Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.     

Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice

To study the contributions of insulin-dependent vs. insulin-independent mechanisms to intravenous glucose tolerance (K(G)), 475 experiments in mice were performed. An intravenous glucose bolus was given either alone or with exogenous insulin or with substances modulating insulin secretion and sensitivity. Seven samples were taken over 50 min. Insulin [suprabasal area under the curve (DeltaAUC(ins))] ranged from 0 to 100 mU. ml(-1). 50 min. After validation against the euglycemic hyperinsulinemic clamp, the minimal model of net glucose disappearance was exploited to analyze glucose and insulin concentrations to measure the action of glucose per se independent of dynamic insulin (S(G)) and the combined effect of insulin sensitivity (S(I)) and secretion. Sensitivity analysis showed that insulin [through disposition index (DI)] contributed to glucose tolerance by 29 +/- 4% in normal conditions. In conditions of elevated hyperinsulinemia, contribution by insulin increased on average to 69%. K(G) correlated with DI but was saturated for DeltaAUC(ins) above 15 mU. ml(-1). 50 min. Insulin sensitivity related to DeltaAUC(ins) in a hyperbolic manner, whereas S(G) did not correlate with the insulin peak in the physiological range. Thus glucose tolerance in vivo is largely mediated by mechanisms unrelated to dynamic insulin and saturates with high insulin.     

Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic beta-cell function and mass through IRS2 in diabetic rats.

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic beta-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic beta-cell mass. This resulted from stimulated beta-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, beta-cell mass was maintained in HF rats just as much as in control rats via increased individual beta-cell size and neogenesis from precursor cells. Consistent with the results of beta-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize beta-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate beta-cell function and mass to overcome insulin resistance in two different pathways.     

CB(1) antagonism restores hepatic insulin sensitivity without normalization of adiposity in diet-induced obese dogs

The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB(1) receptor improves insulin sensitivity (S(I)). However, it is unknown whether this improvement is due to the direct effect of CB(1) blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in S(I) and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB(1) antagonist rimonabant. S(I) was assessed (n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg·kg(-1)·day(-1) RIM; n = 11) and placebo (n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD (week -6) after HFD but before treatment (week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in S(I). Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB(1) receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass.     

Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance

The purpose of the present study was to determine whether fructose is the nutrient mediator of sucrose-induced insulin resistance and glucose intolerance. Toward this end, male rats were fed a purified starch diet (68% of total calories) for a 2-wk baseline period. After this, rats either remained on the starch (ST) diet or were switched to a sucrose (SU, 68% of total calories), fructose/glucose (F/G, 34/34% of total calories), or fructose/starch (F/ST, 34/34% of total calories) diet for 5 wk. Rats then underwent either an intravenous glucose tolerance test (n = 10/diet) or a euglycemic, hyperinsulinemic clamp (n = 8 or 9/diet). Incremental glucose and insulin areas under the curve in SU, F/G, and F/ST were on average 61 and 29% greater than ST, respectively, but not significantly different from one another. During clamps, glucose infusion rates (mg. kg(-1). min(-1)) required to maintain euglycemia were significantly lower (P < 0.05) in SU, F/G, and F/ST (13.4 +/- 0.9, 9. 5 +/- 1.7, 11.3 +/- 1.3, respectively) compared with ST (22.8 +/- 1. 1). Insulin suppression of glucose appearance (mg. kg(-1). min(-1)) was significantly lower (P < 0.05) in SU, F/G, and F/ST (5.6 +/- 0.5, 2.2 +/- 1.2, and 6.6 +/- 0.7, respectively) compared with ST (9.6 +/- 0.4). Insulin-stimulated glucose disappearance (mg. kg(-1). min(-1)) was significantly lower (P < 0.05) in SU, F/G, and F/ST (17. 9 +/- 0.6, 16.2 +/- 1.3, 15.3 +/- 1.8, respectively) compared with ST (24.7 +/- 1.2). These data suggest that fructose is the primary nutrient mediator of sucrose-induced insulin resistance and glucose intolerance.     

