Women Transmits Type 2 Diabetes Mellitus (T2DM) More Than Men: Evidences from Parental Inheritance of T2DM Among Bahrainis.

INTRODUCTION: Heritability in type 2 diabetes mellitus (T2DM) is observed but not well understood. METHODS: In this study, family history and clinical/biochemical data from 789 Bahrainis (418 T2DM, 371 controls) was analyzed. Fasting blood glucose (FBG) and HbA1c were measured and angiotensin-converting enzyme (ACE) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms (SNPs) were analyzed. RESULTS: Patients compared to controls have higher proportions of diabetic mothers (50.2% vs. 32.7%, p=0.005), fathers (35.2% vs. 12.1%, p<0.001) and siblings (56% vs. 15.3%, p<0.001). The proportions of diabetic mothers was higher than the proportions of diabetic fathers among the patients (50.2% vs. 35.2%, p<0.001) and the controls (32.7% vs. 12.1%, p<0.001). Patients born to diabetic mothers compared to the other patients were smaller in age at the time of enrollment in this study (p=0.005), and at onset of T2DM (p<0.001), and also had higher FBG (p=0.033). Interestingly, the prevalence of T1DM was highest amongst the siblings of the controls compared to patients (p=0.04). Finally, the heterozygote I/D genotype of the ACE gene was over expressed in patients born to diabetic mothers when compared to patients born to diabetic fathers, p=0.007. CONCLUSIONS: there was strong clustering of T2DM in families, with significant dominant maternal role in transmission of T2DM and associated severity markers. Patients (T2DM) born to diabetic mothers were genetically and phenotypically different from the other patients.

Improvement of glucose homeostasis in obese diabetic db/db mice given Plasmodium yoelii glycosylphosphatidylinositols.

We have previously reported that infection with Plasmodium yoelii, Plasmodium chabaudi, or injection of extracts from malaria-parasitized red blood cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in streptozotocin (STZ)-diabetic mice. P yoelii glycosylphosphatidylinositols (GPIs) were extracted in chloroform:methanol:water (CMW) (10:10:3), purified by high-performance thin layer chromatography (HPTLC) and tested for their insulin-mimetic activities. The effects of P yoelii GPIs on blood glucose were investigated in insulin-resistant C57BL/ks-db/db diabetic mice. A single intravenous injection of GPIs (9 and 30 nmol/mouse) induced a significant dose-related decrease in blood glucose (P < .001), but insignificantly increased plasma insulin concentrations. A single oral dose of 2.7 micromol GPIs per db/db mouse significantly lowered blood glucose (P < .01). P yoelii GPIs in vitro (0.062 to 1 micromol/L) significantly stimulated lipogenesis in rat adipocytes in a dose-dependent manner both in the presence and absence of 10(-8) mol/L insulin (P < .01). P yoelii GPIs stimulated pyruvate dehydrogenase phosphatase (PDH-Pase) and inhibited both cyclic adenosine monophosphate (cAMP)-dependent protein kinase A and glucose-6-phosphatase (G6Pase). P yoelii GPIs had no effect on the activity of the gluconeogenic enzymes fructose-1,6-bisphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK). This is the first report of the hypoglycemic effect of P yoelii GPIs in murine models of type 2 diabetes. In conclusion, P yoelii GPIs demonstrated acute antidiabetic effects in db/db mice and in vitro. We suggest that P yoelii GPIs, when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes.

Reversal of type 2 diabetes in mice by products of malaria parasites. II. Role of inositol phosphoglycans (IPGs).

We have previously shown that infection with Plasmodium yoelii malaria or injection of extracts from malaria-parasitized red cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in mice made moderately diabetic with streptozotocin. Inositol phosphoglycans (IPGs) are released outside cells by hydrolysis of membrane-bound glycosylphosphatidylinositols (GPIs), and act as second messengers mediating insulin action. The C57BL/Ks-db/db and C57BL/6J-ob/ob mice offer good models for studies on human obesity and Type 2 diabetes. In the present study, we show that a single iv injection of IPG-A or IPG-P extracted from P. yoelii significantly (P < 0.02) lowers the blood glucose in STZ-diabetic, db/db, and in ob/ob mice for at least 4--6 h. Using rat white adipocytes, IPG-P increased lipogenesis by 20--30% in the presence and absence of maximal concentrations of insulin (10(-8) M) (P < 0.01) and stimulated pyruvate dehydrogenase (PDH) phosphatase in a dose-related manner. Both IPG-A and IPG-P inhibited c-AMP-dependent protein kinase (PKA) in a dose-related manner. Compositional analysis of IPGs after 24 h hydrolysis revealed the presence of myo-inositol, phosphorus, galactosamine, glucosamine, and glucose in both IPG-A and IPG-P. However, hydrolysis of IPGs for 4 h highlighted differences between IPG-A and IPG-P. There are some functional similarities between P. yoelii IPGs and those previously described for mammalian liver. However, this is the first report of the hypoglycemic effect of IPGs in murine models of Type 2 diabetes. We suggest that IPGs isolated from P. yoelii, when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes mellitus.

