Basal Plasma Insulin Concentrations Research Articles

P-633 Impact of insulin resistance on reproductive medicine outcomes

Abstract Study question Does Homeostasis Model Assessment for insulin resistance (HOMA-IR) have an influence in reproductive medicine outcomes? Summary answer HOMA-IR is associated with fertility treatment parameters and has a significant influence on reproductive medicine outcomes. What is known already The HOMA model is used to yield an estimate of insulin sensitivity from basal (fasting) plasma insulin and glucose concentrations. Currently, the model has become a widely used clinical tool to evaluate glucose metabolism. Regarding fertility, the relation between polycystic ovary syndrome (PCOS) and insulin resistance (IR) has been studied. Insulin resistance may be potential contributor to impaired treatment outcomes in artificial reproductive technology (ART). Although a few studies have recently been published on the topic the association of HOMA-IR with fertility treatment parameters remains a black box in reproductive medicine research. Study design, size, duration The observational study was designed and conducted at the Kinderwunsch Institut Schenk GmbH (Dobl, Austria). The study included 175 patients (25 men and 150 women), aged 18-45. HOMA-IR was determined for each patient and then correlated with patient’s medical history, fertility treatment parameters and outcomes. Participants/materials, setting, methods HOMA-IR was determined by taking a blood sample during fasting state and measuring plasma values of glucose (mg/dl) and insulin (mU/ml). A HOMA-IR of ≥ 2 was considered as insulin resistance. HOMA-IR was correlated with medical history (polycystic ovarian syndrome (PCOS), endometriosis, Body-Mass-Index (BMI), nicotine abuse) and fertility treatment parameters (sperm quality, number of retrieved oocytes after controlled ovarian stimulation, number of mature and fertilized oocytes, embryo quality and pregnancy rate). Main results and the role of chance An increased HOMA-IR (³2) was observed in 90 patients (51.4%). They suffered from obesity (n = 36; 80%), PCOS (n = 22; 70.97%), ovarian hyperstimulation syndrome (n = 17; 77.27%) and experienced poor embryo quality (n = 249; 91.54%). A significant positive correlation was found between HOMA-IR and PCOS (p < 0.001), obesity (p < 0.001) and number of retrieved oocytes (p < 0.05). The pregnancy rate correlated negatively with the HOMA-IR (p < 0.001). Furthermore, trends of positive correlations of high HOMA-IR in endometriosis, BMI, pathological spermiogram, nicotine abuse and increased number of mature oocytes were determined. The relation between HOMA-IR and the number of retrieved and mature oocytes is consistent with its relation to PCOS. The data show that HOMA-IR is associated with fertility treatment parameters and has a significant influence on ART outcome. Limitations, reasons for caution The number of patients may be seen as a study limitation. Results should be confirmed with a bigger sample size. An interventional study should confirm the role of HOMA-IR in IVF outcomes. Wider implications of the findings These findings may help to better understand the importance of glucose and insulin metabolism in reproduction and suggest that evaluation of HOMA-IR may be a valuable parameter to be considered when collecting patients’ anamnesis prior to starting ART treatment. Trial registration number not applicable

PSVIII-30 Impaired Glucose-Stimulated Insulin Secretion in Intrauterine Growth-Restricted Neonatal Lambs Is Improved By Daily Supplementation of ω-3 Polyunsaturated Fatty Acid Ca2+ Salts

