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D J Chisholm

Publications and source records attributed to D J Chisholm.

At least 91 records · Page 5Linked to original sources
PubMed1988

Closure of the loop by glucose sensing. Physiological and practical considerations.

This review considers factors which determine the minimum desirable operational function of a glucose sensor, based on a consideration of the meal, basal and exercising phases of metabolism in the insulin-dependent diabetic. Augmented insulin release ahead of, or in synchrony with, the arrival of nutrients in the blood stream is important in the normal regulatory mechanism associated with meals. Thus glucose sensors are not suited to be the sole means of determining insulin delivery during meals, and this phase of metabolic control may best be handled by open-loop insulin delivery. However during other phases of metabolic control, glucose sensors with modest response times may have a very useful clinical function.

Biosensing Techniques↗
PubMed1987

Fish oil prevents insulin resistance induced by high-fat feeding in rats.

Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an omega-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic omega-6 fatty acids from safflower oil with long-chain polyunsaturated omega-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus.

Adipose Tissue↗
PubMed1987

Insulin therapy in patients with poorly controlled non-insulin dependent diabetes mellitus.

In spite of maximal doses of sulphonylurea agents, patients with poorly controlled non-insulin dependent diabetes (NIDDM) often do not have improved metabolic control after the introduction of insulin therapy. We have assessed 22 patients with NIDDM who commenced insulin therapy in order to identify those characteristics which were associated with an improvement in glycaemic control. Twelve months after the commencement of insulin therapy, 14 (64%) patients showed a decrease in glycosylated haemoglobin (HbA1) levels; 12 of the 14 (55%) patients had achieved HbA1 levels that were considered to reflect acceptable glycaemic control (HbA1 less than or equal to 11%; reference range, 6%-9%). The HbA1 levels in the other patients either remained unchanged or had increased (one subject). When the subjects who had achieved good glycaemic control with insulin therapy were compared with the remainder of the group, a failure to improve with insulin therapy was associated with a longer duration of diabetes, greater obesity and higher levels of cholesterol and triglycerides before the commencement of insulin therapy. Greater obesity and high levels of circulating lipids were found by means of multiple linear regression analysis to correlate independently with a poor response to insulin therapy. We conclude that standard insulin therapy can improve the majority of patients with poorly controlled NIDDM. However, there is a substantial number of patients, who tend to be obese and have high levels of circulating lipids, whose condition does not improve with insulin therapy, or who require more aggressive dosage increases than are used as a routine.

Adult↗
PubMed1987

Outpatient initiation of insulin therapy in patients with diabetes mellitus.

Before insulin therapy is begun, patients with diabetes are often admitted to hospital. In a retrospective study we have reviewed the initiation of insulin therapy in 54 unselected outpatients (12 of whom were insulin-dependent), when the initial stabilization of therapy was performed predominantly by nurse educators. Most patients found the procedure satisfactory; only one subject indicated dissatisfaction with the regimen and only two indicated that they would have preferred admission to hospital. No patient experienced an acute hypoglycaemic or hyperglycaemic problem that required admission to hospital nor was emergency intervention required during the 12 months that followed the initial stabilization period of insulin therapy. Metabolic control, as measured by glycosylated haemoglobin levels, improved in the majority of both insulin-dependent and non-insulin-dependent patients after 12 months of insulin therapy. A retrospective cost analysis that compared the cost of the outpatient procedure with the cost (hospital-bed costs only) of initiating insulin therapy in a similar group of patients who were admitted to hospital, indicated a saving of $1857 for each outpatient. We conclude that the outpatient initiation of insulin therapy is feasible where the facilities for education about diabetes exist, that it is safe, achieves satisfactory metabolic control, is acceptable to most patients, and offers a considerable saving in costs.

Australia↗
PubMed1987

Cephalic phase metabolic responses in normal weight adults.

The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration.

We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant, p less than 0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p less than 0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%, p less than 0.05 in 6 out of 8 muscles), white adipose (27%, p less than 0.05) and brown adipose tissue (76%, p less than 0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1986

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats.

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1986

Regulation of hepatic glucose output during exercise by circulating glucose and insulin in humans.

