Vastus medialis fat infiltration - a modifiable determinant of knee cartilage loss.

BACKGROUND: There is growing interest in the role of intramuscular fat and how it may influence clinical outcomes. Vastus medialis (VM) is a functionally important quadriceps muscle that helps to stabilise the knee joint. This longitudinal study examined the determinants of VM fat infiltration and whether VM fat infiltration influenced knee cartilage volume. METHODS: 250 participants without any diagnosed arthropathy were assessed at baseline between 2005 and 2008, and 197 participants at follow-up between 2008 and 2010. Ambulatory and sporting activity were assessed and magnetic resonance imaging (MRI) was used to determine knee cartilage volume and VM fat infiltration. RESULTS: Age, female gender, BMI and weight were positively associated with baseline VM fat infiltration (P ≤ 0.03), while ambulatory and sporting activity were negatively associated with VM fat infiltration (P ≤ 0.05). After adjusting for confounders, a reduction in VM fat infiltration was associated with a reduced annual loss of medial tibial (ß = -10 mm(3); 95% CI -19 to 0 mm(3); P = 0.04) and patella (ß = -18 mm(3); 95% CI -36 to 0 mm(3); P = 0.04) cartilage volume. CONCLUSION: This community-based study of healthy adults has shown that VM fat infiltration can be modified by lifestyle factors including weight loss and exercise, and reducing fat infiltration in VM has beneficial effect on knee cartilage preservation. The findings suggest that modifying VM fat infiltration via lifestyle interventions may have the potential to reduce the risk of knee OA.

Improving glucose tolerance by reducing weight gain in a polygenic obese mouse model: use of a high protein diet.

Diets to decrease body weight have limited success in achieving and importantly maintaining this weight loss long-term. It has recently been suggested that energy intake can be regulated by the amount of protein ingested, termed the protein leverage hypothesis. In this study, we determined whether a high protein diet would be effective in achieving and maintaining weight loss in a genetically obese model, the New Zealand Obese (NZO) mouse. NZO and C57BL/6J (C57) control mice were fed a high protein or chow diet for 5 weeks from weaning (3 weeks of age). Body weight and food intake were determined. Mice on the same diet were bred to produce offspring that were fed either a chow or high protein diet. Body weight, food intake, and glucose tolerance were determined. Feeding NZO and C57 mice a high protein diet for 5 weeks resulted in reduced food intake and consequently energy intake and body weight gain compared with mice on a chow diet. NZO mice fed a high protein diet showed a significant improvement in glucose tolerance compared with their chow-fed counterparts, while no difference was seen in C57 mice fed chow or protein diet. The offspring of NZO mice that were fed a high protein diet during gestation and weaning were also lighter and displayed improved glucose tolerance compared with chow fed animals. We conclude that a high protein diet is a reasonable strategy to reduce body weight gain and improve glucose tolerance in the NZO mouse, a polygenic model of obesity.

Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial.

AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

A novel mechanism regulating insulin secretion involving Herpud1 in mice.

AIMS/HYPOTHESIS: Type 2 diabetes results from beta cell dysfunction after prolonged physiological stress, which causes oversecretion of insulin. We recently found that insulin hypersecretion is mediated by at least two genes. Among mouse models of type 2 diabetes, the DBA/2 mouse strain is more susceptible to diabetes than is the C57BL/6J (B6J) strain. One distinctive feature of the DBA/2 mouse is that it hypersecretes insulin, independent of changes in insulin sensitivity; we identified Nnt as a gene responsible for this trait. METHODS: To identify the other gene(s) affecting insulin hypersecretion, we tested a panel of recombinant inbred BXD strains, which have different combinations of B6 and DBA/2 alleles. RESULTS: We found that 25% of the BXD strains hypersecreted insulin in response to glucose. Microarray profiling of islets from high- and low-secretor strains showed that at least four genes were differentially expressed. One gene was consistently underexpressed in islets from both DBA/2 and the high-secretor BXD strains. This gene (Herpud1 or Herp) encodes the 54 kDa endoplasmic reticulum stress-inducible protein (HERP) that resides in the integral endoplasmic reticulum membrane. To test directly whether Herpud1 can interact with Nnt, Herpud1 was either knocked down or overexpressed in MIN6 cells. These results showed that when Herpud1 was suppressed, Nnt expression was reduced, while overexpression of Herpud1 led to increased Nnt expression. Furthermore, Herpud1 suppression resulted in significantly decreased glucose-stimulated insulin secretion in the DBA/2 islets but not B6J islets. CONCLUSIONS/INTERPRETATION: We conclude that Herpud1 regulates insulin secretion via control of Nnt expression.

