Comparative assessment of metal-specific adipogenic activity in zinc and vanadium-citrates through associated gene expression.

Diabetes mellitus comprises a group of metabolic abnormalities due to insulin deficiency and/or resistance. Obesity contributes to diabetes, with a strong causal relationship existing between diabetes and insulin resistance, especially in patients with Diabetes mellitus II. Adipocytes emerge as key constituents of adipose tissue physiology. In their pre-mature form to mature state transformation, adipocytes fully exemplify one of the key adipogenic actions of insulin. Poised to a) gain insight into adipogenesis leading to antidiabetic factors, and b) investigate adipogenesis through careful examination of insulin contributions to interwoven mechanistic pathways, a systematic comparative study was launched involving well-defined metal-citrates (zinc and vanadium), the chemical reactivity of which was in line with their chemistry under physiological conditions. Selection of the specific compounds was based on their common aqueous coordination chemistry involving the physiological chelator citric acid. Cellular maturation of pre-adipocytes to their mature form was pursued in the presence-absence of insulin and employment of closely linked genetic targets, key to adipocyte maturation (Peroxisome proliferator-activated receptor gamma (PPAR-γ), Glucose transporter 1,3,4 (GLUT 1,3,4), Adiponectin (ADIPOQ), Glucokinase (GCK), and Insulin receptor (INS-R)). The results show a) distinct adipogenic biological profiles for the metalloforms involved in a dose-, time- and nature-dependent manner, and b) metal ion-specific adipogenic response-signals at the same or higher level than insulin toward all selected targets. Collectively, the foundations have been established for future exploitation of the distinct metal-specific adipogenic factors contributing to the functional maturation of adipose tissue and their use toward hyperglycemic control in Diabetes mellitus.

Synthetic investigation of binary-ternary Cr(III)-hydroxycarboxylic acid-aromatic chelator systems. Structure-specific influence on adipogenic biomarkers linked to insulin mimesis.

In an attempt to understand the aqueous interactions of Cr(III) with low-molecular mass physiological ligands and examine its role as an adipogenic metallodrug agent in Diabetes mellitus II, the pH-specific synthesis in the binary-ternary Cr(III)-(HA = hydroxycarboxylic acid)-(N,N)-aromatic chelator (AC) (HA = 2-hydroxyethyl iminodiacetic acid/heidaH2, quinic acid; AC = 1,10-phenanthroline/phen) systems was pursued, leading to four new crystalline compounds. All materials were characterized by elemental analysis, UV-Visible, FT-IR, and ESI-MS spectroscopy, cyclic voltammetry, and X-Ray crystallography. Concurrently, the aqueous speciation of the binary Cr(III)-(2-hydroxyethyl iminodiacetic acid) system, complemented by ESI-MS, provided key-details of the species in solution correlating with the solid-state species. The structurally distinct Cr(III) soluble species were subsequently used in an in vitro investigation of their cytotoxic activity in 3T3-L1 fibroblast cultures. Compound 1 exhibited solubility, bioavailability, and atoxicity over a wide concentration range (0.1-100 µΜ) in contrast to 3, which was toxic. The adipogenic potential of 1 was subsequently investigated toward transformation of pre-adipocytes into mature adipocytes. Confirmation of that capacity relied on molecular biological techniques a) involving genes (glucose transporter type 4, peroxisome proliferator-activated receptor gamma, glucokinase, and adiponectin) serving as sensors of the transformation process, b) comparing the Cr(III)-adipogenicity potential to that of insulin, and c) exemplifying the ultimate maturity of adipocytes poised to catabolize glucose. The collective effort points out salient structural features in the coordination sphere of Cr(III) inducing adipogenic transformation relevant to combating hyperglycemia. The multiply targeted mechanistic insight into such a process exemplifies the role of well-defined Cr(III) complex forms as potential insulin-mimetic adipogenic agents in Diabetes mellitus II.

In vitro structure-specific Zn(II)-induced adipogenesis and structure-function bioreactivity correlations.

