Surgical removal of visceral adipose tissue: Effects on insulin action

Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus.     

Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.     

Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance

In-vitro studies have implicated the A(1) adenosine receptor (A(1)AR) of adipocytes in inhibition of lipolysis, stimulation of lipogenesis and enhancement of the action of insulin on glucose metabolism. To determine whether any of these activities were physiologically relevant in an intact animal, A(1)AR was overexpressed in adipose tissue of transgenic mice. Lower plasma free fatty acid (FFA) levels were observed in the transgenic mice relative to the litter-matched controls, supporting a significant physiological role for adipocyte A(1)AR in the control of lipolysis. However, no differences were observed in body weights or body composition. On a high fat diet, both the transgenic mice and the litter matched controls, male and female, became equally obese. Unlike the control mice, however, the transgenic mice did not develop insulin resistance, as demonstrated by serum glucose and insulin levels and glucose and insulin tolerance tests. These findings demonstrate that adipocyte A(1)AR plays an important physiological role in the control of insulin sensitivity in an intact animal and therefore should be considered to be a potential therapeutic target for the treatment of obesity-related insulin resistance and type 2 diabetes.     

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Reduced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression and mitochondrial dysfunction in adipose tissue have been associated with obesity and insulin resistance. Whether this association is causally involved in the development of insulin resistance or is only a consequence of this condition has not been clearly determined. Here we studied the effects of adipose-specific deficiency of PGC-1α on systemic glucose homeostasis. Loss of PGC-1α in white fat resulted in reduced expression of the thermogenic and mitochondrial genes in mice housed at ambient temperature, whereas gene expression patterns in brown fat were not altered. When challenged with a high-fat diet, insulin resistance was observed in the mutant mice, characterized by reduced suppression of hepatic glucose output. Resistance to insulin was also associated with an increase in circulating lipids, along with a decrease in the expression of genes regulating lipid metabolism and fatty acid uptake in adipose tissues. Taken together, these data demonstrate a critical role for adipose PGC-1α in the regulation of glucose homeostasis and a potentially causal involvement in the development of insulin resistance.     

Mechanisms of insulin resistance in rat models of hypertension and their relationships with salt sensitivity.

Several lines of evidence suggest that insulin resistance and the resultant hyperinsulinaemia are causally related to hypertension. Insulin actions are initiated by binding to a high-affinity transmembrane protein receptor which is present in all mammalian cells. These effects are predominant in skeletal muscle, liver, and fat and involve a number of tissue-specific and biochemically diverse events. Less well known are effects of insulin occurring in tissues not usually considered as insulin targets, which are hypothetical contributors to the pro-hypertensive action of the hormone. These effects include activation of renal sodium reabsorption, stimulation of the sympathetic nervous system, growth-promoting activity on vascular smooth muscle cells, and modulation of transmembrane cation transport. Epidemiological investigations have implicated sodium intake in the pathogenesis of hypertension. Because of the sodium-retaining effects of insulin, it has been postulated that insulin resistance with associated hyperinsulinaemia may be critical for the pathogenesis of salt-sensitivity in essential hypertensive subjects. Insulin resistance is present also in strains of rats with genetic hypertension that can be utilized as models to study the molecular mechanisms of this abnormality. In the present article, we summarize the current knowledge of the mechanisms of insulin resistance in rat models of arterial hypertension in which decreased sensitivity to insulin occurs and propose a rationale hypothesis that links insulin resistance with salt-sensitivity and hypertension.     