Abstract Maternofetal heat stress during placental development induces fetal intrauterine growth restriction (IUGR), which in turn reduces birthweight. IUGR-born livestock exhibit deficits in insulin stimulus-secretion coupling and glucose metabolism that contribute to poor growth efficiency. Thus, our objective was to determine whether daily oral supplementation of Ca2+ salts of ω-3 polyunsaturated fatty acids (ω-3 PUFA) to IUGR-born neonatal lambs improves glucose-stimulated insulin secretion and other indicators of metabolic efficiency. Maternal heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation was used to induce IUGR. Lambs were weaned at birth and hand-reared on milk replacer. Beginning at birth, lambs received daily oral boluses of 0.5 mL molasses containing 0 or 0.42 g/kg bodyweight of ω-3 PUFA (Virtus Nutrition). All lambs were fitted with femoral catheters at d 24 and a square-wave hyperglycemic clamp study was performed on d 28 to assess basal (i.e., resting) and glucose-stimulated insulin secretion (GSIS). Blood glucose concentrations did not differ among IUGR lambs (n = 8), IUGR+ω-3 lambs (n = 7), and controls (n = 12), but by study design were increased (P < 0.05) 205% from basal during hyperglycemic periods. Basal plasma insulin concentrations did not differ among groups, but basal glucose-to-insulin ratios were greater (P < 0.05) for IUGR+ω-3 lambs than for controls or IUGR lambs. During hyperglycemia, plasma insulin concentrations were 53% less (P < 0.05) for IUGR lambs but only 30% less (P < 0.05) for IUGR+ω-3 lambs compared with controls. Hyperglycemic glucose-to-insulin ratios were greater (P < 0.05) for IUGR lambs (3.24 ± 0.59) compared with controls (1.10 ± 0.29) and were intermediate for IUGR+ω-3 lambs (2.08 ± 0.86). Blood lactate concentrations did not differ among groups or between periods, but blood pH was was greater (P < 0.05) for IUGR (7.448 ± 0.006) and IUGR+ω-3 lambs (7.439 ± 0.003) compared with controls (7.422 ± 0.004). Blood partial pressure of CO2 was less (P < 0.05) for IUGR lambs (43.0 ± 0.3 mmHg) than for controls (46.7 ± 0.9 mmHg) and was intermediate for IUGR+ω-3 lambs (44.0 ± 0.4 mmHg). Blood HCO3 concentrations and O2-bound hemoglobin were greater (P < 0.05) for IUGR and IUGR+ω-3 lambs than for controls. Blood Na+ tended to be less (P = 0.07) and blood K+ was less (P < 0.05) for IUGR and IUGR+ω-3 lambs than for controls. Blood Ca2+ was less (P < 0.05) for IUGR lambs but not for IUGR+ω-3 lambs than for controls. These findings demonstrate that daily oral supplementation of Ca2+ salts of ω-3 PUFA improved deficits in insulin stimulus-secretion coupling and several other metabolic indicators observed in IUGR-born offspring. However, it did not improve all electrolyte concentrations or acid-base balance of the blood.

Amylopectin Starch Promotes the Development of Insulin Resistance in Rats

Starches that are high in amylopectin are digested and absorbed more quickly than starches with a high amylose content and produce larger postprandial glucose and insulin responses. The aim of this study was to test the hypothesis that feeding rats a diet containing quickly digested starch could promote insulin resistance. Sprague-Dawley rats were fed either a high amylopectin or high amylose diet (two 10-g meals per day), and insulin sensitivity was assessed after 9 wk by intravenous glucose tolerance test (IVGTT). In the rats fed the high amylopectin diet, glucose tolerance was significantly lower (P < 0.05) and the insulin response to IVGTT was twice as high as in rats fed the high amylose diet (P < 0.05). A second study using Wistar rats investigated the time course of these changes. Differences in the insulin response to the IVGTT were not evident at 4 wk but began to emerge at 8 wk, and by 12 wk the insulin response was 100% greater in rats fed the high amylopectin diet (P < 0.05) than in those fed the high amylose diet. In addition, basal plasma insulin concentration was higher in rats fed the high amylopectin diet (P < 0.05). There were no differences, however, in glucose tolerance at any time point. The results suggest that quickly digested starch promotes the development of insulin resistance in rats. The relatively slow time course resembles the normal development of insulin resistance in humans.

