Insulin-glucose Clamp Research Articles

Gender Difference in Type 1 Diabetes: An Underevaluated Dimension of the Disease

Gender difference in all fields of medicine and biology has recently become a topic of great interest. At present, most studies report gender differences in their secondary analysis; however, this information receives scant attention from clinicians, and is often overwhelmed by press trumpeting the overall main positive results. Furthermore, and more importantly, any statistical evaluation of results obtained without specific and careful planning in the study for the topic of research is probably worthless. There are few studies in animals, but these are not typically useful because of the different biology, pharmacodynamics and pharmacokinetics compared to humans. Type 1 diabetes is a disease where gender difference can be easily evaluated. Irrespective of the cause of the loss of pancreatic beta-cell function, the common denominators of all forms of type 1 diabetes are the absence of circulating insulin and a reduction in peripheral insulin sensitivity leading to exogenous injections being required. Consequently, exogenous insulin infusion, with any of the widely used research tools, such as the insulin–glucose clamp, can be easily used to evaluate gender difference. Female patients with type 1 diabetes have many factors that impact glucose level. For example, the hormones that drive the ovulatory/menstrual cycle and the connected change at the time of the menopause have a role on insulin action; thus, one should expect great research emphasis on this. On the contrary, there is a dearth of data available on this topic, and no pump producer has created a gender-specific insulin infusion profile. Patients are usually approached on the basis of their diagnosis. This review is intended to focus on personalized treatment, more specifically on gender, according to the modern way of thinking.

Acceleration of Gastric Emptying by Insulin-Induced Hypoglycemia is Dependent on the Degree of Hypoglycemia.

Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized "non-severe" hypoglycemia into level 1 (<3.9 mmol/L) and 2 (<3 mmol/L) hypoglycemia. Gastric emptying of carbohydrate is a major determinant of postprandial glycemia but its role in hypoglycemia counter-regulation remains underappreciated. "Marked" hypoglycemia (~2.6 mmol/L) accelerates gastric emptying and increases carbohydrate absorption in health and type 1 diabetes, but the impact of "mild" hypoglycemia (3.0-3.9 mmol/L) is unknown. To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L ("marked") and 3.6 mmol/L ("mild"), on gastric emptying in health. Fourteen healthy male participants (mean age: 32.9 ± 8.3 years; body mass index: 24.5 ± 3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus.

Aberrant regulation of glucose production makes a critical contribution to the impaired glycemic control that is observed in type 2 diabetes. Although isotopic tracer methods have proven to be informative in quantifying the magnitude of such alterations, it is presumed that one must rely on venous access to administer glucose tracers which therein presents obstacles for the routine application of tracer methods in rodent models. Since intraperitoneal injections are readily used to deliver glucose challenges and/or dose potential therapeutics, we hypothesized that this route could also be used to administer a glucose tracer. The ability to then reliably estimate glucose flux would require attention toward setting a schedule for collecting samples and choosing a distribution volume. For example, glucose production can be calculated by multiplying the fractional turnover rate by the pool size. We have taken a step-wise approach to examine the potential of using an intraperitoneal tracer administration in rat and mouse models. First, we compared the kinetics of [U-13C]glucose following either an intravenous or an intraperitoneal injection. Second, we tested whether the intraperitoneal method could detect a pharmacological manipulation of glucose production. Finally, we contrasted a potential application of the intraperitoneal method against the glucose-insulin clamp. We conclude that it is possible to 1) quantify glucose production using an intraperitoneal injection of tracer and 2) derive a "glucose production index" by coupling estimates of basal glucose production with measurements of fasting insulin concentration; this yields a proxy for clamp-derived assessments of insulin sensitivity of endogenous production.

Diabetic Kidney Disease: A Call to Action: Preface.

