the amylin receptor analogue pramlintide.

Alcohol and glucose counterregulation during acute insulin-induced hypoglycemia in type 2 diabetic subjects.

To investigate the influence of alcohol on glucose counterregulation and recovery during acute insulin-induced hypoglycemia in type 2 diabetic subjects, 8 diet-treated type 2 diabetic subjects were examined twice after an overnight fast. A graded hyperinsulinemic (1 mU/kg/min, 60 to 195 minutes) euglycemic/hypoglycemic clamp was performed with concomitant infusion of 3-(3)H-glucose to assess glucose turnover. After a euglycemic baseline period (150 to 180 minutes), 200 mL of water was taken either alone or with alcohol (0.4 g/kg body weight). Hypoglycemia (plasma glucose nadir, 2.8 mmol/L) was subsequently induced, and the recovery period followed after discontinuation of insulin and the variable glucose infusion. On both study days, circulating concentrations of insulin and glucose were comparable. Alcohol intake markedly increased plasma lactate (area under the curve [AUC], recovery period) (244 +/- 30 v 12 +/- 4 mmol/L x 240 minutes; P = .00009) and suppressed plasma nonesterified fatty acids (NEFA) (AUC, recovery period) (95 +/- 13 v 161 +/- 18 mmol/L x 240 minutes; P = .0008). No differences were found in the counterregulatory response of catecholamines, cortisol, and growth hormone (GH). However, alcohol intake decreased peak glucagon significantly (155 +/- 12 v 200 +/- 17 pg/mL; P = .038). In diet-treated, mild type 2 diabetic subjects, alcohol does not modify recovery from insulin-induced hypoglycemia.

Effects of the somatostatin analog, octreotide, on glucose metabolism and insulin sensitivity in insulin-dependent diabetes mellitus.

To examine the effect of the somatostatin analog, octreotide, on insulin-mediated glucose uptake, seven insulin-dependent diabetic (IDDM) subjects were studied with and without 4 days of continuous subcutaneous octreotide administration (1 mg/kg/d). Insulin dosage was adjusted after frequent measurements of plasma glucose level. On the third day a hormonal and metabolic blood profile was obtained, and on the fourth day a euglycemic (5 mmol/L), hyperinsulinemic (1 mU/kg/min) clamp was performed in combination with calorimetry and a muscle biopsy. Mean plasma glucose levels on day 3 were similar (7.9 +/- 0.9 v 9.0 +/- 0.6 mmol/L). Growth hormone (GH) (0.39 +/- 0.10 v 0.78 +/- 0.23 mg/L, P < .05), insulin-like growth factor-1 (IGF-1) (127 +/- 17 v 157 +/- 21 mg/L, P < .05), and nonesterified fatty acids (NEFA) (239 +/- 25 v 405 +/- 44 mmol/L, P < .01) were lower following octreotide administration. Insulin requirements were reduced during octreotide administration, resulting in significantly lower insulin levels (27.3 +/- 2.7 v 39.9 +/- 9.9 mU/L, P < .5). During the clamp, glucose and insulin levels wer similar. Following octreotide, glucose disposal (7.33 +/- 0.49 v 6.08 +/- 0.55 mg/kg/min, P < .05) increased and hepatic glucose production (HGP) was more suppressed (-1.56 +/- 0.07 v -0.63 +/- 0.34 mg/kg/min, P < .05, 220 to 270 minutes). Oxidative glucose disposal (indirect calorimetry) was enhanced (3.09 +/- 0.24 v 2.70 +/- 0.37 mg/kg/min, P = .08), whereas glucose storage, as well as the fractional velocity for glycogen synthase activity, were unaltered during octreotide administration. Conversely, octreotide decreased lipid oxidation (0.12 +/- 0.1 v 0.41 +/- 0.15 mg/kg/min, P < .05). In conclusion, a low-dose octrotide infusion for 4 days to IDDM subjects leads to significantly increased insulin sensitivity.

Effects of oral glucose on systemic glucose metabolism during hyperinsulinemic hypoglycemia in normal man.

