Avraham Karasik

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.

Insulin gene expression is restricted to islet β cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by ‘loss-of-function’ studies. We used a ‘gain-of-function’ approach to test whether PDX-1 could endow a non-islet tissue with pancreatic β-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a β-cell phenotype, may provide a valuable approach for generating ‘self’ surrogate β cells, suitable for replacing impaired islet-cell function in diabetics.

Controlled trial of high spermatic vein ligation for varicocele in infertile men

OBJECTIVE To determine whether high ligation is an effective treatment for infertile men with clinical varicocele. DESIGN A randomized, controlled trial of high spermatic vein ligation was carried out. The patients were treated and observed for 3 years. SETTING Infertility treatment clinic and andrology laboratory in a hospital. PATIENTS Infertile men with abnormal semen analysis because of varicocele only. INTERVENTION High ligation 1 year postrecruitment (group A) and at the beginning of the study (group B). RESULTS Among the 20 couples in group A, 2 pregnancies (10%) were achieved within the 1st year of observation period. During the year after high ligation, there were 8 pregnancies (44.4%), and during the 2nd year after high ligation, there were 4 more pregnancies (22.2%). In group B, 15 pregnancies (60%) occurred within the 1st year after operation. Three pregnancies (12%) and 1 pregnancy (4%) occurred during the 2nd and 3rd year, respectively. After operation in all patients of both groups, there was significant improvement in semen parameters, regardless of pregnancy occurrence. The difference in pregnancy rate (PR) between the operated group B and nonoperated group A during the 1st year of study was found to be highly significant. CONCLUSIONS It is concluded that in a population of infertile men presenting varicocele as the only demonstrable factor of infertility, the varicocele is clearly associated with infertility and reduced testicular function, and its correction by ligation improves sperm parameters and fertility rate. Furthermore, the highest PR in both groups occurred during the 1st year postoperation.

Diabetes mellitus and breast cancer

Type 2 diabetes is a serious health problem that affects more than 7% of adults in developed countries. Up to 16% of patients with breast cancer have diabetes, and two major risk factors for type 2 diabetes-old age and obesity-are also associated with breast cancer. Three mechanisms have been postulated to associate diabetes with breast cancer: activation of the insulin pathway, activation of the insulin-like-growth-factor pathway, and regulation of endogenous sex hormones. Comparative cohort studies and case-control studies suggest that type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer. Gestational diabetes mellitus, but not type 1 diabetes, might also be associated with excess risk of breast cancer. Moreover, diabetes and its complications can adversely affect cancer therapy and the use of screening, which will thus affect the outcome of patients with breast cancer.

Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells.

Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue.

Elevated serum uric acid — a facet of hyperinsulinaemia

SummaryIn a representative sample of the adult Jewish population in Israel (n=1016) excluding known diabetic patients and individuals on antihypertensive medications, serum uric acid showed a positive association with plasma insulin response (sum of 1- and 2-hour post glucose load levels) in both males (r=0.316, p<0.001) and females (r=0.236, p<0.001). This association remained statistically significant in both sexes (p<0.001) after accounting by multiple regression analysis for age and major correlates of serum uric acid, i.e. body mass index, glucose response (sum of 1- and 2-hour post load levels), systolic blood pressure and total plasma triglycerides. The net portion of the variance of serum uric acid attributable to insulin response was 12% in males and 8% in females, the total variance accountable by all these variables being 17% and 19% respectively. We conclude that elevated serum uric acid is a feature of hyperinsulinaemia/insulin resistance.

Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials

ABSTRACT Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antihyperglycemic agents that enhance the bodys ability to regulate blood glucose by increasing the active levels of incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). There are numerous DPP-4 inhibitors in development with sitagliptin as the first approved agent for the treatment of patients with type 2 diabetes. Objective: The purpose of this review is to provide an overview of the clinical trial results with sitagliptin. Methods: Clinical trials published between January 2005 (first sitagliptin publication) and November 2007 were included in this review. Medline was searched using the search terms: MK-0431 or sitagliptin. Findings: Sitagliptin, an oral, once-daily, and highly selective DPP-4 inhibitor, has been evaluated in clinical trials as monotherapy, as add-on therapy, or as initial combination therapy with metformin. Sitagliptin provided effective fasting and postprandial glycemic control in a wide range of patients with type 2 diabetes. Markers of β-cell function (HOMA-β and proinsulin/insulin ratio) were improved with sitagliptin treatment. In these clinical trials, sitagliptin was generally well tolerated with an overall incidence of adverse experiences comparable to placebo, a low risk of hypoglycemia or gastrointestinal adverse experiences, and a neutral effect on body weight. The findings presented in this review are limited to the specific patient population enrolled in each clinical trial and for durations for up to 1 year. Future clinical studies should evaluate whether this class of agents has the potential to delay progression and/or prevent type 2 diabetes. Conclusions: Sitagliptin has been shown to be effective and well-tolerated in various treatment regimens and may be considered for both initial therapy and as add-on therapy for patients with type 2 diabetes.

