Diabetes Drug Discovery: hIAPP1-37 Polymorphic Amyloid Structures as Novel Therapeutic Targets.

Human islet amyloid peptide (hIAPP1-37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1-37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1-37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1-37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A-F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

Prevalence of Prehypertension in Mexico and Its Association With Hypomagnesemia.

BACKGROUND: Prehypertension (preHTN) increases the risk of developing hypertension. The objectives of this study were to estimate the prevalence of preHTN in the Mexican adult population and evaluate the association between hypomagnesemia and preHTN. METHODS: This study was a 2-phase, population-based study. In the first phase, 4,272 Mexican adults (aged 20-65 years) were enrolled to determine the prevalence of preHTN. In the second phase, a cross-sectional analysis was performed to evaluate the association between hypomagnesemia and preHTN. The exclusion criteria were chronic diarrhea, malignancy, hepatic and renal diseases, chronic inflammatory disease, and the intake of magnesium supplements. PreHTN was defined as a systolic blood pressure (BP) of 120-139 mm Hg and/or diastolic BP of 80-89 mm Hg, and hypomagnesemia was defined as a serum magnesium concentration <1.8 mg/dl. RESULTS: The prevalence of preHTN was 37.5% (95% confidence interval (CI): 36.0-39.0): 46.7% were men (95% CI: 44.1-49.4) and 33.2% (95% CI: 31.5-5.0) were women. The serum magnesium data were available for 921 participants. Hypomagnesemia was identified in 276 (30.0%; 95% CI: 27.1-33.0) subjects; of them, 176 (63.8%; 95% CI: 58.3-69.6) had preHTN. Individuals with preHTN exhibited lower magnesium levels than individuals without preHTN (1.78±0.36 vs. 1.95±0.37, P < 0.0005). A multiple logistic regression analysis (adjusted for age, sex, smoking, body mass index, waist circumference, fasting glucose, total cholesterol, high-density lipoprotein cholesterol, and triglycerides levels) indicated a significant association between hypomagnesemia and preHTN (odds ratio = 1.78; 95% CI: 1.5-4.0, P < 0.0005). CONCLUSIONS: The prevalence of preHTN in the Mexican population is 37.5%, and hypomagnesemia is strongly associated with preHTN.

Chronic hypoglycemic effect of Malmea depressa root on n5-streptozotocin diabetic rats.

The root of the "Elemuy" tree (Malmea depressa) is highly used in south east Mexico by the Mayan communities to treat type 2 diabetes. The long-term hypoglycemic effect (HbA1c) and the stimulation of insulin secretion resulting from the treatment with butanolic extract was studied using (n5-stz)-induced diabetic rats. We show that after 30 days of daily administration of 10 mg/kg of the butanolic extract, the glucose levels as well as the (HbA1c) levels were lower compared to the control group. This effect was also observed after 45 days of treatment, leading to the conclusion that the effects of chronic butanolic extract treatment are comparable to treatment with the standard drug Bieuglucon. In an acute experiment, we found that a single administration of the extract at a dose of 50 mg/kg stimulates insulin release, which is similar to the result seen with Tolbutamide administration. The new compound, 3-(3-hydroxy-2,4,5-trimethoxyphenyl) propane-1,2 diol, was isolated from the active fraction of the butanolic extract. The results presented here support the utility of the traditional use of the root and suggest that the active fraction of the plant extract could be developed as a phytomedicine.

Hypoglycemic effect of Tournefortia hirsutissima L., on n-streptozotocin diabetic rats.

The hypoglycemic effect of aqueous and butanolic extracts from Tournefortia hirsutissima (Boraginaceae) was determined on neonatal induced streptozotocin diabetic rats (n-STZ). Oral administration of water extracts at doses of 20 and 80mg/kg, and butanolic extracts (8 and 80mg/kg) significantly lowered the plasma glucose levels in diabetic rats within 3h. Glibenclamide was used as reference and showed similar hypoglycemic effect. Our results support the traditional use of the plant as a hypoglycemic agent; we observe a dose-dependent action of the extracts. HPLC analysis confirmed that the aqueous and butanolic extracts had the same chemical composition.

Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia.

Biotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Besides its role as carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism. Several studies have reported a relationship between biotin and blood lipids. In the present work we investigated the effect of biotin administration on the concentration of plasma lipids, as well as glucose and insulin in type 2 diabetic and nondiabetic subjects. Eighteen diabetic and 15 nondiabetic subjects aged 30-65 were randomized into two groups and received either 61.4 micromol/day of biotin or placebo for 28 days. Plasma samples obtained at baseline and after treatment were analyzed for total triglyceride, cholesterol, very low density lipoprotein (VLDL), glucose and insulin. We found that the vitamin significantly reduced (P=0.005) plasma triacylglycerol and VLDL concentrations. Biotin produced the following changes (mean of absolute differences between 0 and 28 day treatment+/-S.E.M.): a) triacylglycerol -0.55+/-0.2 in the diabetic group and -0.92+/-0.36 in the nondiabetic group; b) VLDL: -0.11+/-0.04 in the diabetic group and -0.18+/-0.07 in the nondiabetic group. Biotin treatment had no significant effects on cholesterol, glucose and insulin in either the diabetic or nondiabetic subjects. We conclude that pharmacological doses of biotin decrease hypertriglyceridemia. The triglyceride-lowering effect of biotin suggests that biotin could be used in the treatment of hypertriglyceridemia.