The advent of Zn(II) metallodrugs in metabolic syndrome pathologies generates a strong challenge toward synthetic endeavors targeting well-defined, atoxic and biologically active binary/ternary species of Zn(II). Proper formulation of that metal ion's coordination sphere sets the stage for construction of appropriately configured Schiff ligands based on tromethamine and variably modified vanillin core components. The arising Schiff ligands react with Zn(II) in a defined stoichiometry, thereby delivering new binary Zn(II)-L species with defined physicochemical properties. Analytical (elemental), spectroscopic (FT-IR, Thermogravimetric Analysis) and crystallographic techniques attest to the distinct nature of the derived binary-ternary materials, bearing defined Zn(II):L molecular stoichiometry, variable nuclearity, charge, bulk and balance mix of hydrophilicity-hydrophobicity, thereby providing the physicochemical profile based on which biological studies could ensue. The structurally based selection of species was applied onto in vitro 3T3-L1 cultures, essentially exploring toxicity, migration, morphology, cell differentiation and maturation. The systematic effort toward comparative work on appropriately defined Zn(II) species and insulin in inducing adipogenesis reveals the salient structural features in the Schiff family of ligands configuring Zn(II) so as to promote complex formation sufficient to engage biomolecular targets during the process of initiation and maturation. Molecular targets of importance in adipogenesis were examined under the influence of Zn(II) and their expression levels suggest the structural composition that a Zn(II) ion might have to optimally pursue cell differentiation. Thus, a well-defined selection of binary Zn(II)-L species is tightly associated with the incurred bioactivity, thereby setting the stage for the development of efficient Zn(II) metallodrugs to combat Diabetes mellitus II.

Vitamin D receptor and progesterone receptor protein and gene expression in papillary thyroid carcinomas: associations with histological features.

PURPOSE: Vitamin D receptor (VDR) and progesterone receptor (PR) expression has been described in papillary thyroid carcinoma (PTC) but data regarding association with tumor histological characteristics and localization of the protein expression are scarce. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded specimens from 45 patients with PTC (cases) were retrieved and tumor histological data were recorded. We analyzed gene and protein expression of VDR and PR and gene expression of vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzymes in follicular cancer cells and the adjacent non-neoplastic thyroid tissue (NNTT). RESULTS: VDR mRNA and protein expression was higher in PTC compared with NNTT (p < 0.05). The protein was globally localized in the cytoplasm and cell membranes of the neoplastic cells in all cases, with differences in intensity. Cytoplasmic positivity was stronger in the majority of cases. Membranous positivity was also evident in cases, whereas in NNTT was generally weak and in a low percentage of the cells. Expression of CYP 24A1, but not CYP27B1, was increased in approximately all PTC specimens and was associated with lymph node metastasis and extrathyroidal extension. PR mRNA was increased in 34% and protein expression was present in 57% of cases, and none of NNTT. PR, but not VDR, mRNA expression was significantly associated with the tumor size (r = 0.645, p = 0.007). CONCLUSIONS: We provide evidence for the expression pattern of VDR, PR and CYP24A1 in the progression of PTC. Rapid anti-tumor responses of vitamin D in PTC may be blocked due to inactivation of local vitamin D metabolism.

The molecular basis of bone mechanotransduction.

The skeleton has the ability to perfectly adapt to external forces of the operating environment, by altering its morphology and metabolism in order to meet different needs. This unique adaptive capacity of the skeleton creates an interesting range of biological questions concerning the perception of mechanical or other kinds of signals, the type of receptor, and the molecular pathways involved in this adaptation. Studies of the characteristics of the cellular engineering provide a host of new information that confers to osteocytes the role of the protagonist in the perception and regulation of mechanical effects on the skeleton. The identity of mechanoreceptors is manifold and concerns ion channels, integrins, cell membrane, the cytoskeleton, and other systems. A similar multiplicity characterizes the intracellular signaling. This review describes recent data concerning the outward force reception systems and intracellular transduction pathways of information transfer leading to the continuous adaptation of bone tissue. Increased appreciation of the importance of the mechanical environment in regulating and determining the effectiveness of structural adjustment of the skeleton defines new horizons for the discovery of novel therapeutic approaches to diseases associated with bone loss.

