Matthew S. Hickey

A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?

SUMMARY BACKGROUND DATA We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy. Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year. This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor. METHODS Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity. RESULTS Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group. CONCLUSIONS Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut.

Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle.

The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, approximately 75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15-17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased (P < 0. 05) significantly (means +/- SE, 7.8 +/- 0.5 vs. 9.8 +/- 0.8 mg. kg(-1). min(-1)), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly (P < 0.05) with exercise (3.1 +/- 0.8-fold) compared with the sedentary condition (1.3 +/- 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, ≈75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15-17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased ( P < 0.05) significantly (means ± SE, 7.8 ± 0.5 vs. 9.8 ± 0.8 mg ⋅ kg-1 ⋅ min-1), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly ( P < 0.05) with exercise (3.1 ± 0.8-fold) compared with the sedentary condition (1.3 ± 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.

Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk

In most carbohydrate-containing foods, the blood insulin response is predictable and is closely linked to the foods glycaemic index (GI). A single study, examining whole milk and fermented milk products made from whole milk, recently reported a large dissociation between the GI and insulinaemic index (II) in healthy normal adults. Because the fat component of a food may influence the GI and II, it is unclear if a similar dissociation may exist for skimmed milk in normal adults. We determined the GI and II of both skimmed and whole milk in nine healthy, male (n 6) and female (n 3) subjects (23.6 (sd 1.4) years). No significant (P>0.05) differences existed between GI and II for skimmed and whole milks. Significant (P<0.05) differences were observed between the actual and predicted areas under the insulin curves for both skimmed milk (predicted 1405 (sd 289) pmol x min/l; actual 6152 (sd 1177) pmol x min/l) and whole milk (predicted 1564 (sd 339) pmol x min/l; actual 5939 (sd 1095) pmol x min/l). Consequently, a large and similar dissociation of the GI and II existed for both whole milk (42 (sd 5) and 148 (sd 14)) and skimmed milk (37 (sd 9) and 140 (sd 13)). It is concluded that the dissociation of the GI and II in milk is not related to its fat content.

Modulation of immune function by dietary lectins in rheumatoid arthritis.

Despite the almost universal clinical observation that inflammation of the gut is frequently associated with inflammation of the joints and vice versa, the nature of this relationship remains elusive. In the present review, we provide evidence for how the interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of overt rheumatoid arthritis (RA) via molecular mimicry, a process whereby foreign peptides, similar in structure to endogenous peptides, may cause antibodies or T-lymphocytes to cross-react with both foreign and endogenous peptides and thereby break immunological tolerance. By eliminating dietary elements, particularly lectins, which adversely influence both enterocyte and lymphocyte structure and function, it is proposed that the peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result in a diminution of disease symptoms in certain patients with RA.

Acute β-adrenergic stimulation does not alter mitochondrial protein synthesis or markers of mitochondrial biogenesis in adult men

Exercise-induced expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is dramatically inhibited in mice pretreated with a beta-adrenergic receptor (beta-AR) antagonist, suggesting that beta-ARs play an important role in the regulation of skeletal muscle PGC-1alpha expression, and potentially, mitochondrial biogenesis. Accordingly, we hypothesized that acute beta-AR stimulation would induce transcriptional pathways involved in skeletal muscle mitochondrial biogenesis in humans. Whole body protein turnover (WBPT), myofibrillar protein synthesis (MyPS), skeletal muscle mitochondrial protein synthesis (MiPS), and mitochondrial biogenic signaling were determined in samples of vastus lateralis obtained on two separate occasions in 10 young adult males following 1 h of continuous intravenous administration of saline (CON) or a nonspecific beta-AR agonist [isoproterenol (ISO): 12 ng.kg fat free mass(-1).min(-1)], combined with coinfusion of [1,2](13)C-leucine. beta-AR stimulation induced appreciable increases in heart rate and systolic blood pressure (both P < 0.001) but did not affect mitochondrial biogenic signaling (no change in PGC-1alpha, TFAM, NRF-1, NRF-2, COX, or NADHox expression via RT-PCR; P > 0.05). Additionally, MiPS [CON: 0.099 +/- 0.028, ISO: 0.074 +/- 0.046 (mean +/- SD); P > 0.05] and MyPS (CON: 0.059 +/- 0.008, ISO: 0.055 +/- 0.009; P > 0.05), as well as measures of WBPT were unaffected. On the basis of this investigation, we conclude that acute intravenous beta-AR stimulation does not increase mitochondrial protein synthesis or biogenesis signals in skeletal muscle.