Dietary Fish Oil Does Not Alter Glucose Tolerance in Conscious Rats

We examined the effect of dietary fish oil (MaxEPA) and sunflower seed oil on glucose tolerance in male Wistar rats. Semipurified diets containing 100 g oil/kg diet were administered for 30 d. The fish oil diet contained 26 g (n-3) fatty acids, 16 g eicosapentaenoic acid and 10.4 g docosahexaenoic acid/kg diet. Phospholipids from liver, pancreas, and pancreatic islets were enriched in eicosapentaenoic and docosahexaenoic acids by the fish oil diet. In unfed pentobarbital-anesthetized rats, both basal plasma insulin concentration and insulin responses to intravenous glucose were significantly lower for fish oil-fed rats although glucose responses were similar; however, incremental excursions in plasma insulin over the basal concentrations did not differ. Intravenous glucose tolerance was also examined in conscious unfed rats under minimal restraint. Responses of plasma glucose and insulin were similar for fish oil- and sunflower oil-fed groups. Furthermore, in another experiment, intravenous glucose tolerance tests were similar for conscious rats provided with either 100 g fish oil or corn oil/kg nonpurified diet. Thus, glucose-induced insulin secretion is lower in rats fed fish oil than in rats fed sunflower oil, when tests are conducted in pentobarbital-anesthetized animals but not when tests are performed in conscious rats; there was no effect on plasma glucose in either anesthetized or nonanesthetized rats. Therefore, substitution of (n-3) for (n-6) polyunsaturated fatty acids in tissue phospholipids does not alter plasma glucose or insulin in conscious male Wistar rats.

Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors.

Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.

The effects of dietary nitrate on plasma glucose and insulin sensitivity in sheep.

Nitrate (NO3 ¯ ) is an effective non-protein nitrogen source for gut microbes and reduces enteric methane (CH4 ) production in ruminants. Nitrate is reduced to ammonia by rumen bacteria with nitrite (NO2 ¯ ) produced as an intermediate. The absorption of NO2 ¯ can cause methaemoglobinaemia in ruminants. Metabolism of NO3 ¯ and NO2 ¯ in blood and animal tissues forms nitric oxide (NO) which has profound physiological effects in ruminants and has been shown to increase glucose uptake and insulin secretion in rodents and humans. We hypothesized that absorption of small quantities of NO2 ¯ resulting from a low-risk dose of dietary NO3 ¯ will increase insulin sensitivity (SI ) and glucose uptake in sheep. We evaluated the effect of feeding sheep with a diet supplemented with 18g NO3 ¯ /kg DM or urea (Ur) isonitrogenously to NO3 ¯ , on insulin and glucose dynamics. A glucose tolerance test using an intravenous bolus of 1ml/kg LW of 24% (w/v) glucose was conducted in twenty sheep, with 10 sheep receiving 1.8% supplementary NO3 ¯ and 10 receiving supplementary urea isonitrogenously to NO3 ¯ . The MINMOD model used plasma glucose and insulin concentrations to estimate basal plasma insulin (Ib ) and basal glucose concentration (Gb ), insulin sensitivity (SI ), glucose effectiveness (SG ), acute insulin response (AIRg) and disposition index (DI). Nitrate supplementation had no effect on Ib (p>.05). The decrease in blood glucose occurred at the same rate in both dietary treatments (SG ; p=.60), and there was no effect of NO3 ¯ on either Gb , SI , AIRg or DI. This experiment found that the insulin dynamics assessed using the MINMOD model were not affected by NO3 ¯ administered to fasted sheep at a low dose of 1.8% NO3 ¯ in the diet.

The effects of increased acetate turnover on glucose-induced insulin secretion in lean and obese humans.

Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity. To examine whether rates of acetate turnover are different in lean versus obese humans and whether increased acetate turnover promotes increased GSIS and increased ghrelin secretion in humans. Basal acetate Ra was measured following an overnight fast in lean (BMI: 21.3 ± 1.1 Kg/m2) and obese (30.2 ± 0.9 Kg/m2, P = 0.00001) individuals. The subjects underwent two hyperglycemic (10 mmol/L) clamp studies to measure GSIS during a basal acetate infusion and during a high-dose acetate infusion increasing plasma acetate concentrations ∼5-fold. Basal acetate Ra was 30% higher in the lean compared to the obese subjects (257 ± 27 vs. 173 ± 18 μmol/min; P = 0.025). Basal plasma insulin concentrations were 4-fold higher in the obese than the lean subjects (P = 0.008) and increased 5-fold during hyperglycemia in both groups, independent of changes in plasma acetate concentrations. Fasting plasma ghrelin concentrations were 35% lower in the obese compared to the lean subjects (P = 0.015). During the hyperglycemic clamp, plasma ghrelin decreased by 42% in the lean group (P < 0.022 vs. basal) and did not change in the obese group. Rates of endogenous acetate turnover are ∼30% higher in the lean subjects compared to the obese subjects, and increasing plasma acetate turnover does not promote increased GSIS or ghrelin secretion in either group.

Jiangzhi Capsule improves fructose-induced insulin resistance in rats: Association with repair of the impaired sarcolemmal glucose transporter-4 recycling

Ethnopharmacological relevanceJiangzhi Capsule, originated from an experienced formula in traditional Chinese Medicine, has been listed and used for the management of metabolic abnormalities in Australia for a long time. To better understand Jiangzhi Capsule, this study investigated its effect on insulin resistance. Materials and methodsMale rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. ResultsTreatment with Jiangzhi Capsule (100mg/kg) attenuated fructose overconsumption-induced increases in basal plasma insulin concentrations, the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. The increased plasma glucose concentrations during oral glucose tolerance test were also inhibited. Furthermore, Jiangzhi Capsule had a trend to attenuate the decreased ratios of glucose and non-esterified fatty acids to plasma insulin concentrations. Mechanistically, this insulin-sensitizing action was accompanied by normalization of the downregulated sarcolemmal glucose transporter (GLUT)-4 protein expression and the decreased phosphorylated Akt to total Akt protein ratio in gastrocnemius. ConclusionsThese results suggest that Jiangzhi Capsule ameliorates fructose-induced insulin resistance with a link to repair of the impaired sarcolemmal GLUT-4 recycling through modulation of the ratio of phosphorylated Akt to total Akt in gastrocnemius. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule for the management of insulin resistance-associated disorders.

Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses.

Role of vascular endothelial insulin sensitisation in vascular repair in systemic insulin resistance

