Pioglitazone and reductions in post-challenge glucose levels in patients with type 2 diabetes.

AIM: Pioglitazone (PIO) has been shown to decrease insulin resistance in patients with type 2 diabetes, resulting in lowered blood glucose concentrations, lowered plasma insulin levels and lowered haemoglobin A1C (A1C) values. Postprandial glucose control has been recently recognized as an important target for reducing overall glycemic burden in patients with type 2 diabetes. Some authors assert that reductions in postprandial glucose levels may lead to a decrease in cardiovascular risk, one of the major complications associated with diabetes. METHODS: Data were analysed from a 26-week PIO monotherapy study of 88 patients who underwent a 3-h oral glucose tolerance test (75 g dose) at baseline and last measurement. Change from baseline in area under the curve (AUC) values and hourly glucose concentrations were calculated and analysed at both time points for four medication groups: placebo group and PIO 15, 30 and 45 mg groups. Changes from baseline in fasting plasma glucose (FPG) and A1C also were reported. RESULTS: Glucose AUC was significantly (p < 0.05) different from baseline at 15, 30 and 45 mg doses of PIO. In addition, when compared to placebo, PIO (15, 30 and 45 mg) significantly decreased post-challenge blood glucose AUC (p < 0.05). The mean hourly blood glucose levels at last measurement for PIO 15, 30 and 45 mg all were significantly lower (p < 0.05) than placebo at all four time points. In addition, PIO significantly (p < 0.05) reduced FPG and A1C from baseline to last measurement in a dose-related fashion. CONCLUSIONS: PIO significantly reduced post-challenge glucose levels following an oral glucose challenge, leading to improvements in overall glycemic control. Postprandial glucose lowering is one of several metabolic effects of PIO in addition to decreasing insulin resistance and improving some lipids components. Whether these combined metabolic effects can lead to cardiovascular risk reductions may be confirmed by the pending results of cardiovascular outcomes studies with PIO.

Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes.

Thiazolidinediones may slow the progression of type 2 diabetes by preserving pancreatic beta-cells. The effects of pioglitazone (PIO) on structure and function of beta-cells in KKA(y), C57BL/6J ob/ob, and C57BL/KsJ db/db mice (genetic models of type 2 diabetes) were examined. ob/ob (n = 7) and db/db (n = 9) mice were randomly assigned to 50-125 mg.kg body wt-1.day-1 of PIO in chow beginning at 6-10 wk of age. Control ob/ob (n = 7) and db/db mice (n = 9) were fed chow without PIO. KKA(y) mice (n = 15) were fed PIO daily at doses of 62-144 mg.kg body wt-1.day-1. Control KKA(y) mice (n = 10) received chow without PIO. Treatment continued until euthanasia at 14-26 wk of age. Blood was collected at baseline (before treatment) and just before euthanasia and was analyzed for glucose, glycosylated hemoglobin, and plasma insulin. Some of the splenic pancreas of each animal was resected and partially sectioned for light or electron microscopy. The remainder of the pancreas was assayed for insulin content. Compared with baseline and control groups, PIO treatment significantly reduced blood glucose and glycosylated hemoglobin levels. Plasma insulin levels decreased significantly in ob/ob mice treated with PIO. All groups treated with PIO exhibited significantly greater beta-cell granulation, evidence of reduced beta-cell stress, and 1.5- to 15-fold higher levels of pancreatic insulin. The data from these studies suggest that comparable effects would be expected to slow the progression of type 2 diabetes, either delaying or possibly preventing progression to an insulin-dependent state.

Yohimbine treatment of organic erectile dysfunction in a dose-escalation trial.

Yohimbine has had questionable effects in men with organic erectile dysfunction. We conducted this study to better define the population of men responsive to yohimbine, because tobacco was thought to affect a regimen of yohimbine more than other risk factors. We measured nocturnal penile tumescence with the RigiScan monitor, hormone profiles, answers to the Florida Sexual Health Questionnaire, and clinical responses at baseline and after two different doses of yohimbine in 18 nonsmoking men with erectile dysfunction. Of the 18 men, nine (50%) were successful in completing intercourse in more than 75% of attempts. The yohimbine responders were men with less severe erectile dysfunction as manifested by improved increased rigidity on RigiScan testing, higher Florida Sexual Health Questionnaire scores, and slightly higher levels of serum testosterone. Yohimbine is an effective therapy to treat organic erectile dysfunction in some men with erectile dysfunction.