Plasma Leptin and Exercise Recent Findings

AbstractThe cloning of murine and human obese genes in 1994, and the subsequent identification that the product of the obese gene, leptin, is secreted from adipose tissue, stimulated a tremendous amount of interdisciplinary interest in adipose tissue endocrinology and the potential role of this tissue in the regulation of energy balance. Exercise, with concomitant changes in fuel flux, systemic hormone levels and energy expenditure, may contribute to the regulation of plasma leptin levels and presumably, leptin action. The initial work characterising the leptin-exercise relationship was equivocal. Cross-sectional studies provided some mixed evidence regarding the relationship between aerobic capacity or habitual physical activity and plasma leptin.In contrast, studies on acute bouts of exercise and exercise training interventions have, with few exceptions, suggested that exercise does not alter systemic leptin independent of changes in fat mass. In general, these studies did not carefully control for energy balance, and sampled only a single fasting plasma leptin level. Two recent studies utilising experimental designs in which energy balance was controlled and 24-hour profiles of plasma leptin were determined have provided the most compelling evidence to date of the interaction between exercise, energy balance and systemic leptin in humans. These studies provide a clear explanation for the apparent lack of an acute effect of exercise on systemic leptin and underscore the importance of clearly defining the balance between energy intake and energy expenditure when studying the physiology of leptin. The aim of this brief review is to provide an overview of the interaction between energy expenditure during physical activity and systemic leptin level. Special emphasis will be placed on those studies in which energy intake/balance was carefully controlled.

Lipidomic analysis of human plasma reveals ether-linked lipids that are elevated in morbidly obese humans compared to lean

BackgroundLipidomic analysis was performed to explore differences in lipid profiles between plasma from lean and obese subjects, followed by in vitro methods to examine a role for the identified lipids in endothelial cell pathophysiology.MethodsPlasma was collected from 15 morbidly obese and 13 control subjects. Lipids were extracted from plasma and analyzed using LC/MS, and MS/MS to characterize lipid profiles and identify lipids that are elevated in obese subjects compared to lean.ResultsOrthogonal partial least squares-discriminant analysis (OPLS-DA) modelling showed that lipid profiles were significantly different in obese subjects compared to lean. Analysis of lipids that were driving group separation in the OPLS-DA model and that were significantly elevated in the obese group led to identification of a group of ether-linked phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipids of interest. Treatment of human coronary artery endothelial cells with the ether-linked phosphatidylethanolamine induced expression of cell adhesion molecules, a hallmark of endothelial cell activation. However, oxidized phosphatidylcholine products that can induce endothelial cell activation in vitro, were not significantly different between groups in vivo.ConclusionThese data suggest a role for ether-linked lipids in obesity associated dyslipidemia and vascular disease.

Effect of resistance exercise, with or without carbohydrate supplementation, on plasma ghrelin concentrations and postexercise hunger and food intake

