Occult HBV infection in HIV-infected adults and evaluation of pooled NAT for HBV.

The study aimed to determine the prevalence of occult hepatitis B virus infection among HIV-infected persons and to evaluate the use of a pooling strategy to detect occult HBV infection in the setting of HIV infection. Five hundred and two HIV-positive individuals were tested for HBV, occult HBV and hepatitis C and D with serologic and nucleic acid testing (NAT). We also evaluated a pooled NAT strategy for screening occult HBV infection among the HIV-positive individuals. The prevalence of HBV infection among HIV-positive individuals was 32 (6.4%), and occult HBV prevalence was 10%. The pooling HBV NAT had a sensitivity of 66.7% and specificity of 100%, compared to HBV DNA NAT of individual samples. In conclusion, this study found a high prevalence of occult HBV infection among our HIV-infected population. We also demonstrated that pooled HBV NAT is highly specific, moderately sensitive and cost-effective. As conventional HBV viral load assays are expensive in resource-limited settings such as India, pooled HBV DNA NAT might be a good way for detecting occult HBV infection and will reduce HBV-associated complications.

Directly observed therapy of sofosbuvir/ribavirin +/- peginterferon with minimal monitoring for the treatment of chronic hepatitis C in people with a history of drug use in Chennai, India (C-DOT).

We assessed the feasibility of field-based directly observed therapy (DOT) with minimal monitoring to deliver HCV treatment to people with a history of drug use in Chennai, India. Fifty participants were randomized 1:1 to sofosbuvir+peginterferon alfa 2a+ribavirin (SOF+PR) for 12 weeks (Arm 1) vs sofosbuvir+ribavirin (SOF+R) for 24 weeks (Arm 2). SOF+R was delivered daily at participant chosen venues and weekly peginterferon injections at the study clinic. HCV RNA testing was performed to confirm active HCV infection and sustained virologic response 12 weeks after treatment completion (SVR12). No baseline genotyping or on-treatment viral loads were performed. Median age was 46 years. All were male and 20% had significant fibrosis/cirrhosis. All self-reported history of injection drug use, 18% recent noninjection drug use and 38% alcohol dependence. Six discontinued treatment (88% completed treatment in each arm). Of 22 who completed SOF+PR, all achieved SVR12 (22/25=88%); 15 of 22 who completed SOF+R achieved SVR12 (15/25=60%; P=.05). Among those completing SOF+R, SVR12 was significantly less common in participants reporting ongoing substance use (36% vs 100%) and missed doses. Active substance use and missed doses did not impact SVR with SOF+PR. Field-based DOT of HCV therapy without real-time HCV RNA monitoring was feasible; however, achieving 100% adherence was challenging. SOF+PR appeared superior to SOF+R in achieving SVR12, even when doses were missed with no discontinuations due to side effects. Further exploration of short duration treatment with peginterferon plus direct-acting antivirals is warranted.

Lenalidomide as a novel therapy for gastrointestinal angiodysplasia in von Willebrand disease.

INTRODUCTION: Lenalidomide is a thalidomide analog with anti-angiogenic properties. Previous case reports suggest its efficacy in preventing gastrointestinal bleeding (GIB) secondary to angiodysplasia (AD) in hereditary haemorrhagic telangiectasia and potentially in reversing AD. We present the first case series to explore lenalidomide as a treatment for AD-related GIB in patients with von Willebrand disease (VWD). METHODS: A retrospective chart review was conducted to include patients with VWD, who were evaluated from 2010 to 2013 and who had received lenalidomide to treat recurrent GIB secondary to AD. All patients had failed single-agent use of antifibrinolytic agents. Patients were observed for at least 2 years on therapy. RESULTS: Five patients (3 males; 68.2 ± 4.9 years) with VWD (3 with type 3 and 1 each with types 1 and 2a) and AD were found. Sites of AD included the stomach, duodenum, jejunum and colon. Lenalidomide was started at 5 mg oral daily. Uptitration to 10 and 15 mg in 1 patient each was necessary due to recurrence of GIB. The mean number of endoscopies performed for control of GIB post lenalidomide was significantly lower compared to pretherapy (0.25 vs 5.50; P = .001). Mean bleed-free duration on lenalidomide was 12.6 ± 4.7 months. Three patients have reported no GIB on lenalidomide. CONCLUSION: This case series demonstrates significantly reduced number of endoscopies and increased bleed-free duration with lenalidomide treatment in selected patients with VWD and recurrent GIB from AD. Prospective multicenter trials are needed to further define the role of lenalidomide in the management of GIB from angiodysplasia and VWD.

