Effect of insulin on hepatic bile secretion during normoglycaemia and hyperglycaemia

The roles of hyperosmolality, hyperglycaemia, and insulin in glucose-induced reduction of bile secretion were examined in anaesthetized pigs. Compared with normoglycaemia, intravenous infusion of isotonic glucose reduced bile acid-dependent bile secretion at a plasma glucose concentration of 18 mmol/l, with 34 +/- 4%. Lowering of plasma glucose concentration to normoglycaemia after administration of insulin (10 U/kg body wt. low dose) increased bicarbonate-dependent bile secretion by 23 +/- 3%. Induction of hyperglycaemia (plasma glucose concentration, 16 mmol/l) and the combined infusion of isotonic glucose and the low insulin dose decreased bile secretion by 22 +/- 3%. During hyperglycaemia (plasma glucose concentration, 16 mmol/l) the combined infusion of isotonic glucose and a high dose of insulin (60 U/kg body wt) increased bile acid-dependent bile secretion by 26 +/- 3%. Hyperglycaemia reduces bile secretion without altering plasma osmolality. Endogenous production (or too rapid degradation) of insulin may be too small during intravenous glucose infusion to cope with the metabolic demands of hepatocellular glucose conversion. This may be overcome by administration of insulin in a large dose, which stimulates bile acid secretion.     

Continuous glucose monitoring for treatment adjustment in diabetic pregnancies--a pilot study.

AIMS: To examine the efficacy of a continuous glucose monitoring (CGM) system for treatment adjustment in patients with diabetic pregnancy treated with insulin. METHODS: The study sample consisted of eight women with diabetic pregnancy, six with pre-pregnancy Type 1 diabetes mellitus and two with gestational diabetes (GDM), all being treated with multiple daily insulin injections. Gestational age ranged from 24 to 32 weeks. Data derived from the Continuous Glucose Monitoring System (MiniMed) for 72 h were compared with fingerstick glucose measurements (six to eight times a day), and treatment was adjusted on the basis of the findings. Two to four weeks later, the patients were re-evaluated with CGM. RESULTS: In the first part of the study, an average of 744+/-33 glucose measurements was recorded for each patient with CGM. The mean total time of hyperglycaemia (glucose level >7.7 mmol/l) undetected by the fingerstick method was 152+/-33 min/day. Nocturnal hypoglycaemic events (glucose level <2.7 mmol/l) were recorded in seven patients. Based on the additional information obtained by continuous monitoring, the insulin regimen was changed in all patients. CGM re-evaluation after treatment adjustment showed a reduction in undetected hyperglycaemia to 89+/-17 min/day and in nocturnal hypoglycaemic events, which were recorded in only one patient. CONCLUSIONS: Continuous glucose monitoring may diagnose high blood glucose levels and nocturnal hypoglycaemic events that are unrecognized by intermittent blood glucose monitoring and could serve as a useful tool for the long-term management of diabetic pregnancies. A large prospective study is needed to determine the clinical implications of this new monitoring technique.     

Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement

Many diabetic patients continue to have hyperglycaemia on maximal sulphonylurea therapy. Five different therapeutic options, with the prime aim of achieving normal fasting plasma glucose concentrations, have been compared in 15 asymptomatic, sulphonylurea-treated type 2 diabetic patients in a randomized crossover study of 8-week periods. In 24 h metabolic profiles the overnight mean (+/- 1SD) basal plasma glucose level on sulphonylurea therapy was 8.9 +/- 4.2 mmol/l. This was slightly improved with added metformin therapy (7.3 +/- 4.3 mmol/l, p = 0.013), but reduced to normal by added ultralente insulin (5.2 +/- 3.2 mmol/l, p less than 0.001), ultralente insulin alone (5.1 +/- 1.6 mmol/l, p = 0.005) or by ultralente and soluble insulin (4.7 +/- 1.4 mmol/l, p = 0.003). The mean glycosylated haemoglobin concentration was reduced significantly only by the treatments which included insulin. None of the patients had severe or incapacitating hypoglycaemia and only when on additional soluble insulin did patients show a significant gain in weight. Combining sulphonylurea therapy with ultralente insulin did not significantly improve overall glucose control over treatment with ultralente alone, although the insulin dose required to restore fasting normoglycaemia was significantly lower (median (interquartile range), 25 (12-41) versus 40 (27-80) U/day, p = 0.001). In type 2 diabetic patients who continue to have fasting hyperglycaemia on maximal sulphonylurea therapy, fasting normoglycaemia can be achieved easily, without minimal changes in diet or lifestyle, by means of a basal insulin supplement.     

