Basal Hepatic Glucose Production Research Articles

293-OR: Macrophage-Derived Interleukin-12 Regulates Obesity-Mediated Insulin Resistance in the Liver

Inflammation and insulin resistance play a major role in nonalcoholic fatty liver disease (NAFLD), and IL-12, a pro-inflammatory cytokine primarily secreted by macrophages, is elevated in obesity. Here, we examined the effects of acute treatment with IL-12 in vivo on glucose metabolism in male C57BL/6J mice. Mouse recombinant IL-12 (0.25 μg/hour) or saline (control) was infused for 4 hours, followed by insulin clamps in mice (n=5/group). Glucose infusion rates during clamps were significantly reduced in IL-12-treated mice, resulting in a 34% decrease compared to controls (Fig. 1-2). Basal hepatic glucose production (HGP) did not differ, but clamp HGP was significantly increased in IL-12-treated mice (Fig. 3). As a result, IL-12 treatment caused a 43% decrease in hepatic insulin action compared to controls (Fig. 4). These IL-12 effects were associated with a 4-fold increase in STAT4 tyrosine-phosphorylation (0.071±0.026 vs. 0.018±0.004 in controls) and a 47% decrease in IRS1 protein levels (0.264±0.044 vs. 0.496±0.112 in controls) in the liver. Attenuated liver IL-12 level was further associated with improved hepatic insulin action in diet-induced obese mice with conditional loss of IFNγ signaling in myeloid cells. CONCLUSION: Our findings identify IL-12 as a novel cytokine regulating obesity-mediated insulin resistance and inflammation in the liver and a potential therapeutic target to treat NAFLD. Disclosure R.H.Friedline: None. M.Albusharif: None. A.M.Kim: None. L.H.Kim: None. N.M.Baez torres: None. L.A.Tauer: None. X.Hu: None. J.K.Kim: None. Funding National Institutes of Health (5U2CDK093000)

1727-P: Mice Deficient in Myeloid Cell-Derived Interleukin-1a Are Protected from Diet-Induced Obesity and Insulin Resistance

Interleukin (IL)-1α is a major mediator of inflammation, and functional polymorphism of IL-1α is associated with human obesity. We have recently generated mice with genetic ablation of IL-1α selectively in myeloid cells. On chow diet, Lyz-IL-1α KO mice showed normal metabolic phenotypes. In contrast, when male Lyz-IL-1α KO mice were fed a high-fat diet (HFD), whole body fat mass was markedly reduced in these mice (Figure 1; *P<0.05). Metabolic cage study found that this was mostly due to a 2-fold increase in physical activity in Lyz-IL-1α KO mice (Figure 2). Food intake and energy expenditure were not affected in these mice. We performed a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity in awake mice (n=7). HFD-fed Lyz-IL-1α KO mice were more insulin sensitive than HFD-fed wild type (WT) mice with a 2-fold increase in glucose infusion rates (Figure 3). Whole body glucose turnover and glycolysis were significantly increased in HFD-fed Lyz-IL-1α KO mice (Figure 3). Basal hepatic glucose production (HGP) was not altered, but clamp HGP was reduced by 40% in Lyz-IL-1α KO mice. As a result, hepatic insulin action was markedly increased in HFD-fed Lyz-IL-1α KO mice (Figure 4). In conclusion, these results indicate that Lyz-IL-1α KO mice are protected from diet-induced obesity and insulin resistance, and our findings identify IL-1α as a novel therapeutic target in obesity and type 2 diabetes. Disclosure S. Suk: None. R.H. Friedline: None. H. Noh: None. X. Hu: None. D.A. Tran: None. L.A. Tauer: None. A.M. Kim: None. L.H. Kim: None. J.K. Kim: None. Funding National Institutes of Health (5U2CDK093000)

1914-P: Prolonged (12-Hour) Glucagon Infusion Stimulates Adipocyte Lipolysis and Inflammation In Vivo in Humans

