vitamin-b-12 and Glucose-Intolerance

While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.. We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.. B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4.. These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

Topics: Animals; Appetite Regulation; Behavior, Animal; Blood-Brain Barrier; Drug Stability; Energy Intake; Energy Metabolism; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; HEK293 Cells; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Nausea; Rats, Sprague-Dawley; Recombinant Proteins; Tissue Distribution; Vitamin B 12

Topics: Diabetes Mellitus, Type 2; Disease Progression; Folic Acid; Glucose Intolerance; Humans; Obesity; Placebos; Primary Prevention; Randomized Controlled Trials as Topic; Risk Factors; Vitamin B 12; Vitamin B 6

Our aim was to investigate the association between total serum homocysteine, vitamin B12 and folate levels in pregnant women with gestational diabetes mellitus (GDM), glucose intolerance and compare them with those of glucose tolerant pregnant women.. Serum homocysteine, vitamin B12 and serum folate levels were prospectively measured in a total of 223 pregnant women who were grouped according to their status of glucose tolerance as gestational diabetes (abnormal 1-h and 3-h glucose tolerance test; n = 30), glucose intolerant (abnormal 1-h, but normal 3-h glucose tolerance test; n = 46) or normal controls (normal 1-h glucose test; n = 147).. Mean serum homocysteine concentration of women in gestational diabetes, glucose intolerants and normal controls at 24-28 weeks of gestation was 9.0 +/- 3.1, 8.1 +/- 2.5 and 7.4 +/- 1.6 micromol/l, respectively. The only statistically difference in homocysteine levels was observed between women with gestational diabetes and normal controls (P < 0.01). However, no difference was observed for vitamin B12 and folate levels.. Second trimester serum homocysteine concentrations are higher among women with GDM, as compared to normal controls.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Diabetes, Gestational; Female; Folic Acid; Gestational Age; Glucose Intolerance; Homocysteine; Humans; Pregnancy; Pregnancy Trimester, Second; Reference Values; Vitamin B 12

Limited data are available on the determinants of homocysteinemia or the association between plasma homocysteine (Hcy) levels and prevalent cardiovascular disease (CVD) in maintenance dialysis patients. We assessed etiology of renal failure, residual renal function and dialysis adequacy-related variables, and vitamin status, as determinants of fasting total plasma homocysteine (Hcy) in 75 maintenance dialysis patients. We also assessed the potential interactive effect on plasma Hcy of folate status and a common mutation (ala to val; homozygous val-val frequency approximately 10%) in methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme crucial for the remethylation of homocysteine (Hcy) to methionine. Lastly, we evaluated whether the Hcy levels differed amongst these patients in the presence or absence of prevalent CVD, after adjustment for the traditional CVD risk factors. Fasting total plasma Hcy, folate, pyridoxal 5'-phosphate (PLP; active B6), B12, creatinine, glucose, total and HDL cholesterol levels, and presence of the ala to val MTHFR mutation were determined, and clinical CVD and CVD risk factor prevalence were ascertained. General linear modelling/analysis of covariance revealed: (1) folate status and serum creatinine were the only significant independent predictors of fasting Hcy; (2) there was a significant interaction between presence of the val mutation and folate status, i.e., among patients with plasma folate below the median (< 29.2 ng/ml), geometric mean Hcy levels were 33% greater (29.0 vs. 21.8 microM, P = 0.012) in the pooled homozygotes (val-val) and heterozygotes (ala-val) for the ala to val mutation, vs. normals (ala-ala); (3) there was no association between prevalent CVD and plasma Hcy. Given potentially intractable survivorship effects, prospective cohort studies will be required to clarify the relationship between plasma Hcy or any putative CVD risk factor, and incident CVD in dialysis patients. If a positive association between plasma Hcy and incident CVD can be established in maintenance dialysis patients, the current data provide a rationale for additional folic acid supplementation in this patient population.

Topics: Adult; Aged; Amino Acid Sequence; Cardiovascular Diseases; Cholesterol, HDL; Comorbidity; Creatinine; DNA Mutational Analysis; Female; Folic Acid; Glucose Intolerance; Homocysteine; Humans; Hypertension; Kidney Failure, Chronic; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Peritoneal Dialysis; Polymorphism, Restriction Fragment Length; Prevalence; Renal Dialysis; Risk Factors; Smoking; Vitamin B 12