Low-carbohydrate diet disrupts the association between insulin resistance and weight gain

The cornerstone to treat metabolic syndrome and insulin resistance is dietary intervention. Both low-carbohydrate diet (LCD) and low-fat diet (LFD) have been reported to induce weight loss and improve these conditions. One of the factors associated with a subject's adherence to the diet is satiety. The aim of this study was to evaluate the effects of LCD and LFD on body weight, appetite hormones, and insulin resistance. Twenty guinea pigs were randomly assigned to LCD or LFD (60%:10%:30% or 20%:55%:25% of energy from fat/carbohydrate/protein, respectively) for 12 weeks. Weight and food intake were recorded every week. After this period, animals were killed and plasma was obtained to measure plasma glucose and insulin, appetite hormones, and ketone bodies. Guinea pigs fed LCD gained more weight than those fed LFD. The daily amount of food intake in grams was not different between groups, suggesting that food density and gastric distension played a role in satiety. There was no difference in leptin levels, which excludes the hypothesis of leptin resistance in the LCD group. However, plasma glucagon-like peptide-1 was 47.1% lower in animals fed LCD (P < .05). Plasma glucose, plasma insulin, and insulin sensitivity were not different between groups. However, the heavier animals that were fed LFD had impairment in insulin sensitivity, which was not observed in those fed LCD. These findings suggest that satiety was dependent on the amount of food ingested. The weight gain in animals fed LCD may be related to their greater caloric intake, lower levels of glucagon-like peptide-1, and higher protein consumption. The adoption of LCD promotes a unique metabolic state that prevents insulin resistance, even in guinea pigs that gained more weight. The association between weight gain and insulin resistance seems to be dependent on high carbohydrate intake.     

Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats

Adiposity, particularly increased intra-abdominal fat, is a predisposing factor for the development of insulin resistance in obesity and type 2 diabetes. Visceral fat seems to differ from subcutaneous adipose tissue in adipocytokine production. This fat depot-related difference has been viewed as an important mechanism by which adipose tissue exerts its paracrine/autocrine effects on peripheral tissue in modulating insulin sensitivity. We have studied the relative expression of adiponectin in visceral versus subcutaneous fat in Zucker fatty versus lean rats. Visceral fat, as opposed to subcutaneous fat, exhibited relatively higher levels of adiponectin production in lean animals. However, in Zucker fatty rats, adiponectin expression in visceral fat was suppressed to basal levels, which correlated with significantly reduced plasma adiponectin concentrations and increased insulin resistance. These results suggest that an impaired depot-specific expression of adiponectin is a contributing factor for the development of insulin resistance in Zucker fatty rats.     

Mechanisms of insulin resistance caused by nutrient toxicity.

Insulin resistance, the impaired action of insulin, has been linked to many important consequences, including Type 2 diabetes, hypertension, dyslipidemia, acanthosis nigricans and polycystic ovarian syndrome. Although there are some genetic causes for insulin resistance, the most common cause is an excess of nutrition a condition called "Nutrient Toxicity". Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissues and excess fat can cause insulin resistance in the liver. High fat feeding and fat infusion rapidly lead to the development of insulin resistance caused by impairment in glucose transport. Other studies have shown defects in insulin signaling possibly secondary to activation of Protein Kinase C resulting from the accumulation of active fatty acyl CoA's. Glucose toxicity has been studied both in vivo and in vitro. In vivo it has been shown that rats over-expressing the gluconeogenic enzyme Phosphoenol Pyruvate Carboxykinase (PEPCK) develop insulin resistance in fat and muscle tissues and some features of the metabolic syndrome including mild obesity and dyslipidemia. Excess glucose entry in fat cells results in increased flux through the hexosamine biosynthesis pathway leading to activation of protein kinase C and impairment of glucose transport. Obesity resulting from excess nutrient intake can also cause insulin resistance by an increase in the production of agents that impair insulin action such as TNFalpha and resistin and a decrease in the production of an insulin sensitizing compound adiponectin. Both glucose and free fatty acids acutely stimulate insulin secretion but chronic exposure to high levels of either nutrient leads to impairment of beta cell function. The combination of insulin resistance and beta cell failure leads to diabetes. Nutrient toxicity is thus the driving cause of the diabetes epidemic that is being recorded around the world.     

Clinical approaches to healthier diet modifications.

