Stuart M. Furler

Diet-Induced Muscle Insulin Resistance in Rats Is Ameliorated by Acute Dietary Lipid Withdrawal or a Single Bout of Exercise: Parallel Relationship Between Insulin Stimulation of Glucose Uptake and Suppression of Long-Chain Fatty Acyl-CoA

Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological manipulations intended to lower muscle lipid availability on insulin sensitivity in high-fat–fed rats. Adult male Wistar rats fed a high-fat diet for 3 weeks were divided into four groups the day before the study: one group was fed the normal daily high-fat meal (FM); another group was fed an isocaloric low-fat high-glucose meal (GM); a third group was fasted overnight (NM); and a fourth group underwent a single bout of exercise (2-h swim), then were fed the normal high-fat meal (EX). In vivo insulin action was assessed using the hyperinsulinemic glucose clamp (plasma insulin 745 pmol/l, glucose 7.2 mmol/l). Prior exercise, a single low-fat meal, or fasting all significantly increased insulin-stimulated glucose utilization, estimated at either the whole-body level (P < 0.01 vs. FM) or in red quadriceps muscle (EX 18.2, GM 28.1, and NM 19.3 vs. FM 12.6 ± 1.1 μmol · 100 g−1 · min−1; P < 0.05), as well as increased insulin suppressibility of muscle total long-chain fatty acyl-CoA (LCCoA), the metabolically available form of fatty acid (EX 24.0, GM 15.5, and NM 30.6 vs. FM 45.4 nmol/g; P < 0.05). There was a strong inverse correlation between glucose uptake and LC-CoA in red quadriceps during the clamp (r = −0.7, P = 0.001). Muscle triglyceride was significantly reduced by short-term dietary lipid withdrawal (GM −22 and NM −24% vs. FM; P < 0.01), but not prior exercise. We concluded that muscle insulin resistance induced by high-fat feeding is readily ameliorated by three independent, short-term physiological manipulations. The data suggest that insulin resistance is an important factor in the elevated muscle lipid availability induced by chronic high-fat feeding.

Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM.

Fish oils, containing omega-3 fatty acids (ω3FAs), favorably influence plasma lipoproteins in nondiabetic humans and prevent the development of insulin resistance induced by fat feeding in rats. We studied the effects of fish oils in 10 subjects (aged 42–65 yr) with mild non-insulin-dependent diabetes mellitus (NIDDM). Subjects were fed a standard diabetic diet plus 1) no supplementation (baseline), 2) 10 g fish oil concentrate (30% ω3FAs) daily, and 3) 10 g safflower oil daily over separate 3-wk periods, the latter two supplements being given in radom order by use of a double-blind crossover design. At the end of each diet period, fasting blood glucose (FBG), insulin, and lipids were measured, and insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp performed with [3-3H]glucose. FBG increased 14% during fish oil and 11% during safflower oil supplementation compared with baseline (P < .05), whereas body weight, fasting serum insulin levels, and insulin sensitivity were unchanged. The absolute increase in FBG during each supplementation period correlated with the baseline FBG (fish oil, r = .83, P < .005; safflower oil, r = .75, P = .012). Fasting plasma triglyceride levels decreased during fish oil supplementation in the 4 subjects with baseline hypertriglyceridemia (>2 mM) but were not significantly reduced overall. There was no significant change in fasting plasma total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake. These data indicate that fish oil supplementation should be used with caution in subjects with NIDDM.

The Determinants of Glycemic Responses to Diet Restriction and Weight Loss in Obesity and NIDDM

OBJECTIVE To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, andregional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS Hyperinsulinemic glucose clamps wereperformed in 20 subjects (BMI = 32.0 ± 0.5 [SEM] kg/m2, age = 48.4 ± 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 ± 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (ΔFPG: NGT = −0.4 ± 0.2 mmol/1 and NIDDM = −1.1 ± 0.03 mmol/1, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output(HGO) in both groups (ΔHGO suppression: NGT = 28 ± 15% and NIDDM = 32 ± 8%, P = 0.002). By d28, with 6.3 ± 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity afterweight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.

Muscle long-chain acyl CoA esters and insulin resistance.

Abstract: A common observation in animal models and in humans is that accumulation of muscle triglyceride is associated with the development of insulin resistance. In animals, this is true of genetic models of obesity and nutritional models of insulin resistance generated by high‐fat feeding, infusion of lipid, or infusion of glucose. Although there is a strong link between the accumulation of triglycerides (TG) in muscle and insulin resistance, it is unlikely that TG are directly involved in the generation of muscle insulin resistance. There are now other plausible mechanistic links between muscle lipid metabolites and insulin resistance, in addition to the classic substrate competition proposed by Randles glucose‐fatty acid cycle. The first step in fatty acid metabolism (oxidation or storage) is activation to the long‐chain fatty acyl CoA (LCACoA). This review covers the evidence suggesting that cytosolic accumulation of this active form of lipid in muscle can lead to impaired insulin signaling, impaired enzyme activity, and insulin resistance, either directly or by conversion to other lipid intermediates that alter the activity of key kinases and phosphatases. Actions of fatty acids to bind specific nuclear transcription factors provide another mechanism whereby different lipids could influence metabolism.