Suggested mechanism for the selective excretion of glucosylated albumin. The effects of diabetes mellitus and aging on this process and the origins of diabetic microalbuminuria.

In previous studies in the Sprague-Dawley rat, Williams and coworkers reported the phenomenon of selective urinary excretion of glucosylated albumin (editing, i.e., the percent glucosylation of urinary albumin is more than that of plasma albumin) by the mammalian kidney. Ghiggeri and coworkers subsequently found that the extent of editing is reduced in human diabetics. Moreover, the reduction in editing in diabetes correlates inversely with levels of microalbuminuria. We also find reduction in the extent of editing in diabetic humans. We find a striking inverse correlation not only with the magnitude of microalbuminuria but also with the extent of plasma albumin glucosylation. In contrast, we found little correlation between the reduction in editing and the duration of diabetes in human subjects. Stz induced diabetes in the Sprague-Dawley rat is associated with a striking and rapid reduction in editing which develops virtually with the same kinetics exhibited by the appearance of hyperglycemia. This loss of editing is rapidly reversed by daily administration of insulin but not by aldose reductase inhibitors. Mannitol infusion in anesthetized Wistar rats resulted in an increase in urine volume, GFR, and microalbuminuria, and was also accompanied by a marked reduction in editing. This reduction was rapidly reversed by a cessation of mannitol infusion. We propose here that glucosylated albumin (in contrast to unmodified albumin) is not reabsorbed by the proximal tubule, and thus, is preferentially excreted in the urine. We postulate that the increase in GFR which emerges as a consequence of increased plasma osmolality in diabetes mellitus delivers more albumin to the proximal tubule than can be reabsorbed. This results in a dilution of excreted glucosylated albumin molecules by excreted unmodified albumin, which appears as the early microscopic albuminuria of diabetes. Paradoxically, the fall in apparent editing is accompanied by an absolute increase in the total quantity of glucosylated albumin excreted. In contrast, we found that editing of glucosylated albumin by the normal kidney is found to gradually decline as a function of age without the appearance of microalbuminuria. This suggests that a different mechanism operates to produce the loss of editing seen with aging in man, and as clearly (but in a shorter absolute time intervals) in the Fischer-344 rat.

TNF-alpha inhibits insulin action in liver and adipose tissue: A model of metabolic syndrome.

Several studies suggest that TNF-alpha contributes to the development of insulin resistance (IR). We compared transcriptional profiles of rat H-411E liver cells exposed to insulin in the absence or presence of TNF-alpha. We identified 33 genes whose expression was altered by insulin, and then reversed by TNF-alpha. Twenty-six of these 33 genes created a single network centered around: insulin, TNF-alpha, p38-MAPK, TGFb1; SMAD and STAT1; and enzymes and cytokines involved in apoptosis (CASP3, GADD45B, IL2, TNF-alpha, etc.). We analyzed our data together with other data of gene expression in adipocytes and found a number of processes common to both, for example, cell death and inflammation; intercellular signaling and metabolism; G-Protein, IL-10 and PTEN signaling. Moreover, the two datasets combined generated a single molecular network that further identified PTEN (a phosphatase) as a unique new link between insulin signaling, IR, and apoptosis reflecting the pathophysiology of "metabolic syndrome".

Divergent biological effects of adenosine and dibutyryl adenosine 3',5'-monophosphate on the isolated fat cell.

Adenosine 3',5'-monophosphate stimulated production of carbon dioxide and lipid from glucose, whereas its dibutyryl derivative inhibited this conversion. Addition of the dibutyryl derivative to the isolated fat cell further stimulated lipolysis induced by adrenocorticotropic hormone, whereas addition of adenosine 3',5'-monophosphate inhibited this lipolysis. Hence, measured by these two parameters, the biologic properties of adenosine 3',5'-monophosphate and its dibutyryl derivative are distinctly different.

Factors associated with anaemia in HIV-infected individuals in southern India.