BackgroundInsulin resistance is an independent risk factor for cardiovascular disease. Murine models with global insulin receptor haploinsufficiency (IRKO) show endothelial dysfunction and impaired vascular repair, potentially related to reduced number and function of endothelial progenitor cells and bioavailability of nitric oxide. We hypothesise that endothelium-specific insulin sensitisation, in the context of global insulin resistance, could reverse these vascular abnormalities. Therefore, we have bred IRKO mice with HIRECO mice, which overexpress a human insulin receptor in endothelial cells under the transcriptional regulation of the Tie-2 promoter-enhancer. MethodsDouble-transgenic offspring from HIRECO mice crossed with IRKO mice (HIRECOxIRKO) were compared with IRKO mice after confirming genotype with PCR on DNA extracted from ear samples. Metabolic assessment was done with glucose-tolerance and insulin-tolerance tests, and ELISA was used to measure plasma insulin concentrations. Blood pressure (BP) was measured with tail cuff plethysmography. Femoral artery denuding injury was induced with an angioplasty guide-wire; 4 days later, vessels were explanted after perfusion with Evans blue dye to quantify endothelial denudation. Circulating progenitor cells (CPCs, positive for Sca-1/Flk-1) were counted in peripheral venous blood by fluorescence-activated cell sorting. Continuous data were expressed as means (SD) and analysed with paired and unpaired Student's t tests as appropriate (significance at p<0·05). A minimum of five of each mouse type was used in each comparison, unless otherwise stated. FindingsHIRECOxIRKO and IRKO mice had similar growth profiles (weight at 4 months 28·3 g [3·0] vs 27·4 [0·9], p=0·51) and systolic BP (98 mm Hg [12·4] vs 106 [10·4], p=0·28), with comparable insulin sensitivity on tolerance tests. Basal plasma insulin concentrations were also similar (0·70 ng/mL [0·50] vs 0·76 [0·47], p=0·78; n=7), though HIRECOxIRKO did not display the post prandial hyperinsulinaemia seen in IRKO mice previously and in this study. Vascular repair was significantly enhanced in HIRECOxIRKO after femoral artery wire injury (HIRECOxIRKO 56·9% regeneration [11·1] vs IRKO 46·0% [5·1], p=0·048). This repair was not associated with any improvement in numbers of CPCs, which were similar in the two groups of mice (HIRECOxIRKO 90 Sca-1/Flk-1 positive cells [27] vs IRKO 105 [42], p=0·99]. InterpretationIn HIRECOxIRKO mice, restoration of vascular repair occurred after endothelial wire injury, which has been previously demonstrated as impaired in IRKO mice. This restoration happened even with comparable glucoregulation and BP, suggesting that the effect is related specifically to endothelial insulin sensitisation despite insulin resistance in traditional target tissues. These data are early and exploratory, and sample size was small and from murine colonies; nonetheless, they seem to support the possibility of vascular endothelial insulin sensitisation as a potential therapeutic target in insulin resistant states. A mechanism remains to be established and we are planning assays of endothelial function, angiogenesis, and downstream insulin molecular signalling. FundingBritish Heart Foundation.

Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes

Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity(1), but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit(1,2), lowers glucose concentrations in nonobese type 2 diabetic rats(2–5). Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding(6,7), the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.

Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs

To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.

Disturbances of Basal and Postprandial Insulin Secretion and Clearance in Obese Patients with Type 2 Diabetes Mellitus

Hyperinsulinemia of nondiabetic overweight and obese subjects is associated with weight-dependent increased insulin secretion and decreased insulin clearance. The present analysis examines whether similar effects can be observed in overweight and obese patients with type 2 diabetes mellitus (DM2). Additionally basal and postprandial insulin secretion and clearance were analyzed in relation to duration of disease. In a random sample of 348 DM2 patients basal plasma insulin concentrations were significantly higher in most BMI groups compared to matched nondiabetic (ND) controls. The weight-dependent increase of basal insulin in DM2 was primarily the result of reduced clearance rather than augmented secretion. Postprandial insulin concentrations were lower in DM2 patients and did not show any BMI-related increase. The weight-dependent reduction of postprandial insulin clearance was absent in DM2. At the time of diagnosis basal insulin concentration was higher and secretion was comparable to ND subjects and this did not change with duration of diabetes. The early postprandial insulin response was still comparable between DM2 and ND subjects at the time of diagnosis but deteriorated with longer duration of disease. The later postprandial response at diagnosis (AUC 90-180) was characterized by significantly greater insulin secretion and concentration while later on the 3-fold higher secretion was paralleled by comparable peripheral plasma concentrations due to a significantly greater postprandial insulin clearance in DM2. In conclusion, the present data indicate that apart from disturbances of insulin secretion substantial changes of insulin clearance contribute to inadequate peripheral insulin concentrations in obese DM2 patients.

Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats

Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats. Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR. In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression. These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.