Clinical testing results and high patient satisfaction with a new needle-free device for growth hormone in young children.

Fifty children ages 4-10 yr with type 1 diabetes mellitus volunteered to participate in a study to evaluate and compare a new needle-free device developed for growth hormone delivery. Children answered descriptive questions related to nervousness and worry, hurt or pain, redness or bleeding, and stinging and wetness. Choices for answers for each of these five questions were none, a little, or a lot. None or a little was also combined to give a minimal category. Children also answered four questions that compared the needle-free device to their morning insulin needle injection in reference to ease of use, pain, nervousness, and overall preference. Half the children had single comfort rings inserted to increase the injection pressure. Results indicated no difference in question responses with or without pressure rings. Pain (92%), erythema (96%), worry (90%), stinging (86%) and wetness (96%) were minimal and significant (0.001 > p < 0.03) following all questions. Results of the comparative questionnaire indicated that the device was easier (p < 0.03) to use than needles and significantly preferred (p < 0.001) in 74% of children under age 10.

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency.

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.

Outcome of growth hormone therapy in children with growth hormone deficiency showing an inadequate response to growth hormone-releasing hormone.

Saizen (recombinant growth hormone [GH]), 0.2 mg/(kg x wk), was given in an open-label fashion for an average of 51 mo to 27 children with presumed idiopathic GH deficiency who had withdrawn from a trial of Geref (recombinant GH-releasing hormone [GHRH] 1-29) because of inadequate height velocity (HV) (25 children), the onset of puberty (1 child), or injection site reactions (1 child). Measurements were made every 3-12 mo of a number of auxologic variables, including HV, height standard deviation score, and bone age. The children in the study showed excellent responses to Saizen. Moreover, first-year growth during Saizen therapy was inversely correlated with the GH response to provocative GHRH testing carried out 6 and 12 mo after the initiation of Geref treatment. These findings indicate that GH is effective in accelerating growth in GH-deficient children who do not show or maintain a satisfactory response to treatment with GHRH. In addition, they suggest that the initial response to GH therapy used in this way can be predicted by means of provoc-ative testing.

Increased NADH oxidase activity in the retina of the BBZ/Wor diabetic rat.

This morphological study demonstrates a role for endothelial cells in generating reactive oxygen species in early stages of retinopathy in the BBZ/Wor rat, an obese, noninsulin dependent model of diabetes. Hyperglycemia induced pseudohypoxia results in an imbalance in cytosolic NADH/NAD+. In the oxygen-rich environment of the retina, NADH oxidase generates superoxide radical which is dismutated to hydrogen peroxide. Localization of hydrogen peroxide by the cerium NADH oxidase enzyme activity cytochemical localization technique shows a statistically significant increase of peroxide localization in the central retina of diabetic rats as compared to age-matched, nondiabetic controls. Endothelial cell dysfunction, indicated by leakage of endogenous serum albumin, coincided with areas of NADH oxidase activity localization. In diabetic rats there are increased levels of fibronectin in areas of hydrogen peroxide localization. This in vivo, morphological study is the first demonstration of oxidative injury and endothelial cell dysfunction in the retina of a spontaneous, noninsulin dependent model of diabetes.

Pioglitazone: in vitro effects on rat hepatoma cells and in vivo liver hypertrophy in KKAy mice.

