Possible mechanism by which somatostatin-induced glucagon suppression improves glucose tolerance during insulinopaenia in man

Summary The present study examines the question of whether lowering the basal plasma glucagon concentration alters the response of the liver to an intravenous glucose load under conditions where insulin is present at near-basal concentrations. Acute hyperglycaemia of 220–240 mg/dl was induced by peripheral venous glucose infusion in two groups of normal men who had undergone hepatic vein catheterization. Somatostatin (0.9 mg/h) was infused in both groups together with an infusion of insulin (0.15 mU/kg/min) to maintain arterial insulin levels at 7–12 U/ml. Glucagon (1.5 ng/kg/min) was infused in one group resulting in a rise in plasma glucagon levels from 148±37 to 228±25 pg/ml, thus mimicking basal portal glucagon concentrations, whereas in the second group glucagon was not replaced, resulting in a fall in circulating glucagon levels from 132±21 to 74±15 pg/ml. In the glucagon-deprived group, net splanchnic glucose production (NSGP) fell from 143±31 to –72.5±39 mg/ min (p<0.01), indicating that net splanchnic glucose uptake had occurred. By contrast, NSGP did not change significantly (137±20 vs 151±60 mg/min) in the group in which both insulin and glucagon were replaced during hyperglycaemia. These data thus suggest that during hyperglycaemia, when the insulin concentration is fixed at basal levels, glucagon may play an important role in determining whether or not the liver diminishes its output of glucose and stores glucose in response to a glucose load.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM

Summary In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At −30 min the patients self-injected their usual morning insulin and at −15 min they injected the study drug (either placebo or 30, 60 or 90 μg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with ^99mTc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with ¹¹¹In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal. [Diabetologia (1998) 41: 577–583] Received: 22 September 1997 and in revised form: 14 January 1998     

The post-prandial state in Type 2 diabetes and endothelial dysfunction: effects of insulin aspart.

OBJECTIVE: Recently, much attention has been focused on the possibility that the post-prandial state may be a cardiovascular risk factor in diabetes. The aim of the present study was to evaluate whether the post-prandial state is associated with endothelial dysfunction in patients with diabetes and to explore the effect on this aspect of managing post-prandial hyperglycaemia by insulin aspart. RESEARCH DESIGN AND METHODS: Twenty-three patients with Type 2 diabetes and 10 normal controls were recruited. In the diabetic patients two different tests were performed in each subject: a standard meal preceded by subcutaneous injection of soluble insulin (0.15 U/kg body weight) or of short-acting insulin aspart (0.15 U/kg body weight). These tests were designed to achieve different levels of post-prandial hyperglycaemia. Controls received a single standard meal test. Immediately before, and 1, 2, 4 and 6 h after each meal, blood glucose, triglycerides, free fatty acids and flow-mediated vasodilation were measured. RESULTS: Compared with regular insulin, insulin aspart significantly reduced the area under the curve for post-prandial hyperglycaemia (58.3 +/- 17.6 vs. 68.1 +/- 17.7; P<0.04), and preserved flow-mediated vasodilation, which was decreased in the post-prandial state (39.4 +/- 2.9 vs. 34.1 +/- 2.2; P<0.01). Triglyceride and free fatty acid levels were not differentially affected by the treatment. In normal controls the meal did not affect flow-mediated vasodilation. CONCLUSION: This study shows that the post-prandial state is accompanied by endothelial dysfunction in Type 2 diabetic patients and that insulin aspart improved endothelial function.     