Post-liver transplant leptin results in resolution of severe recurrence of lipodystrophy-associated nonalcoholic steatohepatitis.

We describe the first case of a patient undergoing orthoptic liver transplantation for acquired generalized lipodystrophy-related nonalcoholic steatohepatitis who developed severe recurrence of nonalcoholic fatty liver disease in the first few months posttransplant but responded rapidly to the administration of exogenous leptin. The beneficial effects of therapy were supported by histology along with magnetic resonance spectroscopy studies, which demonstrated that leptin therapy greatly reduced fat deposition in the liver. Leptin therapy may have a role to play in preventing patients with lipodystrophy developing end-stage liver disease or in rescuing such patients who develop disease recurrence postliver transplantation.

A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study.

OBJECTIVE: To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SUBJECTS: Patients >or=18 years old, BMI 27-43 kg m(-2), were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks. MEASUREMENTS: Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints. RESULTS: Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was -5.4, -5.3, -6.7 and -1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group. CONCLUSION: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention.

Impaired glucose uptake is associated with both cardiac hypertrophy and contractile dysfunction, but whether there are common underlying mechanisms linking these conditions is yet to be determined. Using a 'gene dose' Cre-Lox GLUT4-deficient murine model, we examined the effect of suppressed glucose availability on global myocardial gene expression and glycolysis substrate bypass on the function of isolated perfused hearts. Performance of hearts from 22- to 60-week-old male GLUT4 knockout (KO, >95% reduction in GLUT4), GLUT4 knockdown (KD, 85% reduction in cardiac GLUT4) and C57Bl/6 wild-type (WT) controls was measured ex vivo in Langendorff mode perfusion. DNA microarray was used to profile mRNA expression differences between GLUT4-KO and GLUT4-KD hearts. At 22 weeks, GLUT4-KO hearts exhibited cardiac hypertrophy and impaired contractile function ex vivo, characterized by a 40% decrease in developed pressure. At 60 weeks, dysfunction was accentuated in GLUT4-KO hearts and evident in GLUT4-KD hearts. Exogenous pyruvate (5 mM) restored systolic pressure to a level equivalent to WT (GLUT4-KO, 176.8+/-13.2 mmHg vs. WT, 146.4+/-9.56 mmHg) in 22-week-old GLUT4-KO hearts but not in 60-week-old GLUT4-KO hearts. In GLUT4-KO, DNA microarray analysis detected downregulation of a number of genes centrally involved in mitochondrial oxidation and upregulation of other genes indicative of a shift to cytosolic beta-oxidation of long chain fatty acids. A direct link between cardiomyocyte GLUT4 deficiency, hypertrophy and contractile dysfunction is demonstrated. These data provide mechanistic insight into the myocardial metabolic adaptations associated with short and long-term insulin resistance and indicate a window of opportunity for substrate intervention and functional 'rescue'.

Combining biological and psychosocial baseline variables did not improve prediction of outcome of a very-low-energy diet in a clinic referral population.

Consistent, strong predictors of obesity treatment outcomes have not been identified. It has been suggested that broadening the range of predictor variables examined may be valuable. We explored methods to predict outcomes of a very-low-energy diet (VLED)-based programme in a clinically comparable setting, using a wide array of pre-intervention biological and psychosocial participant data. A total of 61 women and 39 men (mean ± standard deviation [SD] body mass index: 39.8 ± 7.3 kg/m2 ) underwent an 8-week VLED and 12-month follow-up. At baseline, participants underwent a blood test and assessment of psychological, social and behavioural factors previously associated with treatment outcomes. Logistic regression, linear discriminant analysis, decision trees and random forests were used to model outcomes from baseline variables. Of the 100 participants, 88 completed the VLED and 42 attended the Week 60 visit. Overall prediction rates for weight loss of ≥10% at weeks 8 and 60, and attrition at Week 60, using combined data were between 77.8 and 87.6% for logistic regression, and lower for other methods. When logistic regression analyses included only baseline demographic and anthropometric variables, prediction rates were 76.2-86.1%. In this population, considering a wide range of biological and psychosocial data did not improve outcome prediction compared to simply-obtained baseline characteristics.