Severe diabetic ketoacidosis: the need for large doses of insulin.

A 21-year-old female with Type 1 diabetes mellitus (DM) presented in ketoacidosis. She received intravenous normal saline and insulin at 6 U/h and 1.26% sodium bicarbonate solution. After the blood glucose had fallen to 9.5 mmol/l, the saline infusion was changed to 5% glucose solution and the insulin infusion rate to 2 to 3 U/h. The next day the patient became more drowsy (Glasgow coma scale 13/15, later falling to 4/15). Computed tomography (CT) scan suggested cerebral oedema and the patient was treated with dexamethasone and mannitol. She remained critically ill for 48 h, eventually making a full recovery. Insulin was given at rates of 8 to 14 U/h, with 10% or 20% glucose infusion to maintain the blood glucose above 5 mmol/l; despite this it was not until the fifth day that her serum bicarbonate became normal. Textbooks usually advise starting insulin at 6 U/h and reducing the infusion rate to 1-4 U/h when the blood glucose falls below a certain level. In this case, even with high rates of insulin infusion, it took 5 days before the patient's serum bicarbonate returned to normal. Thus, in severe diabetic ketoacidosis (DKA), protocols should advise that the insulin infusion be continued at high dose (4 to 6 U/h or more), with appropriate glucose infusion to prevent hypoglycaemia, until the serum bicarbonate is normal or nearly so.     

Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis.

AIM: To assess the utility of near patient blood ketone measurements in predicting diabetic ketoacidosis (DKA) among a group of hyperglycaemic unwell patients presenting to a hospital emergency department. METHODS: Near patient blood beta-hydroxybutyrate (beta-OHB) testing has recently been introduced as a new tool in our hospital Accident and Emergency department (A&E) for patients with a finger-prick glucose of > 11 mmol/l. We reviewed the records of the first 50 patients to have a beta-OHB measurement to establish if they developed DKA or received treatment with intravenous insulin within 48 h of presentation. We then compared the diagnostic power of beta-OHB measurements with other clinical, physiological and biochemical markers of DKA. RESULTS: Nine patients had DKA, eight had a compensated metabolic acidosis secondary to raised serum ketones, and 33 had no evidence of DKA during the following 48 h. The median (range) beta-OHB levels in each group were 6.0 (3.1-6.0) mmol/l, 3.4 (1.2-5.7) mmol/l, and 0.1 (0.0-1.2) mmol/l, respectively. A beta-OHB level of > or = 3.0 mmol/l had a sensitivity of 100% and specificity of 88% for DKA. All those with beta-OHB level > 3.0 mmol/l required treatment with intravenous insulin. CONCLUSION: Measuring beta-OHB when a hyperglycaemic patient is identified could offer a simple method of identifying at an early stage those patients at highest risk of DKA (beta-OHB > 3.0 mmol/l), and redirecting the search for a diagnosis in others (beta-OHB < 1.0 mmol/l).     

