Biomedical subjects

Adria Giacca

Publications and source records attributed to Adria Giacca.

At least 19 recordsLinked to original sources

PubMed2006

Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure.

We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive beta-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of beta-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in beta-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired beta-cell function. In conclusion, 1) the FFA-induced impairment in beta-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the beta-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.

Animals↗

PubMed2006

Oleate-induced decrease in hepatocyte insulin binding is mediated by PKC-delta.

We have previously shown that free fatty acids (FFA) impair hepatic insulin extraction in vivo and thus generate hyperinsulinemia, a suspected risk factor for atherosclerosis and cancer. Hepatic insulin extraction is a receptor-mediated event, which is initiated by hepatocyte insulin binding. In the present study, we investigated the effect of FFA on insulin binding in freshly isolated rat hepatocytes maintained at 10 mM glucose. Hepatocyte insulin binding decreased after 1 h exposure to oleate in a concentration-dependent manner reaching a maximum (35-40%) at 125 microM. Inhibition of FFA oxidation by >90% with the carnitine palmitoyltransferase I (CPT-I) inhibitor methylpalmoxirate (MP, 30 microM) did not prevent the effect of oleate. However, when hepatocytes were treated with the PKC inhibitor bisindolylmaleimide (BIM, 1 microM) the effect of oleate was abolished. Subcellular fractionation and immunoblotting of specific PKC isoforms revealed that oleate-induced hepatic PKC-delta membrane translocation, but did not translocate-epsilon, -theta, -alpha, -betaI and -betaII. These results indicate that PKC-delta activation mediated the FFA-induced decrease in hepatocyte insulin binding under our conditions, and thus provides a mechanistic basis for FFA-induced hyperinsulinemia.

Animals↗

PubMed2006

Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo.

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.

Animals↗

PubMed2006

Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux.

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.

Animals↗

PubMed2006

Direct and indirect effects of insulin on hepatic glucose production in diabetic depancreatized dogs during euglycemia.

Insulin suppresses glucose production (GP) via both extrahepatic (indirect) and hepatic (direct) effects. We have shown that the direct effect, undetectable in moderately hyperglycemic diabetic dogs, is restored by insulin-induced euglycemia. The first aim of the present study was to determine whether euglycemia per se, and not the excess insulin needed to obtain it, restores the direct effect of insulin on GP. Basal insulin was given portally in depancreatized dogs to attain only moderate hyperglycemia, then an additional insulin was given portally or peripherally to match the peripheral insulin levels and thus to obtain a greater hepatic insulinization with portal delivery. Plasma glucose was allowed to fall to euglycemia before a euglycemic clamp was performed. During euglycemia, there was a tendency (P=0.075) for greater suppression of GP by portal than peripheral insulin. Also, there was a significantly different effect of time (P=0.01) on GP in the two groups, with greater suppression over time in the portal group. The second aim was to test the hypothesis that because of inadequate hepatic insulinization and consequent lack of direct inhibition of GP, peripheral insulin replacement requires peripheral hyperinsulinemia to achieve euglycemia. Portal or peripheral insulin was given to achieve euglycemia and basal GP, and insulin levels were measured. More peripheral insulinemia was required with peripheral than portal insulin replacement to maintain similar euglycemia and GP. Our conclusions are as follows: (1) euglycemia per se is sufficient to acutely restore the direct effect of insulin on GP and (2) at euglycemia, peripheral replacement of insulin, as in insulin-treated diabetes, results in peripheral hyperinsulinemia but unchanged basal GP.

Animals↗

PubMed2005

Anti-atherogenic effect of insulin in vivo.

Metabolic syndrome is a risk factor for atherosclerosis and restenosis. In metabolic syndrome, insulin resistance coexists with hyperinsulinemia and hyperlipidemia. Hyperlipidemia has growth-promoting effects, whereas insulin has both growth-promoting and growth-inhibitory effects on vascular smooth muscle cells in vitro. The objective of this study was to investigate the effects of hyperlipidemia and hyperinsulinemia on vascular cell growth in vivo after arterial injury. Rats fed a low-fat diet were treated with either subcutaneous blank (LFC) or insulin (LFI) implants. Rats fed a high-fat diet also received blank (HFC) or insulin (HFI) implants. After 3 days, rats received balloon carotid injury, and 14 days later they were sacrificed to measure neointimal area and proliferation. Hyperinsulinemia was present in LFI and HFI and hyperlipidemia was present in HFC and HFI. Neointimal area was higher in HFC (0.153 +/- 0.009 mm(2), p < 0.05) but lower in LFI (0.098 +/- 0.005, p < 0.01) than LFC (0.127 +/- 0.005). In HFI (0.142 +/- 0.008, p < 0.05) neointimal area was not different from HFC or LFC. In conclusion, insulin reduced neointimal growth, but the effect of insulin was diminished by the high-fat diet. Thus, our results demonstrate an anti-atherogenic effect of insulin in vivo and suggest that in metabolic syndrome insulin resistance rather than hyperinsulinemia is the atherogenic risk factor.