The adipogenic potential of Cr(III). A molecular approach exemplifying metal-induced enhancement of insulin mimesis in diabetes mellitus II.

Insulin resistance is identified through numerous pathophysiological conditions, such as Diabetes mellitus II, obesity, hypertension and other metabolic syndromes. Enhancement of insulin action and\or its complete replacement by insulin-enhancing or insulin-mimetic agents seems to improve treatment of metabolic diseases. Over the last decades, intensive research has targeted the investigation of such agents, with chromium emerging as an important inorganic cofactor involved in the requisite metabolic chemistry. Chromium in its trivalent state has been shown to play a central role in carbohydrate metabolism by enhancing insulin signaling, action, and thus the sensitivity of insulin-sensitive tissues. A very likely link between diabetes and obesity is the adipose tissue, which stores energy in the form of triglycerides and releases free fatty acids. To date, there is paucity of information on the exact mechanism of the chromium effect concerning insulin-activated molecular paths, such as adipogenesis. The aim of the present study is to delve into such an effect by employing a well-defined form of chromium (Cr(III)-citrate) on the a) survival of pre- and mature adipocytes (3T3-L1), b) endogenous cell motility, and c) insulin-enhancing adipogenic capacity. The emerging results suggest that Cr(III)-citrate a) is (a)toxic in a concentration- and time-dependent manner, b) has no influence on cell motility, c) can induce 3T3-L1 pre-adipocyte differentiation into mature adipocytes through elevation of tissue specific biomarker levels (PPAR-γ, GLUT 4 and GCK), and d) exemplifies structurally-based metal-induced adipogenesis as a key process contributing to the development of future antidiabetic metallodrugs.

Efficacy and tolerability of vildagliptin as first line treatment in patients with diabetes type 2 in an outpatient setting.

BACKGROUND: Inhibitors of dipeptidyl-peptidase IV are recommended as second-line therapy in type 2 diabetes (DT2), but data, as a first-line treatment in everyday clinical practice are scarce. To address this issue we conducted a 12-month, clinical study in an outpatient setting, using vildagliptin as the first-line treatment. METHODS: Ninety-one drug naïve patients with DT2 started with vildagliptin monotherapy (100 mg daily) for 4 months and were scheduled to regular 4-monthly visits for 1 year. Patients received add-on treatment with metformin or metformin and glimepiride according to their glycosylated hemoglobin (HbA1c) at each study-visit. RESULTS: HbA1c was significantly decreased with vildagliptin monotherapy from 8.16 % ± 1.60 to 7.52 % ± 1.60, p < 0.001. Only 39 % of the patients achieved the target of HbA1c ≤ 7.0 % at the end of the 4th month. Mean change in HbA1c was significantly correlated with baseline HbA1c values (r = -0.51, p < 0.001). At the end of the study only 35 % of the patients remained on vildagliptin monotherapy while the rest required add-on treatment with metformin or metformin and sulfonylurea. CONCLUSIONS: Vildagliptin is well tolerated either as monotherapy or in combination but the majority of patients require add-on therapy shortly after the beginning of treatment.

Structure-specific adipogenic capacity of novel, well-defined ternary Zn(II)-Schiff base materials. Biomolecular correlations in zinc-induced differentiation of 3T3-L1 pre-adipocytes to adipocytes.

Among the various roles of zinc discovered to date, its exogenous activity as an insulin mimetic agent stands as a contemporary challenge currently under investigation and a goal to pursue in the form of a metallodrug against type 2 Diabetes Mellitus. Poised to investigate the adipogenic potential of Zn(II) and appropriately configure its coordination sphere into well-defined anti-diabetic forms, (a) a series of new well-defined ternary dinuclear Zn(II)-L (L=Schiff base ligands with a variable number of alcoholic moieties) compounds were synthesized and physicochemically characterized, (b) their cytotoxicity and migration effect(s) in both pre- and mature adipocytes were assessed, (c) their ability to effectively induce cell differentiation of 3T3-L1 pre-adipocytes into mature adipocytes was established, and (d) closely linked molecular targets involving or influenced by the specific Zn(II) forms were perused through molecular biological techniques, cumulatively delineating factors involved in Zn(II)-induced adipogenesis. Collectively, the results (a) reveal the significance of key structural features of Schiff ligands coordinated to Zn(II), thereby influencing its (a)toxicity behavior and insulin-like activity, (b) project molecular targets influenced by the specific forms of Zn(II) formulating its adipogenic potential, and (c) exemplify the interwoven relationship between Zn(II)-L structural speciation and insulin mimetic biological activity, thereby suggesting ways of fine tuning structure-specific zinc-induced adipogenicity in future efficient antidiabetic drugs.