Effect of past and concurrent body mass index on prevalence of glucose intolerance and Type 2 (non-insulin-dependent) diabetes and on insulin response

SummaryA representative sample (n=2140) of the Israeli Jewish population aged 40–70 (excluding known diabetic patients), whose body mass index had been measured 10 years earlier, underwent an oral glucose tolerance test and redetermination of body mass index. Irrespective of weight changes, high concurrent and high past body mass index values (≥ 27) were associated with similarly increased rates of glucose intolerance as compared with body mass index values < 27 at both time-points (rate ratio 1.76, 90% confidence limits 1.56–1.99). Glucose intolerance here includes borderline and impaired tolerance as well as Type 2 diabetes. The rate of Type 2 diabetes increased only with increasing past body mass index, while concurrent body mass index had no effect [rate ratios: 2.36 (1.48–3.75) and 1.99 (1.48–2.68) respectively for the medium-(23–26.9) versus-low (<23) and high- (≥ 27) versus-medium past body-mass-index categories]. Weight reduction was associated with only slightly reduced rate of glucose intolerance and had no effect on the rate of diabetes. Mean sum insulin (summed 1 and 2 h levels, mU/l) increased significantly with increasing concurrent body mass index (123, 150 and 190 in the low, medium and high categories) with no effect of past body mass index. It also increased significantly (p < 0.001) in all concurrent body mass index categories from normal tolerance through borderline to impaired tolerance, and decreased significantly (p < 0.001) in diabetes relative to impaired tolerance, although it remained above normal. Means of sum insulin within each glucose tolerance level were similar in the two lower concurrent body mass index categories, with markedly higher (p < 0.001) levels in the high body mass index category. All these findings held after accounting for age, sex, ethnic group and use of antihypertensive medications. We conclude that body mass index ≥ 27 leads to early impairment in glucose tolerance. A prolonged period of obesity is apparently required for the development of Type 2 diabetes and its associated reduced insulin response. The reversibility of the deterioration of glucose tolerance seems to be limited.

Hyperinsulinemia, sex, and risk of atherosclerotic cardiovascular disease.

BackgroundThe possibility that hyperinsulinemia may be involved in the etiology of atherosclerotic cardiovascular disease (CVID) was first suggested 20 years ago. During the last decade, this possibility has received support from three large prospective studies. Methods and ResultsIn the present study, the association between CVID, glucose intolerance, obesity, and hypertension (the GOH conditions) and hyperinsulinemia was examined crosssectionally in a representative sample (n = 1,263) of the adult Jewish population aged 40–70 years in Israel. Previously known diabetics were excluded. CVID comprising clinical or ECG evidence of ischemic heart disease, as well as clinical evidence of cerebrovascular or peripheral vascular disease, was identified in 97 men and 39 women. A significant (p < 0.01) hyperinsulinemia- sex interaction was found for CVD rate, with the adjusted risk ratios (followed by 95% confidence limits), relative to the rate in 298 normoinsulinemic women, being 1.15 (0.68–1.95) in 328 normoinsulinemic men, 0.85 (0.48–1.49) in 277 hyperinsulinemic women, and 2.27 (1.33–3.08) in 360 hyperinsulinemic men. Age-adjusted CVD rates in men versus women were: a) similar and low among all normoinsulinemic normotensives and hyperinsulinemics free of any of the GOH conditions (all rates .6.5%); b) similar and high among normoinsulinemic hypertensives (13.4% versus 10.4%); c) significantly higher in men among hyperinsulinemic normotensives with glucose intolerance and/or obesity (15.2% versus 3.3%; p = 0.02) and all hyperinsulinemic hypertensives (21.5% versus 12.8%; p = 0.04). These trends remained significant after adjusting for age, ethnic group, and blood lipids. ConclusionsTherefore, hyperinsulinemia was associated with excess CVII risk in men but not in women, and all excess CVD risk in men was confined to hyperinsulinemic individuals in the presence of glucose intolerance, obesity, or hypertension.

The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment

A low response to ovarian stimulation in in vitro fertilization poses a unique therapeutic challenge. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as a modality for treatment of this condition. In this study, we analyzed the results of 880 in vitro fertilization treatment cycles with respect to modality of ovarian stimulation, degree of hormonal response, and number of oocytes retrieved. In patients with estradiol (E2)levels less than 501 pg/ml on the day of human chorionic gonadotropin administration, 27% pregnancy rate was achieved with clomiphene citrate (CC) combined with human menopausal gonadotropin (hMG), compared to 15.1% (P <0.005) with hMG alone and 20.8% (NS) with GnRHa and hMG. Pregnancy rates were not lower in these patients compared to patients with higher estradiol levels in the different stimulation protocols, but pregnancy rates were significantly lower in cycles during which three or fewer oocytes were retrieved, compared to those in which four or more oocytes were retrieved (10.8 vs 23.8%; P <0.0005). In low-retrieval cycles pregnancy rates actually decreased with increasing levels of estradiol. Our results indicate that the number of oocytes retrieved is a better prognostic parameter than E2levels in predicting the outcome of in vitro fertilization treatment and that GnRHa in the long protocol do not seem to be superior to CC combined with hMG for the treatment of poor responders.

Insulin-like Growth Factor-1 Inhibits Cell Death Induced by Anticancer Drugs in the MCF-7 Cells: Involvement of Growth Factors in Drug Resistance

The involvement of growth factors in cell survival in the presence of anticancer drugs was investigated. Cell death was induced in the human breast cancer cell line MCF-7, by the structurally and mechanistically unrelated chemotherapeutic drugs puromycin, actinomycin D, 5-fluorouracil, cisplatin, and adriamycin. The effect of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and insulin on cell death was evaluated by two different methods: (1) trypan blue dye exclusion test and (2) lactic dehydrogenase release into the culture medium. IGF-1 inhibited cell death induced by each of the diverse drugs in a concentration-dependent manner reaching a maximal effect at 40 ng/ml. Insulin mimicked the effect of IGF-1 only at supraphysiological concentration with an optimal effect at 10,000 ng/ml. EGF had no effect on cell death up to 100 ng/ml. Our finding that IGF-1 specifically enhanced MCF-7 cell survival in the presence of different anticancer drugs suggests the involvement of growth factors in the mechanism of drug resistance.