Animals↗

PubMed2005

Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides.

Protein ingestion after injection of the glucagon-like peptide-1 receptor agonist Exendin-4 (Ex-4) causes hyperglycemia in rats. The objectives of this study were to determine the components of protein digestion responsible for this effect and to associate it with changes in the concentrations of other metabolites and hormones. Two experiments were conducted. In the first experiment, food-deprived rats were gavaged with intact whey (WP) or albumin protein, their hydrolysates, amino acid mixtures (1 g/2.5 ml), or water 5 min after injection of either PBS or Ex-4 (0.5 microg/rat). Tail vein blood was analyzed for glucose over 2 h. In the second experiment, food-deprived rats were gavaged with WP with or without Ex-4. Groups of conscious rats were killed by decapitation either before, or at selected times after gavage. Plasma concentrations of glucose, amino acids, free fatty acids (FFA), glycerol, insulin, glucagon, and leptin were measured. In experiment 1, blood glucose was higher when intact proteins and protein hydrolysates, but not amino acid mixtures, were given with than without Ex-4 (P < 0.05). In experiment 2, concentrations of glucose, FFA, and the ratio of tyrosine to branched-chain amino acid were higher (P < 0.01), but leptin and essential amino acid concentrations were lower (P < 0.05), and insulin, glucagon, and glycerol were similar when WP was given with or without Ex-4. We conclude that the hyperglycemia caused by the administration of Ex-4 concurrently with dietary protein arises from the action of peptides released during digestion and their interaction with Ex-4 in the regulation of glucose, fatty acid, and amino acid metabolism.

Amino Acids↗

PubMed2005

FK-614, a selective peroxisome proliferator-activated receptor gamma agonist, improves peripheral glucose utilization while decreasing hepatic insulin extraction in alloxan-induced diabetic dogs.

This is the first report of the effects of a nonthiazolidinedione activator of peroxisome proliferator-activated receptor (PPAR) gamma, that is, FK-614 (a benzimidazole derivative), on glucose metabolism in vivo. To investigate the effect of FK-614 on peripheral and hepatic insulin action, we performed hyperinsulinemic-hyperglycemic clamp studies combined with the triple-catheter technique and a double-tracer approach in alloxan-diabetic dogs with (n=5) or without (n=6) treatment with FK-614 (0.32 mg/kg per day orally for 10 days). Throughout the experiment, insulin was infused intraportally at 18 pmol/kg per minute and hyperglycemia (approximately 11 mmol/L) was maintained by a peripheral glucose infusion. After a 45-minute basal period (period I), a portal infusion of glucose labeled with [U-14C]-glucose, was administered for 120 minutes (period II) to measure hepatic glucose uptake. This was followed by 90-minute recovery (period III). FK-614 marginally improved peripheral insulin sensitivity, did not affect hepatic glucose uptake, and surprisingly increased tracer-determined hepatic glucose production (19.0+/-5.0 vs 10.6+/-1.7 mumol/kg per minute, P<.001). Hepatic insulin extraction was decreased by FK-614 (47.8%+/-1.6% vs 55.9%+/-3.4%, P<.01), which led to greater peripheral insulin levels and glucose utilization. FK-614 treatment also decreased the daily insulin requirements (regular insulin, 0.18+/-0.01 vs 0.32+/-0.01 U/kg per day; and NPH insulin, 0.53+/-0.02 vs 0.89+/-0.04 U/kg per day; P<.001) to maintain fasting plasma glucose at approximately 10 mmol/L for 7 days before the experiments. We conclude that FK-614 treatment, at the dose used, improves peripheral glucose utilization because of an improvement in peripheral insulin sensitivity and a decrease in insulin clearance, but impairs hepatic insulin action in alloxan-induced diabetic dogs. The reason for the effects of FK-614 on hepatic glucose and insulin metabolism is unclear but they are both consistent with reports of hepatic steatosis by PPARgamma activation when unopposed by concomitant activation of PPARalpha.