Protein-restriction diet during the suckling phase programs rat metabolism against obesity and insulin resistance exacerbation induced by a high-fat diet in adulthood

Protein restriction during the suckling phase can malprogram rat offspring to a lean phenotype associated with metabolic dysfunctions later in life. We tested whether protein-caloric restriction during lactation can exacerbate the effect of a high-fat (HF) diet at adulthood. To test this hypothesis, we fed lactating Wistar dams with a low-protein (LP; 4% protein) diet during the first 2 weeks of lactation or a normal-protein (NP; 23% protein) diet throughout lactation. Rat offspring from NP and LP mothers received a normal-protein diet until 60 days old. At this time, a batch of animals from both groups was fed an HF (35% fat) diet, while another received an NF (7% fat) diet. Maternal protein-caloric restriction provoked lower body weight and fat pad stores, hypoinsulinemia, glucose intolerance, higher insulin sensitivity, reduced insulin secretion and altered autonomic nervous system (ANS) function in adult rat offspring. At 90 days old, NP rats fed an HF diet in adulthood displayed obesity, impaired glucose homeostasis and altered insulin secretion and ANS activity. Interestingly, the LP/HF group also presented fat pad and body weight gain, altered glucose homeostasis, hyperleptinemia and impaired insulin secretion but at a smaller magnitude than the NP-HF group. In addition, LP/HF rats displayed elevated insulin sensitivity. We concluded that protein-caloric restriction during the first 14 days of life programs the rat metabolism against obesity and insulin resistance exacerbation induced by an obesogenic HF diet.     

Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.     

Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis

Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.     

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.     

Partial restoration of dietary fat induced metabolic adaptations to training by 7 days of carbohydrate diet.

We tested the hypothesis that a shift to carbohydrate diet after prolonged adaptation to fat diet would lead to decreased glucose uptake and impaired muscle glycogen breakdown during exercise compared with ingestion of a carbohydrate diet all along. We studied 13 untrained men; 7 consumed a high-fat (Fat-CHO; 62% fat, 21% carbohydrate) and 6 a high-carbohydrate diet (CHO; 20% fat, 65% carbohydrate) for 7 wk, and thereafter both groups consumed the carbohydrate diet for an eighth week. Training was performed throughout. After 8 wk, during 60 min of exercise (71 +/- 1% pretraining maximal oxygen uptake) average leg glucose uptake (1.00 +/- 0.07 vs. 1.55 +/- 0.21 mmol/min) was lower (P < 0.05) in Fat-CHO than in CHO. The rate of muscle glycogen breakdown was similar (4.4 +/- 0.5 vs. 4.2 +/- 0.7 mmol. min(-1). kg dry wt(-1)) despite a significantly higher preexercise glycogen concentration (872 +/- 59 vs. 688 +/- 43 mmol/kg dry wt) in Fat-CHO than in CHO. In conclusion, shift to carbohydrate diet after prolonged adaptation to fat diet and training causes increased resting muscle glycogen levels but impaired leg glucose uptake and similar muscle glycogen breakdown, despite higher resting levels, compared with when the carbohydrate diet is consumed throughout training.     

Enhancement of beta-cell sensitivity to glucose by oral fat load.

Recent studies have demonstrated that 6 h infusions of lipid emulsion enhance insulin release, whereas 24 h infusions inhibit insulin secretion. How insulin release is modulated after oral fat loading has not yet been elucidated. 17 healthy fasting volunteers were subjected to 3 experiments in random order: test 1 was a frequently sampled i. v. glucose tolerance test (FSIVGTT, 0.3 g/kg glucose), test 2 began with the ingestion of 50 % sunflower oil (1.5 g/kg) followed by FSIVGTT 4 h later. Test 3 was identical to test 2 with i. v. addition of 100 U/kg heparin prior to FSIVGTT. Glucose and insulin data were analyzed by minimal model assumptions - glucose sensitivity of the beta-cells (Theta1), acute insulin response (AIR) (10 min), 3 h insulin release (Theta2), glucose threshold of insulin secretion (h), insulin degradation rate (n), peripheral insulin sensitivity (S(I)), and glucose-dependent glucose disposal (S(G)). After drinking the fat emulsion, FFAs increased to 0.8 +/- 0.3 mmol/l (test 2) and to 3.0 +/- 0.3 mmol/l (test 3). Moderately increased FFA concentrations were associated with elevation of Theta1 (test 1, control 335 +/- 157 vs. test 2: 859 +/- 612 pM x min x mM(-1), p = 0.030). At high plasma FFA levels and in the presence of heparin (test 3), Theta1 was reduced compared to test 2 and unchanged compared to test 1. Theta2 and h were elevated in both tests 2 and 3 compared to test 1. No changes of n, S(I) and S(G) were found. In conclusion, the ingestion of sunflower oil triglyceride emulsion resulted in a 60 % increase in plasma free fatty acids and enhanced the capacity of beta-cells to secrete insulin. Heparin-induced high levels of FFA further augmented the total insulin release and inhibited parameters of glucose responsiveness.     