The control of blood glucose in the critical diabetic patient: a neuro-fuzzy method

Conventional algorithms for regulating insulin infusion rates in those critical diabetic patients submitted to parenteral glucose and insulin infusions do not allow to approach near normal blood glucose (BG) levels since traditional control systems are not fully effective in complex nonlinear systems as BG control is. Thus, we applied fuzzy logic principles and neural network techniques to modify intravenous insulin administration rates during glucose infusion. Forty critically ill, fasted diabetic subjects submitted to glucose and potassium infusion entered the study. They were randomly assigned to two treatment regimes: in group A, insulin infusion rates were adjusted, every 4 h at any step between -1.5 and +1.5 U/h, according to a neuro-fuzzy nomogram; in control group B, insulin infusion rates were modified according to a conventional algorithm. In group A, BG was lowered below 10 mmol/l faster than in group B (8.2+/-0.7 vs. 13+/-1.8 h, P<.02). Mean BG was 7.8+/-0.2 in group A and 10.6+/-0.3 mmol/l in group B (P<.00001). BG values below 4.4 mmol/l were: A=5.8% and B=10.2%. BG values lower than 2.5 mmol/l had never been observed. In conclusion, the neuro-fuzzy control system is effective in improving the BG control in critical diabetic patients without increasing either the number of BG determinations or the risk of hypoglycemia.     

A standardized protocol to achieve normoglycaemia during labour and delivery in women with type 1 diabetes

AIM: To evaluate a standardized protocol for maintaining near-normoglycaemia during labour and delivery in women with type 1 diabetes. METHODS: Over a nine-year period (1997-2005), 229 pregnancies in 174 women with type 1 diabetes were delivered at one centre. The same regimen was used for the induction of labour (group 1) and in women admitted in spontaneous labour (group 2): 10% dextrose (80ml/h) intravenous was given along with short-acting insulin, starting at 1IU/h intravenous via an infusion pump. Capillary blood glucose (CBG) was determined hourly, and the insulin infusion rate was modified accordingly. RESULTS: Labour was induced in 85 cases (37%) and spontaneous in 23 cases (10%), and an elective C-section was performed in 121 cases (53%). Maternal glycaemia during labour was 6.1+/-1.6 (range: 3.9-9.2)mmol/l in group 1, and 6.9+/-2.0 (range: 4.7-12.0)mmol/l in group 2. Maternal glycaemia at delivery was 5.8+/-1.5 (range: 3.4-9.4) and 6.3+/-1.9 (range: 4.1-11.4)mmol/l in groups 1 and 2, respectively. Women who underwent an elective C-section were not included in the standardized protocol and had higher glycaemia at delivery 7.1+/-2.0 (range: 2.7-13.5)mmol/l. Neonatal hypoglycaemia occurred in 30 infants (13%), and was only associated with preterm delivery. CONCLUSION: Using a standardized simple protocol during labour, maternal glycaemia was maintained within a near-normal range in 80-85% of cases.     

Hyperglycaemia stimulates pyloric motility in normal subjects.

The motor correlates of the delay in gastric emptying produced by hyperglycaemia were investigated in 11 healthy volunteers. Fasting gastroduodenal motility was measured during euglycaemia (blood glucose concentration 3-5 mmol/l) and during hyperglycaemia induced by intravenous dextrose (blood glucose concentration 12-16 mmol/l). Antral, pyloric, and proximal duodenal pressures were recorded by a sleeve/sidehole manometric assembly positioned across the pylorus, with the aid of measurements of transmucosal potential difference. During hyperglycaemia there was stimulation of isolated pyloric pressure waves when compared with the euglycaemia period (p less than 0.05). This was associated with inhibition of antral pressure waves (p less than 0.05). In nine of the 11 subjects an episode of duodenal 'phase III like' activity occurred within 15 minutes of the onset of hyperglycaemia. It is proposed that the stimulation of localised pyloric contractions and inhibition of antral contractions contribute to the delayed gastric emptying induced by hyperglycaemia. Abnormal gastric motility in patients with diabetes mellitus may be the result of hyperglycaemia itself, rather than irreversible autonomic neuropathy.     

