Background The insertion/deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with increased coronary heart disease (CHD), although the mechanism of this association is not apparent. We tested the hypothesis that the deletion allele of the ACE gene is associated with insulin resistance. Methods and Results We related ACE genotype to components of the insulin-resistance syndrome in 103 non–insulin-dependent diabetic (NIDDM) and 533 nondiabetic white subjects. NIDDM subjects with the DD genotype had significantly lower levels of specific insulin (DD 38.6, ID 57.1, and II 87.4 pmol · L −1 by ANOVA, P =.011). Non–insulin-treated subjects with the DD genotype had increased insulin sensitivity by HOMA % (DD 56.4%, II 29.4%, P =.027) and lower levels of des 31,32 proinsulin (DD 3.3, II 7.6 pmol · L −1 , P =.012) compared with II subjects. There were no differences in prevalence of CHD or levels of blood pressure, serum lipids, or plasminogen activator inhibitor–1 (PAI-1) activity between the three ACE genotypes. In nondiabetic subjects there were no differences in insulin sensitivity, levels of insulin-like molecules, blood pressure, PAI-1, serum lipids, or CHD prevalence between the three ACE genotypes. Conclusions We conclude that increased cardiovascular risk of the DD genotype is not mediated through insulin resistance or abnormalities in fibrinolysis. Conversely, we report an increased sensitivity in NIDDM subjects with the ACE DD genotype.

Plasminogen activator inhibitor 1 (PAI-1) activity is increased in patients with non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to their excess risk of cardiovascular disease. We examined the determinants of PAI-1 activity in 146 NIDDM subjects by using specific assays of insulin and intact and des-31,32-proinsulin and measures of insulin resistance, relating these measurements to serum lipids, hypoglycemic therapy, and a common 4G/5G polymorphism in the promoter region of the PAI-1 gene. Subjects were treated with insulin, sulfonylurea, sulfonylurea plus metformin, metformin, and diet alone. In the whole group, PAI-1 activity correlated significantly with serum triglycerides (r = 0.39, P < 0.001), specific insulin (r = 0.29, P < 0.001), intact proinsulin (r = 0.24, P = 0.004), and des-31,32-proinsulin (r = 0.30, P < 0.001) and in subjects not on insulin (n = 110), with insulin sensitivity (r = -0.42, P < 0.001). There was a significant difference in PAI-1 activity among the three genotypic groups (P = 0.016); subjects with the genotype 4G/4G had PAI-1 levels one-third higher than those with the 5G/5G genotype. In the 4G/4G group, PAI-1 activity correlated significantly with triglyceride levels (r = 0.65, P < 0.0001). There was no significant difference in PAI-1 activity in the different treatment groups despite a significant difference in concentrations of intact and des-31,32-proinsulin. In a multiple regression model, insulin sensitivity and the interaction between PAI-1 4G/5G genotype and triglyceride were the strongest determinants of PAI-1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Markers of endothelial dysfunction and concentrations of proinflammatory cytokines in Type II diabetes are not influenced by improved glycaemic control over 16 weeks. Improved metabolic control with insulin could, however, be associated with reduced concentrations of the acute phase marker C-reactive protein.

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A 29 year old woman with difficult to control acromegaly and a pituitary macroadenoma responded to pegvisomant therapy and subsequently conceived with her first cycle of in-vitro fertilization and intra-cytoplasmic sperm injection. Pregnancy was complicated by gestational diabetes, pituitary gland enlargement and deteriorating visual fields. Conservative management with elective cesarean section was performed at 32 weeks gestation. A healthy boy was delivered who remains developmentally normal at 1 year. This complex case required intricate care by a multidisciplinary team and is likely to represent the first in many cases of assisted conception on pegvisomant therapy for active acromegaly. Keywords Case reportA 29 year old Caucasian woman was diagnosed with acromegaly following a two year history of secondary amenorrhea, change in physical appearance and sweating. The diagnosis was confirmed with an oral glucose tolerance test and radiological imaging that demonstrated a 2.2 cm pituitary tumor compressing the optic chiasm. A bi-temporal visual field defect was confirmed using binocular Goldman perimetry.Over a four-year period, she underwent four transphenoidal hypophysectomies and received 53 Gy radiotherapy. Despite a reduction in tumor size (Fig. 1) and the use of somatostatin analogues, she failed to achieve biochemical cure and her insulin-like growth factor-I (IGF-I) level remained persistently high (96-120 nmol/L; normal range 16-52 nmol/L). Hydrocortisone and thyroxine replacement was required for pituitary deficiency.She was desperate to conceive and was counseled on the effect of pregnancy on acromegaly and the risks of pituitary tumor enlargement. After failing to conceive with clomifene therapy she was referred to the assisted conception unit. Her husband was discovered to be oligoasthenozoospermic and they were counseled for in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).To achieve control of her acromegaly, she was started on daily subcutaneous injections of 20 mg pegvisomant, a highly selective growth hormone receptor (GHR) antagonist, and octreotide was discontinued. Her IGF-I subsequently normalized for the first time in 5 years.Pituitary down regulation was achieved with a GnRH analogue and she required four days of 300 IU recombinant FSH which was increased to 450 IU on day five of stimulation for a further 11 days for super-ovulation. She produced a total of 14 follicles and transvaginal ultrasound-guided oocyte Springer

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General practitioners and hospital physicians should be alert to those patients returning from abroad on effective 'herbal' medications that these may in fact contain an active ingredient.

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