As guest editor for this Diabetes Spectrum From Research to Practice section, I am pleased to introduce a tour de force on the theme topic of diabetic kidney disease (DKD). My journey in diabetes began as an observer. In youth, during the early 1970s, I watched my tennis partner, Cindy, struggle with the complexities of her blood glucose control, while still striving to play competitively. Her episodes of hypoglycemia were scary, and urine glucose testing just did not cut it. The era of self-monitoring of blood glucose was still years away, but eventually we got there. Fast forward to medical school days in the late 1970s. I remember what a breakthrough it was to have “chemsticks” to check blood glucose at the bedside of hospitalized patients. Diabetes educators appeared on the wards and taught the patients (and us) just how to do it. A new age in diabetes care had surely arrived. Throughout medical school, and then a residency in internal medicine, I was captivated by the physiology of metabolic disorders and the application of science to medicine. During this formative time, Dr. Mark E. Molitch was one of my inspirational mentors. I admired his commitment to advancing care for people with diabetes that has endured over the many years that followed our time together in the early 1980s. With his great wisdom and perception, he has penned a compelling editorial for the current issue titled, “Diabetic Kidney Disease: Much Progress, but Still More to Do” (p. 154). After residency, my next stop was fellowship training in endocrinology and metabolism. I was thrust into a world of insulin-glucose clamp studies with concurrent physiological assessments related to glucose counterregulation. And, we did these studies in real people with diabetes. I was amazed that they actually volunteered for such intensive, time-consuming, and …

Indices of Insulin Suppression of Non-Esterified Fatty Acids Measured During an Oral Glucose Challenge and Their Association with the Insulin-Glucose Clamp Index and Central Adiposity

To determine the indices of insulin-induced NEFA suppressibility derived from the oral glucose tolerance test (OGTT) that are best associated with the standard measure derived from the insulin-glucose clamp and with central adiposity. Sixteen men and 10 women, aged 20 to 35 years, without any disease or family history of type 2 diabetes, underwent a 75 g OGTT and a 2-step euglycemic clamp with low- and high-dose insulin infusions (10 and 40 mU/kg/min). OGTT indices of NEFA suppressibility were: area under the curve (AUC) of NEFA, AUCNEFA×AUCinsulin, NEFA T50, insulin concentration at T50 (EC50) and negative slope of the log-linear portion of NEFA suppression curve corrected by AUCinsulin (NegSlopeLnNEFA/AUCIns). NEFA insulin suppression during the clamp was calculated by ΔNEFA/Δinsulin at low-dose insulin (from baseline=positive results). Central adiposity was estimated mainly by the waist-to-hip ratio (WHR) and glucose insulin sensitivity, by the M/I value (clamp, high-dose insulin). OGTT-derived indices of insulin-induced NEFA suppression significantly associated with clamp ΔNEFA/Δinsulin: AUCNEFA×AUCinsulin (r=0.54), EC50 (r=0.50), NegSlopeLnNEFA/AUCIns (r=–0.44) and %reductionNEFA/AUCinsulin (r=–0.42). The only index significantly associated with WHR: AUCNEFA×AUCinsulin (r=0.55). Based on a step-wise regression analysis, the variables significantly and independently associated with WHR were: AUCNEFA×AUCinsulin (p=0.002) and AUCglucose (p=0.01) (model R2=0.49). AUCNEFA×AUCinsulin may represent the best OGTT-derived parameter to estimate sensitivity to insulin suppression of lipolysis because, in our sample, it was the only one significantly correlated with central adiposity. Moreover, among all metabolic parameters measured in our study, AUCNEFA×AUCinsulin and AUCglucose were the two main factors independently associated with central adiposity.