Pioglitazone increases insulin sensitivity in vivo and in vitro. The effects of this agent on insulin-induced DNA synthesis and hepatic cell growth have not been determined. We examined the ability of pioglitazone to enhance basal and insulin-stimulated DNA synthesis in rat H4IIE (H4) hepatoma cells, and to alter liver weight and histology in diabetic KKAy mice. Treatment of H4 cells with increasing concentrations of pioglitazone for 30 h increased basal DNA synthesis 1.6- to 1.8-fold. With pioglitazone pretreatment and submaximal insulin concentrations, DNA synthesis was significantly increased from 2.1-fold (insulin 10(-12) mol/l alone) to 3.9-fold (insulin 10(-12) mol/l + pioglitazone 10(-6) mol/l). At maximal concentrations of insulin, the enhancement of DNA synthesis increased from 7.4-fold (insulin 10(-8) mol/l alone) to 16.2-fold (insulin 10(-8) mol/l + pioglitazone 10(-6) mol/l). Glyburide did not increase basal or insulin-stimulated DNA synthesis. In diabetic KKAy mice, serum glucose levels decreased and body weight, liver weight and liver weight as a percentage of body weight increased following pioglitazone treatment. Histological studies demonstrated marked hepatocyte distension. Our findings suggest that pioglitazone acts as an insulin sensitizer in rat hepatoma cells, increasing basal and insulin-stimulated DNA synthesis, and stimulating fat synthesis and liver hypertrophy in diabetic KKAy mice.

Comparison of results of nocturnal penile tumescence and rigidity in a sleep laboratory versus a portable home monitor.

OBJECTIVES: To validate the results of the home penile tumescence monitor versus the sleep laboratory studies of erectile function. METHODS: We used both methods to study 18 episodes of rigidity and 19 episodes of tumescence in 10 subjects with erectile dysfunction before and after the use of an experimental vasodilating medication. RESULTS: The tumescence measurement in the sleep laboratory compared favorably with the changes in tumescence with the RigiScan portable home monitor: at the base (r = 0.70; P < 0.001), and at the tip (r = 0.84; P < 0.001). In measuring rigidity, the buckling pressure in the sleep laboratory compared favorably with the RigiScan measurements of percent average rigidity at the base (r = 0.56; P = 0.017), at the tip (r = 0.62; P = 0.006), and mean rigidity of the base and tip (r = 0.64; P = 0.004). In a comparison of the buckling pressure with the new RigiScan Plus quantitative program, there was good correlation with the rigidity activity units at the base (r = 0.70; P = 0.001) and at the tip (r = 0.72; P < 0.001). A clinical estimate of penetrable rigidity correlates with the RigiScan base rigidity of 55% to 60% and tip rigidity of about 50%. CONCLUSIONS: The portable home monitor is a viable and cost-effective clinical tool to measure nocturnal penile activity.

Reduction of penile nitric oxide synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type II) rats with erectile dysfunction.

Erectile dysfunction occurs frequently in human diabetes, and it is sometimes associated with hypogonadism. These conditions also develop in a model of insulin-dependent (type I) diabetes, the BB/WORdp (diabetic prone) rat but have not yet been investigated in the model of insulin-resistant (type II) diabetes, the BBZ/WOR rat. It is also unknown whether diabetes-related impotence is due to reduced levels of the mediator of penile erection, nitric oxide, caused by a decrease of nitric oxide synthase (NOS) in the penis. To clarify these questions, groups (n = 5-6) of diabetic BB/WORdp (insulin-maintained) and BBZ/WOR rats were age-matched with diabetic-resistant BB/WORdr and non-diabetic BB/WORdp rats and submitted to determinations of serum glucose, testosterone, and penile reflexes (cups and flips). Erectile dysfunction was found in all of type I and in most of type II diabetic animals (glycemias of 25.0 and 31.1 mM), at the selected mean ages of 310 and 180 days old, respectively. This was evidenced by over 95% decreases of erectile reflexes in both types of diabetes and was accompanied by 75% reduction of serum testosterone. Soluble NOS activity was measured in penile tissue from the diabetic rats with impaired erectile reflexes and in the corresponding controls, by the (3H)-L-arginine/citrulline conversion assay. The neuronal NOS isoform (nNOS) content was determined by a semiquantitative western blot assay. Both types of diabetes showed a marked decrease of penile NOS activity (74 and 55%, respectively), and a lower reduction of penile nNOS content (47 and 33%, respectively). No endogenous NOS inhibitor was detected in the diabetic type I penile cytosol by cross-mixing NOS activity assays. Our data support a common etiology for erectile dysfunction present in rats with types I and II diabetes mellitus and suggest that the etiology is related to a decrease of penile NOS derived in part from serum androgen deficiency.

