c-peptide and Anovulation

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

Topics: Adult; Anovulation; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Black People; C-Peptide; Case-Control Studies; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Gene Expression; Genotype; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Nerve Tissue Proteins; Promoter Regions, Genetic; Sex Factors

Highly active females are at risk of athletic menstrual irregularities including anovulatory menstrual cycles, oligomenorrhea and even amenorrhea. On the other hand, the functional relationship between endocrine pancreas and ovaries is supported by numerous studies indicating that disturbed female sex hormone secretion coexists with insulin resistance and glucose intolerance. However, the relationship between circulating beta islet and ovarian hormones in regularly menstruating active women with ovulatory and anovulatory menstrual cycle has not been studied.. A total of 32 regularly menstruating women participated in the study. Prospective subjects monitored their BBT for 3 months before the study. The determination of plasma progesterone levels between days 5-8 and again between days 19-22 of the menstrual cycles made possible the classification of subjects as ovulating or non-ovulating. Plasma 17-beta-estradiol, testosterone, insulin, proinsulin, C-peptide and glucose concentrations were assayed on the same menstrual cycle days as progesterone.. There were no differences in circulating insulin, C-peptide and glucose between non-ovulating and ovulating women. In contrast, in non-ovulating subjects plasma proinsulin concentrations between days 19-22 were slightly, but significantly higher than between days 5-8 of the menstrual cycle (P<0.05). Exclusively in non-ovulating women significant and positive correlation was noted between circulating proinsulin and 17-beta-estradiol in data collected from both days 5-8 and 19-22 of the menstrual cycle (P<0.008).. Our results indicate that in the face of low circulating progesterone and subsequent anovulation circulating 17-beta-estradiol slightly, but significantly, affect either pancreatic beta-cell biosynthetic activity or proinsulin hepatic and/or renal clearance.

Topics: Adult; Anovulation; Blood Glucose; C-Peptide; Exercise; Female; Gonadal Steroid Hormones; Humans; Insulin; Menstrual Cycle; Proinsulin

To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions.. Prospective, nonrandomized study.. Academic research environment.. Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio.. Variable hyperglycemic-hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration.. Glucose utilization and EGP.. In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic-hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic-hyperinsulinemic infusions.. Glucose use and EGP in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.

Topics: Adolescent; Adrenal Glands; Adult; Anovulation; Blood Glucose; Body Composition; C-Peptide; Female; Glucagon; Human Growth Hormone; Humans; Hyperandrogenism; Insulin; Insulin Resistance; Leuprolide; Middle Aged; Ovary; Prospective Studies; Steroids