Design, synthesis and characterization of novel binary V(V)-Schiff base materials linked with insulin-mimetic vanadium-induced differentiation of 3T3-L1 fibroblasts to adipocytes. Structure-function correlations at the molecular level.

Among the various roles of vanadium in the regulation of intracellular signaling, energy metabolism and insulin mimesis, its exogenous activity stands as a contemporary challenge currently under investigation and a goal to pursue as a metallodrug against Diabetes mellitus II. In this regard, the lipogenic activity of vanadium linked to the development of well-defined anti-diabetic vanadodrugs has been investigated through: a) specifically designing and synthesizing Schiff base organic ligands L, bearing a variable number of terminal alcohols, b) a series of well-defined soluble binary V(V)-L compounds synthesized and physicochemically characterized, c) a study of their cytotoxic effect and establishment of adipogenic activity in 3T3-L1 fibroblasts toward mature adipocytes, and d) biomarker examination of a closely-linked molecular target involving or influenced by the specific V(V) forms, cumulatively delineating factors involved in potential pathways linked to V(V)-induced insulin-like activity. Collectively, the results a) project the importance of specific structural features in Schiff ligands bound to V(V), thereby influencing the emergence of its (a)toxicity and for the first time its insulin-like activity in pre-adipocyte differentiation, b) contribute to the discovery of molecular targets influenced by the specific vanadoforms seeking to induce glucose uptake, and c) indicate an interplay of V(V) structural speciation and cell-differentiation biological activity, thereby gaining insight into vanadium's potential as a future metallodrug in Diabetes mellitus.

Effects of intracerebroventricular infusion of somatostatin-14 on peripheral glucoregulation in dogs.

Somatostatin (SST) is an inhibitory hormone that regulates numerous biological processes and circulates in two bioactive isoforms: SST-14 and SST-28. SST-14 is the predominant form in the hypothalamus and regulates the secretion of growth hormone (GH) (directly) and of thyroid-stimulating hormone (indirectly). In the periphery, SST is a potent inhibitor of glucagon and insulin secretion. In the present study, we aimed to investigate the effect of i.c.v. administration of SST-14 on glucose metabolism. Twenty healthy adult dogs randomly received either a bolus i.c.v. infusion of 5, 25 or 50 µg of SST-14 or an equivalent amount of artificial cerebrospinal fluid through an epicranial apparatus during fasting. The same experiment was repeated during concomitant intraduodenal infusion of glucose solution through a Mann-Bollman fistula. Serum levels of glucose, insulin and glucose-dependent insulinotrophic peptide (GIP), plasma SST and serum GH levels were assayed. Circulating levels of SST and GH did not change significantly during i.c.v. infusions. Bolus infusion of 50 µg of SST-14 produced an increase in serum glucose levels at 10 min (94 ± 2.5 mg/dl at baseline versus 101 ± 3 mg/dl, P = 0.04) and significantly suppressed insulin levels, reaching maximal suppression at 60 min after infusion (9 ± 1.3 µIU/ml at baseline versus 4.6 ± 0.5 µIU/ml P = 0.04) in fasting animals. Similar results were obtained during intraduodenal infusion of glucose through a Mann-Bollman fistula. GIP levels did not change significantly during i.c.v. administration of SST-14. Intracerebroventricular infusion of SST-14 increases glucose and suppresses insulin levels in the periphery independently of circulating SST levels.

Major histocompatibility complex class II (DRB1*, DQA1*, and DQB1*) and DRB1*04 subtypes' associations of Hashimoto's thyroiditis in a Greek population.