Leptin responses to glucose infusions in obesity-prone rats

The secretion of leptin is dually regulated. In fasting animals, plasma leptin concentrations reflect body fat stores, whereas the incremental leptin response to fasting or refeeding most likely reflects insulin-mediated energy flux and metabolism within adipocytes. Impaired secretion of leptin in either pathway could result in obesity. We therefore measured plasma leptin concentrations in fasted animals and plasma leptin concentrations after an intravenous glucose infusion in a rat model of obesity. Young Sprague-Dawley (S-D) and Fischer 344 (F344) rats had similar percent body fat and fasting glucose and fasting leptin concentrations. However, F344 animals had higher insulin concentrations and leptin responses to intravenous glucose than did the S-D animals. The animals were then fed a control or high-fat diet for 6 wk. High-fat fed animals gained more weight and body fat than did the control fed animals. Control and high-fat fed F344 animals gained approximately 40% (P < 0.0001) more weight and >100% (P < 0.01) more body fat than did the S-D animals. Fasting leptin concentrations and leptin concentrations after intravenous glucose infusions and feeding were more than double (P < 0.05) in F344 animals compared with S-D animals. Whether an animal is fed a control or high-fat diet had little effect on the leptin response to intravenous glucose. In conclusion, young, lean F344 animals, before the onset of obesity, demonstrated a greater acute leptin response to intravenous glucose than similarly lean S-D animals. After a 6-wk diet, F344 animals had a greater percent increase in body weight and insulin resistance and exhibited higher fasting leptin concentrations and a greater absolute leptin response to intravenous glucose compared with the S-D animals. The chronic diet (control or high fat) had little impact on the acute leptin response to intravenous glucose. F344 animals exhibit leptin resistance in young, lean animals and after aging and fat accumulation.     

Islets in early life are resistant to detrimental effects of a high-fat maternal diet: a study in rats

Offspring of rats fed high-fat diets during pregnancy and lactation develop glucose intolerance and islet dysfunction in adulthood. Because other models of developmental programming of glucose intolerance are associated with defective islet development, we investigated whether high-fat exposure during fetal or neonatal life impairs islet development and function, thereby contributing to islet dysfunction in later life. Female rats were fed control or high-fat diets and their pups cross-fostered after birth to represent 4 groups with each combination of control and high-fat diet for the natural and foster mother. In a time course study, pups were kept with the natural mother until weaning. Pancreases were analysed for insulin content, beta cell mass, and islet number. Isolated islets were studied for insulin secretory responses and susceptibility to palmitate-induced apoptosis assessed by caspases 3/9 activity. Pancreatic insulin content and beta cell mass were increased in pups exposed to maternal high-fat diets after birth, whereas glucose-stimulated insulin secretion from islets of high-fat offspring at 5 and 11 days of age was lower than controls. Islets from control rats of 2-14 days of age were resistant to the pro-apoptotic effects of palmitate seen in older animals. The immature beta cell is therefore insensitive to toxic effects of palmitate and may compensate for the inhibitory effects on insulin secretion by increasing beta cell mass. The data suggest that susceptibility to glucose intolerance in offspring of dams fed high-fat diets may not be a consequence of deleterious effects on beta cell mass in early life.     

Biometric evidence of diet-induced obesity in Lew/Crl rats

Although Lew/Crl rats are central to a classic model of renal transplantation and may provide a valid system for evaluating the effect of obesity on transplantation outcomes, their response to high-fat diet has not been evaluated sufficiently. The objective of this study was to evaluate biometric and basic metabolic data of Lew/Crl rats fed a 60% kcal, lard-based, very high-fat diet (HFD) compared with those fed a 10% kcal fat control diet (CD). Rats were maintained for 17 wk; body parameters and caloric intake were monitored weekly. Biometric data were collected and calculated before and after euthanasia. Serum was evaluated for liver enzyme activity and total bilirubin, glucose, triglyceride, cholesterol, insulin, leptin, and creatinine concentrations, and urine was evaluated for protein, glucose, specific gravity, and ketones. Tissues were harvested, weighed, and evaluated histologically. Compared with CD rats, HFD rats consumed more calories and weighed more after 3 wk. After 17 wk, HFD rats had significantly increased body weight, girth, volume, epididymal fat pad weight, omental weight, and body fat. In addition, HFD rats had mild elevations in some liver enzymes and a lower serum triglyceride concentration than did CD rats. Histologic assessment and other metabolic markers of disease were not different between the 2 groups. Lew/Crl rats fed a 60% kcal HFD become obese, but they lack significant metabolic abnormalities frequently associated with obesity in other rat strains.     