Glucose control in mobile type 1 (insulin-dependent) diabetic patients by means of a semi-automatic feedback controlled insulin infusion system

Summary A portable insulin dosing device (Siemens) was used together with a programmable pocket calculator and a glucose analyzer for short-term adaptation of continuous intravenous insulin infusion to blood glucose alterations. A special algorithm was developed which utilizes a given blood glucose value and the glucose rate of change obtained from two to four consecutive samples as input variables. In contrast to current techniques of feedback-regulation, which require continuous glucose monitoring, intermittent blood sampling allows greater mobility of patients. With the semi-automatic feedback system, euglycaemic control was obtained for 12-h periods in ten Type 1 (insulin-dependent) diabetic patients (maximum value 9.50 mmol/l, minimum value 2.83 mmol/l). Severe hypoglycaemia occurred in no case and additional control by glucose infusion appeared to be unnecessary. Light exercise after termination of insulin dose for standard meals led to glycaemic excursions with a rapid decrease (mean 1.08±0.09 mmol/l), followed by a rebound (0.59±0.07 mmol/l) in each patient. The amplitude of these excursions decreased with increasing distance from the peak of the meal dose. Comparison of feedback-control alone with feedback by glucose plus preprogrammed dose (4 U/h) at the onset of the test meal revealed lower post-prandial glucose levels (post-prandial maximum±SEM: 6.49±0.18 versus 7.71±0.79 mmol/l) and a lower infusion rate of insulin for the combined regimen (mean postprandial maximum±SEM: 8.4±1.2 versus 12.0±0 IU/h). The system is useful for programming of portable infusion devices and studies based on euglycaemic control in unrestrained patients.     

Intensive monitoring for post-transplant diabetes mellitus and treatment with dipeptidyl peptidase-4 inhibitor therapy

AimCurrent monitoring practices fail to diagnose patients with post-transplant hyperglycaemia and tend to delay initiation of treatment, which potentially results in adverse graft and morbidity outcomes. This real-world study set out to assess the impact on insulin resistance indices of a new clinical pathway for diagnosis and treatment of hyperglycaemia following renal transplantation.MethodsA hundred and forty-seven adult renal transplant recipients, without pre-existing diabetes, from a single centre were included. Patients transplanted between January 2008 to September 2015 formed the historical cohort. Patients transplanted between October 2015 and February 2018 were subject to a new clinical pathway - if they had fasting blood sugar levels more than 7 mmol/L or random blood glucose levels more than 11.1 mmol/L, they had early introduction of oral therapy, using the DPP-4 inhibitor linagliptin.ResultsIn the historical cohort, 19.8% were diagnosed with PTDM, compared to 46.3% in the protocol cohort. Amongst patients with PTDM, there was a significant difference in HOMA-IR (p = 0.02) between the historical cohort (median HOMA-IR 3.33) and the protocol cohort (median HOMA-IR 2.21). There was a significant difference at each time point (0,1,2-h measurements) of blood glucose levels form oral glucose tolerance testing between patients with and without PTDM in the historical cohort (p < 0.001), but no difference between patients in the protocol cohort.ConclusionDetection of PTDM was higher with the new clinical pathway. Early treatment of hyperglycaemia resulted in better insulin resistance scores. Larger prospective controlled studies focussing on early detection and management of PTDM with linagliptin are warranted.     