Hashimoto's thyroiditis (HT) is an autoimmune disease resulting from complex interactions between genetic and environmental factors. The disease is associated with certain human leukocyte antigen (HLA) class II alleles in various populations. We aimed to determine in this study, for the first time in a Greek population, the association of HLA-DRB1*, -DQA1*, and -DQB1* alleles with HT. HLA-DRB1*, -DQA1*, and -DQB1* alleles' and -DRB1*04 subtypes' distribution was evaluated in 125 patients with HT and in 500 healthy control individuals by using a DNA-based sequence-specific primer method. Chi(_)squared tests and Bonferroni correction method were applied in the statistical analysis of the data. Significantly higher frequency of DRB1*04 (24.8% vs 7.7%, P < 0.0001) was observed in HT patients, while HLA-DRB1*07 was significantly decreased (2.8% vs 7.9%, P < 0.05). HLA-DRB1*04 subtyping showed a significant increase of DRB1*0405 (21% vs 7.8%, P < 0.0001) in HT patients. Also significant high frequencies of DQB1*0201 (14.8% vs 8.2%, P < 0.001), DQB1*0302 (18.8% vs 7.0%, P < 0.0001), and DQA1*0301 (25.6% vs 7.8%, P < 0.0001) were recorded in the patient group. Conducting the first research of this kind in a Greek population, our study tries to provide an evaluation of the prevalence of HT relating to HLA-DRB1*0405, and we report a relative risk of 2.7 for HT in a Greek population.

Insulin sensitivity increase after calcium supplementation and change in intraplatelet calcium and sodium-hydrogen exchange in hypertensive patients with Type 2 diabetes.

AIMS/HYPOTHESIS: To investigate the effect of oral calcium (Ca(2+)) supplementation on insulin sensitivity measured by the euglycaemic hyperinsulinaemic clamp, intraplatelet cationic concentration of Ca(2+) ([Ca(2+)](i)) and the transmembrane sodium-hydrogen exchanger (NHE) activity in erythrocytes in subjects with Type 2 diabetes and hypertension. PATIENTS AND METHODS: In this parallel randomized controlled single-blinded trial, 31 patients were allocated to receive either 1500 mg of Ca(2+) orally, daily (n = 15) or no treatment (n = 16) for 8 weeks. At baseline and at the end of the 8-week period insulin sensitivity, [Ca(2+)](i) and the first isoform of NHE (NHE-1) activity were measured. RESULTS: At the end of the study, subjects who received Ca(2+) supplementation showed higher insulin sensitivity (Delta M-value 0.32 +/- 0.5 mmol/min P < 0.05) and lower [Ca(2+)](i) (125.0 +/- 24.7 to 80.4 +/- 10.6 nmol/l, P < 0.05, mean +/- sem) and NHE-1 activity (79.5 +/- 10.0 to 52.1 +/- 6.4 mmol Na/l red cell/h, P < 0.05). None of the above parameters were changed in the control group. Simple regression analysis demonstrated the change in [Ca(2+)](i) significantly determined insulin sensitivity change (beta = -0.36, P < 0.05). CONCLUSIONS/INTERPRETATION: Oral Ca(2+) supplementation improves insulin sensitivity in patients with Type 2 diabetes and hypertension. These changes are likely to be mediated by changes in intracellular ionic Ca(2+). NHE-1 activity was also reduced after Ca(2+) supplementation but its role in insulin sensitivity requires further investigation.

Intracerebroventricular infusion of neuropeptide Y modulates VIP secretion in the fasting conscious dog.