Assessment of proteinuria and neuropathy in the nonimmunosuppressed BB diabetic rat after abdominal intratesticular islet transplantation.

Only limited studies are available that assess diabetic complications following islet cell transplantation. Our objectives were to quantitate urine total protein, sural nerve morphometry, and sexual function in the diabetic BB/WOR male rat following islet cell transplantation into the abdominal testis. Success of islet cell transplantation was determined by nonfasting, morning, twice-weekly serum glucose and 12-hr fasting glucose, total glycosylated hemoglobin, and HbA1c after six months of diabetes and prior to death. Results showed that 9 of 16 rats were transplanted successfully for a period of at least six months. Pretransplant glucose was 21.9 +/- 4.67 (SD) mM/L and posttransplant glucose was 6.44 +/- 72 mM/L. The 12-hr fasting glucose ranged from 4.61 to 9.28 mM/L in animals prior to death, and glycosylated hemoglobins were not different from controls. Total urinary protein was significantly (P < 0.01) less than untreated diabetic rats (5.66 +/- 1.96 vs. 16.6 +/- 3.7 mg/24 hr) and not different from controls. Penile reflexes and serum testosterone remained normal in islet cell-transplanted animals. Sural nerve morphometry was normal, with 29.2% fewer abnormalities (paranodal swelling, paranodal demyelination, myelin wrinkling, Wallerian degeneration, and segmental demyelination) than untreated diabetic BB/WOR rats. We conclude that abdominal, intratesticular islet transplantation normalizes fasting blood glucose and glycosylated hemoglobin. In addition, the improvement in metabolic control at six months of diabetes was associated with normal total urinary protein, sural nerve morphometry, and sexual function.

Use of the Florida Sexual History Questionnaire to differentiate primary organic from primary psychogenic impotence.

A recent study demonstrated the Florida Sexual History Questionnaire (FSHQ) is reliable and valid when used to discriminate impotent from nonimpotent men. This study examined the ability of the FSHQ to discriminate between men with primary psychogenic and primary organic impotence in a sample of impotent diabetics and a larger group of impotent men. The hit rate in the diabetic sample was 81% using an eight-item discriminant function, and 70% using the total score. Hit rates in the larger sample were significant but lower (73% and 66%). The results suggest that the FSHQ has concurrent validity in terms of discriminating primary organic from primary psychogenic impotence.

Erectile and copulatory dysfunction in chronically diabetic BB/WOR rats.

The pituitary-testicular axis, penile reflexes, and copulatory behavior were studied in male BB diabetic rats from 10 to 40 wk of diabetes. Serum testosterone was diminished from 18 to 28 wk of diabetes, and the responses to human chorionic gonadotropin stimulation were blunted. Serum luteinizing hormone (LH) in diabetic rats did not differ from that of the control rats before or after LH-releasing hormone stimulation. Serum follicle-stimulating hormone and prolactin levels were also similar to controls. After 26 wk of diabetes, androgen-sensitive reproductive accessory organs were significantly reduced in size. This also was true for the androgen-sensitive bulbocavernosus and ischiocavernosus muscles. Penile reflexes in these animals from 20 to 32 wk of diabetes were consistently reduced in number and demonstrated prolonged latency. Copulatory behavior was evaluated in these animals at 25 and 28 wk of diabetes and revealed a reduced number of BB diabetic rats showing normal behavior at 25 wk of diabetes. At 28 wk of diabetes, mount latency, intromission latency, ejaculatory latency, and the postejaculatory interval were all prolonged compared with controls. In addition, the number of diabetic animals showing normal behavior was reduced compared with controls. These studies demonstrate that chronically BB diabetic rats develop diminished testosterone and erectile dysfunction that precedes ejaculatory dysfunction in a similar fashion as impotence in diabetic men. We suggest that further studies in this animal model may be critical to the better understanding and treatment of impotence in diabetic men.

