Measurement of gastric emptying by radiopaque markers in patients with diabetes: correlation with scintigraphy and upper gastrointestinal symptoms.

BACKGROUND: Scintigraphy, the gold standard to measure gastric emptying, is expensive and not widely available. Therefore, we compared emptying of radiopaque markers (ROM) from the stomach, by use of fluoroscopy, with scintigraphy in patients with insulin-treated diabetes. METHODS: On the same day we measured gastric emptying of 20 ROM using fluoroscopy and scintigraphic emptying of a standard solid meal. The subjects also completed a validated gastrointestinal (GI) symptom questionnaire. KEY RESULTS: We included 115 patients with insulin-treated diabetes (median age 53, range 21-69 years; 59 women). A moderately strong correlation was demonstrated between scintigraphic (% retained at 2 h) and ROM emptying (markers retained at 6 h) (r = 0.47; P < 0.0001). Eighty-three patients had delayed gastric emptying with scintigraphy, whereas only 29 patients had delayed emptying of ROM. Of the 29 patients with delayed emptying of ROM, 28 also had delayed scintigraphic emptying. The sensitivity and specificity of the ROM test was 34% and 97%, respectively. Significant correlations were only noted between scintigraphic gastric emptying and GI symptom severity, with the strongest correlations for fullness/early satiety (r = 0.34; P < 0.001) and nausea/vomiting (r = 0.30; P < 0.001). CONCLUSIONS & INFERENCES: A gastric emptying test with ROM is a widely available screening method to detect delayed gastric emptying in patients with diabetes, where a positive result seems reliable. However, a normal ROM test does not exclude delayed gastric emptying, and if the clinical suspicion of gastroparesis remains, scintigraphy should be performed. Results from scintigraphy also correlate with GI symptom severity, which ROM test did not.

Short-term effects of metformin in type 2 diabetes.

BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined the early effects on glucose and lipid metabolism and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in the first week, 500 mg twice daily during week 2 and 1000 mg twice daily during weeks 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared to baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total cholesterol and low-density lipoprotein cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes, metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.

Short-term effects of metformin in type 2 diabetes.

BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined early effects on glucose and lipid metabolism, and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in week 1, 500 mg twice daily in week 2 and 1000 mg twice daily in week 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared with baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total and LDL-cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.

Pathogenesis and treatment of diabetic vascular disease - illustrated by two cases.

This publication is a summary of the presentations given at the First JIM Grand Round held at the Sahlgrenska University Hospital on 15 March 2006. The Grand Round was based on two case reports; a patient with type 2 diabetes and pronounced macrovascular disease and another patient with early microvascular disease combined with the macrovascular complications. The pathogenesis of the vascular complications and the current treatment regimens were discussed in relation to the history and examinations performed in these patients.

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.

Insulin resistance and intima-media thickness in the carotid and femoral arteries of clinically healthy 58-year-old men. The Atherosclerosis and Insulin Resistance Study (AIR).

OBJECTIVE: To examine whether insulin resistance was associated with ultrasound-assessed measures of atherosclerosis in men with varying degrees of obesity. DESIGN: A random selection of subjects from the general population were divided into quintiles of a body mass index/blood glucose score that was shown to be a valid and reproducible index of the degree of insulin sensitivity as assessed by the clamp technique. Every fourth man in quintiles 1 and 5 and every 20th man in quintiles 2-4 (in total, 104 men) were selected for an ultrasound examination of the carotid and femoral arteries and a euglycaemic hyperinsulinaemic clamp examination, adjusted for fat-free mass. SETTING: A university hospital. SUBJECTS: A total of 104 clinically healthy 58-year-old men of Swedish ancestry. RESULTS: The mean common carotid artery intima-media thickness (IMT), but not the common femoral IMT, correlated significantly with glucose infusion rate (GIR) (r = - 0.20, P < 0.05), systolic blood pressure (r = 0.20, P < 0.05), pulse pressure (r = 0.23 P < 0.01), heart rate (r = 0.20, P < 0.05), HDL cholesterol (r = - 0.18, P < 0.05), log triglycerides (r = 0.28, P < 0.01), apoA1 (r = - 0.20, P < 0.05), apoB (r = 0.21, P < 0.05), LDL particle size (r = - 0.22, P < 0.05) and plasma insulin (r = 0.20, P < 0.05). In a multiple regression, common carotid IMT was independently associated with log triglycerides (beta = 0.25, P = 0.012) and pulse pressure (beta = 0.21, P = 0.031) (R2 = 8.7%, P = 0.005) CONCLUSIONS: Insulin sensitivity, measured with the gold standard euglycaemic hyperinsulinaemic clamp method, showed similar associations with ultrasound-assessed measures of atherosclerosis in the carotid arteries as established cardiovascular risk factors, but only triglycerides and pulse pressure contributed independently to the variability in the common carotid intima-media thickness.