Anaemia accelerates disease progression and increases mortality among HIV-infected individuals. Few studies have characterized this problem in developing countries. Haemoglobin values of adults presenting to an HIV tertiary care center in India between 1996 and 2007 were collected (n = 6996). Multivariate logistic regression analysis was performed to examine associations among anaemia, HIV progression and co-morbidities. Overall, anaemia prevalence was 41%. Twenty percent of patients with CD4 counts >500 cells/microL were anaemic, compared with 64% of those with CD4 counts <100 cells/microL (P < 0.001). In multivariate analysis, CD4 count <100 cells/microL (odds ratio [OR]:5.0, confidence interval [CI]:4.0-6.3), underweight body mass index (OR:4.8, CI:3.6-6.5), female gender (OR:3.1, CI:2.8-3.6) and tuberculosis (TB) (OR:1.6, CI:1.4-1.8) were significantly associated with anaemia. In this setting, management of anaemia should focus on antiretroviral therapy, nutritional supplementation and TB control. The high anaemia prevalence among patients meeting criteria for antiretroviral therapy highlights the need for increased access to non-zidovudine nucleoside reverse transcriptase inhibitors in developing countries.

Establishment of T-lymphocyte subset reference intervals in a healthy adult population in Chennai, India.

Estimation of CD4+ T-lymphocytes continues to be an important aspect for monitoring HIV disease progression and response to antiretroviral therapy. Most of the diagnostic laboratories often rely on western text books for CD4+ T-lymphocyte reference values, which could, often be unreliable for usage in local settings. Therefore, we attempted to establish the reference values for T-lymphocyte subsets among healthy adults in a cross-sectional study carried out at the YRG Centre for AIDS Research and Education (YRG CARE) in Chennai, south India, in 213 (84 female and 129 male) healthy, HIV-1/2 seronegative adults as volunteers. Whole blood specimens were processed for CD4+, CD8+ T-lymphocyte estimation and haematological parameters. The established range of CD4+ T-lymphocyte counts for men and women were 383-1347 cells/microl (mean 865 and median 845 cells/microl) and 448-1593 cells/microl (mean 1021 and median 954 cells/microl), respectively. Women had significantly higher absolute CD4+ Tlymphocyte counts (P<0.001) and CD4+:CD8+ T-lymphocyte ratio as compared to men. The established normal range of CD4+ T-lymphocyte % was 21-59 (mean 40.2 and median 40.1). The influence of age was not observed in any of the parameters except CD4+/CD8+ T-lymphocyte ratio with the >45 yr age group. Further studies with greater sample size may be required to define the staging of HIV disease in relation to the normal CD4 T-lymphocyte count in the general population.

Diversity of hepatitis C virus infection among HIV-infected people who inject drugs in India.

The availability of generic direct acting antivirals (DAAs) for hepatitis C virus (HCV) treatment has prompted many low-and-middle-income countries to launch HCV elimination programs. Because the efficacy of some of these generic DAAs varies by HCV viral subtype, information on subtype distribution can contribute important information to these elimination programs. We conducted a cross-sectional serosurvey to characterize HCV subtype diversity among HIV positive people who inject drugs (PWID) across 14 cities in India. Of 801 HIV positive PWID sampled, 639 tested HCV antibody positive (78.9%). Among 105 samples sequenced, genotype 3 (58.1%) was the most commonly observed followed by genotype 1 (36.2%) and genotype 6 (5.7%). Of the genotype 3 infections, 65% were subtype 3a and 35% were subtype 3b. Of the genotype 1 infections, 94% were subtype 1a and 6% were subtype 1b. All genotype 6 samples were subtype 6n. There was some variability in genotype diversity depending on geographic region and PWID epidemic stage with greater diversity observed in older PWID epidemics. One sequence, HY018, did not cluster with any known reference sequences in phylogenetic analysis. Nearly 80% of HIV infected PWID across India are co-infected with HCV, and subtype prevalence and genetic diversity varied by region and PWID epidemic stage. HCV elimination programs in India will need to consider HCV subtype.

Comorbidities among HIV-infected injection drug users in Chennai, India.