Assessment of basic medical sciences in an integrated systems-based curriculum.

Basic medical sciences at Sultan Qaboos University (SQU) are taught in a systems-based curriculum. During the development of the courses different formats have been used for the written examinations and also different types of questions. This paper compares students' performance in relation to examination format and to types of questions used. The formats were non-coordinated (NCAs), each discipline having a separate paper; coordinated (CAs), questions from various disciplines being given in the same paper but with separate sections for each discipline; and integrated assessments (IAs), questions being grouped under structure, function, and problem-based integrated long essays. The types of questions used were multiple choice (MCQs), short essays (SEQs), and structured integrated long essays (SILEQs). Students performed better in SEQs than in MCQs. Our analyses also show that SILEQs measure skills similar to those of MCQs and SEQs combined. Students performed best in NCAs. In CAs, students concentrated on those disciplines carrying most weight in the final grade. Currently we use IAs consisting of two parts: part I, comprising MCQs and SEQs, and part II, comprising SILEQs. To date, students are performing better in part II than in part I. We suggest that it is prudent to use different types of questions to measure students' knowledge and skills when IAs are used for systems-based courses.

Effect of LDL and serum from diabetic subjects on DNA synthesis in HIT-cells in culture.

The effect of lipoprotein-deficient serum (LPDS) with and without added low-density lipoprotein (LDL), isolated from diabetic subjects, on the replication of SV40-transformed islet cells (HIT cells) was investigated. Whole serum as well as LPDS preparations stimulated DNA synthesis maximally when added to the culture medium at a final concentration of 0.1%. The addition of LDL at 25 and 175 micrograms protein/ml medium did not cause further stimulation. On the contrary, the higher concentrations resulted in a significant inhibition. These results suggest that previously observed stimulation of DNA synthesis in smooth muscle cells by LDL from diabetic subjects is most likely due to the presence of growth factors in the serum of these patients and not to LDL per se.

Changes in collagen content of the diaphragm in rats of different ages.

Rat diaphragm showed a nine to ten-fold increase in the dry and wet weights and a four-fold increase in its surface area between 21 and 540 days of age. The increase was the most rapid between days 21 and 90, thereafter a non-significant trend of increase was maintained at least up to 360 days of age followed by a tendency to decrease. The total collagen content of the diaphragm paralleled the increase in surface area with progressing age. The collagen content significantly dropped when expressed relative to the dry weight of the diaphragm, between 21 and 90 days of age. This trend was maintained till 180 days of age but thereafter significantly rise was seen. These later changes may be due to elenated synthesis and/or reduced degradation of collagen, and may contribute to the decline in contractility of the diaphragm as age advances.

Collagen of the dystrophic hamster diaphragm.

The collagen content of the diaphragm was measured in normal and dystrophic hamsters aged 130 and 270 days. The diaphragm collagen content was greater in dystrophic hamsters than in control hamsters of the same age. The effect was greater in the older hamsters whether the collagen content was expressed in terms of the percentage of dry weight, in relation to surface area, or as total collagen. This increase was apparently at the expense of muscle tissue and may be a major factor contributing to respiratory muscle weakness as dystrophy advances.

The collagen composition of the dystrophic hamster diaphragm.

1. Diaphragms from BIO 14.6 dystrophic hamsters had lower dry weights and higher collagen content than did controls, BIO F1B. 2. The increase in pepsin-solubilized collagen affected mainly types III and V, and there was a concomitant decrease in the beta and high molecular weight (HMW) collagen aggregates. 3. These findings are similar to the observations in myotonia congenita and imply that the dystrophic process increases collagen synthesis. 4. In addition, there is possibly a genetic mutation of amino acids at points of contact of collagen monomers. 5. Alternatively, there may be reduced hydroxylation of lysine residues and hence in the degree of glycosylation of collagen resulting in decreased cross-linking and aggregation.

Glucose metabolism and beta receptor function in atopic asthmatics.