There is a strong relation between diet and risk factors for cardiovascular diseases. Generally a high fat consumption will increase the serum cholesterol level. Different fatty acids have different effects on total cholesterol, LDL and HDL lipoproteins and therefore on the risk for cardiovascular diseases. This knowledge was translated into guidelines for a healthy diet and in advices to use less fat. In reality it was not easy for physicians to reach a substantial reduction in total cholesterol by limiting the fat consumption. A recent investigation in Belgium showed that the median reduction obtained by dietary changes through general practitioners was only 3.5%. In medical education not much attention is paid to the communication of the "fat message". In addition, individual patients have frequently multiple risk factors e.g. abdominal obesity, insulin resistance, diabetes, hypertension and a sedentary lifestyle. Therefore in the clinical setting an integrated approach is needed, in which dietary advice is supported by behavioural therapy and suggestions to increase physical activity. Currently there is a debate on the preference of a low fat or a modified fat diet. A low fat diet is rich in carbohydrates and a modified fat diet is rich in mono-unsaturated fatty acids. Recent investigations in diabetic patients are in favour of a modified fat diet. This has the advantage that in practice the possibilities for realizing a low saturated fat diet are increased.     

Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue

OBJECTIVE: Trans-fatty acids (TFAs) are formed during partial hydrogenation of vegetable oils and are shown to be more atherogenic than saturated fatty acids (SFAs). Our previous study showed that dietary TFAs decrease adipose tissue insulin sensitivity to a greater extent than SFAs in rats. We hypothesized that the effects of these fatty acids on insulin sensitivity could be mediated through an alteration in gene expression. In the current study we have investigated the effects of dietary TFAs or SFAs on expression of genes associated with insulin sensitivity in rat adipose tissue. DESIGN AND METHODS: Male weanling Wistar/NIN rats were divided into four groups and fed one of the following diets containing 10% fat (g/100 g diet) differing only in the fatty acid composition for 3 months: control diet (3.7% linoleic acid (LA)), SFA diet (5% SFA), TFA diet 1 (1.5% TFA + 1% LA) and TFA diet 2 (1.5% TFA + 2% LA). The mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), lipoprotein lipase (LPL), glucose transporter-4 (GLUT4), resistin and adiponectin was analyzed in epididymal fat using RT-PCR. The effects of TFA were studied at two levels of LA to understand the beneficial effects of LA over the effects of TFA. RESULTS: Both dietary SFA and TFA upregulated the mRNA levels of resistin. Dietary SFA downregulated adiponectin and GLUT4 and upregulated LPL, while TFA downregulated PPARgamma and LPL. The effects of dietary TFA on PPARgamma and resistin were not counteracted by increased LA (TFA diet 2). CONCLUSION: The effects of SFAs on the aforementioned genes except PPARgamma could be extrapolated towards decreased insulin sensitivity, while only the alteration in the mRNA levels of PPARgamma and resistin could be associated with insulin resistance in TFA-fed rats. These findings suggest that dietary SFAs and TFAs alter the expression of different genes associated with insulin sensitivity in adipose tissue.     

Diet-genotype interactions in the early development of obesity and insulin resistance in mice with a genetic deficiency in tumor necrosis factor-α

The onset of insulin resistance, the sites of action, and the mechanisms through which tumor necrosis factor-α (TNF-α) exacerbates the increase in adiposity and the development of insulin resistance in mice fed high-fat (HF) diet remain unclear. Here we investigated the effect of TNF-α deficiency on adiposity and insulin resistance during the initial 1 to 4 weeks of HF feeding. We examined body weight; the distribution of white adipose tissue (WAT); homeostasis model assessment; and levels of leptin, resistin, and adiponectin in the initial 4 weeks of HF feeding in TNF-α knockout (KO) mice and wild-type (WT) controls. Through 4 weeks of HF feeding, KO mice, unlike WT mice, maintained normal insulin sensitivity. Although WT-HF and KO-HF mice had similar levels of WAT at this time, KO-HF mice had more subcutaneous and less epididymal fat than WT-HF mice. The KO-HF mice also had less liver fat than the WT-HF mice. Finally, KO-HF mice had lower plasma levels of resistin than WT-HF mice. These data demonstrate that genetic lack of TNF-α protects insulin sensitivity during the early phase of HF feeding in the absence of altered total WAT. The data also suggest that the mechanism maintaining insulin sensitivity in the absence of TNF-α may involve redirection of the fat deposition to the metabolically more inert subcutaneous depot or decreases in circulating resistin and resultant decrease in liver fat deposition. The efficacy of therapeutic measures designed to counteract the effects of TNF-α may be increased during the early stages of obesity and insulin resistance.     