Hyperglucagonemia is a characteristic feature of T2DM and contributes to the metabolic disturbances. Although some rodent studies have suggested that glucagon stimulates lipolysis in adipocytes, the long-term effect of hyperglucagonemia on adipose tissue metabolism and glucose homeostasis in vivo in humans is unclear. The aim of the present study was to examine the effect of 12-hour glucagon infusion on hepatic glucose production (HGP) and adipocyte metabolism in healthy individuals. 8 NGT subjects (5M/3F, age=35±5, BMI = 24±1) received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) with 3-3H-glucose infusion followed by subcutaneous adipose tissue biopsy at 6AM. On a different day the subjects returned for a repeat study with infusion (6PM to 6AM) of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml. Plasma glucose increased transiently after the start of glucagon and declined to baseline levels at 6AM. Plasma insulin levels increased significantly following glucagon compared to saline (20±7 vs. 8±3 mU/L, p<0.05) and remained elevated at 6AM. Basal HGP (3.2±0.1 vs. 2.9±0.1 mg/kg/min, p<0.01) and fasting plasma FFA concentrations (0.70±0.1 vs. 0.39±0.1 mM, p<0.01) were increased after 12-hour glucagon infusion despite increased plasma insulin levels, indicating severe hepatic and adipocyte insulin resistance. Lipolysis-related gene expression in adipose tissue biopsy were upregulated following 12-hour glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p<0.05). Plasma concentration of inflammatory markers were also increased after 12-hour glucagon infusion (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p<0.05). Overall, these results demonstrate that prolonged physiologic hyperglucagonemia causes marked hepatic and adipocyte insulin resistances, stimulates lipolysis and increases plasma FFA, and induces adipocyte and systemic inflammation. Disclosure D. Tripathy: None. M. Fourcaudot: None. L. Norton: None. R.A. DeFronzo: None. X. Chen: None.

Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion

BackgroundRedirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. MethodsGlucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. ResultsLLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30–40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. ConclusionsCancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

Mild sustained physiological hyperglycemia impairs hepatic insulin sensitivity in healthy individuals with normal glucose tolerance

Previous studies have shown that chronic hyperglycemia exacerbates skeletal muscle insulin resistance and worsens β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity stays unclear. This paper is the Chinese translation of Mild physiologic hyperglycemia induces hepatic insulin resistance in healthy normal glucose-tolerant participants , published on Journal of Clinical Endocrinology & Metabolism [Tripathy D, Merovci A, Basu R, et al. J Clin Endocrinol Metab, 2019, 104(7): 2842-2850] after obtaining the copyright of the original journal. This study examined the effect of sustained physiologic hyperglycemia on endogenous glucose production(EGP) in 16 healthy individuals with three-step hyperinsulinemic euglycemic clamp. The results showed that sustained physiologic hyperglycemia for only 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in healthy persons with normal glucose tolerance, indicating the role of glucotoxicity in the increase of hepatic glucose production in type 2 diabetes. Key words: Hyperglycemia; Insulin resistance; Normal glucose tolerance

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

In the current study we investigate the mechanisms of action of short acting inhaled insulin Exubera®, on hepatic glucose production (HGP), plasma glucose and free fatty acid (FFA) concentrations. 11 T2D (Type 2 Diabetes) subjects (age = 53 ± 3 years) were studied at baseline (BAS) and after 16-weeks of Exubera® treatment. At BAS and after 16-weeks subjects received: measurement of HGP (3-3H-glucose); oral glucose tolerance test (OGTT); and a 24-h plasma glucose (24-h PG) profile. At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h PG profile (212 ± 17 to 141 ± 8 mg/dl), FFA fasting (665 ± 106 to 479 ± 61 μM), post-OGTT (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl). The basal HGP decreased significantly and the insulin secretion/insulin resistance (disposition) index increased significantly. There were no episodes of hypoglycemia and no change in pulmonary function at EOS. After 16-weeks of inhaled insulin Exubera® we observed a marked improvement in glycemic control by decreasing HGP and 24-h PG profile, and decreased FFA and triglyceride concentrations.

1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p<0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p<0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production. Disclosure X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.

Decrease of FGF19 contributes to the increase of fasting glucose in human in an insulin-independent manner.

