Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes.

We compared the efficacy of twice-daily doses of remogliflozin etabonate (RE) and once-daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12-week, double-blind, randomized, active- and placebo-controlled trial, 336 treatment-naïve subjects with type 2 diabetes and an HbA1c of 7.0-9.5% (53-80 mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000 mg twice daily), matching placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p < 0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p < 0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice-daily RE resulted in a dose-ordered improvement in glycaemic control and was generally well tolerated.

Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes.

The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0-≤9.5% (53-80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose-response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed.

GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus.

AIMS: This clinical trial assessed whether a potent, selective GPR109A agonist, GSK256073, could, through inhibition of lipolysis, acutely improve glucose homeostasis in subjects with type 2 diabetes mellitus. METHODS: Thirty-nine diabetic subjects were enrolled in the randomized, single-blind, placebo-controlled, three-period crossover trial. Each subject received placebo and two of four regimens of GSK256073 for 2 days. GSK256073 was dosed 5 mg every 12 h before breakfast and supper (BID), 10 mg every 24 h before breakfast (QD), 25 mg BID and 50 mg QD. RESULTS: The change from baseline weighted mean glucose concentration for an interval from 24 to 48 h after the initial drug dose was significantly reduced for all GSK256073 regimens, reaching a maximum of -0.87 mmol/l (-1.20, -0.52) with the 25 mg BID dose. Sustained suppression of non-esterified fatty acid (NEFA) and glycerol concentrations was observed with all GSK256073 doses throughout the 48-h dosing period. Serum insulin and C-peptide concentrations fell in concert with glucose concentrations and calculated HOMA-IR scores decreased 27-47%, consistent with insulin sensitization. No marked differences were evident between either 10 and 50 mg total daily doses or QD versus BID dosing. CONCLUSIONS: Administration of a GPR109A agonist for 2 days significantly decreased serum NEFA and glucose concentrations in diabetic subjects. Glucose improvements were associated with decreased insulin concentrations and measures of enhanced insulin sensitivity. Improved glucose control occurred with GSK256073 doses that were generally safe and not associated with events of flushing or gastrointestinal disturbances.

Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients.

AIMS: Remogliflozin etabonate (RE) is the pro-drug of remogliflozin (R), a selective inhibitor of renal sodium-dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). METHODS: In a double-blinded, randomized, placebo-controlled trial, subjects who were drug-naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24-h glucose profiles and oral glucose tolerance tests. RESULTS: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24-h UGE increased in RE treatment groups. Compared with the placebo group, 24-h mean (95% CI) changes in plasma glucose were -1.2 (-2.2 to -0.3) (100 mg BID), -0.8 (-1.7 to 0.2) (1000 mg QD) and -1.7 (-2.7 to -0.8) mmol/l (1000 mg BID). CONCLUSIONS: Administration of RE for 12 days is well-tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects.

AIMS: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers. METHODS: In this single-blind, randomized, placebo-controlled trial, 39 subjects (18-60 years, body mass index 19.9-35.0 kg/m(2)) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC((0-7 days)))] and maximum plasma drug concentration (C(max)) for cohorts 2-5 during week 1. RESULTS: Albiglutide had a terminal elimination half-life (T(1/2)) of 6-8 days and time to maximum observed plasma drug concentration (T(max)) of 3-4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea. CONCLUSIONS: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.

Evidence that the brain of the conscious dog is insulin sensitive.

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84 +/- 6 vs. 86 +/- 6 microU/ml) but differing insulin levels in the head (84 +/- 6 vs. 195 +/- 5 microU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56 +/- 2 mg/dl) at a value similar to that seen during head insulin infusion (58 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792 +/- 198 vs. 2394 +/- 312 pg/ml), norepinephrine (404 +/- 33 vs. 778 +/- 93 pg/ml), cortisol (6.8 +/- 1.8 vs. 9.8 +/- 1.6 micrograms/dl) and pancreatic polypeptide (722 +/- 273 vs. 1061 +/- 255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6 +/- 0.2 to 4.3 +/- 0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6 +/- 0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes.

A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion.