Severe asthma and diabetes have been reported not to co-exist in the same patient. Various studies have attributed this to the possible association of asthma with hyperinsulinism, increased responsiveness to insulin or to beta-blockade. Previous studies have not addressed all these possible mechanisms in the same patient. In this prospective study, 7 atopic asthmatics and 7 age and sex-matched healthy controls underwent glucose, insulin and glucagon tolerance tests. The results showed no evidence of hyperinsulinism or increased responsiveness to insulin. Intravenous administration of glucagon, however, showed a lesser increase of glucose and insulin in asthmatics. Since glucagon has a beta-agonist effect on the liver and activates glycogenolysis and gluconeogenesis via beta-receptor stimulation and stimulates insulin secretion by activating adenylate cyclase of pancreatic beta-cells through beta-receptors, the results of glucagon tolerance test in our study may therefore suggest the presence of partial beta-blockade in atopic asthmatics.

Changes in amniotic fluid cathepsins with gestational age.

Activities of the cysteine proteinases cathepsins B and H and of the chymotrypsin-like cathepsin G were determined in amniotic fluid of rats during the last third of gestation. Activities of cathepsins B and G were found to significantly increase with increasing gestational age while cathepsin H activity decreased. It was concluded that cathepsins may participate in the destabilization of fetal membranes and therefore may contribute to their rupture.

Maternal, amniotic fluid and cord blood metabolic profile in normal pregnant and gestational diabetics during recurrent withholding of food.

In order to advise regarding the religious practice of withholding food, we studied the metabolic changes after successive 15 days of recurrent fasting of 13 hours every day in maternal plasma and liquor amnii of obese normal gravids and gestational diabetics in their third trimester. There were no significant differences between those who fasted that period for one day prior to elective cesarean section (CS) and those who fasted the same period repeatedly for 15 days. The fasted gravids had significant rises in glycerol, beta-hydroxybutyrate (BOHB) and nonesterified fatty acids (NEFA) (P less than 0.0001, P less than 0.005 and P less than 0.01, respectively) in maternal plasma, compared to unfasted gravid groups and ungravid fasted group. No significant metabolic difference was found in the liquor amnii withdrawn from fasted and unfasted groups. The influence of such short term of starvation on the fetal metabolic profile was studied in the cord blood during cesarean section (CS). Glucose, glycerol and NEFA were significantly lower in arterial than in venous cord plasma (P less than 0.05, P less than 0.01 and P less than 0.01, respectively) indicating that the fetus could utilize these substrates. Positive correlation was found between the levels of BOHB in the mother and venous cord plasma on the one hand and their levels in the arterial cord plasma and liquor amnii on the other hand implying that this substrate passes unutilized through the fetus to the liquor amnii. A pregnant woman in the third trimester should not withhold food for long periods.

Plasma dopamine beta-hydroxylase: rapid diagnostic test for recurrent hereditary polyserositis.

The diagnosis of recurrent hereditary polyserositis (RHP; also known as familial Mediterranean fever) remains one of exclusion since there has been no specific diagnostic laboratory test. A previous study suggested that the disorder is related to abnormal catecholamine metabolism. Plasma dopamine beta-hydroxylase (DBH) activity was assayed spectrophotometrically in 91 RHP patients and 162 controls. The activity was significantly higher in untreated symptom-free patients and in patients with acute attacks, than in controls (mean [SEM] 155.8 [14.1] vs 43.3 [1.9] mumol/min/1 p less than 0.0001). Colchicine treatment reduced DBH activity to control levels. The test showed a high diagnostic accuracy and specificity for RHP, whether the patient was symptom-free or having an acute attack. Moreover, it is easy to carry out.

Effect of recombinant IL-1 isomers on fetal and adult islet cell function and replication.

Natural human interleukin and the recombinant human IL-1 alpha and beta isomers were tested for effects on both fetal and adult rat isolated pancreatic islets. IL-1 alpha inhibited both replication and insulin secretion and decreased the insulin content of both islets. In contrast, the beta isomer did not affect fetal islets. It is concluded that the two isomers may have different avidities for the same receptors, or that receptors are expressed at different stages of differentiation.

Validation of the use of 32P-orthophosphate as a probe for monitoring DNA replication in pancreatic islet cells.

This study aims at validating the use of 32P-orthophosphate as a probe for monitoring DNA replication instead of [3H]-thymidine where the specific activity of the latter is affected by perturbation of the cellular environment. It was found that to obtain a clean DNA fraction for determining the incorporation of the label, protein must be removed by the use of Proteinase K, and RNA by alkaline hydrolysis. Alkaline hydrolysis of RNA was found superior to RNAse digestion in not leaving behind large RNA fragments that may contaminate the DNA fraction.

Premature rupture of fetal membranes changes in collagen type.

Collagen from the chorioamnion units from premature and term pregnancies was solubilized by limited pepsin digestion and subjected to SDS-PAG electrophoresis. Collagen types were quantitated by densitometry. It was found that collagen type III decreases and collagen type V tends to increase as gestational age advances. Investigating the relative abundance of collagen types at various membrane sites from term pregnancies revealed that type V decreases in the amnion as the rupture site is approached. It is concluded that since type V collagen is more resistant to collagenases, its decrease may predispose that particular site to rupture.