The ileum-derived fibroblast growth factor 19 (FGF19) plays key roles in hepatic glucose homeostasis in animals in an insulin-independent manner. Here, we analyzed the association of FGF19 with glucose effectiveness (GE, the insulin-independent glucose regulation), as well as hepatic glucose production (HGP) in Chinese subjects. GE was measured by frequently sampled intravenous glucose tolerance test (FSIVGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance (I-IGT), and isolated-impaired fasting glucose (I-IFG) subjects. The oral glucose tolerance test-derived surrogate of GE (oGE) was determined in NGT, I-IFG, combined glucose intolerance (CGI), and type 2 diabetes (T2DM) subjects. HGP was assessed by labeled ([3-3H]-glucose) hyperinsulinemic-euglycemic clamp in NGT subjects. Insulin secretion and sensitivity were calculated by the hyperglycemic and hyperinsulinemic-euglycemic clamps in a subgroup of NGT, I-IGT, and I-IFG subjects. Serum FGF19 levels were determined by ELISA. FGF19 positively correlated with GE (r = 0.29, P = 0.004) as determined by FSIVGTT. The result was further confirmed by oGE (r = 0.261, P < 0.001). FGF19 was negatively associated with FPG (r = - 0.228, P = 0.025), but the association no longer existed after adjusting for GE (r = - 0.177, P = 0.086). FGF19 was negatively associated with basal HGP (r = - 0.697, P = 0.006). However, the correlation between FGF19 and insulin secretion and sensitivity were not found. FGF19 levels are associated positively with GE and negatively with HGP. The increase of FPG in human is at least partially due to the decrease of FGF19 in an insulin-independent manner.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. EGP. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Thioesterase superfamily member 2 promotes hepatic insulin resistance in the setting of glycerol-3-phosphate acyltransferase 1–induced steatosis

Hepatic insulin resistance in the setting of steatosis is attributable at least in part to the accumulation of bioactive lipids that suppress insulin signaling. The mitochondria-associated glycerol-3-phosphate acyltransferase 1 (GPAT1) catalyzes the first committed step in glycerolipid synthesis, and its activity diverts fatty acids from mitochondrial β-oxidation. GPAT1 overexpression in mouse liver leads to hepatic steatosis even in the absence of overnutrition. The mice develop insulin resistance owing to the generation of saturated diacylglycerol and phosphatidic acid molecular species that reduce insulin signaling by activating PKCϵ and by suppressing mTORC2, respectively. Them2, a mitochondria-associated acyl-CoA thioesterase, also participates in the trafficking of fatty acids into oxidative versus glycerolipid biosynthetic pathways. Them2-/- mice are protected against diet-induced hepatic steatosis and insulin resistance. To determine whether Them2 contributes to hepatic insulin resistance due to hepatic overexpression of GPAT1, recombinant adenovirus was used to overexpress GPAT1 in livers of chow-fed Them2+/+ and Them2-/- mice. Hepatic GPAT1 overexpression led to steatosis in both genotypes. In the setting of GPAT1 overexpression, glucose tolerance was reduced in Them2+/+ but not Them2-/- mice, without influencing whole-body insulin sensitivity or basal hepatic glucose production. Improved glucose tolerance in Them2-/- mice was associated with reduced PKCϵ translocation. Preserved insulin receptor activity was supported by Thr-308 phosphorylation of Akt following GPAT1 overexpression in Them2-/- hepatocytes. These findings suggest a pathogenic role of Them2 in the biosynthesis of glycerolipid metabolites that promote hepatic insulin resistance.

Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis

Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A-dependent phosphorylation of Foxo1 at Ser276 Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&amp;lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&amp;lt;0.05). Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production. Disclosure D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Combining Various Methods to Assess Insulin Sensitivity in Nonobese Rat after Sleeve Gastrectomy.

Sleeve gastrectomy (SG) procedure has been proved to improve insulin sensitivity and sustain anti-diabetic effects. Our aim is to co-use several methods to measure insulin sensitivity and investigate the effect of SG on hepatic and peripheral insulin sensitivity at early and long-term stages of postoperation. Thirty 11-week-old male Goto-Kakizaki rats were divided into SG, sham-operated SG (SOSG), and control groups. They were observed before operation and for 36 weeks of postoperation. Insulin tolerance test (ITT) and homeostasis model of assessment for insulin resistance index(HOMA-IR)were used to measure insulin resistance before operations and at 2 and 36 weeks of postoperation; Pyruvate challenge test (PCT) was administrated to assess the gluconeogenesis capability in order to reflect hepatic insulin sensitivity before operation and at 2 and 36 weeks of postoperation; Hyperinsulinemic euglycemic clamps (HIEC) was conducted before operation and at 2 and 36 weeks of postoperation to calculate the endogenous hepatic glucose production (HGP) at the basal and steady-state for evaluation of hepatic insulin sensitivity, and calculate the exogenous glucose infusion rate (GIR) at the steady-state for evaluation of peripheral insulin sensitivity. The data showed that compared with rats in the sham and control groups, rats in SG group had 1) significantly lower AUCITT, HOMA-IR and AUC PCT values at 2 and 36 weeks of postoperation, 2) lower basal state HGP, but not steady-state GIR at 2 weeks of postoperation, and 3) significantly different basal and steady-state HGP and steady-state GIR at 36 weeks of postoperation. In addition, the basal and steady-state HGP and the steady-state GIR were significantly different between rats in SG group at 2 and 36 weeks of postoperation. This study explored insulin sensitivity of rats after SG by jointly using a variety of techniques. The results showed that SG time-dependently improved the hepatic and peripheral insulin sensitivity.