The effect of glucose and insulin infusion on the fall of ketone bodies during treatment of diabetic ketoacidosis

During the treatment of diabetic ketoacidosis intravenous glucose is infused when blood glucose has fallen to around 14 mmol l-1. The use of hypertonic (10%) glucose has been recommended in order to hasten the clearance of blood ketone bodies. In a randomized controlled study 17 patients presenting with severe diabetic ketoacidosis were allocated to one of two regimens of intravenous glucose and insulin when blood glucose had fallen to less than 14 mmol l-1. Nine patients were given 5% glucose containing 10 U l-1 insulin and 8 patients received 10% glucose with 40 U l-1 insulin. Fluid was infused at a rate of 250 ml h-1 for 6 h. At the start of the infusions blood glucose had fallen from levels at presentation to 12.8 +/- 1.1 mmol l-1 (mean +/- SE) in the group which subsequently received the low infusion rate and to 13.7 +/- 0.9 mmol l-1 in the subsequent high infusion rate group. With glucose/insulin infusion blood glucose after 6 h was 11.5 +/- 0.9 mmol l-1 (low infusion rate group) and 15.7 +/- 1.3 mmol l-1 (high infusion rate group). This difference between groups at 6 h was significant (p less than 0.05). Over the 6 h of infusion the fall in blood total ketone bodies was significantly greater in the group receiving the higher rate of glucose/insulin infusion (7.34 +/- 0.57 vs 5.18 +/- 0.57 mmol l-1; p less than 0.05). Despite the greater fall in total ketone bodies in this group there was no difference in the improvement in capillary blood pH or bicarbonate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Validation of a glucose-insulin-potassium infusion algorithm in hospitalized diabetic patients

OBJECTIVES: Validation of a novel glucose-insulin-potassium (GIK) infusion algorithm to optimize metabolic control in hospitalized diabetic patients. SUBJECTS: We randomized 33 diabetic patients admitted to Sahlgrenska University Hospital with acute internal medicine diseases to either GIK infusion or multiple injection therapy (MIT). The GIK infusion rate and the MIT were controlled according to special algorithms. The treatment efficacy was evaluated through comparisons of capillary blood glucose eight times on day 2 of the study. RESULTS: The GIK infusion led to significantly lower mean blood glucose when compared with MIT [10.1 (9.0-11.2) vs. 12.3 (9.3-14.4) mmol L(-1), median and interquartile range, P < 0.01]. Four episodes of hypoglycaemia without loss of consciousness were recorded in the GIK group whereas no hypoglycaemic event occurred in the MIT group. A mean of 1 (1-3) episodes of blood glucose levels above 12.0 mmol L(-1) were recorded in the GIK group compared with 3.5 (1.5-5.0) in the MIT group, P < 0.01. CONCLUSIONS: The algorithm used for the GIK infusion gave an acceptable level of metabolic control and this insulin infusion protocol is safe enough to be used by the nursing staff on a general internal medicine ward.     

Continuous subcutaneous insulin infusion versus injection therapy: a randomized cross-over trial under usual diabetic clinic conditions

Twelve C-peptide negative insulin-dependent diabetic patients participated in a randomized cross-over study of 6 months treatment with twice or thrice daily insulin injection therapy and continuous subcutaneous insulin infusion (CSII). Standard, non-intensified management conditions were maintained throughout. Glycosylated haemoglobin levels were similar on both regimens (9.2 +/- 0.5% versus 9.0 +/- 0.4%; CSII vs injection therapy; (mean +/- SEM). Capillary blood glucose concentrations before breakfast (5.2 +/- 0.4 mmol/l vs 9.1 +/- 0.8 mmol/l), after lunch (6.5 mmol/l +/- 0.8 vs 7.9 +/- 1.0 mmol/l) and before the evening meal (5.0 +/- 0.7 mmol/l vs 7.7 +/- 0.7 mmol/l) were lower on CSII, as were 24-hour urine glucose excretion and total insulin dose (39.3 +/- 2.2 vs 49.8 +/- 4.0 U/day). There was a significant positive correlation between fasting blood glucose values and glycosylated haemoglobin on injection but not pump treatment. Thus although blood glucose control at some individual daytime points appeared lower on CSII, overall diabetic control was similar on the two regimens.     