Combined hypertriglyceridemic and insulin-glucose clamps for the characterization of substrate oxidation and plasma elimination of a long-chain triglyceride emulsion in healthy men

This study examines the effect of glucose and insulin on the plasma elimination rate and oxidation of a fat emulsion by using indirect calorimetry in conjunction with lipid and insulin-glucose clamp techniques. Ten healthy subjects were studied on 2 occasions in a randomized, open, crossover study. On one occasion, a hypertriglyceridemic (HTG) clamp was administrated alone; and, on the other, HTG and insulin-glucose (IG) clamps were administrated simultaneously. During HTG clamps, serum triglyceride (TG) concentration was maintained at 4 mmol × L −1. During the IG clamp, insulin was administered at a rate of 20 mU × m −2 × min −1; and the glucose level was maintained at 7 mmol × L −1. Continuous indirect calorimetry was carried out throughout the study period. The infusion rate required to maintain stable serum TG concentrations did not differ between the 2 clamps. Mean free fatty acid concentration was lower during the HTG/IG than during the HTG clamp (0.40 ± 0.04 vs 0.82 ± 0.07 mmol × L −1; P < .001). However, the increases in β-OH-butyrate levels were significantly lower in the HTG/IG compared with the HTG clamp (0.09 ± 0.04 vs 0.55 ± 0.09 mmol × L −1; P < .001). Energy expenditure and the respiratory quotient were significantly higher at steady state in the HTG/IG than in the HTG clamp: 1.47 ± 0.06 vs 1.34 ± 0.04 kcal × min −1 ( P < .01) and 0.85 ± 0.01 vs 0.79 ± 0.01 ( P < .01), respectively. Insulin and glucose did not significantly change plasma TG disposal rate ( P = .0987) or total lipid oxidation ( P = .3204) in this metabolic situation with an abundant supply of both carbohydrates and lipids. β-OH-butyrate increased during both clamps, indicating an ongoing hepatic fatty oxidation despite the administration of glucose/insulin.

Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt

High-dose aspirin treatment improves fasting and postprandial hyperglycaemia in patients with type 2 diabetes, as well as in animal models of insulin resistance associated with obesity and sepsis. In this study, we investigated the effects of aspirin treatment on inducible nitric oxide synthase (iNOS)-mediated insulin resistance and on S-nitrosylation of insulin receptor (IR)-beta, IRS-1 and protein kinase B (Akt) in the muscle of diet-induced obese rats and also in iNos (also known as Nos2)-/- mice on high fat diet. Aspirin (120 mg kg-1 day-1 for 2 days) or iNOS inhibitor (L-NIL; 80 mg/kg body weight) were administered to diet-induced obese rats or mice and iNOS production and insulin signalling were investigated. S-nitrosylation of IRbeta/IRS-1 and Akt was investigated using the biotin switch method. iNOS protein levels increased in the muscle of diet-induced obese rats, associated with an increase in S-nitrosylation of IRbeta, IRS-1 and Akt. These alterations were reversed by aspirin treatment, in parallel with an improvement in insulin signalling and sensitivity, as measured by insulin tolerance test and glucose clamp. Conversely, while aspirin reversed the increased phosphorylation of IkappaB kinase beta and c-Jun amino-terminal kinase, as well as IRS-1 serine phosphorylation in diet-induced obese rats and iNos -/- mice on high-fat diet, these alterations were not associated with the improvement of insulin action induced by this drug. Our data demonstrate that aspirin treatment not only reduces iNOS protein levels, but also S-nitrosylation of IRbeta, IRS-1 and Akt. These changes are associated with improved insulin resistance and signalling, suggesting a novel mechanism of insulin sensitisation evoked by aspirin treatment.

Surrogate measures of insulin resistance: of rats, mice, and men

to the editor: In studies of human metabolic physiology a number of surrogate measures of insulin resistance have been proposed, and their relationships to formal measures of whole body insulin sensitivity made by classical insulin-glucose clamp measures have been assessed ([2][1], [8][2], [11][3

Effects of smoking cessation, acute re‐exposure and nicotine replacement in smokers on AIR® inhaled insulin pharmacokinetics and glucodynamics

* Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers. * This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR((R)) inhaled insulin pharmacokinetics and glucodynamics. * We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. * Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response. To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT). Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8-12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD. Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced. Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.