Intracerebroventricular (icv) injection of neuropeptide Y (NPY), which is a widely-distributed neurotransmitter, into the paraventricular nuclear area has been shown previously to increase secretion of insulin and glucagon from the pancreatic islets. Vasoactive intestinal polypeptide (VIP) is a 28-amino-acid peptide that is associated with the mobilisation of energy during situations of energy depletion, such as fasting and exercise. VIP has also been reported to alter insulin and glucagon levels in a glucose-dependent manner. The aim of this study was to determine whether icv infusion of NPY affected VIP secretion in dogs. Intracerebroventricular injections (0.5 ml) were administered through a stereotactic apparatus to six healthy dogs. This prototype epicranial apparatus was positioned surgically to allow the easy and exact localisation of the third ventricle for infusion or sampling. Doses of 5, 10, and 25 microg NPY, dissolved in artificial cerebrospinal fluid (aCSF), were infused for a total of 30 min using a Harvard infusion pump. For control experiments, aCSF alone was injected. Blood samples were taken 15 min before icv injection (basal), immediately after injection, and at 5, 10, 15, 30, 45, 60, 90, and 120 min after, to determine the levels of glucose, insulin, glucagon, and VIP. Intracerebroventricular infusion of NPY resulted in a short-term increase in VIP secretion, followed by a more gradual and lengthier decrease in VIP levels. The secretion of insulin and glucagon increased significantly with all three doses of NPY. Intracerebroventricular infusion of NPY increased secretion of insulin and glucagon from the pancreas. The rapid change in the levels of VIP suggested the possibility of neural regulation by NPY.

Osteoclastogenesis--current knowledge and future perspectives.

The strength and integrity of the human skeleton depends on a delicate equilibrium between bone resorption by osteoclasts and bone formation by osteoblasts. This equilibrium is continuously compromised by a variety of genetic, humoral, and mechanical alterations. In osteoporosis, this balance shifts in favor of osteoclasts, and bone resorption exceeds bone formation. More detailed knowledge of the biology of osteoclasts and osteoclastogenesis has shown that the involved procedures can provide opportunities for developing therapeutic agents. Osteoclastogenesis is a multi-complex procedure that includes many stages, and each one of them presents as a potential target for therapeutic intervention, except for the stage of commitment of pre-osteoclasts,at least for the time being. Because the osteoclast is derived from the pluripotent hematopoietic stem cell, any intervention in this stage could result in serious adverse effects from the hematopoietic system. On the contrary, intervention in the later stages of differentiation, multi-nucleation, and activation, has proved to be very promising in the development of novel potent anti-resorptive agents. In the present review we summarized the current knowledge related to osteoclast differentiation and the new developing targets of pharmacological intervention in each stage of this extremely complicated and not completely elucidated process.

Intracerebroventricular infusion of neurotensin suppresses gastric acid secretion in dogs.

Synthetic neurotensin (NT) was infused intracerebroventricularly in 14 mongrel dogs to study the effects of the peptide on gastric secretion and on gastrin and NT levels. The infusion was performed with a specific apparatus, and gastric fluid was collected with a Pavlov pouch. NT was given in two series of experiments: as a bolus intracerebroventricular injection of 269.8 pmol/kg and as a continuous intracerebroventricular infusion at a rate of 539.6 pmol/kg/h for 30 min. The bolus injection caused a very significant decrease of gastric fluid volume, a significant decrease of HCl output and a significant increase of its pH, while serum immunoreactive gastrin increased significantly. The continuous infusion of NT caused similar changes in gastric secretion. The plasma NT levels did not change. In conclusion, the intracerebroventricular administration of NT increases the serum gastrin levels, decreases the volume and HCl content of gastric fluid, and increases its pH.

Changes in gastric secretion after intracerebroventricular infusion of bombesin in dogs.

Synthetic bombesin (BBS) was infused intracerebroventricularly in 14 mongrel dogs, to study the effects of the peptide on gastric secretion and on gastrin and neurotensin levels. The infusion was performed with a specific apparatus, and gastric fluid was collected with a Pavlov pouch. BBS was given in two series of experiments: as a bolus intracerebroventricular injection of 308.6 pmol/kg and as a continuous intracerebroventricular infusion at a rate of 617.3 pmol/kg/h for 30 min. The bolus injection caused a very significant decrease of gastric fluid volume, a significant decrease of HCl output, and a significant increase of its pH, while serum immunoreactive gastrin increased significantly. The continuous infusion of BBS caused similar changes in gastric secretion. The plasma neurotensin levels did not change. In conclusion, the intracerebroventricular administration of BBS increases the serum gastrin levels, decreases the volume and HCl content of gastric fluid, and increases its pH.

