Insulin action in muscle and adipose tissue in type 2 diabetes: The significance of blood flow

Under normal metabolic conditions insulin stimulates microvascular perfusion(capillary recruitment) of skeletal muscle and subcutaneous adipose tissue and thus increases blood flow mainly after meal ingestion or physical exercise.This helps the delivery of insulinitself but also that of substrates and of other signalling molecules to multiple tissues beds and facilitates glucose disposal and lipid kinetics.This effect is impaired in insulin resistance and type 2 diabetes early in the development of metabolic dysregulation and reflects early-onset endothelial dysfunction.Failure of insulin to increase muscle and adipose tissue blood flow results in decreased glucose handling.In fat depots,a blunted postprandial blood flow response will result in an insufficient suppression of lipolysis and an increased spill over of fatty acids in the circulation,leading to a more pronounced insulin resistant state in skeletal muscle.This defect in blood flow response is apparent even in the prediabetic state,implying that it is a facet of insulin resistance and exists long before overt hyperglycaemia develops.The following review intends to summarize the contribution of blood flow impairment to the development of the atherogenic dysglycemia and dyslipidaemia.     

Role of insulin and insulin resistance in androgen excess disorders

Insulin has complex effects on cell growth, metabolism and differentiation, and these effects are mediated by a cell-surface bound receptor and eventually a cascade of intracellular signaling events. Among the several metabolic and growth-promoting effects of insulin, insulin resistance is defined as an attenuated effect of insulin on glucose metabolism, primarily the limited export of blood glucose into skeletal muscle and adipose tissue. On the other hand, not all the signaling pathways and insulin-responsive tissues are equally affected, and some effects other than the metabolic actions of insulin are overexpressed. Ovaries and the adrenal glands are two examples of tissues remaining sensitive to insulin actions where insulin may contribute to increased androgen secretion. Polycystic ovary syndrome (PCOS) is the most common form of androgen excess disorder (AED), and its pathogenesis is closely associated with insulin resistance. Patients with idiopathic hirsutism also exhibit insulin resistance, albeit lower than patients with PCOS. Although it is not as evident as in PCOS, patients with congenital adrenal hyperplasia may have insulin resistance, which may be further exacerbated with glucocorticoid overtreatment and obesity. Among patients with severe insulin resistance syndromes, irrespective of the type of disease, hyperinsulinemia promotes ovarian androgen synthesis independently of gonadotropins. It is highly debated in whom and how insulin resistance should be diagnosed and treated among patients with AEDs, including PCOS. It is not suitable to administer an insulin sensitizer relying on only some mathematical models used for estimating insulin resistance. Instead, the treatment decision should be based on the constellation of the signs, symptoms and presence of obesity; acanthosis nigricans; and some laboratory abnormalities such as impaired glucose tolerance and impaired fasting glucose.     

Lipid Mobilization Following Roux-en-Y Gastric Bypass Examined by Magnetic Resonance Imaging and Spectroscopy

Background  Recent developments of magnetic resonance imaging (MRI) and spectroscopy have made it possible to quantify lipid deposited in different tissues. To what extent an improvement of glucose tolerance shortly after Roux-en-Y gastric bypass surgery (RYGBP) is reflected in lipid levels in liver and skeletal muscle, markers of insulin resistance, has not been clarified. Methods  Whole-body MRI and MR spectroscopy (MRS) of liver and muscle and measurements of biochemical markers of glucose and lipid metabolism were performed at baseline and 1, 6, and 12 months following surgery in seven morbidly obese women. Volumes of adipose tissue depots and liver and muscle lipids were assessed from the MRI/MRS data. Results  At 1 month postoperatively, body mass index and visceral and subcutaneous adipose tissues were reduced by 9%, 26%, and 10%, respectively, whereas no reductions in intrahepatocellular or skeletal intramyocellular lipid concentrations were found. Free fatty acid and beta-hydroxybutyrate levels were elevated two- and sixfold, respectively; glucose and insulin levels were lowered, indicating increased insulin sensitivity. Further weight loss up to 1 year was associated with reductions in all investigated lipid depots investigated, with the exception of the intramyocellular compartment. Conclusion  RYGBP causes rapid lipid mobilization from visceral and subcutaneous adipose depots and enhanced free fatty acid flux to the liver. An exceptional disconnection between liver fat and insulin sensitivity occurs in the early dynamic phase after surgery. However, in the late phase, the energy restriction imposed by the surgical procedure also reduces the liver lipids, but not the intramyocellular lipids.     

Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice

Our aim was to study whether the absence of apolipoprotein (apo) C3, a strong inhibitor of lipoprotein lipase (LPL), accelerates the development of obesity and consequently insulin resistance. Apoc3(-/-) mice and wild-type littermates were fed a high-fat (46 energy %) diet for 20 weeks. After 20 weeks of high-fat feeding, apoc3(-/-) mice showed decreased plasma triglyceride levels (0.11 +/- 0.02 vs. 0.29 +/- 0.04 mmol, P < 0.05) and were more obese (42.8 +/- 3.2 vs. 35.2 +/- 3.3 g; P < 0.05) compared with wild-type littermates. This increase in body weight was entirely explained by increased body lipid mass (16.2 +/- 5.9 vs. 10.0 +/- 1.8 g; P < 0.05). LPL-dependent uptake of triglyceride-derived fatty acids by adipose tissue was significantly higher in apoc3(-/-) mice. LPL-independent uptake of albumin-bound fatty acids did not differ. It is interesting that whole-body insulin sensitivity using hyperinsulinemic-euglycemic clamps was decreased by 43% and that suppression of endogenous glucose production was decreased by 25% in apoc3(-/-) mice compared with control mice. Absence of apoC3, the natural LPL inhibitor, enhances fatty acid uptake from plasma triglycerides in adipose tissue, which leads to higher susceptibility to diet-induced obesity followed by more severe development of insulin resistance. Therefore, apoC3 is a potential target for treatment of obesity and insulin resistance.     

Nutrition,insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome

Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index(BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome(MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods(fat). However, high-carbohydrate rich(CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering highdensity lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.     

Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice

The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin(ob/ob) mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased approximately 70%. In response to a glucose challenge, Scd1(-/-) leptin(ob/ob) mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1(-/-) leptin(ob/ob) mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of beta-cells, resulting in an increased risk of diabetes.     

Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat: a link between catch-up growth and later metabolic syndrome

Catch-up growth, a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases, is characterized by hyperinsulinemia and an accelerated rate for recovering fat mass, i.e., catch-up fat. To identify potential mechanisms in the link between hyperinsulinemia and catch-up fat during catch-up growth, we studied the in vivo action of insulin on glucose utilization in skeletal muscle and adipose tissue in a previously described rat model of weight recovery exhibiting catch-up fat caused by suppressed thermogenesis per se. To do this, we used euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose technique. After 1 week of isocaloric refeeding, when body fat, circulating free fatty acids, or intramyocellular lipids in refed animals had not yet exceeded those of controls, insulin-stimulated glucose utilization in refed animals was lower in skeletal muscles (by 20-43%) but higher in white adipose tissues (by two- to threefold). Furthermore, fatty acid synthase activity was higher in adipose tissues from refed animals than from fed controls. These results suggest that suppressed thermogenesis for the purpose of sparing glucose for catch-up fat, via the coordinated induction of skeletal muscle insulin resistance and adipose tissue insulin hyperresponsiveness, might be a central event in the link between catch-up growth, hyperinsulinemia and risks for later metabolic syndrome.     

Adipose tissue fibrosis

The increasing prevalence of obesity causes a major interest in white adipose tissue biology. Adipose tissue cells are surrounded by extracellular matrix proteins whose composition and remodeling is of crucial importance for cell function. The expansion of adipose tissue in obesity is linked to an inappropriate supply with oxygen and hypoxia development. Subsequent activation of hypoxia inducible factor 1 (HIF-1) inhibits preadipocyte differentiation and initiates adipose tissue fibrosis. Thereby adipose tissue growth is limited and excess triglycerides are stored in ectopic tissues. Stressed adipocytes and hypoxia contribute to immune cell immigration and activation which further aggravates adipose tissue fibrosis. There is substantial evidence that adipose tissue fibrosis is linked to metabolic dysfunction, both in rodent models and in the clinical setting. Peroxisome proliferator activated receptor gamma agonists and adiponectin both reduce adipose tissue fibrosis, inflammation and insulin resistance. Current knowledge suggests that antifibrotic drugs, increasing adipose tissue oxygen supply or HIF-1 antagonists will improve adipose tissue function and thereby ameliorate metabolic diseases.     

Tissue-specific effects of rosiglitazone and exercise in the treatment of lipid-induced insulin resistance

Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat-fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulin-stimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase alpha1 activity; increased expression of Akt1, peroxisome proliferator-activated receptor gamma coactivator 1, and GLUT4; and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce divergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.     

CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness

High levels of intramyocellular triglycerides are linked to insulin resistance and reflect conditions in which fatty acid uptake exceeds the myocyte oxidative capacity. CD36 facilitates fatty acid uptake by myocytes, and its level is increased in diabetic muscle. We examined whether high CD36 levels would increase lipid content and susceptibility of myocytes to fatty acid-induced insulin resistance. C2C12 myoblasts with stable fivefold overexpression of CD36 (+CD36) were generated and differentiated into myotubes. CD36 expression increased palmitate uptake, oxidation, and lipid incorporation but had no effect on cell triglyceride content. Importantly, glycerol release increased fourfold, indicating enhanced triglyceride turnover and suggesting that CD36 promotes futile cycling of fatty acids into triglyceride. When +CD36 myotubes were incubated with excess palmitate, CD36 enhancement of glycerol release was blunted, triglyceride content increased above wild-type cells, and insulin resistance of glucose metabolism was observed. In contrast to palmitate, oleate-treated +CD36 cells exhibited enhanced glycerol release and no alteration in triglyceride content or insulin responsiveness. Furthermore, increased expression of hormone-sensitive lipase was measured with CD36 expression and with oleate treatment. In conclusion, high futile cycling of fatty acids is important for maintaining low triglyceride content and insulin responsiveness of myocytes. The findings provide a new perspective related to the etiology of lipid accumulation and insulin resistance in myocytes.     

Blood lipid profile in ischaemia reperfusion injury

BACKGROUND: Lipid components are considered to play an important role in ischaemia reperfusion injury although the mechanism of their action remains unknown. Accumulation of lipid metabolites in ischaemic tissues is a consistent observation, but exactly how these lipids are cleared from the tissues by the circulating blood during reperfusion is still open to speculation. In the present study, levels of blood lipids (fatty acids, phospholipids, triglycerides, cholesterol, lysolecithin and lysolecithin platelet activating factor (lyso PAF)) and the enzyme phospholipase A2 were determined in an experimental animal model (dogs) of ischaemic reperfusion injury. METHODS: The injury was induced by 4 h of aortic clamping followed by 2 h of reperfusion (unclamping). Blood samples were collected before clamping and at predetermined time intervals (0, 15, 60 and 120 min) after the release of clamp. The lipid contents were analysed and compared with sham-treated control dogs. RESULTS: The results showed significantly elevated levels of triglycerides and phospholipase A2, during ischaemia and reperfusion in experimental animals indicating tissue damage in the ischaemic phase continuing into the reperfusion phase and the risk of systemic damage from these toxic substances. Total fatty acid content in the circulating blood showed decreasing trends during the same time interval, which suggested possible reduced clearance of accumulated fatty acids from the affected tissues. Serum cholesterol, phospholipids, lyso PAF and lysolecithin did not show any significant variation compared with control dogs. CONCLUSIONS: It is possible that the delayed clearance of fatty acids may be due to the presence of fatty acids binding proteins in the ischaemic tissue, which trap these fatty acids in the tissues during ischaemic reperfusion injury. The prolonged retention of the accumulated fatty acids in the tissues in association with elevated triglycerides and phospholipase A2 activity may contribute to ischaemia reperfusion injury.     

Chronic triiodothyronine supplementation does not improve the lipoprotein disorders of mildly uremic rats

The present study was performed to appreciate the potential role that thyroid deficiency could play in the energy homeostasis and lipid metabolism of experimental chronic renal failure. For this purpose, 12 uremic rats that were supplemented with T3 (0.4 microgram/100 g body weight/day) during 5 weeks by means of osmotically driven minipumps were compared to 12 unsupplemented uremic rats and 12 control rats. The chronic supplementation of uremic rats with T3 induced no significant change in body weight gain or in the serum concentration of insulin, glucose, glycerol, nonesterified fatty acids, total triglycerides (TG), total cholesterol, and total choline phospholipids. Similarly, the metabolism of TG-rich lipoproteins was not affected by the supplementation with T3 in these uremic rats as appreciated by TG production or TG degradation (adipose tissue lipoprotein lipase activity). T3 administration induced a significant decrease in serum beta-hydroxybutyrate concentration and an increase in serum lactate concentration. Furthermore, heparin-releasable hepatic TG lipase activity as expressed per total liver mass was decreased in uremic rats treated with T3. The latter changes were observed in the absence of modifications of serum glucose or TG concentration. We conclude from these observations that rats with a moderate degree of chronic uremia do not seem to have a cellular thyroid deficiency sufficient to disturb their energy or lipid metabolism.     

Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance

Adipose tissue glyceroneogenesis generates glycerol 3-phosphate, which could be used for fatty acid esterification during starvation. To determine whether increased glyceroneogenesis leads to increased fat mass and to explore the role of obesity in the development of insulin resistance, we overexpressed PEPCK, a regulatory enzyme of glyceroneogenesis in adipose tissue. Transgenic mice showed a chronic increase in PEPCK activity, which led to increased glyceroneogenesis, re-esterification of free fatty acids (FFAs), increased adipocyte size and fat mass, and higher body weight. In spite of increased fat mass, transgenic mice showed decreased circulating FFAs and normal leptin levels. Moreover, glucose tolerance and whole-body insulin sensitivity were preserved. Skeletal muscle basal and insulin-stimulated glucose uptake and glycogen content were not affected, suggesting that skeletal muscle insulin sensitivity is normal in transgenic obese mice. Our results indicate the key role of PEPCK in the control of FFA re-esterification in adipose tissue and, thus, the contribution of glyceroneogenesis to fat accumulation. Moreover, they suggest that higher fat mass without increased circulating FFAs does not lead to insulin resistance or type 2 diabetes in these mice.     

Energy substrates in parenteral nutrition]

The most appropriate nutriment for total parenteral feeding (TPF) must be nutritionally efficient, safe and easy to use. Glucose is the most used carbohydrate as it has most of these qualities, as well as a high rate of metabolism by all tissues. It has not been clearly demonstrated that the administration of exogenous insulin with glucose improves nitrogen retention. Substitutes for glucose, such as fructose, maltose, galactose or polyols (xylitol, surbitol, glycerol) are not really superior to glucose itself. On the other hand, they have major side-effects. Therefore, they are not much used as energy substrates for TPF, at least not for long term TPF. Intravenous fat emulsions have taken an important place as a source of energy during TPF. Fat emulsions containing long chain triglycerides (LCT) supply essential fatty acids (EFA) (linolenic and linoleic acids), thus preventing EFA deficiency. The metabolism of fat emulsions is influenced by various factors: age, metabolic and nutritional status, the amount of glucose intake, insulin deficiency, sepsis, heparin therapy. Recently, medium chain triglycerides (MCT) have been proposed as an alternative energy source. The latter are cleared more rapidly from the blood, and are therefore less liable to be deposited in the liver and adipose tissue; they are also oxidized more quickly and more completely. MCT are safe to use at a rate of less than 0.12 g.kg-1.h-1 and with a MCT/LCT ratio less than 3 to 1. The simultaneous administration of glucose prevents an acceleration of ketogenesis. MCT/LCT emulsions are a safe and effective source of calories. It is important that those patients for whom such nutriment may be of particular interest should be identified. Fat emulsions associated with glucose seem to be more efficient in terms of nitrogen sparing effect than glucose alone. They also avoid the problems due to the infusion of large amounts of glucose (excessive carbon dioxide production, fatty infiltration of the liver), while there is no EFA deficiency. If the infusion of TPF nutriment must be continuous in intensive care patients, or during the postoperative period, cyclic nocturnal parenteral nutrition over a 12 or 16 hour period may be used in patients who are not in a catabolic state, or only mildly so. This is a safe and efficient method of nutritional support, which reduces the incidence rate of TPF-induced cholestasis.     

interrelationships between ghrelin,insulin and glucose homeostasis: physiological relevance

Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated(AG) and unacylated(UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesityrelated disorders. However, due to the complexity ofits biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.     

Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies

Increased supply of fatty acids to muscle and liver is causally involved in the insulin resistance syndrome. Using a tissue microdialysis technique in Wistar and Zucker fatty (ZF) rats, we determined tissue glycerol levels as a marker of lipolysis in gastrocnemius muscle (gMT), subcutaneous adipose (SAT), and visceral adipose tissue (VAT) as well as the reduction of plasma free fatty acids, glycerol, and triglycerides caused by the antilipolysis-specific adenosine-A1 receptor agonist (ARA). In Wistar and ZF rats, ARA significantly lowered dialysate glycerol levels in SAT, VAT, and gMT. Whereas in SAT and VAT the decrease in dialysate glycerol indicated adipocytic antilipolysis, this decrease in gMT was not caused by a direct effect of ARA on intramyocellular lipolysis, as demonstrated by the lack of inhibition of the protein kinase A activity ratio in gMT. In addition, no differences of the fed-starved-refed dynamics of intramyocellular triglyceride levels compared with untreated controls were measured by in vivo (1)H-spectroscopy, excluding any adenylate cyclase-independent antilipolysis in muscle. Treatment with ARA resulted in pronounced reductions of plasma free fatty acids, glycerol, and triglycerides. Furthermore, in ZF rats, ARA treatment caused an immediate improvement of peripheral insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp technique.