Prediction of Arrhythmic Events with Positron Emission Tomography: PAREPET study design and methods

Background In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD. Objectives PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality. Methods Patients with documented ischemic cardiomyopathy, an ejection fraction of ≤ 35%, and with no plans for coronary revascularization will be recruited. Major exclusion criteria include: history of resuscitated SCD, sustained VT, ICD discharge, or unexplained syncope; recent myocardial infarction (30 days), percutaneous coronary intervention (3 months), coronary bypass surgery (1 year); or comorbidities that would be expected to reduce life expectancy to < 2 years. All patients will undergo transthoracic echocardiography, and dynamic cardiac positron emission tomography to quantify resting perfusion ( 13N-ammonia), norepinephrine uptake as an index of sympathetic innervation ( 11C- meta-hydroxyephedrine), and metabolic viability ( 18F-2-deoxyglucose during glucose–insulin clamp). The development of SCD or cardiovascular mortality will be determined by telephone follow-up every three months. In patients with an implantable cardiac defibrillator, appropriate device discharge will be considered a surrogate for SCD. Conclusion The PAREPET study will prospectively determine whether the amount of viable dysfunction myocardium and/or cardiac sympathetic dysinnervation is associated with the risk of SCD. It is anticipated that the results of this trial will more specifically identify myocardial substrates of SCD. This will help target therapies intended to reduce arrhythmic death to those patients with the greatest likelihood of benefit.

Reply to Comment on: Wannamethee SG, Lowe GDO, Shaper AG, Rumley A, Lennon L, Whincup PH (2004) Insulin resistance, haemostatic and inflammatory markers and coronary heart disease risk factors in Type 2 diabetic men with and without coronary heart disease. Diabetologia 47:1557–1565

To the Editor: We thank the authors for their letter regarding our paper, drawing attention to concerns about the validity of the homeostasis model assessment (HOMA) in elderly people with diabetes [1]. The two papers that the authors refer to suggest that the relation between HOMA and the insulin–glucose clamp gold standard may be weak or perhaps absent in patients with diabetes, although both these studies are based on small numbers of subjects [2, 3]. We agree that HOMA may not be the best measure of insulin resistance in elderly subjects with diabetes, an issue on which we have commented in our Discussion section. However, we do believe that in the present study, the HOMA model is likely to have had some validity as an indicator of insulin resistance in subjects with diabetes for two main reasons. Firstly, in the majority (72%) of these subjects with diabetes, blood glucose concentration was below 9.5 mmol/l, the level above which there has been particular concern about HOMA validity [4]. Secondly, among these subjects, HOMAwas significantly correlated with BMI (r=0.30; p<0.0001) as well as with markers of the insulin resistance syndrome, including waist circumference, triglycerides and HDL cholesterol (r=0.30, r=0.43 and r=−0.34 respectively; all p<0.0001). We would also point out that at present there is no alternative simple measure of insulin resistance suitable for use in populationbased studies. We agree that more evidence is needed to confirm the validity of HOMA in elderly subjects with diabetes, or to provide an alternative measure of insulin resistance for use among such patients. In this cross-sectional study, we also observed that increasing HOMA is associated with increasing prevalence of CHD, suggesting that HOMA may also be a predictor of CHD in these older diabetic patients. Further prospective studies examining whether HOMA predicts the risk of incident CHD in older diabetic patients will help to resolve this issue.

Absolute quantitation of left ventricular wall and cavity parameters using ECG-gated PET