The widespread use of oral glucose in the treatment of hypoglycemia is mainly empirically based, and little is known about the time lag and subsequent magnitude of effects following its administration. To define the systemic impact and time course of effects following oral glucose during hypoglycemia, we investigated 7 healthy young men twice. On both occasions, a 6-hour hyperinsulinemic (1.5 mU/kg/min)-hypoglycemic clamp was performed to ensure similar plasma glucose profiles during a stepwise decrease toward a nadir less than 50 mg/100 mL after 3 hours. On the first occasion, subjects ingested 40 g glucose and 4 g 3-ortho-methylglucose ([3-OMG] to trace glucose absorption) dissolved in 400 mL tap water after 3.5 hours. The second examination was identical except for the omission of 40 g oral glucose, and glucose levels were clamped at hypoglycemic concentrations similar to those recorded on the first examination. Plasma glucose curves were superimposable, and all participants reached a nadir less than 50 mg/100 mL. Similar increases in growth hormone (GH) and glucagon were observed in both situations. The glucose infusion rates (GIRs) were lower after oral glucose, with the difference starting after 5 to 10 minutes, being statistically significant after 20 minutes, and reaching a maximum of 8.5 +/- 1.6 mg/kg/min after 40 minutes. Circulating 3-OMG increased after 20 minutes. In both situations, infusion of insulin resulted in insulin levels of approximately 150 microU/mL and a suppression of C-peptide levels from 2.0 to 1.1 nmol/L (P < .01). After glucose ingestion, both serum C-peptide and glucagon-like peptide-1 (GLP-1) increased (C-peptide from 1.1 +/- 0.05 to 1.4 +/- 0.05 nmol/L and GLP-1 from 3.2 +/- 0.8 to 18.1 +/- 3.3 pmol/L), in contrast to the situation without oral glucose (P < .05). Isotopically determined glucose turnover was similar. In conclusion, our data suggest that oral glucose affects systemic glucose metabolism rapidly after 5 to 10 minutes. Quantitatively, the immediate impact is relatively small, with the gross impact observed after approximately 40 minutes. Future studies aiming to identify therapeutic oral agents with prompt effect seem warranted.

Metabolic effects of growth hormone in humans.

Growth hormone (GH) has acute actions to stimulate lipolysis and ketogenesis after 2 to 3 hours, effects that may be important in the adaptation to stress and fasting. This is accompanied by a decrease in insulin sensitivity in both liver and muscle. These combined effects may be very deleterious to insulin-dependent diabetic patients, in whom increased GH secretion may precipitate and maintain acute metabolic derangement (ketoacidosis) and be a major initiator of the dawn phenomenon. On the other hand, augmented GH secretion plays a beneficial role in the defense against hypoglycemia, in particular during prolonged hypoglycemia and in patients with impaired ability to secrete other counterregulatory hormones appropriately. It is also certain that GH is a potent anabolic hormone in terms of promoted nitrogen retention, but the extent to which these well-known actions are direct or secondary to hyperinsulinemia, increased activity of insulin-like growth factors (IGFs), or release of protein-conserving lipid intermediates has eluded precise characterization.

The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus.

To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 microg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 AM to 4:30 PM) was performed. Serum fructosamine was decreased after pramlintide (314+/-14 micromol/L) compared with placebo (350+/-14 micromol/L, P = .008). On the profile day, the mean plasma glucose (8.3+/-0.7 v 10.2+/-0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359+/-41 v 340+/-35 pmol/L). Mean blood glycerol values were reduced (0.029+/-0.004 v 0.040+/-0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274+/-0.012 v 0.246+/-0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8+/-7.3 v 72.4+/-8.0 ng/L, P = .005) and lunch (47.6+/-9.0 v 60.9+/-8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 microg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.

Effects of hyperinsulinaemia and hypoglycaemia on circulating leptin levels in healthy lean males.