Effects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats

The effects of long-term cranberry consumption on age-related changes in endocrine pancreas are not fully understood. Here we treated male Fischer 344 rats with either 2% whole cranberry powder supplemented or normal rodent chow from 6 to 22 month old. Both groups displayed an age-related decline in basal plasma insulin concentrations, but this age-related decline was delayed by cranberry. Cranberry supplementation led to increased β-cell glucose responsiveness during the oral glucose tolerance test. Portal insulin concentration was 7.6-fold higher in rats fed cranberry, coupled with improved β-cell function. However, insulin resistance values were similar in both groups. Total β-cell mass and expression of pancreatic and duodenal homeobox 1 and insulin within islets were significantly enhanced in rats fed cranberry relative to controls. Furthermore, cranberry increased insulin release of an insulin-producing β-cell line, revealing its insulinotropic effect. These findings suggest that cranberry is of particular benefit to β-cell function in normal aging rats.

Hypoglycaemic effect of Calamintha officinalis Moench. in normal and streptozotocin-induced diabetic rats.

The purpose of this study was to investigate the effects of a water extract from the aerial parts of Calamintha officinalis Moench., after either a single dose or daily oral administration for 15 days, on plasma blood glucose concentrations and basal insulin levels in normal and streptozotocin-induced diabetic rats (STZ diabetic rats). The results clearly demonstrated the hypoglycaemic effect of this plant extract in both normal and STZ diabetic rats. In addition, no changes were observed in basal plasma insulin concentrations after treatment with this plant in normal or STZ diabetic rats, indicating that the underlying mechanism of the plant's pharmacological action seems to be independent of insulin secretion. We conclude that the aqueous C. officinalis extract exhibits a significant hypoglycaemic effect in normal and STZ diabetic rats without affecting basal plasma insulin concentrations, and supports, therefore, its traditional use by the Moroccan population.

Consumption of a High-Fat Diet Containing Lard during the Growth Period in Rats Predisposes Them to Favorably Respond to the Diet in Later Life

To investigate whether preferential fat intake by adult rats could be linked to fat-feeding of rats during the growth period, this paper describes the next two studies. Three groups of 4-wk-old male rats in study 1 received one of three diets: control diet (CTD), low-fat high-carbohydrate diet (LFD), and high-fat low-carbohydrate diet (HFD). After 6 wk (dietary treatment period), 6 rats in each of the groups were sacrificed and the remaining rats were placed on a self-selection regimen of fat-protein diet (FPD) and carbohydrate-protein diet (CPD) for 3 wk (self-selection period). After the dietary treatment period, liver weight and plasma insulin concentration of the LFD group and perirenal fat tissue weight and plasma triacylglycerol and leptin concentrations of the HFD group were higher than those of the CTD group. Although no significant difference in fat energy ratio (F ratio) of combination diets self-selected by the three groups was observed, the F ratios of the combination diets were higher than that of the CTD. After the self-selection period, liver weight and plasma insulin concentration of the LFD group and plasma triacylglycerol concentrations of the HFD group decreased. These data suggested that the dietary selection pattern of the rats was associated with a reduced basal plasma insulin concentration. Three groups of rats in study 2 were placed on a self-selection regimen of the LFD and the HFD after being fed one of three diets (LFD, CTD and HFD) for 6 wk. Although the F ratio of the combination diet consumed by the CTD and the LFD groups was similar to that of the combination diet consumed by rats in study 1, the F ratio of the combination diet consumed by the HFD group was higher than that of other groups. These findings suggest that consumption of the fatty food during the growth period predisposed them to favorably respond to the diet that had become familiar to them in later life.

Regulation of net hepatic glycogenolysis and gluconeogenesis by epinephrine in humans