Review of 3-year outcomes of a very-low-energy diet-based outpatient obesity treatment programme.

Obesity is a complex disorder that requires a multidisciplinary treatment approach. This review evaluated 3-year outcomes of a very-low-energy diet (VLED)-based programme at a tertiary hospital multidisciplinary weight management clinic. Medical records of all patients who agreed to undertake the VLED programme and who did not undergo bariatric surgery during the 3-year follow-up period were examined. Baseline data collection included demographic and anthropometric characteristics, childhood onset of obesity and co-existing medical conditions. Weight was modelled using a linear mixed effects analysis. Logistic regression analyses were used to model the probability of continuing to attend the clinic and to identify pre-treatment factors associated with longer duration of attendance. Data from 1109 patients were included. A total of 231 patients (19.2%) were still attending the clinic 3 years after their initial appointment. Mean weight loss among patients who attended the clinic for 3 years was 6.4 kg (3.5%, 95% confidence interval [CI] 2.8, 4.2%). People who were prescribed pharmacotherapy maintained greater weight loss at 3 years (7.7% vs. 2.3% without pharmacotherapy, 95% CI for difference 3.9, 7.0%). People who had an onset of obesity in childhood, who had co-existing hypertension or coronary artery disease, and who did not currently smoke were more likely to continue to attend the clinic for up to 3 years. In summary, in an outpatient weight management clinic, patients who undertook a VLED-based programme and continued in follow-up achieved a clinically significant weight loss at 3 years, particularly if pharmacotherapy was used for weight loss maintenance.

Evolution of insulin resistance in New Zealand obese mice.

The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. Hyperglycemia is due to increased hepatic glucose production (HGP), decreased glucose uptake, and impaired insulin secretion. It is unknown if these defects are coinherited or if one precedes and causes the others. The aim of this study was to determine the earliest defects in the evolution of the syndrome in the New Zealand obese (NZO) mouse, a polygenic model of NIDDM. NZO and control NZC mice were studied at 4-5 and 20 wk of age. Glucose turnover and glucose uptake in individual tissues were measured basally and during a hyperinsulinemic clamp. First-phase insulin secretion was measured after an intravenous glucose load. HGP was higher in the NZO mice both basally and during the clamp at both ages. At 4-5 wk of age, there was evidence of insulin insensitivity in brown adipose tissue, soleus, diaphragm, red quadriceps, and red gastrocnemius but not in heart, white quadriceps, and white gastrocnemius. In 20-wk-old mice, insulin responsiveness was decreased in white and brown adipose tissue and soleus muscle but not in heart, diaphragm, red and white quadriceps, and red and white gastrocnemius. First-phase insulin secretion (percentage rise above basal) 3 min after the glucose bolus was impaired in NZO mice at both ages. We conclude that hepatic glucose overproduction, brown adipose tissue and skeletal muscle insulin resistance, and impaired first-phase insulin secretion are all early abnormalities in the NZO mouse.

Role of the oropharynx in regulation of glycemia.

Previous studies have demonstrated that reflexes originating from the oral cavity at the start of food intake are necessary to ensure a normal glucose tolerance. In our experiment, the underlying mechanisms of these reflexes were studied in conscious, freely moving rats bearing chronic catheters. A double-isotope technique was used to measure, under non-steady-state conditions, rates of total glucose appearance (total Ra), total glucose disappearance (Rd), gut glucose absorption (gut Ra), hepatic glucose production (HGP), and the metabolic clearance rate of glucose (MCRg). In random order, 1 wk apart, rats either spontaneously drank 1 ml of a 60% glucose solution or were given the same dose into the stomach via a chronic gastric catheter. Glycemia and insulinemia were lower when glucose was taken orally than when the same amount of the substrate was administered intragastrically. Total Ra after glucose administration was the same in both groups throughout the experiment. Despite lower insulin and glucose values, the increase in Rd was initially higher in the oral group than in the intragastric group. This was accompanied by initial higher MCRg values in the oral group than in animals that received the glucose load directly into their stomachs. We conclude that a series of reflexes elicited by oral glucose ingestion improve glucose tolerance by increasing the efficiency of glucose disposal in the early stages after a glucose load, with a smaller amount of insulin released.