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production, Leading to Improved Insulin Sensitivity.

The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.

Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions.

Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1(-/-) mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired activation of the master tumor suppressor p53 and treatment with an Scd1 inhibitor extended survival of tumor-prone TP53(-/-) mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression mediated by hepatic SirT1 and resulting in the activation of a key lipid synthetic enzyme, with potential therapeutic implications.

Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons

Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain.

Renoprotective effects of metformin

Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.

GLP‐2 receptor is required for glucose homeostasis and energy balance

Glucagon‐like peptides (GLP‐1/2) are co‐secreted from enteroendocrine L cells and preproglucagon neurons, and proposed as key promoters of glucose homeostasis and insulin sensitivity after gastric bypass surgery. GLP‐2 receptor (GLP‐2R) activation stimulates intestinal growth and absorption, while decreasing gut motility to inhibit food intake. However, it is unknown if GLP‐2 plays a physiological role in the long‐term control of energy balance and glucose homeostasis. To determine the physiological relevance of GLP‐2R in glycemic control and body adiposity, we generated Glp2r knockout (KO) mice. First, we validated that Glp2r mRNA and protein were not expressed in the KO gut and brain, and GLP‐2‐stimulated cell proliferation was negated in the KO gut. In comparison with wide‐type (WT) littermates, Glp2r KO mice displayed higher (+38%) fat body mass and lower lean body mass. The KO mice had higher food intake during refeeding while basal energy expenditure was not altered. Moreover, the KO mice displayed higher levels of fasting glucose and slower removal of postprandial glucose. After ip glucose challenge, the KO mice showed glucose intolerance. Using 6,6‐2H2‐glucose and 2H2O tracers, we quantified that the KO mice had higher basal hepatic glucose production (5.44 ± 0.20 vs 7.02 ± 0.26 mmol/kg/h, respectively, for the WT and KO mice), while they had lower glucose infusion rate (GIR) during hyperinsulinemic euglycemic clamp. Furthermore, iv infusion of GLP‐2 (500 pmol/kg/h) increased the GIR by +33% in the WT mice, but not in the KO mice. GLP‐2‐mediated improvement in insulin sensitivity was largely attributed to enhancing glucose disappearance rate during insulin stimulation. Our data indicate that Glp2r deficiency displays fasting hyperglycemia, glucose intolerance, and insulin resistance, pointing to a novel physiological role of GLP‐2R in glucose homeostasis and insulin sensitivity. In addition, Glp2r deficiency displays hyperphagic obesity, revealing a long‐term effect of GLP‐2R in energy balance.

Restoration of Euglycemia After Duodenal Bypass Surgery Is Reliant on Central and Peripheral Inputs in Zucker fa/fa Rats

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system–derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.

FORMULATION AND IN-VITRO EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF GLIPIZIDE

Diabetes mellitus is a metabolic disorder caused by insufficient production of endogenous insulin, with or without resistance to insulin action, resulting in hyperglycaemia. In type 1 diabetes mellitus, there is a failure in production of insulin as a result of destruction of the cells of the pancreas, and patients require treatment with insulin whereas type 2 diabetes can be characterised by defects in both insulin action (i.e. insulin resistance) and insulin secretion, and is associated with elevated basal hepatic glucose production. Glipizide is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from the pancreas and is typically prescribed to treat type II diabetes. Different formulations were prepared by varying the concentration of HPMC used as polymers. The effect of varying concentration of hydrophilic polymers (HPMC 5cps and 15 cps) was studied on the release pattern of glipizide. Sustained release glipizide matrix tablets were prepared by wet granulation and compression of hydroxypropylmethyl cellulose (5 cps and 15 cps), drug and other excipients mixture. The promising formulation was compared with the marketed sample of suatained release glynase in terms of release pattern. The release rate of a glipizide from matrix tablet was decreased with increasing the concentration as well as viscosity polymer. This might be probably due to increased swelling and reduced erosion rate of matrix tablet. The formulation 13 (F13) showed the similar result as marketed sample of sustained release glynase tablets in terms of release rate. Key Words: Glipizide, Hydroxy propyl methyl cellulose (HPMC), Viscosity grades