Reduced sensitivity of penile mechanoreceptors in aging rats with sexual dysfunction.

Male sexual activity gradually declines with age in most mammalian species and may be associated with a decrease in vibrotactile sensitivity of the penis. This study was designed to determine if the penile mechanoreceptors in aging rats exhibit reduced sensitivity to vibrotactile stimuli. Electrophysiological and behavioral data was obtained from mature adult (9 months) and old (23 months) rats. Single penile mechanoreceptor afferent fibers from aging animals exhibited a decrease in the ability to transduce high-frequency vibratory stimuli when compared to afferents from mature adult animals. In addition, there was a reduction in single-fiber and sensory nerve conduction velocity. Copulatory performance was reduced in the aging animals as determined by the inability to ejaculate with a receptive female. The results of this study demonstrate that the male rat exhibits an age-related decrease in penile vibrotactile sensitivity mediated by mechanoreceptor afferents which may be partly responsible for the decrease in parameters of sexual activity.

Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat.

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation and treatment of sexual dysfunction in men with diabetes mellitus.

Sexual dysfunction is common among men with Type I and Type II diabetes. Tests of nocturnal penile tumescence (NPT) combined with waking tumescence and questionnaires can more accurately differentiate between primary organic and primary psychogenic impotence. This ability to differentiate the etiology of erectile dysfunction avoids the inappropriate use of penile injections and costly surgical procedures which are unnecessary in treatment of diabetic patients with primary psychogenic impotence. In patients with primary organic impotence, several new treatments are available which result in high patient satisfaction.

Reliability and validity of the Florida Sexual History Questionnaire.

The Florida Sexual History Questionnaire (FSHQ) is a brief 20-item questionnaire designed to assess male sexual dysfunction. The validity and reliability of the scale were examined in 33 diabetic impotent males and 58 nondiabetic, age-equivalent nonimpotent males. The FSHQ was found to have high internal consistency and split-half reliability and significantly discriminated between nonimpotent and impotent subjects. Among diabetic impotent subjects, some of the test items were correlated significantly with physiological measures of sexual functioning. However, the FSHQ failed to discriminate between diabetics diagnosed as having organic or psychogenic impotence. This latter finding is discussed within the context of recent suggestions that it may not be possible to draw a clear dichotomy between organic and psychogenic impotence.

Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats.

Rats with short-term diabetes show a greater than 50% reduction of serum testosterone and increased lipid in Leydig cells but normal testicular structure. The purpose of this study was to determine the extent of testicular pathology (morphology index), integrity of the blood-testis barrier, daily sperm production (DSP), number of Leydig cells per testis (LC/T), and total trunk testosterone (TTT) in diabetic rats (BBWORdp) with long-term hyperglycemia (300-350 mg/dl for greater than 180 days) and to evaluate its effects on fertility potential. Results were compared with similarly aged normoglycemic rats (BBWORdr) and normal control Wistar rats. After 6 mo of diabetes, testis weights, DSPs, TTTs, and the morphology index were significantly reduced. The LC/T was not different from BBWORdr rats. The blood-testis barrier appeared intact, although structural abnormalities were noted in Sertoli-Sertoli junction complexes. There was a significant reduction in the number of pregnancies per rat and implantations per pregnancy in matings utilizing the diabetic BBWORdp rat and control Wistar female rats. Results indicate that long-term diabetes with sustained hyperglycemia leads to significant testicular dysfunction associated with decreased fertility potential.

Hyperthyroidism in a cocaine-dependent patient.

Although clinical manifestations of cocaine use are similar to the signs and symptoms of hyperthyroidism and research suggests that cocaine may affect the thyroid, no occurrences of cocaine-associated thyroid toxicity have been reported. The authors report a case of Graves' disease in a cocaine-dependent patient and propose that the patient's cocaine use may have precipitated thyroid toxicity.