The relative contributions of net hepatic glycogenolysis (NHG) and gluconeogenesis to rates of glucose production during a physiological increment in plasma epinephrine concentrations, independent of changes in plasma insulin concentrations, were determined in seven fasting, healthy young subjects. Plasma insulin concentrations were kept constant by infusing somatostatin (0.1 microg.kg(-1).min(-1)) and replacing basal insulin (24 pmol.m(-2).min(-1)). Epinephrine (1.2 microg.m(-2).min(-1)) was infused for 90 min while NHG was assessed directly by (13)C magnetic resonance spectroscopy. The rate of glucose production was assessed using [6,6-(2)H(2)]glucose, and gluconeogenesis was calculated as the difference between the rate of glucose production and NHG. Plasma epinephrine concentrations increased rapidly from approximately 100 to approximately 2,000 pmol/l (P < 0.00001) accompanied by an increase in plasma glucose concentrations from 4.3 +/- 0.2 to 13.3 +/- 0.3 mmol/l at 90 min (P = 0.00001). This increase in plasma epinephrine concentration resulted in a 2.5-fold increase in glucose production (from 14.4 +/- 1.0 micromol.kg(-1).min(-1) to 35.7 +/- 2.0 micromol.kg(-1).min(-1), P < 0.0001), which lasted for approximately 60 min (phase 1), after which glucose production decreased to 31.2 +/- 1.9 micromol.kg(-1).min(-1) (P < 0.0001 vs. basal) during the last 30 min of the epinephrine infusion (phase 2). Hepatic glycogen concentrations decreased almost linearly during phase 1, and rates of NHG were 19.9 +/- 3.0 micromol.kg(-1).min(-1) (P = 0.005 vs. basal), which could account for approximately 60% of glucose production. During phase 2, NHG decreased to 7.3 +/- 2.8 micromol.kg(-1).min(-1) (P = 0.02 vs. peak), accounting for only approximately 20% of glucose production. In conclusion, in the presence of basal plasma insulin and glucagon concentrations, a physiological increase in plasma epinephrine concentrations stimulates glucose production with an initial, 60-min transient phase caused by stimulation of NHG and a second phase that can mostly be attributed to a twofold increase in rates of gluconeogenesis.

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

To examine the association between insulin resistance in skeletal muscle and liver in non-diabetic subjects. A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic-hyperinsulinaemic clamp performed with (3)[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin-stimulated rate of total glucose disposal during the insulin clamp divided by steady-state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP x FPI). Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty-eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty-three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2-h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. In non-diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2-h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.

Role of meal carbohydrate content for the imbalance of plasma amino acids in patients with liver cirrhosis

Imbalance of circulating branched chain amino acids (BCAA) versus aromatic amino acids (AAA) and hyperinsulinemia are common metabolic alterations in patients with liver cirrhosis. The aim of this study was to characterize the effect of the carbohydrate component of a protein-rich mixed meal on postprandial plasma concentrations of 21 amino acids, insulin and C-peptide in patients with compensated liver cirrhosis. Furthermore, the effect of a dietary intervention on the metabolic alterations in cirrhotic patients was examined. Eighteen patients with cirrhosis and 12 healthy volunteers received a protein-rich meal (pork filet 200 g) with or without carbohydrates (bread 50 g, glucose 20 g). A subgroup of four cirrhotic patients received an isoenergetic (117 kJ/kg bw) carbohydrate-enriched (60%) and -restricted (20%) diet for 7 days each. In the cirrhotic patients, basal plasma insulin and C-peptide concentrations were significantly elevated. The ingestion of a protein-rich meal without additional carbohydrates led to a significantly greater increase of insulin and C-peptide in the cirrhotic patients compared to controls. Postprandial increases of leucine and isoleucine were reduced, whereas those of phenylalanine were higher in cirrhotic patients. The addition of carbohydrates led to higher insulin and C-peptide plasma concentrations in cirrhotic patients. Postprandial BCAA increases were more impaired in the cirrhotic group after additional carbohydrate ingestion (46%vs 82%). After the carbohydrate-restricted diet for 7 days BCAA plasma levels increased but the BCAA/AAA ratio remained unaltered. The carbohydrate content of a meal enhances reduction of BCAA plasma concentrations in clinically stable cirrhotic patients. An imbalanced BCAA/AAA ratio cannot be avoided by a carbohydrate-reduced diet alone, supporting mandatory BCAA supplementation.