Dietary-induced hypertrophic--hyperplastic obesity in mice

Metabolically intact NMRI mice and genetically obese NZO mice were fed ad lib. either a high-carbohydrate diet (standard) or a high-fat diet for a period of about 11 (NMRI mice) or 38 (NZO mice) wk. In both strains of mice, body weight increased more in the groups fed the high-fat diet. However, caloric intake by NMRI mice fed the high-fat diet was less than that of the controls. In NMRI mice fed the high-fat diet, epididymal and subcutaneous fat cell volumes increased; when these mice were fed the standard diet, only epididymal fat cell volume increased. Epididymal and subcutaneous fat cell numbers increased only in the group fed the high-fat diet. In NMRI mice fed either diet, the postprandial blood glucose was lower in older animals, but plasma insulin remained unchanged. The glucose tolerance deteriorated insignificantly. In NZO mice fed either diet, epididymal fat cell volumes and fat cell numbers increased. In this strain of mice the postprandial blood glucose and plasma insulin exhibited the strain-specific pattern, independent of the diet. In older animals fed either diet the glucose tolerance decreased.     

Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone

To evaluate the relationship between the development of obesity, nervous system activity, and insulin secretion and action, we tested the effect of a 2-mo high-fat diet in rats (HF rats) on glucose tolerance, glucose-induced insulin secretion (GIIS), and glucose turnover rate compared with chow-fed rats (C rats). Moreover, we measured pancreatic and hepatic norepinephrine (NE) turnover, as assessment of sympathetic tone, and performed hypothalamic microdialysis to quantify extracellular NE turnover. Baseline plasma triglyceride, free fatty acid, insulin, and glucose concentrations were similar in both groups. After 2 days of diet, GIIS was elevated more in HF than in C rats, whereas plasma glucose time course was similar. There was a significant increase in basal pancreatic NE level of HF rats, and a twofold decrease in the fractional turnover constant was observed, indicating a change in sympathetic tone. In ventromedian hypothalamus of HF rats, the decrease in NE extracellular concentration after a glucose challenge was lower compared with C rats, suggesting changes in overall activity. After 7 days, insulin hypersecretion persisted, and glucose intolerance appeared. Later (2 mo), there was no longer insulin hypersecretion, whereas glucose intolerance worsened. At all times, HF rats also displayed hepatic insulin resistance. On day 2 of HF diet, GIIS returned to normal after treatment with oxymetazoline, an alpha(2A)-adrenoreceptor agonist, thus suggesting the involvement of a low sympathetic tone in insulin hypersecretion in response to glucose in HF rats. In conclusion, the HF diet rapidly results in an increased GIIS, at least in part related to a decreased sympathetic tone, which can be the first step of a cascade of events leading to impaired glucose homeostasis.     

Post-natal diet determines insulin resistance in fetally malnourished, low birthweight rats (F1) but diet does not modify the insulin resistance of their offspring (F2)

We examined the effects of prenatal and postnatal nutrition on birthweight and insulin sensitivity, indicated by the glucose/insulin (G/I) ratio, in adult rats (F1 generation) and in their adult offspring (F2 generation). Rat pups (F1) whose dams consumed low-protein diets during gestation (malnourished) consumed either nutritionally adequate (control) or high-fat diets ad libitum post-weaning. The offspring of these rats (F2) were maintained on the same diets as their respective dams. Separate pups (F1) whose dams consumed high-fat diets during gestation (over-nourished) were maintained on high-fat diets post-weaning, as were their offspring (F2). Birthweights were significantly reduced in all fetally malnourished F1 animals. At approximately 70 d of age, fasting insulin sensitivity in over-nourished F1 rats was significantly reduced compared to controls regardless of whether they were malnourished or over-nourished in utero; however, fetally malnourished F1 rats consuming control diets post-natally had significantly greater fasting insulin sensitivity than control animals. At 30 and 120 min post-glucose load, insulin sensitivity was reduced 12-65% in both groups of over-nourished F1 rats as compared to the fetally malnourished F1 rats consuming the control diet. Birthweights were significantly lower in F2 animals whose dams (F1) were fetally malnourished and weaned to high fat diets. Insulin sensitivity was significantly reduced in all F2 animals versus control animals, regardless of dietary treatment. Thus, post-natal diets alter insulin sensitivity in fetally malnourished, adult rats; and maternal malnutrition during gestation results in insulin resistance in offspring, irrespective of offsprings' birthweight or diet.     