Animals↗

PubMed2005

Muscle-specific Pten deletion protects against insulin resistance and diabetes.

Pten (phosphatase with tensin homology), a dual-specificity phosphatase, is a negative regulator of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Pten regulates a vast array of biological functions including growth, metabolism, and longevity. Although the PI3K/Akt pathway is a key determinant of the insulin-dependent increase in glucose uptake into muscle and adipose cells, the contribution of this pathway in muscle to whole-body glucose homeostasis is unclear. Here we show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation in soleus but, surprisingly, not in extensor digitorum longus muscle compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Muscle Pten may be a potential target for treatment or prevention of insulin resistance and diabetes.

Animals↗

PubMed2004

The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.

Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mm to cells differentiated at 25 mm glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mm glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.

3T3-L1 Cells↗

PubMed2004

Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic beta-cell line MIN6.

Oligonucleotide microarrays were used to define oleic acid (OA)-regulated gene expression and proteomic technology to screen protein kinases in MIN6 insulinoma cells. The effects of oxidative stress caused by OA and potential protective effects of N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), on global gene expression and beta-cell function were investigated. Long-term exposure of MIN6 cells to OA led to a threefold increase in basal insulin secretion, a 50% decrease in insulin content, an inhibition of glucose-stimulated insulin secretion (GSIS), and a twofold increase in the level of ROS. The addition of NAC normalized both the OA-induced insulin content and ROS elevation, but it failed to restore GSIS. Microarray studies and subsequent quantitative PCR analysis showed that OA consistently regulated the expression of 45 genes involved in metabolism, cell growth, signal transduction, transcription, and protein processing. The addition of NAC largely normalized the expression of the OA-regulated genes involved in cell growth and differentiation but not other functions. A protein kinase screen showed that OA regulated the expression and/or phosphorylation levels of kinases involved in stress-response mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and cell cycle control pathways. Importantly, these findings indicate that chronic OA exposure can impair beta-cell function through ROS-dependent and -independent mechanisms.

Acetylcysteine↗

PubMed2003

N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress.

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.

Acetylcysteine↗

PubMed2003

Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensin II type I receptor blocker.

BACKGROUND: ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated. METHODS AND RESULTS: We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35+/-5 versus 54+/-4 mmol x kg(-1) x min(-1), P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73+/-11% versus 27+/-18%, P<0.05), and greater glucose disposal at high-dose insulin (135+/-5 versus 92+/-4 mmol x kg(-1) x min(-1), P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B2 receptor antagonist) and NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium. CONCLUSIONS: OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B2 receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Angiotensin Receptor Antagonists↗

PubMed2003

Mechanisms of the free fatty acid-induced increase in hepatic glucose production.

The associations between obesity, insulin resistance, and type 2 diabetes mellitus are well documented. Free fatty acids (FFA), which are often elevated in obesity, have been implicated as an important link in these associations. Contrary to muscle glucose metabolism, the effects of FFA on hepatic glucose metabolism and the associated mechanisms have not been extensively investigated. It is still controversial whether FFA have substantial effects on hepatic glucose production, and the mechanisms responsible for these putative effects remain unknown. We review recent progress in this area and try to clarify controversial issues regarding the mechanisms responsible for the FFA-induced increase in hepatic glucose production in the postabsorptive state and during hyperinsulinemia.

Animals↗

PubMed2003

Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites.

To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO - EGP), hepatic glucose 6-phosphate (G-6-P) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6-P), and EGP (P < 0.001). During the clamp compared with the basal experiments, 2-h insulin infusion increased GC and in vivo glucokinase activity (GC/TGO; P < 0.05) and suppressed EGP (P < 0.05) but failed to significantly affect TGO and in vivo glucose-6-phosphatase activity. IH decreased the ability of insulin to increase GC and in vivo glucokinase activity (P < 0.01), and at 7 h, it also decreased the ability of insulin to suppress EGP (P < 0.001). G-6-P content was comparable in all groups. In vivo glucose-6-phosphatase and glucokinase activities did not correspond to their in vitro activities as determined in liver tissue, suggesting that stable changes in enzyme activity were not responsible for the FFA effects. The data suggest that, in overnight-fasted rats, FFA increased basal EGP and induced hepatic insulin resistance at different sites. 1) FFA increased basal EGP through an increase in TGO and in vivo glucose-6-phosphatase activity, presumably due to a stimulatory allosteric effect of fatty acyl-CoA on glucose-6-phosphatase. 2) FFA induced hepatic insulin resistance (decreased the ability of insulin to suppress EGP) through an impairment of insulin's ability to increase GC and in vivo glucokinase activity, presumably due to an inhibitory allosteric effect of fatty acyl-CoA on glucokinase and/or an impairment in glucokinase translocation.