Current knowledge of the regulatory mechanisms of leptin synthesis and release is limited. To elucidate the role of short-term hyperinsulinaemia and hypoglycaemia on circulating levels of leptin, 7 healthy lean men underwent a 360-min hyperinsulinaemic (insulin infusion rate: 1.5 mU/kg/min) clamp in two conditions: (i) during 360 min of euglycaemia and (ii) during 120 min of euglycaemia followed by 240 min of graded hypoglycaemia (nadir 2.9 +/- 0.1 mmol/l). During hyperinsulinaemic euglycaemia, serum leptin levels were initially stable and then rose gradually after 180 min to a peak value of 147 +/- 7% of baseline (ANOVA, p < 0.01). During the hypoglycaemic clamp, the leptin profile differed from that of euglycaemic conditions (p < 0.01) since the increase was postponed and reduced. In both clamp studies, leptin dynamics contrasted with the changes in a control study performed in 7 other men whose serum leptin fell significantly (p < 0.05) to 77 +/- 4% of baseline values during a 360-min fast (following overnight fasting). It is concluded that hyperinsulinaemia for more than 3 h increases circulating levels of leptin in lean males, whereas hyperinsulinaemia with concomitant hypoglycaemia leads to transient suppression. The exact nature of the underlying mechanisms, e.g. changes in levels of insulin, glucose, various substrates, glucose turnover and/or counterregulatory hormones, remains to be determined.

Influence of hyperglycemia on glucose uptake and hepatic glucose production in non-dialyzed uremic patients.

To determine whether the deranged glucose metabolism in uremia, in addition to insulin resistance can be attributed also to reduced glucose-induced glucose uptake, a two-step sequential hyperglycemic clamp (plasma glucose: 120 and 300 mg/dl) was performed in 6 non-dialyzed uremic and 8 healthy subjects. A constant infusion of somatostatin (300 micrograms/h) and soluble insulin (0.2 mU/kg/min) resulted in peripheral serum insulin slightly higher than basal in both uremics (16 +/- 3 and 22 +/- 3 microU/ml; step 1 and 2, respectively) and controls (20 +/- 2 and 22 +/- 1 microU/ml). The glucose-induced glucose uptake (3-3H-glucose) assessed as the difference between step 2 and 1 glucose disposal at the final 30 min of each step was markedly reduced in uremics (3.2 +/- 0.5 mg/kg/min) compared to healthy subjects (5.7 +/- 0.8 mg/kg/min; p less than 0.03). However, the percentage increment in glucose uptake from step 1 to step 2 hyperglycemia was comparable in the two groups (134 +/- 27 and 148 +/- 17%). Modest hyperglycemia (120 mg/dl) and slightly raised insulinemia resulted in comparable suppression of the endogenous (hepatic) glucose production (EGP) in healthy (1.6 +/- 0.2 mg/kg/min) and uremic subjects (1.5 +/- 0.3 mg/kg/min). In controls, pronounced hyperglycemia (300 mg/dl) further reduced EGP (0.6 +/- 0.3 mg/kg/min; p less than 0.01) while EGP in uremics on the contrary tended to rise (2.0 +/- 0.4 mg/kg/min; p = 0.09), thus indicating an abnormal reaction of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of glipizide on glucose metabolism and muscle content of the insulin-regulatable glucose transporter (GLUT 4) and glycogen synthase activity during hyperglycaemia in type 2 diabetic patients.

To examine whether sulphonylureas influence hyperglycaemia-induced glucose disposal and suppression of hepatic glucose production (HGP) in type 2 diabetes mellitus, a 150-min hyperglycaemic (plasma glucose 14 mmol/l) clamp with concomitant somatostatin infusion was used in eight type 2 diabetic patients before and after 6 weeks of glipizide (GZ) therapy. During the clamp a small replacement dose of insulin was given (0.15 mU/kg per min). Isotopically determined glucose-induced glucose uptake was similar before and after GZ administration which led to improved glycaemic control (basal plasma glucose 12.2 +/- 1.3 vs 8.9 +/- 0.7 mmol/l; P < 0.01). Glucose-induced suppression of HGP was, however, more pronounced during GZ treatment (0.96 +/- 0.14 vs 1.44 +/- 0.20 mg/kg per min; P < 0.02). Following GZ treatment hyperglycaemia failed to stimulate glycogen synthase activity. Moreover, GZ resulted in a significant increase in the immunoreactive abundance of the insulin-regulatable glucose transport protein (GLUT 4) (P < 0.02). In conclusion, these results suggest that GZ therapy in type 2 diabetic patients enhances hepatic sensitivity to hyperglycaemia, while glucose-induced glucose uptake remains unaffected. In addition, GZ tends to normalize the activity of glycogen synthase and increases the content of GLUT 4 protein in skeletal muscle.