Background Electrocardiography (ECG)–gated scintigraphy demonstrates promising results for the simultaneous assessment of myocardial glucose metabolism and contractile function. In this study a method was evaluated for absolute quantitation of left ventricular wall and cavity parameters with the use of fluorine 18 fluorodeoxyglucose (FDG) ECG-gated positron emission tomography (PET). Methods and results A previously developed 2-dimensional mathematical model was implemented for computer-automated identification of endocardial and pericardial borders. The accuracy and precision were tested in a heart phantom and in healthy subjects. Twelve healthy men aged 64 ± 8 years were studied by use of cine magnetic resonance imaging (MRI) and ECG-gated FDG-PET during euglycemic glucose-insulin clamp. At increasing image noise levels, the estimated cavity volume of the heart phantom was within 2 mL of the actual volume, and no significant difference was found between actual and estimated wall thicknesses. Endocardial wall motion as assessed by ECG-gated PET in the healthy subjects was systematically underestimated compared with MRI. This underestimation correlated linearly with endocardial excursion during PET end diastole as measured by MRI. Myocardial end-diastolic wall thickness was systematically overestimated by PET, whereas end-systolic thickness deviated less than 1 mm from MRI. Cavity volumes measured by PET correlated linearly with MRI, with a tendency toward an underestimation of end-diastolic cavity volumes by PET. Conclusions Absolute measures of cardiac structure and function may be obtained with a reasonable degree of accuracy by use of ECG-gated PET imaging. However, a high ECG-gating frequency appears to be required to obtain measurements comparable to what may be achieved by MRI.

Clinical outcomes of medical or surgical therapy in patients below age 40 with acute diverticulitis

In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD.PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality.Patients with documented ischemic cardiomyopathy, an ejection fraction of ≤ 35%, and with no plans for coronary revascularization will be recruited. Major exclusion criteria include: history of resuscitated SCD, sustained VT, ICD discharge, or unexplained syncope; recent myocardial infarction (30 days), percutaneous coronary intervention (3 months), coronary bypass surgery (1 year); or comorbidities that would be expected to reduce life expectancy to < 2 years. All patients will undergo transthoracic echocardiography, and dynamic cardiac positron emission tomography to quantify resting perfusion (13N-ammonia), norepinephrine uptake as an index of sympathetic innervation (11C-meta-hydroxyephedrine), and metabolic viability (18F-2-deoxyglucose during glucose–insulin clamp). The development of SCD or cardiovascular mortality will be determined by telephone follow-up every three months. In patients with an implantable cardiac defibrillator, appropriate device discharge will be considered a surrogate for SCD.The PAREPET study will prospectively determine whether the amount of viable dysfunction myocardium and/or cardiac sympathetic dysinnervation is associated with the risk of SCD. It is anticipated that the results of this trial will more specifically identify myocardial substrates of SCD. This will help target therapies intended to reduce arrhythmic death to those patients with the greatest likelihood of benefit.

Detection of symptoms by adolescents and young adults with type 1 diabetes during experimental induction of mild hypoglycemia: role of hormonal and psychological variables.

To identify hormonal, psychological, and demographic predictors of symptom detection and accuracy of blood glucose estimation during mild hypoglycemia in adolescents and young adults with type 1 diabetes. During an insulin-glucose clamp study, 53 adolescents and 19 young adults estimated blood glucose levels and reported symptoms at euglycemia and after 30 min of mild hypoglycemia (3.3 mmol/l). Epinephrine and pancreatic polypeptide were measured, and both change in anxiety level during hypoglycemia and baseline level of anxiety were measured with the Spielberger Anxiety Inventory. Elevated levels of anxiety during euglycemia were used as an indicator of the psychological trait "negative affectivity." Previous studies have suggested that individuals with higher negative affectivity are more internally focused and, therefore, more likely to report somatic and visceral changes. During mild hypoglycemia, 42% of the sample subjects reported an increase in autonomic symptoms; 29% reported an increase in neuroglycopenic symptoms, and 28% estimated blood glucose levels accurately (within 10% of actual). Hormonal excursions did not predict any outcome, but higher anxiety levels during the euglycemic baseline were associated with better detection of hypoglycemic symptoms and more accurate estimation of blood glucose values after controlling for change in anxiety level during hypoglycemia. Psychological factors such as elevated anxiety levels ("negative affectivity") can influence blood glucose estimation and symptom detection in adolescents and young adults and may explain why some individuals are more adept than others at reducing their risk of severe hypoglycemia after participation in a formal blood glucose awareness training program.

Effect of highly purified eicosapentaenoic acid ethyl ester on insulin resistance and hypertension in Dahl salt-sensitive rats.