We have tested the hypothesis that hepatic glucose output (Ra) during exercise in humans is subject to feedback control by circulating glucose within a control range that is determined by the circulating insulin concentration. Three exercise protocols based on 60-min cycle ergometer exercise at 55% maximal O2 consumption were used: 1) control, 2) insulin infusion with a euglycemic clamp, and 3) insulin infusion with a fixed-rate glucose infusion. Ra was measured using a constant infusion of [3H]glucose. During the glucose clamp there was no Ra response to exercise. There were significant inverse relationships between Ra and plasma glucose during control exercise (r = -0.73, P less than 0.001) and exercise with fixed-rate glucose and insulin infusion (r = -0.96, P less than 0.001). During the fixed-rate glucose and insulin infusion, plasma glucose fell from the commencement of exercise but stabilized at a lower level. These results are interpreted in terms of a simple difference controller where Ra is proportional to the deviation of plasma glucose from a defined set point. Insulin affects Ra and regulates the steady-state glucose level by altering the sensitivity of this control system.

Adult↗
PubMed1985

Exercise-induced hepatic glucose output is precisely sensitive to the rate of systemic glucose supply.

It has previously been established that a glucose infusion causing hyperglycemia and alterations in the levels of glucoregulatory hormones suppresses the exercise-induced increment in systemic glucose appearance (Ra). In an attempt to define the mechanisms responsible for this suppression of Ra, five normal subjects were exercised for 60 minutes on a bicycle ergometer at 60% Vo2 max on two occasions. On both occasions Ra was measured by a nonsteady state technique using a constant infusion of 3-3H-glucose. On the second occasion, an IV infusion of glucose was administered in a stepwise fashion to simulate in timing and magnitude the measured Ra response from the first study. Endogenous glucose production in the second study, estimated by subtracting the amount of glucose infused from the measured Ra response, did not increase above basal (endogenous glucose output response = 0.5 +/- 8.4 mmol/60 min v control study 60.2 +/- 6.6 mmol/60 min, P less than 0.01). The suppression of Ra was associated with a small but significant effect on venous plasma glucose (increment above basal less than 0.3 mmol/L, P less than 0.05) and a significant change in glucose metabolic clearance rate during the second 30 minutes of exercise. Serum insulin, C-peptide, cortisol, growth hormone, and plasma glucagon responses to exercise were not significantly affected by glucose infusion and the ratio of circulating insulin to glucagon was also not affected. These results indicate that hepatic glucose output during exercise is precisely sensitive to glucose supply. The feedback inhibition is presumably mediated by a small increase in plasma glucose but cannot readily be accounted for by changes in glucoregulatory hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

In vivo dose response curves of insulin action in heart: anomalous effects at high insulin doses.

The euglycaemic hyperinsulaemic clamp technique in conscious unrestrained rats was used to compile insulin dose response curves of glucose metabolism in the heart in vivo. An estimate of heart glucose uptake (Rg') was obtained using [3H]-2-deoxyglucose and glucose disposal was examined by measuring cardiac glycogen content. Elevation of insulin from 29 to 54 mU/l resulted in a significant increase in Rg' in heart from 41 +/- 6 to 77 +/- 4 mumol/100 g/min (P less than 0.01) with no effect on glycogen content. This is consistent with increased glucose oxidation. At 150 mU/l of insulin both Rg' and glycogen synthesis were increased. Glycogen content increased from 18.5 +/- 1.7 mumol/g under basal conditions to 27.9 +/- 1.6 mumol/g with insulin. However, at subsequent insulin doses producing plasma levels exceeding 600 mU/l there was an anomalous reversal of Rg' back to basal levels while glycogen content was significantly elevated (2.4-fold, P less than 0.01). This effect may be related to feedback inhibition of tissue glycogen on glucose transport or to accumulation of tissue metabolites such as glucose-6-phosphate. The dose response curve for insulin stimulated Rg' in heart does not resemble either the whole body glucose utilization curve or that in individual skeletal muscles.

Animals↗
PubMed1985

Dose-response curves for in vivo insulin sensitivity in individual tissues in rats.

A technique is described for examining in vivo insulin action on glucose utilization in individual tissues in the intact conscious rat. Indices of tissue glucose metabolic rate Rg' and of the percentage of total glucose uptake incorporated into specific storage products (Cf) are derived from tissue analysis after bolus administration of 2-[3H]deoxyglucose and [14C]glucose during the plateau phase of the euglycemic clamp. The effects of insulin elevation have been examined in several tissues. Rg' in diaphragm increased 10-fold over basal (maximal) with a half-maximal sensitivity (ED50) of 150 mU/l. This was similar to the ED50 for net whole body glucose utilization of 133 mU/l. In adipose tissue Rg' increased by twofold and Cf into lipids by sixfold; both were near maximal at 150 mU/l (ED50 of 60 mU/l). A small but significant insulin effect (Rg' increased 2-fold) was found in lung. Insulin did not significantly increase Cf into total liver lipids or glycogen. The methodology described here significantly increases the usefulness of the glucose clamp technique in the study of insulin action. Dose-response curves for insulin action during the euglycemic clamp vary considerably among different target tissues in the rat.