Allosteric Regulation↗

PubMed2003

Free fatty acid-mediated impairment of glucose-stimulated insulin secretion in nondiabetic Oji-Cree individuals from the Sandy Lake community of Ontario, Canada: a population at very high risk for developing type 2 diabetes.

The Oji-Cree population of the Sandy Lake region of Ontario, Canada, has the third highest prevalence of type 2 diabetes in the world. Changes in their diet and physical activity over the past half-century, particularly the marked increase in consumption of dietary fats, are felt to be important factors accounting for this epidemic. The aim of the present study was to examine the beta-cell response to a 48-h approximately twofold elevation of plasma free fatty acids (FFAs) (induced by Intralipid and heparin infusion) in members of the Sandy Lake Oji-Cree population (n = 12) and to compare the response to that in healthy age-matched nondiabetic Caucasian subjects (n = 16). The insulin secretion rate, insulin sensitivity index (S(I)), and disposition index (D(I)) (an index of insulin secretion that takes into account the ambient S(I)) were assessed in response to a 4-h graded intravenous glucose infusion followed by a 20 mmol/l 2-h hyperglycemic clamp. Total insulin secretory response to the graded glucose infusion did not change after a 48-h FFA elevation versus saline control in Caucasians and increased by approximately 30% in Oji-Cree individuals (P = 0.04 for difference between the two groups). Infusion of heparin-Intralipid reduced S(I) by approximately 40% in both groups (P = 0.002). Although D(I) was markedly reduced by heparin-Intralipid infusion in Caucasians (by approximately 40%), it was reduced by only 15% in Oji-Cree individuals (P = 0.03 for difference of response between the two groups). However, S(I) and D(I) in the Oji-Cree individuals were already much lower than in Caucasians at baseline, in keeping with the very high risk of type 2 diabetes in this population. It is concluded that Oji-Cree individuals from a community at very high risk for developing type 2 diabetes are not more susceptible to the FFA-induced desensitization of glucose-stimulated insulin secretion than healthy non-Natives and, in fact, appear to be less susceptible. Whether this reflects an inherent resistance to lipotoxicity or an already-present lipotoxic effect in this population will require further study.

Blood Glucose↗

PubMed2003

Direct measure of insulin sensitivity with the hyperinsulinemic-euglycemic clamp and surrogate measures of insulin sensitivity with the oral glucose tolerance test: correlations with aberrant crypt foci promotion in rats.

The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.

Animals↗

PubMed2002

The effect of chronic insulin delivery via the intraperitoneal versus the subcutaneous route on hepatic triglyceride secretion rate in streptozotocin diabetic rats.

Chronic intraperitoneal or subcutaneous insulin administration increases triglyceride secretion rate (TGSR) in normal rats. We wished to determine the effect of this treatment on TGSR and the hepatic lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in diabetic rats. Streptozotocin-diabetic rats, untreated (D), diabetic rats treated with insulin (3 U/day for 21 days) intraperitoneally (IP) or subcutaneously (SC) and non-diabetic rats (N) were studied. TGSR was determined using Triton WR-1339. Fasting glucose and triglyceride levels, high in D, were normalized by insulin treatment regardless of route. Peripheral insulin levels were lowest in D and highest in SC, portal insulin levels were lowest in D and highest in IP. Non-esterified fatty acid levels were not elevated in D, presumably due to adipose tissue depletion. TGSR was reduced in D (P<0.05) and was normalized following insulin administration, regardless of route. ACC activity was normal, but FAS was decreased in D (P<0.05). ACC and FAS were normal in both IP and SC. Thus, in streptozotocin-diabetic rats, chronic intraperitoneal or subcutaneous insulin treatment increases TGSR and FAS activity from their low levels in insulin-deficient rats to levels equal to but not higher than those in normal rats.

Acetyl-CoA Carboxylase↗