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to lard on the development of hypertension and insulin resistance in Dahl salt-sensitive (Dahl-S) rats fed a high-sucrose diet (HSD), a model of salt-sensitive hypertension. After 16 weeks of treatment, the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test significantly increased in the HSD-EPA-E group compared with the HSD-water or -lard control group. The GIR was approximately three times higher in the HSD-EPA-E group versus the HSD-water or -lard control group, and it was about 70% of the rate in the calorically deprived control group fed a low-fat-high-fiber diet (LF-HFD). In addition, EPA-E significantly suppressed the elevation of plasma glucose and insulin levels after oral glucose loading. These results indicate that EPA-E prevents the development of insulin resistance in Dahl-S rats fed a HSD. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase in C18:2, C20:5, and C22:5 components in the HSD-EPA-E group and, conversely, a significant decrease in C16:0, C20:4, and C22:6. The present results indicate that the beneficial effect of EPA-E on insulin resistance in Dahl-S rats fed a HSD is likely dependent on the modification of phospholipid components in the skeletal muscle membrane. These findings suggest that EPA-E might prevent the development of insulin resistance in dietary obesity. In addition, the HSD-EPA-E group showed a significant increase in the level of uncoupling protein (UCP) in brown adipose tissue as compared with the HSD-water or -lard control group. However, EPA-E had no effect on the development of hypertension and obesity in Dahl-S rats fed the HSD.

High dose insulin does not increase glucose transfer across the blood-brain barrier in humans: a re-evaluation.

This study re-evaluates previously published data on blood-brain barrier transfer coefficients in humans exposed to high insulin levels. In this study of seven volunteers, global blood-brain barrier permeability to glucose and phenylalanine was measured by means of the intracarotid double-indicator method before, during, and after an insulin-glucose clamp. Data were reanalyzed by means of a mathematical model that takes capillary heterogeneity and labelled glucose backflux from the brain into account. The permeability-surface area product (PS) for glucose transport from the blood into the brain, PS1, was 0.145 (0.102-0.211) (median and quartiles), 0.146 (0.113-0.259), and 0.157 (0.133-0.181) ml g-1 min-1 before, during, and after insulin challenge, respectively. In six of the subjects, PS for transport from brain to blood over the brain glucose distribution volume, PS2/Ve decreased under hyperinsulinemia, from a baseline value of 6.56 (3.0-14.9) to 3.86 (1.41-5.32), and restored to a value of 3.8 (2.8-12.1) min-1 after insulin challenge. This decrease in PS2/Ve is probably due to an increase in the brain glucose distribution volume induced by an insulin induced increased intracellular glucose uptake during the experiment. For phenylalanine (n = 5), PS1 was unchanged before, during, and after insulin challenge. In hyperinsulinemia, PS3/Ve for phenylalanine decreased in all subjects. We conclude that acutely elevated high plasma insulin levels in humans does not alter the brain uptake of glucose or phenylalanine from the blood. It seems, however, that high plasma insulin levels induce an increase in the movement of D-glucose and L-phenylalanine from the brain interstitial fluid into the intracellular compartment.

Physiological variations in blood glucose concentration affect oesophageal motility and sensation in normal subjects.

A marked elevation in the blood glucose concentration (approximately 15 mmol L-1) slows oesophageal peristalsis. Recent studies indicate that changes in blood glucose within the normal postprandial range affect gastric motility and emptying. The aim of this study was to investigate whether such alterations in blood glucose also affect oesophageal motility. In eight healthy subjects oesophageal motility and sensation to balloon distension were measured on two separate days while blood glucose concentrations were stabilized with an insulin-glucose clamp at 4 mmol L-1 and 8 mmol L-1. Peristaltic velocity in the proximal oesophagus and over the oesophagus as a whole was faster at a plasma glucose concentration of 8 mmol L-1 compared with those at 4 mmol L-1 (proximal 3.3 +/- 0.3 cm s-1 vs 2.6 +/- 0.2 cm s-1, P < 0.05, total 3.1 +/- 0.2 cm s-1 vs 2.7 +/- 0.2 cm s-1, P < 0.005) but there were no differences in wave amplitude or duration, or basal lower oesophageal sphincter pressure (LOSP). The threshold for initial perception of oesophageal distension was lower at a plasma glucose of 8 mmol L-1 (2.9 +/- 0.5 mL vs 4.9 +/- 1.0 mL, P < 0.05). physiological variations in plasma glucose concentration influence oesophageal motility and sensation. These observations suggest that in order to minimize effects of varying plasma glucose levels on oesophageal motility, manometry should be performed under the same fasting or fed conditions when oesophageal motor function is evaluated.

Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long-Evans Tokushima Fatty Rat, a model of spontaneous non-insulin-dependent diabetes mellitus

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to the effects of lard, olive oil, safflower oil, or distilled water as the control on the development of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous non—insulin-dependent diabetes mellitus (NIDDM) with obesity. After 17 or 18 weeks of treatment, the glucose infusion rate (GIR) in the euglycemic insulin-glucose clamp test only showed a significant increase in EPA-E-treated rats compared with control rats given distilled water alone as the vehicle. The GIR in EPA-E-treated animals was approximately three times greater than in the controls. This is the first report to display the influence of various fatty acids on the development of insulin resistance in OLETF rats. We demonstrated that EPA-E prevents the onset of insulin resistance, whereas olive oil and safflower oil have no effect and lard exacerbates insulin resistance. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase of the C18:2, C20:5, and C22:5 components in EPA-E-treated rats and, conversely, a significant decrease in C20:4. In addition, EPA-E-treated rats showed a significant increase in GLUT4 mRNA in skeletal muscle when compared with control rats. Our results indicate that the beneficial effect of EPA-E on insulin resistance in OLETF rats is likely to be dependent on modification of the phospholipid components of the skeletal muscle membrane. These findings suggest that dietary fatty acids may play a key role in the development of insulin resistance in patients with NIDDM.

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease.

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quantitated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, -430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 +/- 9 micromol x min(-1) X kg(-1) body wt [mean +/- SD]), compared with healthy control subjects (40 +/- 17 micromol x min(-1) x kg(-1) body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 +/- 9 micromol x min(-1) x kg(-1) body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 +/- 28 micromol x min(-1) x 100 g(-1) in NIDDM patients, 72 +/- 17 micromol x min(-1) x 100 g(-1) in CAD patients, and 76 +/- 10 micromol x min(-1) x 100 g(-1) in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.

Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus

BACKGROUND & AIMS: Marked hyperglycemia slows and hypoglycemia accelerates gastric emptying. The aim of this study was to determine the effect of physiological changes in blood glucose gastric emptying. METHODS: In 8 healthy subjects and 9 patients with insulin-dependent diabetes mellitus (IDDM) without gastrointestinal tract symptoms or evidence of neuropathy, gastric emptying of a mixed meal was measured by scintigraphy. Using an insulin-glucose clamp, the blood glucose concentration was stabilized at 4 and 8 mmol/L on 2 separate days. RESULTS: The intragastric retention of the solid meal component at 100 minutes was 55.2% +/- 4.5% at 8 mmol/L vs. 36.7% +/- 5.5% at 4 mmol/L (P = 0.004) in normal subjects and 44.2% +/- 4.2% vs. 35.7% +/- 4.2% (P = 0.004) in patients with IDDM. The time taken for 50% emptying of the liquid meal was 57.0 +/- 10.8 minutes at 8 mmol/L vs. 32.2 +/- 12.6 minutes at 4 mmol/L (P = 0.002) in normal subjects and 41.3 +/- 3.4 minutes vs. 29.1 +/- 3.5 minutes (P = 0.002) in patients with IDDM. CONCLUSIONS: Changes in blood glucose within the normal postprandial range have a significant impact on gastric emptying in both normal subjects and patients with IDDM. (Gastroenterology 1997 Jul;113(1):60-6)