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

Aims/hypothesis The aim of this study was to explore whether fat cell size in human subcutaneous and omental adipose tissue is independently related to insulin action and adipokine levels. Materials and methods Fat cells were prepared from abdominal subcutaneous biopsies obtained from 49 type 2 diabetic and 83 non-diabetic subjects and from omental biopsies obtained from 37 non-diabetic subjects. Cell size and insulin action on glucose uptake capacity in vitro were assessed in isolated fat cells. Insulin sensitivity in vivo was assessed with euglycaemic-hyperinsulinaemic clamps. Fasting blood samples were collected and adipokines and NEFA were measured. Results Negative correlations were found between subcutaneous fat cell size and insulin sensitivity assessed as M-value during clamp and as insulin action on glucose uptake in fat cells in vitro. This was seen in non-diabetic subjects after including age, sex and BMI in the analyses. No such relationship was found in type 2 diabetic subjects. In both groups, subcutaneous fat cell size correlated positively and independently with plasma levels of leptin but not to any of the other assessed adipokines. In non-diabetic subjects, omental fat cell size was independently and negatively correlated with insulin action in subcutaneous, but not omental, fat cells in vitro. Conclusions/interpretation Fat cell enlargement is associated with insulin resistance in non-diabetic individuals independently of BMI. This was not seen in type 2 diabetic subjects, suggesting that after development of type 2 diabetes other factors, not related to fat cell size, become more important for the modulation of insulin resistance.     

Understanding the pathogenesis of type 2 diabetes: can we get off the metabolic merry-go-rounds?

The aetiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. The concordance of NIDDM in identical twins and differences in the prevalence rate of NIDDM between different racial groups suggest a genetic cause. Hyperglycaemia in established diabetes is caused by a combination of hepatic insulin resistance, impaired peripheral (muscle and fat) glucose uptake and a defect in glucose-mediated insulin secretion. However, it is not known if these defects are all inherited or if one can cause the others. This uncertainty is due to the fact that hyperglycaemia per se can cause defects in insulin action and insulin secretion that resemble those found in NIDDM. Furthermore the elevated free fatty acid (FFA) levels found when NIDDM is associated with obesity are known to cause both peripheral and hepatic insulin resistance. Recently we have demonstrated the mechanism by which elevated FFA levels can cause hepatic insulin resistance. However, we also have evidence that the converse holds in that genetically engineered hepatic insulin resistance in a transgenic rat model leads to obesity. Thus an understanding of the pathogenesis of NIDDM is complicated by the fact that hyperglycaemia and obesity can be both causes and consequences of insulin resistance. To overcome these difficulties, studies in young, euglycaemic diabetes-prone subjects have been conducted. Results suggest that there may be different causes for NIDDM in different racial groups.     

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

Summary 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 3 H-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<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<0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%,p< 0.05 in 6 out of 8 muscles), white adipose (27%,p<0.05) and brown adipose tissue (76%,p<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. We conclude that high fat feeding, without a major increase in body weight or basal hyperinsulinaemia, causes widespread but varying degrees of in vivo insulin resistance in peripheral tissues, with major effects in principally oxidative skeletal muscle.     

Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome

BACKGROUND: Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin-lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long-term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low-calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated. METHODS: Forty obese women with PCOS were enrolled in the study. After a 1-month diet, according to single-blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured. RESULTS: We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low-calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA-S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination. CONCLUSIONS: We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.     