Fetal diabetes in rats and its effect on placental glycogen

Summary The role of fetal insulin in placental glycogen accumulation, which occurs despite insulin deficiency in maternal diabetes, was studied in rats. Streptozotocin was injected into fetuses of non-diabetic and streptozotocin-diabetic mothers on days 19.5 and 20.5 of gestation, causing fetal hypoinsulinaemia and pancreatic insulin depletion. Placental glycogen content of either 1.6 mg/g in non-diabetic rats or 6.5 mg/g in diabetic rats was not affected by fetal streptozotocin treatment. Glycogen distribution was also measured in the placenta to assess the effect of fetal hypoinsulinaemia on glycogen content in its fetal segment. The glycogen concentration ratio between the fetal and maternal segments in diabetic rats was 0.3 and increased to 0.5 in diabetic rats, without being affected by fetal hypoinsulinaemia. There was no significant effect of fetal hypoinsulinaemia on the activities of placental glycogen synthase or glycogen phosphorylase, both in nondiabetic and diabetic rats. Fetal hypoinsulinaemia was associated, however, with a marked decrease in fetal liver glycogen together with a decrease in fetal liver weight, which was more pronounced than the decrease in fetal body weight. Administration of insulin to the streptozotocin-treated fetuses restored the impaired glycogen synthesis (measured by incorporation of U-[¹⁴C]-glucose and ³H₂O in the fetal liver) without affecting glycogen synthesis in the placenta. These results demonstrate: (1) placental glycogen metabolism in contrast to fetal liver glycogen metabolism, is not regulated by fetal insulin; (2) the reduced fetal liver weight and its glycogen content, rather than hyperglycaemia, are the salient features of fetal insulin deficiency; and (3) placental glycogen accumulation in diabetes is related to the hyperglycaemia of maternal origin and not to the changes in maternal or fetal insulin availability.     

Insulin pump therapy

Intensive insulin therapy is the mainstay of diabetes care as it prevents or delays the long term complications of Type 1 diabetes mellitus. Insulin pump therapy can deliver improved diabetes control and at the same time reduce the number and serious nature of any hypoglycaemic episodes. The therapy is not associated with an increased risk of diabetic ketoacidosis. Pump therapy should follow National Institute for Health and Care Excellence Guidelines and be instigated and supported by teams experienced in insulin pump therapy, with skills and competences to ensure sustained positive outcomes. Continuous glucose monitoring further improves blood glucose control providing continuous feedback with warnings of rapid changes in glucose and/or attainment of high or low glucose concentrations. Continuous glucose monitoring is cost effective by reducing fear of hypoglycaemia, blood glucose finger prick testing and a marked reduction in hypoglycaemic episodes. The hybrid closed loop systems offering algorithm driven insulin adjustment based on sensor readings are now commercially available bringing into play more effective and safer insulin delivery with a further step change in diabetes control and well being.     

Continuous on-line glucose measurement by microdialysis in a central vein. A pilot study

Introduction

Tight glucose control in the ICU has been proven difficult with an increased risk for hypoglycaemic episodes. Also the variability of glucose may have an impact on morbidity. An accurate and feasible on-line/continuous measurement is therefore desired. In this study a central vein catheter with a microdialysis membrane in combination with an on-line analyzer for continuous monitoring of circulating glucose and lactate by the central route was tested.

Methods

A total of 10 patients scheduled for major upper abdominal surgery were included in this observational prospective study at a university hospital. The patients received an extra central venous catheter with a microdialysis membrane placed in the right jugular vein. Continuous microdialysis measurement proceeded for 20 hours and on-line values were recorded every minute. Reference arterial plasma glucose and blood lactate samples were collected every hour.

Results

Mean microdialysis-glucose during measurements was 9.8 ± 2.4mmol/l.No statistical difference in the readings was seen using a single calibration compared to eighth hour calibration (P =0.09; t-test). There was a close agreement between the continuous reading and the reference plasma glucose values with an absolute difference of 0.6+0.8mmol, or 6.8+9.3% and measurements showed high correlation to plasma readings (r = 0.92). Thelimit of agreement was 23.0%(1.94 mmol/l) compared to arterial plasma values with a line of equality close to zero.However, in a Clarke-Error Grid 93.3% of the values are in the A-area,and the remaining part in the B-area.Mean microdialysis-lactate was 1.3 ± 1.1mmol/l. The measurements showed high correlation to the blood readings (r = 0.93).

Conclusion

Continuous on-line microdialysis glucose measurement in a central vein is a potential useful technique for continuous glucose monitoring in critically ill patients, but more improvements and testingare needed.