Adipose Tissue↗
PubMed1985

Muscle glucose metabolism in exercising rats: comparison with insulin stimulation.

We describe here a technique using bolus 2-[3H]deoxyglucose (2-[3H]DG) administration for estimating the glucose metabolic rate (R'g) in individual tissues of the rat during exercise. After 50 min of treadmill running at a moderate work load various tissues were analyzed for accumulation of phosphorylated 2-[3H]DG and/or glycogen mass. There was considerable heterogeneity in R'g in response to exercise among different muscles, despite similar basal values. R'g increased 32-fold above basal in soleus (to 90.4 +/- 5.7 mumol X 100 g-1 X min-1), 42-fold in red gastrocnemius (to 71.2 +/- 1.6), 5-fold in white gastrocnemius (to 7.0 +/- 0.8), and 2-fold in extensor digitorum longus (to 4.1 +/- 1.0) during exercise. There was a close relationship between muscle glycogen depletion and R'g within different muscles. In view of the magnitude of the increase in R'g during exercise, this method provides a very sensitive index of muscle fiber recruitment during exercise. The pattern of exercise-stimulated R'g in muscles of different fiber composition was similar to that seen with insulin stimulation. However, moderate exercise alone produced increments in R'g (soleus and red gastrocnemius) that were significantly higher (P less than 0.005) than that observed during maximal insulin stimulation even though whole body glucose utilization was slightly higher during maximal insulin stimulation. These data emphasize the heterogeneity of the response in different muscles during exercise and suggest that intracellular events beyond glucose transport may be rate limiting under the influence of one or both of these stimuli.

Animals↗
PubMed1985

Effects of exercise training on in vivo insulin action in individual tissues of the rat.

It has previously been suggested that exercise training leads to increased whole body insulin sensitivity. However, the specific tissues and metabolic pathways involved have not been examined in vivo. By combining the euglycemic clamp with administration of glucose tracers, [3H]2-deoxyglucose (2DG), [14C]glucose, and [3H]glucose, in vivo insulin action at the whole body level and within individual tissues has been assessed in exercise-trained (ET, running 1 h/d for 7 wk) and sedentary control rats at four insulin doses. Whole body insulin sensitivity was significantly increased in ET. In addition, the skeletal muscles, soleus, red and white gastrocnemius, extensor digitorum longus (EDL), and diaphragm all showed increased sensitivity of insulin-stimulated 2DG uptake with training. With the exception of EDL, no significant difference in insulin-mediated glycogen synthesis between control and ET could be found. Therefore, the increased insulin-induced 2DG uptake observed in muscle following training is apparently directed towards glucose oxidation. In ET animals, adipose tissue exhibited a significant increase in insulin-mediated 2DG uptake and [14C]glucose incorporation into free fatty acids but there was no difference from control in any parameters measured in lung or liver. EDL and white gastrocnemius, which are not primarily involved during exercise of this type, also demonstrated increased insulin sensitivity following training. In conclusion, exercise training results in a marked increase in whole body insulin sensitivity related mainly to increased glucose oxidation in skeletal muscle. This effect may be mediated by systemic as well as local factors and is likely to be of therapeutic value in pathological conditions exhibiting insulin resistance.

Adipose Tissue↗
PubMed1984

Insulin responses to varying profiles of subcutaneous insulin infusion: kinetic modelling studies.

Refinement of continuous subcutaneous insulin infusion for diabetes therapy requires improved knowledge of subcutaneous insulin absorption kinetics. We have used kinetic modelling to quantitate systemic insulin delivery produced by subcutaneously-infused insulin (i.e. simulated meal and basal delivery). Profiles were studied in normal subjects, with endogenous insulin suppressed. Paired studies of intravenous insulin infusion enabled systemic insulin delivery to be quantitated. High rate subcutaneous delivery (10 U in 5 min) resulted in a systemic delivery of approximately 8 U in 4 h. Increasing infused insulin concentration delayed systemic delivery (p less than 0.025). Both continuous and pulsatile low-rate infusions (2.4 U/h) gave similar slow increases in systemic delivery to 1 U after 4 h. Computer fitting to a two-pool model of the subcutaneous space suggested a low rate of insulin degradation for all profiles (rate constant less than 10%/h). We conclude that: systemic insulin delivery following subcutaneous infusion conforms reasonably to a two-pool model, subcutaneous insulin degradation is low regardless of input profile, a long delay in basal systemic delivery should be taken into account when initiating or resuming interrupted subcutaneous insulin infusion. Kinetic modelling of subcutaneous insulin absorption should be useful to predict the impact of programming strategies for continuous subcutaneous insulin infusion therapy.