Taste-induced changes in plasma insulin and glucose turnover in lean and genetically obese rats.

Cephalic-phase insulin release (CPIR) and the changes in glucose turnover induced by saccharin ingestion were studied in freely moving lean and genetically obese fa/fa rats equipped with chronic catheters for blood sampling. Six-hour-fasted lean and obese rats were trained to drink 1 ml sodium saccharin (0.15%) or 1 ml glucose (70%), and blood samples were taken before and after the stimuli. As early as 1-1.5 min poststimulus, there was a significant increase in CPIR in lean and obese rats. The amplitude of the CPIR induced either by saccharin or by glucose in the obese rats was significantly higher than it was in the lean rats. The effect of saccharin ingestion on the hepatic glucose production (HGP) and the rate of glucose disappearance (Rd) was studied in 6-h-fasted lean and obese rats, under non-steady-state conditions, according to a method previously validated. Saccharin ingestion produced a significant increase in HGP and Rd in lean and obese rats compared with basal values. The saccharin-induced increments in HGP and Rd were higher in the obese than in the lean animals. We conclude that saccharin (through taste) appears to elicit parasympathetic (insulin release) and sympathetic (HGP increase) reflexes in lean and obese rats. These taste-induced changes in plasma insulin and glucose turnover are exaggerated in the obese rats and may participate in obesity and in insulin resistance of the overall syndrome.

Mechanism of abnormal oral glucose tolerance of genetically obese fa/fa rats.

The genetically obese fa/fa rat is glucose intolerant when tested in a conscious state after the spontaneous ingestion of a glucose solution. The aim of this study was to investigate the mechanism(s) underlying the abnormal oral glucose tolerance test of obese animals with the non-steady-state measurement of glucose turnover proposed by Steele et al. in 1968. Our results show that the total rate of glucose appearance is enhanced in obese compared with lean animals. This abnormality is not due to an increased gut glucose absorption but to a lack of suppression and even a transient stimulation of hepatic glucose production after the ingestion of glucose. The rate of glucose utilization by the obese animals is somewhat increased compared with controls or unchanged when expressed as glucose metabolic clearance rate, thus excluding this parameter from the factors contributing to the observed glucose intolerance. The results obtained with genetically obese rats agree with those reported for type II diabetes in humans. The observed defect of the obese group could be related to an abnormal regulation of insulin counterregulatory hormone(s) or of hepatic innervation as well as to other defects of hepatic glycogen handling.

Gliclazide therapy is associated with potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects.

Six obese, non-insulin-dependent diabetic subjects were studied before and 3 mo after treatment with the sulfonylurea gliclazide, 40-80 mg b.i.d. Fasting plasma glucose fell significantly from 13.4 +/- 1.6 (SEM) to 8.6 +/- 1.2 mmol/L, accompanied by a significant reduction from 40.6 +/- 3.7 to 29.8 +/- 2.8 mM X h of the plasma glucose response to 75 g oral glucose. Fasting plasma insulin showed a nonsignificant increase from 24.8 +/- 2.0 to 31.3 +/- 2.3 mU/L. The percent specific binding of tracer 125I-insulin to erythrocytes and monocytes did not change significantly (from 9.8 +/- 1.7 to 8.5 +/- 0.7 for erythrocytes and 1.7 +/- 0.3 to 1.6 +/- 0.4 for monocytes). Glucose utilization was measured at three levels of insulin infusion (40, 100, and 300 mU/kg/h) by the euglycemic clamp technique. Overall there was a significant (P less than 0.05) increase in the disappearance rate (Rd) and metabolic clearance rate (MCRg) for glucose at the two higher insulin infusion rates (MCRg: 3.3 +/- 0.7 to 5.1 +/- 0.7 and 5.9 +/- 0.9 to 7.9 +/- 0.9 ml/kg/min), but not at the lowest infusion rate (MCRg: 3.6 +/- 0.8 to 3.3 +/- 0.6). Thus, the chronic hypoglycemic effect of gliclazide in obese diabetic subjects was associated with an improvement in insulin-mediated glucose utilization at high plasma insulin concentrations. This enhanced effect of insulin after gliclazide treatment was not accompanied by increased monocyte or erythrocyte insulin binding, which suggests that it was due to potentiation of postbinding insulin-sensitive pathways.

Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse model of NIDDM.

The New Zealand obese mouse, a model of NIDDM, is characterized by hyperglycemia, hyperinsulinemia, and hepatic and peripheral insulin resistance. The aim of this study was to investigate the biochemical basis of hepatic insulin resistance in NZO mice. Glycolytic and gluconeogenic enzyme activities were measured in fed and overnight fasted 19- to 20-wk-old NZO and control New Zealand chocolate mice. The NZO mice were twice as heavy as the NZC mice. The activity of the glycolytic enzymes glucokinase and pyruvate kinase was higher, whereas that of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase was lower in fed and fasted NZO mice. These enzyme changes are consistent with a normal response to the hyperinsulinemia in NZO mice. In contrast, the activity of the third regulated gluconeogenic enzyme, fructose-1,6-bisphosphatase, was similar in fed and fasted NZO and NZC mice despite the higher insulin and glucose levels in the NZO mouse. This enzyme is primarily regulated by the powerful inhibitor fructose-2,6-bisphosphate. The levels of this metabolite were measured and found to be increased in both the fed and fasted states in the NZO mouse, suggesting that the activity of the bifunctional enzyme that regulates the level of inhibitor (6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase) is normally regulated in the NZO mouse. We conclude that most insulin-responsive gluconeogenic and glycolytic enzymes are normally regulated in the NZO mouse, but an abnormality in the regulation of fructose-1,6-bisphosphatase may contribute to the increase hepatic glucose production in these mice.

Impaired suppression of gluconeogenesis induced by overexpression of a noninsulin-responsive phosphoenolpyruvate carboxykinase gene.

Despite detailed knowledge of the regulation of individual steps in the gluconeogenic pathway, the relative importance of each step to the overall control of gluconeogenesis by insulin is not known. The aim of this study was to determine the role of phosphoenolpyruvate carboxykinase (PEPCK) in the regulation of gluconeogenesis by insulin. Clones of the rat hepatoma cell line H4IIE-C3 were produced, overexpressing a PEPCK gene, driven by a promoter not responsive to insulin. In these cells basal gluconeogenesis from 2-[14C]pyruvate was increased 2.1-fold compared to controls (4.63 +/- 0.49 nmol/10(5) cells vs. 2.21 +/- 0.24 nmol/10(5) cells after 3 h, P < 0.05, n = 5). Increased gluconeogenesis was associated with an increase in basal PEPCK mRNA levels (1.9-fold) and enzyme activity (2.8-fold). Insulin (10(-7) M) suppressed basal gluconeogenesis, PEPCK mRNA levels, and enzyme activity in control cells, but no detectable decrease was observed in PEPCK-transfected cells. These experiments provide direct evidence in intact cells that PEPCK is the rate-limiting enzyme in gluconeogenesis from pyruvate and show that insulin's action to inhibit gluconeogenesis is predominantly on the inhibition of PEPCK transcription.

Impaired glucose tolerance and increased weight gain in transgenic rats overexpressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene.

The effects of an overexpressed, non-insulin-responsive gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32), on glucose homeostasis were investigated. Transgenic rats harboring a metallothionein-driven PEPCK gene (lacking the entire PEPCK upstream-regulatory region) expressed transgene PEPCK mRNA in the key gluconeogenic tissues, liver and kidney. Female transgenic rats, studied at 10 weeks of age, showed mild fasting hyperglycemia (6.9 +/- 0.2 vs. 5.9 +/- 0.1 mM P = 0.002 n = 6), hyperinsulinemia (92.2 +/- 4.0 vs. 54.0 +/- 6.6 pM, P = 0.001, n = 6), impaired glucose tolerance and increased weight gain (178.3 +/- 3.2 vs. 153.4 +/- 2.5 g, P = 0.001, n = 16 and n = 13 transgenic and control rats, respectively). Despite hyperinsulinemia at this age, kidneys of transgenic rats maintained a significant 20% elevation of total PEPCK enzyme activity, while total liver PEPCK activity was not reduced. This study suggests that an insulin-resistant step in the gluconeogenic pathway can lead to glucose intolerance and an increase in weight. These rats offer the unique opportunity to study the metabolic consequences of chronic, mild excess glucose supply, as seen in non-insulin-dependent diabetes.

Obesity and the female sex, risk factors for knee osteoarthritis that may be attributable to systemic or local leptin biosynthesis and its cellular effects.