Psychometric properties of the Swedish version of the Well-Being Questionnaire in a sample of patients with diabetes type 1.

OBJECTIVES: The aim of the present investigation was to further test the psychometric properties of a Swedish version of the Well-Being Questionnaire (WBQ) in order to determine whether it could be suitable for measuring health-related quality of life among type 1 diabetic patients. METHODS: In total, 94 patients who fulfilled the inclusion criteria were selected for the study and of these 85% participated. Reliability was tested with Cronbach's alpha coefficient and the internal validity by means of principal component analysis and multitrait analysis. To test the external validity, comparisons were made with two other questionnaires, the Short form-36 and a Swedish Mood Adjective Check List. RESULTS: The results show that, above all, the Swedish version of the WBQ measures psychological well-being, and thus must also be complemented with scales that measure other consequences of the illness and/or treatment, i.e. physical symptoms. The questionnaire has low discriminatory validity between subscales, which casts doubt on the appropriateness of using the four subscales as separate measures. The two scales measuring anxiety and depression are not sensitive enough for use among type 1 diabetics without complications and high or normal levels of psychological well-being. CONCLUSIONS: The Well-Being Questionnaire alone does not give any more information about subjective health status among type 1 diabetic patients than, for example, the generic SF-36.

The euglycemic hyperinsulinemic clamp examination: variability and reproducibility.

The aim was to examine the reproducibility of the euglycemic hyperinsulinemic clamp method. From a random population sample of 60-year-old clinically healthy men, 32 subjects with varying degrees of insulin sensitivity were recruited. Conventional 2-h clamp examinations were carried out at an interval of 2 weeks. Insulin was infused intravenously (priming for 10 min and thereafter 1.0 mU/kg body wt/min). Glucose was infused concomitantly aiming at a whole blood glucose of 5 mmol/L. The glucose infusion rate (GIR) was adjusted for body weight or fat free mass (FFM), the latter measured with dual-energy X-ray absorptiometry. During the final hour of each examination (60-120 min) the mean whole blood glucose concentrations were 5.06+/-0.15 and 5.09+/-0.17 mmol/L, respectively. Of the different time intervals studied, the glucose infusion rate during the final hour (GIR60-120) showed the highest correlation and lowest coefficient of variation (GIR60-120 adjusted by FFM: r=0.70, coefficient of variation=14.7%). Adjustment of GIR for weight instead of FFM underestimated insulin sensitivity in obese men. GIR60-120 adjusted for FFM tended to increase during the second examination. The measurement error was constant across all GIR. In summary, the euglycemic hyperinsulinemic clamp method has a coefficient of variation around 15%. The glucose infusion rate should be adjusted for fat free mass.

Smoking cessation improves insulin sensitivity in healthy middle-aged men.

Cigarette smokers have recently been shown to exhibit insulin resistance, dyslipidaemia and markers of the insulin resistance syndrome (IRS). The aim of this study was to examine the effects of smoking cessation on insulin sensitivity and IRS. Forty male, non-obese healthy smokers participated in this open parallel study with 8 weeks of follow-up. Seventeen subjects were able to stop smoking, while 23 subjects continued to smoke and served as a controls group. Anthropometric and metabolic data were measured. Degree of insulin sensitivity was determined with the euglycaemic hyperinsulinaemic clamp technique. Smoking cessation increased insulin sensitivity and improved the lipoprotein profile in spite of a modest increase in body weight. Initial smoking habits correlated positively with the increase in BMI as well as the improvements in the metabolic variables after smoking cessation. These data support the view that smoking causes insulin resistance and IRS, and also demonstrate that the beneficial metabolic effects of smoking cessation override the effects of an accompanying modest increase in body weight.

The effect of metoprolol treatment on insulin sensitivity and diurnal plasma hormone levels in hypertensive subjects.