Lowering of the plasma FFA level in intact fasted rats by infusion of nicotinic acid (NA) caused essentially complete ablation of insulin secretion (IS) in response to a subsequent intravenous bolus of arginine, leucine, or glibenclamide (as previously found using glucose as the beta-cell stimulus). However, in all cases, IS became supranormal when a high FFA level was maintained by co-infusion of lard oil plus heparin. Each of these secretagogues elicited little, if any, IS from the isolated, perfused "fasted" pancreas when tested simply on the background of 3 mM glucose, but all became extremely potent when 0.5 mM palmitate was also included in the medium. Similarly, IS from the perfused pancreas, in response to depolarizing concentrations of KCl, was markedly potentiated by palmitate. As was the case with intravenous glucose administration, fed animals produced an equally robust insulin response to glibenclamide regardless of whether their low basal FFA concentration was further reduced by NA. In the fasted state, arginine-induced glucagon secretion appeared to be independent of the prevailing FFA concentration. The findings establish that the essential role of circulating FFA for glucose-stimulated IS after food deprivation also applies in the case of nonglucose secretagogues. In addition, they imply that (i) a fatty acid-derived lipid moiety, which plays a pivotal role in IS, is lost from the pancreatic beta-cell during fasting; (ii) in the fasted state, the elevated level of plasma FFA compensates for this deficit; and (iii) the lipid factor acts at a late step in the insulin secretory pathway that is common to the action of a wide variety of secretagogues.

A Systems Model for Ursodeoxycholic Acid Metabolism in Healthy and Patients With Primary Biliary Cirrhosis.

A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements. Simulations were performed for patients with PBC under two competing hypotheses: one for inhibition of ileal absorption of both UDCA and conjugates and the other only of conjugates. The simulations predicted distinctly different bile acid distribution patterns in plasma and bile. The UDCA model adapted to patients with PBC provides a platform to investigate a complex therapeutic drug interaction among UDCA, UDCA conjugates, and inhibition of ileal bile acid transport in this rare disease population.

Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats.

Cross-sectional studies in human subjects have used 1H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (lowfat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle. Both the high-fat diet and drug treatment significantly impaired insulin sensitivity, as measured with the hyperinsulinemic-euglycemic clamp. Insulin-mediated glucose disposal (IMGD) fell from 12.57 +/- 0.72 in the low-fat group to 9.79 +/- 0.59, 8.96 +/- 0.38, and 7.32 +/- 0.28 micromol x min(-1) x 100 g(-1) in the low-fat + etoxomir, lard, and lard + etoxomir groups, respectively. We used HMRS, which distinguishes between fat within the myocytes and fat associated with contaminating adipocytes located in the muscle bed, to assess the IMCL content of isolated soleus muscle. A tight inverse relationship was found between IMGD and IMCL, the correlation (R = 0.96) being much stronger than that seen between IMGD and either fat mass or weight. In conclusion, either a diet rich in saturated fat or prolonged inhibition of fatty acid oxidation impairs IMGD in rats via a mechanism related to the accumulation of IMCL.

Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans.

In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either saline or nicotinic acid (NA) to deplete their plasma FFA pool, followed by an intravenous bolus of glucose. NA treatment resulted in a fall in basal insulin concentrations of 35 and 45% and in the area under the insulin response curve (area under the curve [AUC]) to glucose of 47 and 42% in the 24- and 48-h fasted individuals, respectively. The 48-h fasted subjects underwent the same procedure with the addition of a coinfusion of Intralipid plus heparin (together with NA) to maintain a high concentration of plasma FFAs throughout the study. The basal level and AUC for insulin were now completely normalized (C-peptide profiles paralleled those for insulin). To assess the effect of an overnight fast, nonobese (n = 6) and obese (n = 6) subjects received an infusion of either saline or NA, followed by a hyperglycemic clamp (200 mg/dl). The insulin AUC in response to glucose was unaffected by lowering of the FFA level in nonobese subjects, but fell by 29% in the obese group. The data clearly demonstrate that in humans, the rise in circulating FFA levels after 24 and 48 h of food deprivation is critically important for pancreatic beta-cell function both basally and during subsequent glucose loading. They also suggest that the enhancement of GSIS by FFAs in obese individuals is more prominent than that seen in their nonobese counterparts.

Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The need for a reliable screening test for classical congenital adrenal hyperplasia prompted development of newborn screening programs. Worldwide incidence of classical congenital adrenal hyperplasia in this report was taken from newborn screening programs in France, Italy, Japan, New Zealand, Scotland, and the United States. Two populations in which the occurrence of congenital adrenal hyperplasia among live births has been reported with greater than usual frequency are the Yupik Eskimos of southwestern Alaska (1:282) and the people of La Reunion, France (1:2,141). Aside from these populations, 1,093,310 newborns were screened between 1980 and 1988, of whom 77 had congenital adrenal hyperplasia. Thus, worldwide incidence of this disorder was estimated at 1:14,199 live births for homozygous patients, 1:60 for heterozygous subjects, with a gene frequency of 0.0083. Incidence of congenital adrenal hyperplasia among whites was estimated to be 1:11,909 (41:488,279) for homozygous patients, 1:55 for heterozygous subjects with a gene frequency of 0.0091. Incidence for the salt-wasting form of congenital adrenal hyperplasia was 1:18,850 (58:1,093,310) compared with 1:57,543 (19:1,093,310) for congenital adrenal hyperplasia in the simple virilizing form. Thus, salt-wasting congenital adrenal hyperplasia was three times more common than simple virilizing congenital adrenal hyperplasia. Estimated incidence of congenital adrenal hyperplasia in white populations in Italy and France (1:10,866) was higher than in Scotland (1:17,098), New Zealand (1:14,500). The incidence in an Asian population (Japan) (1:15,800) did not differ significantly from that of the white population. In four of five populations, overall incidence was higher than previously reported, as was the frequency of the salt-wasting form (75% v 50% to 66%), suggesting improved case detection by newborn screening.(ABSTRACT TRUNCATED AT 250 WORDS)

Compartmental modeling of glucagon kinetics in the conscious dog.

The aim of the present study was to examine glucagon metabolism and distribution using both compartmental-modeling approaches and steady-state organ-balance techniques in conscious, overnight-fasted dogs. Arterial plasma glucose concentrations were clamped at 14 mmol/L with a variable exogenous glucose infusion. Somatostatin was infused to block endogenous secretion of insulin and glucagon. Insulin was replaced intraportally at 2.4 pmol.kg-1.min-1 to maintain basal insulin concentrations in the range from 70 +/- 4 to 95 +/- 12 pmol/L. Glucagon was not given during the control period, but was subsequently infused peripherally in four 1-hour steps of 1.0, 3.0, 6.0, and 3.0 ng.kg-1.min-1. Glucagon levels increased from 0 to 68 +/- 6, 195 +/- 19, 378 +/- 47, and 181 +/- 20 ng/mL. Compartmental analysis of glucagon concentrations showed that glucagon was distributed in one compartment with a volume approximately equal to the plasma volume. The metabolic clearance rate of glucagon was 17.6 mL.kg-1.min-1. The liver cleared 24% of glucagon, and the kidneys, 17%.

Rates of glucagon activation and deactivation of hepatic glucose production in conscious dogs.

To determine the time course of glucagon activation and deactivation of hepatic glucose production (HGP), studies were conducted in 18-hour fasted, conscious dogs. Somatostatin was infused with insulin replaced intraportally at 1.8 pmol x kg(-1) x min(-1) and glucagon replaced peripherally at 1.0 ng x kg(-1) x min(-1). After a 2-hour control period, glucagon infusion was either (1) increased fourfold for 4 hours (GGN 4X), (2) increased fourfold for 30 minutes and returned to a basal rate for 3.5 hours (GGN 4X/1X), or (3) fixed at the basal rate for 4 hours (GGN 1X). In the latter two protocols, glucose was infused peripherally to match glucose concentrations observed during GGN 4X. Glucose turnover was determined by deconvolution with the impulse response of the glucose system described by a two-compartment, time-varying model identified from high-performance liquid chromatography (HPLC)-purified [3-3H]glucose tracer data. In GGN 4X, HGP was stimulated from 15.2 +/- 0.9 micromol x kg(-1) x min(-1) to 52.7 +/- 6.5 micromol x kg(-1) x min(-1) after just 15 minutes, but it decreased over the subsequent 3 hours to a rate 25% above basal. In GGN 4X/1X, the increase in HGP during the first 30 minutes equaled that observed in GGN 4X, but when glucagon infusion was returned to basal, HGP decreased in 15 minutes to rates equal to those observed in GGN 1X. The times for half-maximal activation and deactivation of glucagon action were equal (4.5 +/- 1.0 and 4.0 +/- 1.1 minutes, respectively). The very rapid and sensitive hepatic response to glucagon makes pancreatic glucagon release a key component of minute-to-minute glucose homeostasis.

Counterregulation by epinephrine and glucagon during insulin-induced hypoglycemia in the conscious dog.