Effects of growth hormone on glucose metabolism.

Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp. 1 diabetes or high dose GH treatment) the diabetogenic actions of GH become apparent. In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact beta-cell function these changes are counterbalanced by hyperinsulinemia--such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality ('Reavens syndrome X'). When stimulated with insulin these patients exhibit insulin resistance at the liver, in adipose tissue and in muscle. Few elaborate studies on the effects of GH on glucose metabolism in GH deficient patients have been conducted. These patients are hypersensitive to the actions of insulin on glucose metabolism and there is some evidence that when GH initially is given to such patients in the GH deprived state, paradox insulin-like effects of GH may be observed. Whether this may relate to increased activity of insulin-like growth factors is unsettled.

Glucose metabolism in chronic renal failure with reference to GH treatment of uremic children.

Growth retardation is a common feature in children with end-stage renal failure (ESRF). Medical management of renal insufficiency rarely normalizes growth and optimistic reports on the effect of rhGH treatment on growth velocity may presage more extensive use of rhGH in pediatric nephrology. Ample evidence has shown beneficial effects of GH replacement therapy in both childhood and adolescent hypopituitarism. However, the remarkably few side effects of treatment reported in these conditions cannot necessarily be extrapolated to children with ESRF. Uremia is associated with a wide range of metabolic and hormonal derangements including decreased glucose tolerance. This is mainly due to impaired insulin-stimulated glucose disposal in peripheral tissues and insufficient insulin-induced suppression of hepatic glucose production. Insulin-stimulated glucose uptake in skeletal muscle in ESRF is reduced by 30-50% as compared to that in healthy subjects, and a reduction may be detected even in subjects with a more moderate reduction in renal function (GFR around 25 ml/min). Dialysis therapy improves the disturbed insulin action significantly. The cause of the insulin resistance in ESRF is multifactorial. Impaired physical fitness, accumulation of uremic toxins, raised levels of GH and glucagon, metabolic acidosis, dyslipidemia and the medication applied may all contribute. If exogenous GH administration is added to the already marked uremic insulin resistance, insulin action may be severely disturbed and the secondary hyperinsulinism further magnified. However, frank diabetes mellitus does not develop unless the beta cells fail to meet the enhanced demands. This will probably occur only in patients with a beta-cell genotype pivotal for the phenotypic expression of non-insulin dependent diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Nerve conduction velocity in man: influence of glucose, somatostatin and electrolytes.

Insufficient metabolic control in diabetes mellitus is associated with a reversible reduction in nerve conduction velocity, but the mechanism behind this phenomenon is unknown. To examine the effect of acute hyperglycaemia on nerve conduction eight non-diabetic men (20-49 years of age) with no signs of peripheral neuropathy were studied before and after 3 h of hyperglycaemic clamping (plasma glucose approximately 15 mmol/l), while insulin secretion was suppressed by somatostatin [Study 1]. Nerve conduction velocity, as determined in the proximal part of the median nerve, fell by 2.8 +/- 3.0 m/s (2p-value: 0.033). However, during euglycaemic clamping (plasma glucose approximately 5 mmol/l) in five non-diabetic men (19-38 years of age) infused solely with somatostatin [Study 2], a comparable decrement in nerve conduction velocity was found (1.7 +/- 1.3 m/s, 2p-value: 0.043). In both studies relative hypoinsulinaemia was present. Serum-sodium decreased significantly (143 +/- 1 mmol/l vs 137 +/- 1 mmol/l [Study 1] and 143 +/- 1 mmol/l vs 142 +/- 2 mmol/l [Study 2]), while serum-potassium increased. In conclusion, the slight but significant reduction in nerve conduction velocity observed in both studies appears to be correlated to electrolyte changes. However, an effect of hypersomatostatinaemia or the hormonal changes associated with this cannot be excluded, while short-term hyperglycaemia per se seems to be without effect on nerve conduction velocity.