Diet-induced insulin resistance precedes other aspects of the metabolic syndrome

This study wasdesigned to examine the effects of a high-fat refined-sugar (HFS) or alow-fat complex-carbohydrate (LFCC) diet on insulin-stimulated skeletalmuscle glucose transport, plasma insulin, blood pressure, plasmatriglycerides, plasma glycerol, body weight, and body fat in femaleFischer rats. Insulin-stimulated glucose transport was significantlyreduced in the HFS group at 2 wk, 2 mo, and 2 yr, whereas serum insulinwas significantly elevated at all time points. Blood pressure was notsignificantly elevated in the HFS group until 12 mo, and all HFSanimals were hypertensive by 18 mo. Glycerol, triglycerides, andabdominal fat cell size were not significantly different at 2 wk butwere significantly elevated in the HFS rats at 2 and 6 mo. Body weight was similar in both groups until 20 wk on the diet, when the HFS ratsstarted to gain more weight. These results demonstrate that insulinresistance and hyperinsulinemia occur before the other manifestationsof the metabolic syndrome and that diet, not obesity, is the underlyingcause.

     

Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose

Chronic hyperglycemia has been shown to induce either a lack of response or an increased sensitivity to glucose in pancreatic beta-cells. We reinvestigated this controversial issue in a single experimental model by culturing rat islets for 1 wk in 10 or 30 mmol/l glucose (G10, Controls; or G30, High-glucose islets) before testing the effect of stepwise glucose stimulation from G0.5 to G20 on key beta-cell stimulus-secretion coupling events. Compared with Controls, the glucose sensitivity of High-glucose islets was markedly increased, leading to maximal stimulation of oxidative metabolism and both triggering and amplifying pathways of insulin secretion in G6 rather than G20, hence to loss of glucose effect above G6. This enhanced glucose sensitivity occurred despite an approximately twofold increase in islet uncoupling protein 2 mRNA expression. Besides this increased glucose sensitivity, the maximal glucose stimulation of insulin secretion in High-glucose islets was reduced by approximately 50%, proportionally to the reduction of insulin content. In High-glucose islets, changes in (45)Ca(2+) influx induced by glucose and diazoxide were qualitatively similar but quantitatively smaller than in Control islets and, paradoxically, did not lead to detectable changes in the intracellular Ca(2+) concentration measured by microspectrofluorimetry (fura PE 3). In conclusion, after 1 wk of culture in G30, the loss of glucose stimulation of insulin secretion in the physiological range of glucose concentrations (G5-G10) results from the combination of an increased sensitivity to glucose of both triggering and amplifying pathways of insulin secretion and an approximately 50% reduction in the maximal glucose stimulation of insulin secretion.     

S(G), S(I), and EGP of exercise-trained middle-aged men estimated by a two-compartment labeled minimal model

To examine the effects of physical training on glucose effectiveness (S(G)), insulin sensitivity (S(I)), and endogenous glucose production (EGP) in middle-aged men, stable-labeled frequently sampled intravenous glucose tolerance tests (FSIGTT) were performed on 11 exercise-trained middle-aged men and 12 age-matched sedentary men. The time course of EGP during the FSIGTT was estimated by nonparametric stochastic deconvolution. Glucose uptake-specific indexes of glucose effectiveness (S(2*)(G) x 10(2): 0.81 +/- 0.08 vs. 0.60 +/- 0.05 dl. min(-1). kg(-1), P < 0.05) and insulin sensitivity [S(2*)(I) x 10(4): 24.59 +/- 2.98 vs. 11.89 +/- 2.36 dl. min(-1). (microU/ml)(-1). kg(-1), P < 0.01], which were analyzed using the two-compartment minimal model, were significantly greater in the trained group than in the sedentary group. Plasma clearance rate (PCR) of glucose was consistently greater in the trained men than in sedentary men throughout FSIGTT. Compared with sedentary controls, EGP of trained middle-aged men was higher before glucose load. The EGP of the two groups was similarly suppressed by approximately 70% within 10 min, followed by an additional suppression after insulin infusion. EGP returned to basal level at approximately 60 min in the trained men and at 100 min in the controls, followed by its overshoot, which was significantly greater in the trained men than in the controls. In addition, basal EGP was positively correlated with S(2*)(G) . The higher basal EGP and greater EGP overshoot in trained middle-aged men appear to compensate for the increased insulin-independent (S(2*)(G)) and -dependent (S(2*)(I)) glucose uptake to maintain glucose homeostasis.