To evaluate the effect of metoprolol on insulin sensitivity and diurnal plasma hormone levels, seven mildly hypertensive subjects were investigated (four men and three women, age 52 +/- 8, body mass index 25.4 +.- 1.9, mean +/- SD). The study had a placebo-controlled, double-blind, crossover design with 6 weeks' metoprolol treatment (100 mg b.i.d) vs. placebo. At the end of each treatment period 24-h blood samples were collected continuously for diurnal analysis of hormone levels and a hyperinsulinaemic euglycaemic clamp combined with [3-3H]-D-glucose infusion was performed. Insulin sensitivity was evaluated by means of three different methods: diurnal plasma insulin and glucose levels; glucose consumption; and insulin sensitivity index during euglycaemic clamp conditions. Fasting blood glucose and insulin concentrations as well as mean plasma diurnal levels of insulin, growth hormone, testosterone and cortisol were similar after placebo and metoprolol treatment, whereas noradrenaline and adrenaline levels were significantly increased after metoprolol. During the clamp, plasma insulin was significantly higher after metoprolol treatment than after placebo treatment (56 +/- 3 vs. 64 +/- 2 mU L(-1), P < 0.05). Consequently, the insulin sensitivity index [glucose infusion rate (GIR)/ plasma insulin] was lower after metoprolol treatment (16.1 +/- 2.6 vs. 10.2 +/- 1.2, P < 0.05), although GIR was not significantly changed. We suggest that the insulin sensitivity index may not accurately reflect the insulin effect as the plasma level of insulin was significantly increased during insulin infusion but not at 24 h, possibly because of alteration of distribution and/or degradation rate of exogenous insulin. Thus, the likelihood of metoprolol inducing insulin resistance in hypertensive subjects may be less than previously proposed.

Peripheral afferent stimulation of decentralized sympathetic neurons activates lipolysis in spinal cord-injured subjects.

Spinal cord-injured (SCI) subjects exhibit a normal lipolytic rate despite the failure of centrally mediated sympathoexcitatory stimuli to activate lipolysis. Peripheral afferent stimulation below the lesion level induces an exaggerated autonomic reaction in SCI with lesion levels above T5, ie, so-called autonomic dysreflexia. The metabolic effects of induced dysreflexia were investigated in five SCI subjects (age, 35 +/- 8 years; duration of paresis, 15 +/- 7.5 years [mean +/- SD]; lesion level, T3 to T4, n = 2, C7, n = 3) following bladder stimulation. Subcutaneous glycerol concentrations were measured by microdialysis above and below the lesion level. Diurnal plasma noradrenaline (NA) and adrenaline levels were continuously monitored in seven SCI subjects (lesion level T3 to T4, n = 2; C4 to C7, n = 5). Bladder stimulation resulted in an increased mean arterial pressure ([MAP] 81 +/- 8 to 114 +/- 11 mm Hg, P < .05), a decreased heart rate (70 +/- 3 to 54 +/- 4 beats/min, P < .05), and an increased plasma NA (0.70 +/- 0.49 v 3.27 +/- 1.56 nmol/L, P < .05). Interstitial glycerol was increased in the decentralized region (89 +/- 12 to 135 +/- 21 mumol/L, P < .05), whereas no reaction was found in the centrally innervated region. Plasma concentrations of glycerol and insulin increased. Diurnal monitoring showed periods of increased plasma NA sufficient to induce lipolysis (> 1.4 nmol/L) during 20% of the registration period. The data suggest that peripheral afferent stimulation below the lesion level increases NA release and activates lipolysis and that frequent episodes of activation are found in SCI subjects with tetraplegia or high paraplegia.

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension.

BACKGROUND: Insulin resistance and hyperinsulinaemia has been suggested as a pathogenetic mechanism in hypertension. METHODS: In this investigation the renal response to insulin was studied in normotensive subjects with a positive family history of hypertension in two generations (n = 14), in one weight-matched (n = 11) and one lean (n = 13) control group. During hyperinsulinaemia (euglycaemic hyperinsulinaemic clamp technique) we determined renal haemodynamics (clearances of 51Cr-EDTA and PAH) and urinary sodium excretion. Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. RESULTS: In subjects with a positive family history of hypertension, hyperinsulinaemia did not influence renal plasma flow (RPF) or glomerular filtration rate (GFR) but urinary sodium excretion decreased by 50%. Estimated proximal tubular sodium reabsorption was unaffected by insulin while estimated distal fractional sodium reabsorption increased, P < 0.01. At the end of the clamp a low-dose infusion of angiotensin II (0.1 ng/kg per min) was superimposed. GFR and RPF then decreased significantly concomitant with urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFR in both groups, increased RPF in the lean control group and 15-25% reduction in sodium excretion. No alteration was seen in estimated proximal tubular sodium reabsorption, but estimated distal tubular sodium reabsorption increased (P < 0.05) in the lean control group. Angiotensin II elicited a further increase in distal fractional tubular sodium reabsorption in both groups (P < 0.05). CONCLUSION: In normotensive subjects with a positive family history of hypertension, in contrast to control subjects without such history, hyperinsulinaemia caused a marked decrease in urinary sodium excretion in presence of unchanged RPF and GFR indicating a renal tubular effect of insulin located at distal site of the renal tubules. Angiotensin II caused further sodium retention, probably due to an effect on renal haemodynamics.