Islet cell growth and function. A reappraisal of the role of progesterone and prednisolone.

The mechanism of the inhibitory effect of steroid hormones, progesterone and prednisolone on the incorporation of [3H]-thymidine into pancreatic islet cell DNA was investigated. Treatment with either hormone had no effect on the incorporation of 32P-orthophosphate into islet cell DNA. Both prednisolone (10 microM) and progesterone (3 microM) markedly stimulated the activity of the enzyme thymidylate synthetase of islet cells possibly leading to increased synthesis of endogenous thymidine which resulted in dilution of the [3H]-thymidine added to the islets in tissue culture. Prednisolone (10 microM) significantly increased both insulin biosynthesis and release, while at 5 microM it was effective in increasing only insulin release. In contrast, progesterone at the two concentrations employed did not affect insulin biosynthesis or release. The smaller doses of both hormones markedly stimulated the total protein biosynthesis.

Studies on the activity of individual plants of an antidiabetic plant mixture.

A blood glucose lowering extract of a mixture of five plants in use by Kuwaiti diabetics was studied for the identification of its active component(s). Only the extracts of myrrh and aloe gums effectively increased glucose tolerance in both normal and diabetic rats. The remaining components, gum olibanum, Nigella sativa seeds and gum assafoetida were without effect.

Regulation of pancreatic islet cell replication: an inquiry into the controversy regarding the effects of steroid hormones.

The controversial issue of the effects of prednisolone and 17 beta-estradiol on replication of fetal rat pancreatic islets in culture was studied using 32P and [3H]thymidine as probes for studying DNA synthesis. DNA synthesis was not affected by the steroid hormones, as was evident from the rate of incorporation of 32P into total DNA. Decreased incorporation of [3H]thymidine into DNA found in islets treated with either of these steroids seemed to reflect an inhibitory effect of these hormones on thymidine kinase, leading to decreased phosphorylation of labeled thymidine. In addition, the hormones stimulated the activity of thymidylate synthetase, thus enhancing the endogenous synthesis of thymidine and thereby diluting the specific activity of the [3H]thymidine added to the cultured islets. Further support for a lack of inhibition of growth of islet cells treated with steroid hormones was provided by the observation that prednisolone increased uridine kinase activity and RNA biosynthesis, both of which may participate in the growth of cells preceding mitosis and (the latter) in protein hormone biosynthesis.

Site variability in the solubility of collagen of human fetal membranes.

The extractability of collagen was examined in different sites of amnion and chorion from term deliveries. Sequential extraction with NaCl, acetic acid and CaCl2 showed that soluble collagen accounted for 1.5% of the proteins extracted. Saline extracted more collagen from the amnion than from the chorion. Acetic acid and CaCl2 extracted decreasing and increasing amounts of collagen from the amnion and chorion respectively. The concentration of collagen decreased linearly in the chorion as the rupture site was approached. The results indicate differences in the nature of collagen between amnion and chorion as well as in various sites in the latter.

Amino acid concentrations in maternal plasma and amniotic fluid in relation to fetal insulin secretion during the last trimester of pregnancy in gestational and type I diabetic women and women with small-for-gestational-age infants.

Free amino acid concentrations were determined in maternal plasma and amniotic fluid (AF) under standardized and unstressed conditions in four groups of women comprising 6 gestational and 13 type I diabetics, 10 women with small-for-gestational-age (SGA) infants, and 18 healthy control women between 36 and 39 weeks of gestation. Plasma values for branched chain amino acids (the sum of leucine, isoleucine and valine) did not differ significantly between the four groups. The corresponding values in AF were significantly higher (P less than 0.05) in the type I diabetic group and significantly lower (P less than 0.05) in the gestational diabetic group as compared to the control group. The mean AF C-peptide concentration was elevated but not significantly so in gestational (0.69 nmol/l) or type I diabetic (0.54 nmol/l) pregnancies and significantly lower (P less than 0.05) in women with SGA infants (0.28 nmol/l) as compared to the control group (0.38 nmol/l). There was a significant correlation between C-peptide in AF and branched chain amino acids in maternal plasma (r = 0.63; P less than 0.05) as well as to maternal blood glucose (r = 0.79; P less than 0.01) in the type I diabetic group, which merely suggests a greater beta cell reactivity to insulin secretagogues in offspring of diabetic mothers. The correlation between AF C-peptide and branched chain amino acids in maternal plasma was significantly inverse in women with SGA infants (r = -0.75; P less than 0.05). Both individual, branched chain, or total amino acid concentration in AF were unrelated to AF C-peptide.