A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of morning hyperglycaemia: determinants of fasting blood glucose concentrations in insulin-treated diabetics

A rise in blood glucose concentration at the end of the night, and consequent morning hyperglycaemia, are well recognized events in some diabetic patients. In 94 patients on twice daily insulin injections we have examined the prevalence and extent of morning hyperglycaemia, and its relation to control, insulin therapy, and insulin antibody levels. Blood glucose reached the highest level of the day before or after breakfast in 83% of patients, and in 50% this value was 2 mmol/l greater than any other time of day. Patients with higher fasting concentrations did not have worse blood glucose control over the rest of the day. No correlation was found between fasting blood glucose concentrations and the evening dose of intermediate acting insulin or the level of insulin antibodies. No consistent change in fasting blood glucose concentrations occurred with changes in antibody levels in patients switched between pork and beef insulin. Morning hyperglycaemia was as common with both insulin species. Pre- and post-breakfast hyperglycaemia is common and significant in insulin-treated diabetic patients. It is not directly related to diabetic control at other times of the day, and is independent of insulin species and insulin antibody levels.     

Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats

Summary Glucose-induced insulin secretion is impaired in the presence of chronic hyperglycaemia. Insulin secretion was studied in a diabetic rat model prior to the beta cells becoming non-responsive to glucose in order to map out the sequence of changes that accompany chronic hyperglycaemia. In vitro pancreas perfusions were carried out 1 and 2 weeks after a 90% pancreatectomy; controls underwent a sham pancreatectomy. One week post 90% pancreatectomy: (i) non-fasting plasma glucose values were 2–3 mmol/l above normal, (ii) the in vitro insulin response to 16.7 mmol/l glucose was 20 ± 4% of shams, a response that was appropriate for the surgical reduction in beta-cell mass, (iii) the beta-cell sensitivity for glucose was increased as reflected by left-shifted dose-response curves for glucose-induced insulin secretion (half maximal insulin output 5.7 mmol/l glucose vs 16.5 mmol/l glucose in shams) and glucose potentiation of arginine-induced insulin secretion (half maximal insulin output 3.5 mmol/l glucose vs 14.8 mmol/l glucose in shams). This heightened beta-cell sensitivity for glucose was not a result of the hyperglycaemia, because similarly reduced half-maximal insulin responses were found after a 60% pancreatectomy, a surgical procedure in which plasma glucose values remained normal. In summary, a rise in beta-cell sensitivity for glucose precedes the loss of glucose-induced insulin secretion in diabetic rats.     

Effect of acute hyperglycaemia on gall bladder contraction induced by cholecystokinin in humans.

This study examined the effect of acute hyperglycaemia, induced by intravenous glucose, on gall bladder motility. Six healthy volunteers were studied in random order on three occasions during normoglycaemia and hyperglycaemia with blood glucose concentrations stabilised at 8 and 15 mmol/l. Gall bladder volumes, measured with ultrasonography, were studied before and during infusion of stepwise increasing doses of cholecystokinin (CCK-33; 0.25, 0.5, and 1.0 IDU.kg-1.h-1). Each dose was given for 30 minutes. Pancreatic polypeptide (PP) secretion was determined as an indirect measure of cholinergic tone. Infusion of CCK-33 resulted in significant dose dependent reductions in gall bladder volume in all three experiments. Compared with normoglycaemia the gall bladder contraction was significantly (p < 0.05) reduced during infusion of 0.25 and 0.5 IDU kg-1.h-1 CCK-33 in the 8 mmol/l hyperglycaemic experiment, and during infusion of 0.25, 0.5, and 1.0 IDU kg-1.h-1 CCK-33 in the 15 mmol hyperglycaemic experiment. During hyperglycaemia basal plasma PP concentrations and PP secretion in response to CCK-33 were significantly (p < 0.05) reduced. It is concluded that blood glucose concentrations affect gall bladder motility, that an acute hyperglycaemia at 8 and 15 mmol/l reduces the gall bladder responsiveness to CCK-33 in a dose dependent manner, and that hyperglycaemia reduces basal and CCK-33 stimulated plasma PP concentrations, suggesting impaired cholinergic activity during hyperglycaemia.     