Leptin in relation to the lipodystrophy-associated metabolic syndrome

Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome.     

Age‐related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians

It is widely known that advancing age is associated with impaired glucose handling. A unifying hypothesis explaining the relationship between aging and insulin resistance might encompass four main pathways, namely: (a) anthropometric changes (relative and absolute increase in body fat combined with a decline in fat free mass) which could be the anatomic substrate for explaining the reduction in active metabolic tissue; (b) environmental causes, mainly diet style and physical activity; (c) neuro-hormonal variations [decline in plasma dehydroepandrosterone sulphate (DHEAS) and IGF-1]; and finally (d) the rise in oxidative stress. Indeed previous studies have also investigated the occurrence and the degree of insulin resistance in healthy centenarians. Such data demonstrated that age-related insulin resistance is not an obligatory finding in the elderly and that healthy centenarians have a preserved insulin action compared to aged subjects. Why insulin action is preserved in centenarians is still not known. Nevertheless, a possible approach to the question is to outline the centenarians' anthropometric, endocrine and metabolic characteristics in order to design a clinical picture of such metabolic "successful aging". According to the remodeling theory of age, the preserved insulin action in centenarians might be the net result of the continuous adaptation of the body to the deleterious changes that occur over time. Nevertheless, only future longitudinal studies specifically designed to investigate the relationship between extreme old age and degree of insulin sensitivity will provide a conclusive answer with regard to the pathophysiology of adaptive metabolic changes occurring in the elderly.     

Dietary fatty acids and insulin resistance

High-fat diets have been associated with insulin resistance, a risk factor for both Type II diabetes and heart disease. The effect of dietary fat on insulin varies depending on the type of fatty acid consumed. Saturated fatty acids have been consistently associated with insulin resistance. On the other hand, medium and long-chain fatty acid intakes are associated with insulin sensitivity, as are high intakes of ϕ3 fatty acids. Trans fatty acids appear to potentiate insulin secretion, at least in the short-term, to a greater degree than cis fatty acids. This may reflect chronic alterations in insulin sensitivity, although this remains to be tested. In summary, although it must be emphasized that all diets high in fat cause insulin resistance relative to high-carbohydrate diets, it appears that dietary saturated, short-chain and ϕ6 fatty acids have the most deleterious effects on insulin action.     

Lipolysis and the antilipolytic effect of insulin in adipocytes from rats adapted to a high-protein diet

Free fatty acid (FFA) mobilization during fasting was investigated in rats fed a high-protein, carbohydrate-free (HP) diet (70% casein, 8% fat, wt/wt) or a balanced diet (66% carbohydrate, 17% casein, 8% fat) for 30 to 40 days. In vivo, rats on the HP diet showed reduced rates of plasma FFA increase during fasting. Their blood sugar remained unchanged and was higher than that of control rats 24 hours after removal of food. In the fed state, serum insulin levels were smaller in HP-fed rats but did not differ significantly in the two experimental groups during fasting. In vitro, the rates of glycerol and FFA release by epididymal fat pads obtained from fasted rats were similar in rats consuming the HP diet. Fat cells isolated from rats on the HP diet also had reduced rates of basal lipolysis. Furthermore, they showed a significant increase in responsiveness to the lipolytic action of noradrenaline and an increase in both sensitivity and responsiveness to the inhibitory effect of insulin on noradrenaline-stimulated lipolysis. Adipocytes from HP-fed and control rats had mean diameters of 51 and 60 mu, respectively, and estimated average volumes of 90 and 142 pL. On the basis of existing data on the correlation between size and lipolytic activity of fat cells, the smaller size of the adipocytes from HP-fed rats might account for the lower rate of basal lipolysis but not for the increased response to the hormones. The increased sensitivity of fat cells to the antilipolytic action of insulin may have been an important factor in the reduced lipomobilization during fasting in rats under the high-protein regimen.