Obesity and the female sex represent significant risk factors for osteoarthritis (OA). Few studies have demonstrated a metabolic link between obesity and OA, strengthening the likelihood that biomechanical factors mediate this relationship, possibly via the redistribution of increased body mass to weight-bearing joints. However, it is less plausible that the biomechanical factors that contribute toward the incidence of OA at weight-bearing joints, such as the knee, are similar to those at non-weight bearing joints, such as in the hand. This may suggest that non-examined or unidentified biomechanical and/or systemic factors may be important contributors to the aetiology of OA. Recent developments that have helped to better appreciate the pathophysiology of obesity offer new hope to understanding the link between obesity and OA. The discovery of the obesity gene (ob) and its product leptin may have important implications for the onset and progression of OA. For instance, the greater total body fat of the average adult female may partially account for the gender disparity toward OA, given that females theoretically demonstrate higher levels of adipose derived systemic leptin concentrations than their male counterparts. However, while it was previously thought that adipose cells were only capable of leptin production, osteoblasts and chondrocytes are also capable of leptin synthesis and secretion, inferring that local leptin production may be of great importance. For instance, significant levels of leptin were observed in the cartilage and osteophytes of people with OA, yet few chondrocytes produced leptin in the cartilage of healthy people. Leptin has also been demonstrated to induce anabolic activity in the chondrocytes of rats, which may ultimately confer structural joint changes. This paper hypothesizes that leptin may be an unexamined systemic or local factor that may mediate the metabolic link between obesity and OA and partially account for the gender disparity toward the disease.

Influenza immunization in adults with diabetes mellitus.

The antibody responses to influenza vaccination of a group of adult diabetic patients were compared with responses in a healthy group of regular volunteer vaccinees. The initial and final geometric mean hemagglutination-inhibiting antibody titers were lower in the patient group, but the relative increase in titers was greater for each of the vaccine components. The percentage of fourfold rises in individual titers was greater in the diabetic group than in the control group. It was concluded that patients with diabetes mellitus responded normally to influenza vaccination. This was confirmed in an additional study. There was no significant difference in the antibody responses of patients treated with insulin or oral antidiabetic agents. There was no impairment of diabetic control as a result of influenza vaccination when this was evaluated by measuring the concentration of glycosylated hemoglobin, or by random blood glucose estimations. There was no significant change in the serum insulin level after immunization in patients on oral diabetic agents. It was concluded that influenza vaccination was safe and effective in adult diabetic patients.

Low-dose acarbose improves glycemic control in NIDDM patients without changes in insulin sensitivity.

OBJECTIVE: To examine the impact on metabolic control in NIDDM patients of the alpha-glucosidase inhibitor, acarbose, when administered at a low dose in powdered form. RESEARCH DESIGN AND METHODS: Six subjects were recruited for a double-blind cross-over trial using 25 mg powdered acarbose and a placebo 3 times a day with meals for 3 mo. In addition to parameters of diabetes control and body weight, glucose turnover and insulin sensitivity were measured with the hyperinsulinemic/euglycemic clamp technique combined with tracer kinetics. RESULTS: None of the subjects showed significant changes in FPG levels or body weight either on the 3-mo course of acarbose or placebo. HbA1c fell significantly from 10.6 +/- 1.0 to 9.4 +/- 1.3% (P = 0.05) during treatment with acarbose but failed to change on placebo (10.1 +/- 1.0 to 11.1 +/- 2.0%; P = 0.36). Basal HGP and glucose utilization were unchanged during either of the treatment periods, and hyperinsulinemia produced a similar degree of suppression of HGP before and after each treatment. At a physiological concentration, insulin failed to stimulate glucose clearance in these diabetic patients, and no improvement was seen with acarbose treatment. No changes in plasma lipids or lipoprotein profiles were demonstrated after 3 mo on acarbose. In acute studies, it was shown that administration of acarbose at a dose of 25 mg powder per meal significantly decreased the postprandial glycemic excursion. CONCLUSIONS: When administered in the powdered form at the low dose of 25 mg 3 times/day with meals over 3 mo, acarbose was well tolerated by the NIDDM patients and was without side effects. It improved glycemic control by reducing postprandial hyperglycemia, but had no effect on glucose turnover, insulin sensitivity, or lipid profile.