BACKGROUND & OBJECTIVE: HIV-infected injection drugs users (IDUs) are known to have high rates of co-infections. A few reports exist on comorbidities among HIV-infected IDUs in India. We carried out a retrospective study to analyse data on comorbidities in India and treatment challenges faced when treating HIV-infected IDUs in India. METHODS: A retrospective chart review of 118 HIV-infected IDUs who accessed care at the YRG Centre for Substance Abuse-Related Research, Chennai, between August 2005 and February 2006 was done. Demographic, laboratory and clinical information was extracted from medical records. Descriptive demographic and clinical characteristics and distributions of comorbidities across CD4 cell count strata were analysed. RESULTS: All IDUs were male with a median age of 35.5 yr. The majority were married with average monthly income less than INR 3000 per month. The prevalence of hepatitis B and C infections were 11.9 and 94.1 per cent, respectively. Other common co-morbidities included oral candidiasis (43.2%), tuberculosis (33.9%), anaemia (22.9%), lower respiratory tract infections (16.1%), cellulitis (6.8%), herpes zoster (9.3%) and herpes simplex (9.3%). Among participants with CD4+ < 200 cells/microl, the prevalence of TB was 60 per cent. INTERPRETATION & CONCLUSION: IDUs in Chennai were commonly co-infected with HBV, HCV and tuberculosis, complicating use of antiretroviral and anti-tuberculous therapy. The current regimens available for the management of HIV and TB in India may need to be re-assessed for IDUs given the potential for increased rates of hepatotoxicity.

Simulated hyperglycemic hyperosmolar syndrome. Impaired insulin and epinephrine effects upon lipolysis in the isolated rat fat cell.

These investigations were designed to evaluate the effect of excess glucose and sodium chloride on lipolysis in the isolated adipocyte under normal and modelled pathological conditions simulating the hyperglycemic hyperosmolar syndrome. Isolated rat fat cells were incubated in the presence of various combinations of sodium chloride, glucose, epinephrine, and insulin. Lipolysis was measured as glycerol and free fatty acid release, and total medium osmolarity as milliosmoles per liter by freezing point depression. Basal lipolysis was unaffected by changes in osmolarity with sodium chloride, but glucose and glucose plus sodium chloride increased basal glycerol release. Increasing osmolarity with sodium chloride diminished the lipolytic response to epinephrine. Increasing osmolarity with glucose augmented the lipolytic response to epinephrine up to a total medium osmolarity of 550 mosmol. Higher osmolarities produced with glucose suppressed the epinephrine-induced lipolytic response.When the hyperglycemic hyperosmolar syndrome was simulated with 100 mM glucose and 50 mM sodium chloride (total osmolarity = 460 mosmol) the epinephrine-stimulated lipolysis dose-response curve in the isolated fat cell was shifted to the right. Furthermore, in the presence of 100 mM glucose + 50 mM sodium chloride, physiological concentrations of insulin were less effective in opposing epinephrine-stimulated lipolysis. In the presence of 50 mM glucose and 25 mM sodium chloride (total osmolarity = 370 mosmol) epinephrine-stimulated lipolysis measured as free fatty acid release was decreased by 50%. Under conditions simulating the hyperglycemic hyperosmolar syndrome in the isolated rat adipocyte, altered lipolysis reflects impaired effectiveness of both insulin and epinephrine as antilipolytic and lipolytic hormones, respectively. Furthermore, the attenuated response to both hormones appears to be primarily a function of extracellular solute composition. The lack of ketosis is the result of diminished release of free fatty acids from peripheral adipose cells.

Time-course of insulin degradation in perifused isolated rat adipose cells.

Isolated fat cells from rat epididymal adipose tissue were preincubated with 50 microU/ml (0.33 nM) 125I-insulin at 23 degrees C to enhance binding while retarding degradation. The fat cells were then perifused at that temperature to remove unbound 125I-insulin, and fractions of perifusate were collected each minute. The temperature of the cells in the perifusion chamber was then rapidly increased to 37 degrees C, and perifusion was continued. The fat cells degraded a portion of the bound 125I-insulin measured by loss of immunoprecipitability with excess antisera to insulin. The percentage of degraded 125I-insulin dissociating from the fat cells increased progressively with time at 37 degrees C, and the rateof dissociation of 125I-insulin degradation products showed a first-order dependence on the amount of degraded 125I-insulin bound to the cells. To explain this first-order dependence it is necessary to postulate a "processing" step after binding and before degradation. The first-order rate constant at 37 degrees C is 0.023 +/- 0.004 min-1. Fast and slow dissociating components can be resolved from kinetic plots of the dissociation of undegraded 125I-insulin (immunoprecipitable) from the isolated fat cells. The antilipolytic activity of the 125I-insulin on epinephrine-stimulated lipolysis is evident over much of the time-course of dissociation. A model for the degradation of insulin bound to isolated fat cells is discussed.

Perifusion of isolated rat adipose cells. Modulation of lipolysis by adenosine.