Effects of amylin and the amylin agonist pramlintide on glucose metabolism.

Since the discovery of the pancreatic islet hormone amylin in 1987, its metabolic effects have been investigated in a number of studies in animals and humans. Data from some early animal studies suggested that amylin might be associated with the development of insulin resistance, but other studies found that amylin had no effect on insulin sensitivity. More recently, studies performed using the human amylin analogue pramlintide in patients with Type 1 diabetes found that the hormone has no influence on either insulin-stimulated glucose uptake or the restraining effect of insulin on hepatic glucose production during periods of euglycaemia. Furthermore, during insulin-induced hypoglycaemia, pramlintide appears to increase the plasma concentrations of cortisol and growth hormone, and to stimulate the release of the gluconeogenic substrate lactate by the skeletal muscles. Taken together with evidence that, in short-term studies, pramlintide improved glycaemic control in patients with Type 1 diabetes who were also treated with insulin, these data suggest that pramlintide may have a role in the management of patients with diabetes. However, longer-term studies are required to ascertain whether these findings are sustained over time.

Forearm substrate exchange during hyperinsulinaemic hypoglycaemia in normal man.

To assess muscle substrate exchange during hypoglycaemia, 8 healthy young male subjects were studied twice during 2 h of hyperinsulinaemic euglycaemia followed by 4 h of (1) hypoglycaemia (plasma glucose < 2.8 mmol l-1), and (2) euglycaemia. Insulin was infused at a rate of 1.5 mU kg-1 min-1 throughout. When compared to euglycaemia, hypoglycaemia was associated with: (1) increment in circulating glucagon (65 +/- 8 vs 23 +/- 4 ng l-1, p < 0.05), growth hormone (19.9 +/- 3.6 vs 2.6 +/- 1.3 micrograms l-1, p < 0.05), adrenaline (410 +/- 88 vs 126 +/- 32 ng l-1, p < 0.05) and increased suppression of C-peptide (0.5 +/- 0.1 vs 1.0 +/- 0.1 micrograms l-1, p < 0.05) along with a modest lowering of insulin (103 +/- 10 vs 130 +/- 13 mU l-1, p < 0.05); (b) decrease in plasma glucose level (3.0 +/- 0.07 vs 5.0 +/- 0.12 mmol l-1, p < 0.05), forearm glucose uptake (0.21 +/- 0.09 vs 1.21 +/- 0.21 mmol l-1, p < 0.05) and requirement for exogenous glucose (5.6 +/- 1.1 vs 13.2 +/- 0.9 mg kg-1 min-1 p < 0.005) together with an impaired suppression of isotopically determined endogenous glucose production (0.34 +/- 0.5 vs -2.3 +/- 0.3 mg kg-1 min-1, p < 0.05); (3) exaggerated increase in blood lactate (1680 +/- 171 vs 1315 +/- 108 mumol l-1, p < 0.05) and a decrease in alanine (215 +/- 18 vs 262 +/- 19 mumol l-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.

AIMS: Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans. METHODS: Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2). RESULTS: Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2). CONCLUSIONS: Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.

Aspects of secretion and actions of amylin: interplay between amylin and other hormones.

Amylin is a second beta-cell hormone, co-localized and co-secreted with insulin in response to nutrient stimuli. Amylin is released in a pulsatile pattern similar to insulin. It is mostly expressed in pancreatic islet cells but smaller amounts are present elsewhere, e.g. in the central nervous system. Apparently amylin (and amylin analogues) has actions capable of modifying glucose homeostasis. It suppresses arginine-stimulated and postprandial glucagon secretion, inhibits insulin secretion and slows gastric emptying. Furthermore, amylin seems to be a satiety agent. In vitro and in vivo studies in animals have demonstrated that amylin may induce insulin resistance. However, it exerts no effect on insulin sensitivity in humans. The literature on the possible actions of amylin/amylin analogues on secretion of growth hormone (GH) is limited. Hypothetically, amylin treatment could be of relevance to improve glycemic control in diabetes mellitus. Muticenter trials with an amylin analogue are ongoing and results are being awaited with interest.