We assessed the combined role of epinephrine and glucagon in regulating gluconeogenic precursor metabolism during insulin-induced hypoglycemia in the overnight-fasted, adrenalectomized, conscious dog. In paired studies (n = 5), insulin was infused intraportally at 5 mU.kg-1.min-1 for 3 h. Epinephrine was infused at a basal rate (B-EPI) or variable rate to simulate the normal epinephrine response to hypoglycemia (H-EPI), whereas in both groups the hypoglycemia-induced rise in cortisol was simulated by cortisol infusion. Plasma glucose fell to approximately 42 mg/dl in both groups. Glucagon failed to rise in B-EPI, but increased normally in H-EPI. Hepatic glucose release fell in B-EPI but increased in H-EPI. In B-EPI, the normal rise in lactate levels and net hepatic lactate uptake was prevented. Alanine and glycerol metabolism were similar in both groups. Since glucagon plays little role in regulating gluconeogenic precursor metabolism during 3 h of insulin-induced hypoglycemia, epinephrine must be responsible for increasing lactate release from muscle, but is minimally involved in the lipolytic response. In conclusion, a normal rise in epinephrine appears to be required to elicit an increase in glucagon during insulin-induced hypoglycemia in the dog. During insulin-induced hypoglycemia, epinephrine plays a major role in maintaining an elevated rate of glucose production, probably via muscle lactate release and hepatic lactate uptake.

Cord blood thyrotropin screening for primary hypothyroidism on Caribbean island: a rapid communication.

Screening programs using determinations of serum thyroxine have demonstrated that congenital hypothyroidism occurs in one in 4,000 live births in North America. More than 90 percent of affected infants have primary hypothyroidism with elevated plasma thyrotropin (TSH) levels. Since the feasibility of newborn screening and incidence of congenital hypothyroidism in other less well developed areas of the world is not well defined, a study was undertaken of neonatal primary hypothyroid screening infants born on the Caribbean island of St. Lucia in the Lesser Antilles. Three hundred thirteen cord blood samples were collected on filter paper and transported 3,000 miles to Loyola University of Chicago, Stritch School of Medicine (LUMC). From LUMC, the samples were transported to the Illinois State Metabolic Screening Laboratory for determination of TSH by radioimmunoassay (RIA). In this group of newborns, the mean TSH level in cord blood was 10.23 +/- 0.29 microIU per ml (SEM). It is concluded that screening programs for neonatal primary hypothyroidism can be performed using reference laboratories far removed from the population under observation.

Early neural network development history: the age of Camelot.

What the authors refer to as the first of four ages in the development of neural networks is discussed. It begins about a century ago with the American psychologist William James, and ends in 1969 with the publication of the book by M. Minsky and S. Papert on perceptrons. The history of this period is reviewed, focusing on people rather than just on theory or technology. The contributions of a number of individuals are discussed and related to how neural network tools are being implemented today. The selection of individuals discussed is somewhat arbitrary and not exhaustive, as the intent is to provide a broad sampling of people who contributed to current neural network technology. Besides James, the authors cover the work of W.C. McCulloch and W. Pitts (1943), D. Hebb (1949), and B. Widrow and M. Hoff (1960).

Economic issues in managed care.

Economic issues abound in managed care. The advent of health insurance in the United States, which was created to ensure payment to hospitals, diminished an early emphasis on charity care. Escalating health care costs have ensued. Today, economic considerations dictate the need to control health care expenditures while guaranteeing responsible care. Managed care organizations can achieve both goals by establishing financial partnerships with physicians while instituting quality-control audits, management review teams, and home-care arrangements.

MARC ES: a computer program for estimating medical information storage requirements.

During combat, documentation of medical treatment information is critical for maintaining continuity of patient care. However, knowledge of prior status and treatment of patients is limited to the information noted on a paper field medical card. The Multi-technology Automated Reader Card (MARC), a smart card, has been identified as a potential storage mechanism for casualty medical information. Focusing on data capture and storage technology, this effort developed a Windows program, MARC ES, to estimate storage requirements for the MARC. The program calculates storage requirements for a variety of scenarios using medical documentation requirements, casualty rates, and casualty flows and provides the user with a tool to estimate the space required to store medical data at each echelon of care for selected operational theaters. The program can also be used to identify the point at which data must be uploaded from the MARC if size constraints are imposed. Furthermore, this model can be readily extended to other systems that store or transmit medical information.