Incubation of isolated rat epididymal fat cells is associated with the accumulation of adenosine in the incubation medium. To more clearly define the effect of adenosine on lipolysis, isolated rat epididymal adipocytes were studied with the perifusion system. Various combinations of epinephrine, adenosine, and adenosine deaminase were perifused through the adipocytes. Exogenous adenosine, 0.001-10.0 muM, had no discernible influence upon unstimulated lipolysis; but exogenous adenosine inhibited epinephrine-sensitive lipolysis in a concentration-dependent manner. Cells perifused with 0.3 muM epinephrine plus 0.001 muM adenosine did not show any impairment of the lipolytic response to 0.3 muM epinephrine alone. Adenosine, 0.01 muM, inhibited the response to epinephrine by 50%; response to 0.3 muM epinephrine plus 0.1 muM adenosine was similar to the basal rate. Perifusion with adenosine deaminase significantly increased basal lipolysis to 30% of the epinephrine response. Adenosine deaminase and epinephrine were synergistic in stimulating lipolysis to 180% of the response to epinephrine alone. Isolated fat cells were incubated for 30 min, and the cell-free used medium was perifused through fresh fat cells. Epinephrine in used medium was less effective in promoting lipolysis than epinephrine in fresh buffer. High-pressure liquid chromatography identified adenosine in the used medium. Bovine serum albumin possessed adenosine deaminase activity but accounted for negligible conversion of adenosine to inosine. Adenosine is shown to have a modulating effect upon basal and hormone-stimulated lipolysis in the perifusion system. Sufficient endogenous adenosine (<0.01 muM) is present to maximally affect basal lipolysis. Hormone-stimulated lipolysis, although inhibited somewhat by endogenous adenosine, requires the addition of exogenous adenosine for complete inhibition.

Inhibition of insulin degradation by nonsuppressible insulin-like activity.

Nonsuppressible insulin-like activity, provided by three sources, was evaluated for its effect on the proteolytic degradation of insulin utilizing insulin protease obtained from rat liver homogenate as well as liver cell membranes. All three preparations of nonsuppressible insulin-like activity were found to be competitive inhibitors of insulin degradation. In addition human plasma was fractionated yielding an acetone precipitate which was found to have nonsuppressible insulin-like activity and to be a competitive inhibitor of insulin protease.

The reversible inhibition by carbonyl cyanide m-chlorophenyl hydrazone of epinephrine-stimulated lipolysis in perifused isolated fat cells.

Lipolysis stimulated in perifused isolated fat cells by 0.5 micrometers epinephrine is an ATP-dependent process which can be monitored by measuring the release of glycerol. The stimulated lipolysis is inhibited to 10 micrometers carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an uncoupler of oxidative phosphorylation. If 20-micrometers glucose is continuously present in the perifusion medium during and after treatment with epinephrine and CCCP, the inhibition of the stimulated lipolysis is reversible when the CCCP is discontinued; otherwise it is not readily reversible. Since 20 micrometers 2-deoxyglucose will not substitute for glucose, metabolism of glucose beyond phosphorylation by hexokinase is concluded to be necessary in order to maintain the reversibility of the inhibition of CCCP. Substitution of 10 micrometers succinate for glucose also did not preserve the reversibility of the CCCP inhibition, and there was no significant difference in the amount of decrease of ATP in fat cells incubated with CCCP and epinephrine in the presence of glucose as compared to the decrease observed in the presence of succinate. The mechanism by which glucose maintains reversibility of the inhibition of stimulated lipolysis by CCCP is therefore not clear.

Deprivation and repletion of androgen in vivo modifies triacylglycerol synthesis by rat hepatocytes.

Given the same quantity of fatty acid, livers from male rats esterify less fatty acid and secrete less triacylglycerol in very-low-density lipoprotein than do livers from female animals. To elucidate the role of testosterone in maintenance of this male pattern, conversion of [1-14C]oleic acid into triacylglycerol was assessed in vitro by rat hepatocytes (male) following gonadectomy and replacement with testosterone. Following castration, incorporation of fatty acid into triacylglycerol was increased. In contrast, esterification of exogenous fatty acid into phospholipid, cholesteryl esters, and diacylglycerol was unchanged. Treatment with testosterone (75 micrograms/day) reduced incorporation of exogenous fatty acid into triacylglycerol. Higher doses of testosterone (200 or 100 micrograms/day) modified the effect, such that inhibition was observed only at low oleate (0.5 mM) concentrations. At higher substrate concentrations (1.0-2.0 mM) the inhibitory effect was no longer observed. Further, a similar dose-dependent effect of testosterone was observed following in vivo treatment of castrate females with testosterone. These data support the concept of a regulatory role of testosterone in hepatic triacylglycerol synthesis. These findings also demonstrate a biphasic effect of testosterone, an effect that is dependent not only upon the dose of testosterone administered, but also on the concentration of fatty acid to which the hepatocyte is exposed in vitro.