The effects of resistance exercise with and without carbohydrate (CHO) supplementation on hunger, postexercise food intake, and plasma ghrelin, an orexigenic gastric peptide, are poorly characterized. We examined the individual and combined effects of a resistance exercise bout and CHO consumption on plasma ghrelin and postexercise food intake. Twenty-one apparently healthy young male participants ([mean +/- SD] age = 20 +/- 1.8 years, body mass index = 24.8 +/- 3.3 kg/m(2)) completed in random order 3 treatment conditions: (1) ExCHO-80-minute resistance exercise bout while consuming CHO ( approximately 77 g CHO, 306 kcal); (2) ExPLA-identical exercise with a non=caloric placebo; and (3) NoExCHO-no-exercise trial of quiet sitting and CHO consumption. Blood samples were obtained before, during, and immediately postexercise, and 110 minutes after exercise. At 2 hours postexercise, they were provided a buffet of food from which they ate ad libitum. There was a significant time x treatment interaction for plasma ghrelin caused by a decline from pre- to postexercise in the 2 exercise conditions compared with an increase over time in the NoExCHO condition. At 110 minutes postexercise, ghrelin was 21% and 13% lower in ExCHO and ExPLA compared with NoExCHO (both Ps < .05). However, despite the lower ghrelin concentrations for the 2 exercise conditions, the subjective ratings of hunger were not lower for these conditions compared with the NoExCHO. There were no differences in absolute ad libitum energy intake from the buffet among the 3 conditions, but relative energy intake from the buffet accounting for the estimated cost of exercise was lowest among the 2 exercise conditions. We conclude that (1) weight lifting lowers plasma ghrelin concentrations during exercise and attenuates its rise during the postexercise period in young men and (2) the lower plasma ghrelin concentration is not associated with lower subjective feelings of hunger measured 100 minutes postexercise, but is associated with a lower relative food intake.

Regulators of Human White Adipose Browning: Evidence for Sympathetic Control and Sexual Dimorphic Responses to Sprint Interval Training

The conversion of white adipose to the highly thermogenic beige adipose tissue has been proposed as a potential strategy to counter the unfavorable consequences of obesity. Three regulators of this conversion have recently emerged but information regarding their control is limited, and contradictory. We present two studies examining the control of these regulators. Study 1: In 10 young men, the plasma concentrations of irisin and fibroblast growth factor 21 (FGF21) were determined prior to and during activation of the sympathetic nervous system via hypoxic gas breathing (FIO2 = 0.11). The measurements were performed twice, once with and once without prior/concurrent sympathetic inhibition via transdermal clonidine administration. FGF21 was unaffected by basal sympathetic inhibition (338±113 vs. 295±80 pg/mL; P = 0.43; mean±SE), but was increased during hypoxia mediated sympathetic activation (368±135); this response was abrogated (P = 0.035) with clonidine (269±93). Irisin was unaffected by sympathetic inhibition and/or hypoxia (P>0.21). Study 2: The plasma concentration of irisin and FGF21, and the skeletal muscle protein content of fibronectin type III domain containing 5 (FNDC5) was determined in 19 young adults prior to and following three weeks of sprint interval training (SIT). SIT decreased FGF21 (338±78 vs. 251±36; P = 0.046) but did not affect FNDC5 (P = 0.79). Irisin was decreased in males (127±18 vs. 90±23 ng/mL; P = 0.045) and increased in females (139±14 vs. 170±18). Collectively, these data suggest a potential regulatory role of acute sympathetic activation pertaining to the browning of white adipose; further, there appears to be a sexual dimorphic response of irisin to SIT.

High Resistance / Low Repetition vs. Low Resistance / High Repetition Training: Effects on Performance of Trained Cyclists

In order to investigate the effects of a resistance training modality on cycling performance, 23 trained club-level cyclists were placed into high resistance/low repetition (H-Res), low resistance/high repetition (H-Rep), or cycling-only groups for a 10-week program. All 3 groups followed the same cycling plan, but the H-Res and H-Rep groups added resistance training. Testing pre and post consisted of a graded incremental lactate profile test on an ergometer, with blood lactate being sampled. &OV0312;O2 values were measured to determine economy. Maximum strength testing of 4 strength exercises targeting the lower extremity musculature was conducted with the H-Res and H-Rep groups. There were significant gains in all 4 resistance training exercises (p = 0.05) for both H-Res and H-Rep, with the H-Res group having significantly greater gains than the H-Rep group had in the leg press exercise (p = 0.05). There were, however, no significant group × training differences (p < 0.05) found between the 3 training groups on the cycling test in lactate values or economy. It appears that for this population of cyclists, neither H-Res nor H-Rep resistance training provided any additional performance benefit in a graded incremental cycling test when compared with cycling alone over a training time of this length. It is possible that with this population, various factors such as acute fatigue, strength, and aerobic gains from the cycling training, in addition to well-developed bases of strength and conditioning from previous training, reduced differences between groups in both strength gains and cycling performance.