The insulin sensitizer, BRL 49653, reduces systemic fatty acid supply and utilization and tissue lipid availability in the rat

Thiazolidinediones are oral insulin-sensitizing agents that may be useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). BRL 49653 ameliorates insulin resistance and improves glucoregulation in high-fat-fed (HF) rats. It is known that thiazolidinediones bind to the peroxisome proliferator-activated receptor (PPAR gamma) in fat cells, but the extent to which the improved glucoregulation and hypolipidemic effects relate to adipose tissue requires clarification. We therefore examined BRL 49653 effects on lipid metabolism in HF and control (high-starch-fed [HS]) rats. The diet period was 3 weeks, with BRL 49653 (10 mumol/kg/d) or vehicle gavage administered over the last 4 days. Studies were performed on animals in the conscious fasted state. In HF rats, rate constants governing 3H-palmitate clearance were unaffected by BRL 49653. This finding, taken with a concurrent decrease of fasting plasma nonesterified fatty acids (NEFA) (P < .01, ANOVA), demonstrated that systemic NEFA supply and hence absolute utilization are reduced by BRL 49653. Hepatic triglyceride (TG) production (HTGP) assessed using Triton WR1339 was unaffected by diet or BRL 49653. In liver, BRL 49653 increased insulin-stimulated conversion of glucose into fatty acid in both HF (by 270%) and HS (by 30%) groups (P < .05). Relative to HS rats, HF animals had substantially elevated levels of muscle diglyceride (diacylglycerol[DG] by 240%, P < .001). BRL 49653 significantly reduced muscle DG in HF (by 30%, P < .05) but not in HS rats. The agent did not reduce the intake of dietary lipid. In conclusion, these results are consistent with a primary action of BRL 49653 in adipose tissue to conserve lipid by reducing systemic lipid supply and subsequent utilization. The parallel effects of diet and BRL 49653 treatment on insulin resistance and muscle acylglyceride levels support the involvement of local lipid oversupply in the generation of muscle insulin resistance.

Blood Glucose Control by Intermittent Loop Closure in the Basal Mode: Computer Simulation Studies with a Diabetic Model

A semiclosed loop, bedside insulin infusion system using a simple basal infusion algorithm consisting of a linear transition between two insulin delivery rates as blood glucose (BG) increases has been developed. A theoretical study using computer simulation has now been undertaken to examine the effect of BG sampling frequency and algorithm parameters on BG control. A model for BG control by exogenous insulin in the individual with diabetes was developed from a model for healthy subjects and from clinical data in the literature. Results of computer simulation using this model showed a decrease in BG stability as the sampling interval increased from 1 to 4 h. Simulations also showed a decrease in BG stability as the sensitivity of the control algorithm increased. Choice of an appropriate basal control algorithm involved a compromise between stability, sampling interval, and metabolic control. We conclude that satisfactory metabolic control can be obtained using intermittent BG sampling in the basal state; sampling at intervals of 3 h combined with a basal control algorithm whereby insulin delivery rate increases linearly from 0.5 to 2.5 U/h over the BG range 2–12 mmol/L appears suitable for most diabetic persons. Three-hour sampling offers a good compromise between degree of metabolic control and clinical effort involved.

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)

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

objective We aimed to investigate the impact of a longacting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly

2-deoxy-d-glucose metabolism in individual tissues of the rat in vivo

The nature of and rates of loss of products of systemic radiolabelled 2-deoxy-D-glucose in rat tissues in vivo were investigated to validate the use of this tracer to measure rates of metabolism of circulating glucose by tissues in vivo. Apparent first order rate constants for loss of products ranged from 8.0 +/- 0.10 (SD) X 10(-3) min-1 (liver) to 2.2 +/- 0.8 X 10(-3) min-1 (skeletal muscle). 2-deoxyglucose 6-phosphate was the major product found in all tissues examined except liver; all tissues contained other minor products. Products were effectively trapped by rat tissues in vivo allowing the use of this tracer for the measurement of rates of circulating glucose utilisation by tissues in vivo.

Relationship of adiponectin with insulin sensitivity in humans, independent of lipid availability

Objective: To test in humans the hypothesis that part of the association of adiponectin with insulin sensitivity is independent of lipid availability.