Risk for severe hypoglycaemia with unawareness in GH-deficient patients during the insulin tolerance test

OBJECTIVE: The insulin tolerance test (ITT) has been suggested as the gold standard for diagnosing GH deficiency (GHD). The ITT is, however, potentially hazardous. Glucose monitoring during the ITT varies between centres and there is surprisingly little information on the actual level of blood glucose nadir and the duration of hypoglycaemia in patients undergoing the ITT. The aim of the present study was to closely monitor the blood glucose level and to register the presence of symptoms and signs of hypoglycaemia during the ITT. DESIGN AND PATIENTS: Sixteen patients (seven women), aged 22-59 years were consecutively recruited for an ITT, and showed GHD (peak GH < 3 microg/l). RESULTS: In five (31%) of the patients unawareness of hypoglycaemia was recorded, the median nadir blood glucose level was 1.4 mmol/l (range 1.1-1.9) and the duration of blood glucose < 2.2 mmol/l was 25 min (range 20-33). The remaining 11 patients were symptomatic, and tiredness (n=6) and dizziness (n=3) were the most frequent symptoms. In these symptomatic patients the median nadir blood glucose level was 1.3 mmol/l (range 1.0-1.6) and the duration of blood glucose < 2.2 mmol/l was 25 min (range 15-30). CONCLUSIONS: In patients with GHD subjected to the ITT, symptoms of hypoglycaemia were scarce and a third showed unawareness. Close blood glucose monitoring is recommended at the ITT as low nadir blood glucose levels and long duration of hypoglycaemia may be present irrespective of symptoms of hypoglycaemia. Recommendations for intervention with intravenous glucose, at unacceptable low blood glucose levels or at prolonged hypoglycaemia, are warranted.     

The effects of insulin and short-term hyperglycaemia on myocardial blood flow in young men with uncomplicated Type I diabetes

AIMS/HYPOTHESIS: Insulin enhances coronary vasodilation in healthy subjects. We tested whether insulin is able to induce coronary vasodilation in Type I (insulin-dependent) diabetic mellitus patients. Additionally, the effect of short-term hyperglycaemia on myocardial perfusion was studied. METHODS: Myocardial blood flow was quantitated basally and during adenosine infusion (140 microg/kg per min i.v.) with or without simultaneous insulin infusion (1 mU/kg per min for 60 min) in nine non-smoking Type I diabetic males (HbA(1c) 7.4+/-1.0%) without diabetic complications and 10 healthy non-diabetic otherwise matched males using positron emission tomography and (15)O-water. Diabetic patients were studied on two occasions, once during normoglycaemia (plasma glucose ~6 mmol/l) and once during hyperglycaemia (approximately 10 mmol/l) induced by reducing the dose of insulin for two days. RESULTS: Resting myocardial blood flow was similar in the studied groups (NS). Hyperaemic adenosine stimulated flow was 23% lower in diabetic than in non-diabetic subjects (3.09+/-0.72 vs 4.0+/-1.13 ml x g(-1) x min(-1), p<0.05). Insulin increased significantly adenosine stimulated flow by 23% in diabetic and 17% in non-diabetic subjects (NS between the groups). Hyperglycaemia for two days had no effect on flow values when compared to the values during normoglycaemia (NS). CONCLUSION/INTERPRETATION: Insulin has similar vasodilative effects on coronary arteries in diabetic and non-diabetic subjects. Short-term hyperglycaemia does not alter myocardial blood flow or abolish insulin induced vasodilation in these patients. Insulin induced coronary vasodilation might contribute to the known beneficial effect of intensive insulin therapy on myocardial ischaemia in diabetic patients.     

No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man

Summary In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose · kg ideal body weight^–1· min^–1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p<0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p<0.005) and C-peptide (p<0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/ml). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for glucose toxicity to the Beta-cells.