Cyclic nucleotide phosphodiesterase. Insulin activation detected in adipose tissue by gel electrophoresis.

In rat adipose tissue, insulin (100 muU./ml.) increases the activity of cyclic AMP (but not cyclic GMP) phosphodiesterase (PDE). Radioisotopic assay, autoradiography, and histochemical stains demonstrated that cyclic nucleotide PDE activity is associated with multiple bands of protein separable by polyacrylamide gel electrophoresis. The insulin activation of cyclic AMP PDE, however, was limited to a single band corresponding to the "low" Km enzyme specific for cyclic AMP; insulin had no effect on the "high" Km enzyme or on PDE bands with activity directed toward cyclic GMP. These data support the concept that insulin may modulate the activity of at least one of the cyclic AMP phosphodiesterases.

Insulin degradation by mononuclear cells.

Mononuclear cells from peripheral blood possess insulin receptors that are altered in number or binding affinity in certain metabolic diseases as obesity. The monocyte, and not the lymphocyte, is the cell with the capacity to specifically bind insulin. Furthermore, this binding appears to mirror the receptor status on such insulin target tissues as liver, muscle, and fat. Since liver, muscle, and fat also degrade insulin, mononuclear cells from the blood of normal volunteers were examined for insulin-degrading activity. Intact cells were incubated with 125I-insulin and the amount of degraded insulin was measured by the trichloroacetic acid-precipitation technique. Insulin-degrading activity increased when the number of cells and the time of incubation were increased. Total insulin binding behaved in a similar fashion. Very little degradation was seen at 4 degrees or 15 degrees. The Km for insulin-degrading activity was 7.03 X 10(-8) M. Homogenized mononuclear cells degraded two to five times more insulin than did intact cells and also demonstrated cell concentration, time, and temperature dependence for degradation. The Km of degradation for homogenized mononuclear cells was 2.2 X 10(-8) M. Subcellular fractionation revealed significant degrading activity in the 100,000 X g supernatant, but little activity in the 100,000 X g pellet. A purified lymphocyte preparation did not bind insulin and contained little insulin-degrading activity.

Cyclic AMP phosphodiesterase in diabetes. Effect of glyburide.

Low-Michaelis constant cAMP phosphodiesterase (PDE; EC3.1.4.C) activity is inhibited in tissues of rats with type I ketosis-prone diabetes and is restored to normal by insulin treatment. To determine whether the oral hypoglycemic agent glyburide affected tissue cAMP PDE activity in non-insulin-dependent oral agent-treatable diabetes, cAMP PDE activity was measured in the liver and fat of animals rendered diabetic by low-dose streptozocin (STZ-DM) and treated for 3 wk with oral glyburide (360 micrograms/kg). The results were compared with PDE activity in the liver and fat of untreated STZ-DM and normal control rats. At the time of death, low-Km cAMP PDE activity [as maximum velocity (Vmax)] in STZ-DM rats was decreased to 66% of control values in the liver and to 65% in fat (P less than .001). PDE activity was restored toward normal by glyburide treatment: 91% in the liver (P less than .01) and 80% in fat (P less than .05). Calmodulin and calmodulin-like activity (PDE-activator activity) in the liver and fat was decreased in diabetes and restored toward normal after glyburide treatment (P less than .05). These data demonstrate that oral agents as well as insulin can restore the activity of cAMP PDE in the low-dose STZ-DM model, which is in some ways similar to type II diabetes.

Insulin binding and degradation by muscles from streptozotocin-diabetic rats.

Insulin degradtion by muscle was examined in normal, streptozotocin-induced diabetic rats, and diabetic rats treated with insulin. Insulin degradation by the 100,000 X g supernatant fractions was identical in all three groups, but insulin metabolism by the intact epitrochlaris muscle was significantly increased in diabetic animals. Insulin treatment of the diabetic animals partially restored the activity toward normal. Specific binding of 125l-insulin to the intact muscles was also increased in the diabetic animals. Streptozotocin diabetes, therefore, increased the binding and degradation of insulin by intact muscle but did not alter the insulin degradation by the total soluble intracellular degradative activity.