Adult↗
PubMed1984

Low subcutaneous degradation and slow absorption of insulin in insulin-dependent diabetic patients during continuous subcutaneous insulin infusion at basal rate.

As information on the absorption kinetics and local degradation of infused insulin is relevant to programming strategies for continuous subcutaneous insulin infusion, we examined the time relationship of systemic insulin appearance and quantitated subcutaneous degradation during a near-basal rate of continuous subcutaneous insulin infusion in five insulin-dependent diabetic patients. Plasma free insulin was monitored for 8 h during and 3 h after a subcutaneous (abdominal wall) infusion of neutral insulin at 2.4 U/h. An identical intravenous infusion (2-4 h) was given on a separate occasion. Plateau levels of free insulin were not significantly different during the subcutaneous (37 +/- 8 mU/l) and intravenous (40 +/- 7 mU/l) infusions. Fitting of the free insulin data to our two-pool model of the subcutaneous space gave a mean estimate of 9.2 units insulin (= 3.8 h infusion) for the subcutaneous depot after 8 h. Model estimates of systemic insulin appearance, as a percentage of subcutaneous infusion rate, were 59% and 93% after 4 and 8 h respectively, and 76% 2 h after cessation of infusion. In insulin-dependent diabetic patients subcutaneous degradation of infused insulin is negligible but local accumulation in the subcutaneous space is considerable. The delay in absorption has important clinical implications for interruption and resumption of continuous subcutaneous insulin infusion and also for programming of variable basal rates.

Absorption↗
PubMed1984

Hypoglycemic episodes during continuous subcutaneous insulin infusion: decreased frequency but increased susceptibility.

There has been concern regarding the susceptibility of patients on continuous subcutaneous insulin infusion (CSII) to hypoglycemic episodes. This study has examined glycemic control, the frequency of hypoglycemic reactions and the counterregulatory response to an IV insulin infusion fo 2.4 units per hour in five brittle insulin-dependent diabetics before and during CSII. CSII was associated a significant reduction in glycosylated hemoglobin, standard deviation of blood glucose estimations and daily insulin dosage. The frequency of symptomatic hypoglycemic reactions was reduced (mean 14/4 weeks pre CSII, 5/4 weeks post CSII, p less than 0.05). However, after CSII the IV insulin caused a more rapid fall in blood glucose from the physiological to the hypoglycemic range while growth hormone and cortisol responses were both reduced (p less than 0.05) and the deficient glucagon response was not improved. Thus, although the frequency of reported hypoglycemic reactions was reduced by CSII, susceptibility to hypoglycemia due to excess insulin delivery was enhanced, owing to increased insulin sensitivity and/or additional impairment of the counterregulatory response.

Adult↗
PubMed1984

Effect of exercise training on whole-body insulin sensitivity and responsiveness.

Exercise training causes a decline in basal and glucose-stimulated plasma insulin levels and improves glucose tolerance. Furthermore evidence has been presented for effects on both insulin receptors and postreceptor events. However, it is unclear how these changes affect the in vivo dose-response relationship between insulin levels and whole-body glucose utilization. The aim was to examine the effect of exercise training on this relationship and distinguish between changes in insulin sensitivity and responsiveness. Euglycemic clamps were performed in trained (ET, running 1 h/day for 7 wk), sedentary (CON), and sedentary food-restricted ( SFR ) rats. ET rats showed no increase in maximal net glucose utilization in response to insulin (ET 29.5 +/- 0.6 vs. CON 28.2 +/- 1.5 mg X kg-1 X min-1, NS), whereas insulin sensitivity was increased as indicated by the insulin concentration causing half-maximal stimulation (ED50) (49 +/- 20 for ET and 133 +/- 30 mU/l for CON). Thus 7 wk of moderate exercise training resulted in a significant shift of whole-body insulin sensitivity to place ED50 well within the physiological range of insulin concentrations. This would undoubtedly result in improved glucose disposal in the postprandial state and emphasizes the potential benefit of exercise in obesity and type II diabetes.

Animals↗