Effects of nicotinic acid therapy on plasma lipoproteins and very low density lipoprotein apoprotein C subspecies in hyperlipoproteinemia.

The effects of long term treatment with nicotinic acid on lipids, lipoproteins, and the plasma distribution of very low density lipoproteins (VLDL) apoprotein C (ApoC) subspecies were studied in 33 patients with types IIa (n = 9), IIb (n = 11), and IV (n = 13) hyperlipidemias. After 6 months of treatment, a significant decrease in triglyceride, total cholesterol, and low density lipoprotein (LDL) cholesterol levels occurred. High density lipoprotein (HDL) cholesterol increased significantly by 31.1%, 41.8%, and 32.0% in types IIa, IIb, and IV, respectively (P less than 0.01 for all). A significant negative correlation existed between changes in HDL cholesterol and triglycerides (r = -0.613; P less than 0.02) in all groups studied. Therapy also produced changes in VLDL, LDL, and HDL protein concentrations. VLDL protein decreased from 20.9 +/- 3.9 to 15.2 +/- 1.0 mg/dl (P less than 0.05) in type IIa. In types IIb and IV, mean VLDL protein decreased from 44.7 +/- 8.2 to 27.1 +/- 3.9 mg/dl (P less than 0.001) and from 46.3 +/- 7.1 to 30.6 +/- 4.9 mg/dl (P less than 0.001), respectively. LDL protein decreased significantly, and HDL protein increased in type IIa only. Gel isoelectric focusing of VLDL before and after nicotinic acid in types IIb and IV hyperlipidemia produced a significant increase in the VLDL ApoC-II component with simultaneous decreases in the total VLDL ApoC-III subspecies. This resulted in increases in the ApoC-II to ApoC-III area ratio from 0.50 +/- 0.1 to 1.02 +/- 0.2 (P less than 0.001) in type IIb and from 0.62 +/- 0.07 to 0.88 +/- 0.13 (P less than 0.01) in type IV, respectively. The ApoE subspecies and the ApoE-III to ApoE-II area ratio did not change significantly. Our results show that nicotinic acid produces a significant improvement in the lipoprotein profiles of these patients.

Effects of amino acids and gastric inhibitory polypeptide on insulin release in dogs.

Insulin release following intravenous administration of an amino acid solution with and without a simultaneous infusion of varying amounts of porcine gastric inhibitory polypeptide (GIP) was studied in dogs. Group I received a 10-amino acid mixture (300 mosmol/kg iv) at 16.6 ml/min for 1 h; group II, amino acid mixture plus 0.5 micrograms.kg-1.h-1 porcine GIP; group III, amino acid mixture plus 1.0 micrograms.kg-1.h-1 of GIP; group IV (a and b) received either 0.5 or 1.0 micrograms.kg-1.h-1 of GIP alone. Compared to group I, groups II and III had a greater insulin response during the first 30 min of the infusion. Group] IV (a and b) showed no insulin release. Glucose concentrations showed no significant change in all groups. From these results, it is concluded that insulin release after intravenous infusion of an amino acid mixture plus GIP is greater than after amino acids or GIP alone. It appears that this effect is more pronounced in the early phase of insulin release.

Pancreatic polypeptide in acute pancreatitis and small-bowel infarction in dogs.

Serum and urine concentrations of pancreatic polypeptide (PP) were measured during experimental acute hemorrhagic pancreatitis and small-bowel infarction in dogs. The mean serum PP concentration in animals with pancreatitis increased markedly after 1 hr and remained elevated, while the mean serum PP concentration in the animals with infarction showed a late trend to increase. The urine PP concentration in pancreatitis increased nonsignificantly, whereas, during bowel infarction, there was no increase. In the infarction group, PP clearance correlated with the serum PP concentration. During pancreatitis, PP was cleared independently of the serum PP concentration. The results suggest that during acute hemorrhagic pancreatitis there is an acute release of PP related to immediate cell injury in the pancreas. The high serum concentration of PP may lead to an override of the normal renal handling of PP. In small-bowel infarction there may be a delayed mode of PP release.