The artificial pancreas: two alternative approaches to achieve a fully closed-loop system with optimal glucose control.

INTRODUCTION: Diabetes mellitus type 1 is a chronic disease that implies mandatory external insulin delivery. The patients must monitor their blood glucose levels and administer appropriate insulin boluses to keep their blood glucose within the desired range. It requires a lot of time and endeavour, and many patients struggle with suboptimal glucose control despite all their efforts. MATERIALS AND METHODS: This narrative review combines existing knowledge with new discoveries from animal experiments. DISCUSSION: In the last decade, artificial pancreas (AP) devices have been developed to improve glucose control and relieve patients of the constant burden of managing their disease. However, a feasible and fully automated AP is yet to be developed. The main challenges preventing the development of a true, subcutaneous (SC) AP system are the slow dynamics of SC glucose sensing and particularly the delay in effect on glucose levels after SC insulin infusions. We have previously published studies on using the intraperitoneal space for an AP; however, we further propose a novel and potentially disruptive way to utilize the vasodilative properties of glucagon in SC AP systems. CONCLUSION: This narrative review presents two lesser-explored viable solutions for AP systems and discusses the potential for improvement toward a fully automated system: A) using the intraperitoneal approach for more rapid insulin absorption, and B) besides using glucagon to treat and prevent hypoglycemia, also administering micro-boluses of glucagon to increase the local SC blood flow, thereby accelerating SC insulin absorption and SC glucose sensor site dynamics.

Increased prevalence of diabetes and polycystic ovary syndrome in women with a history of preterm birth: a case-control study.

OBJECTIVE: To test the hypothesis that endocrine and metabolic factors predispose to preterm birth. DESIGN: A cross-sectional, case-control study. SETTING: Namsos Hospital district (Namsos, Norway). POPULATION: Women from the Namsos Hospital district with previous preterm births (n = 114) were compared with matched controls with term births (n = 127). METHODS: A clinical examination including transvaginal ultrasound was performed. Fasting blood samples were collected and an oral glucose tolerance test was performed. MAIN OUTCOME MEASURES: The prevalence of polycystic ovary syndrome (PCOS) diagnosis (Rotterdam criteria) and serum levels of androgens, glucose and insulin. RESULTS: Twenty-nine of 114 women (25.4%) met the PCOS criteria among women with preterm birth, compared with 18 of 127 (14.2%) among controls (P = 0.03). Eight (7.1%) women with preterm birth were diagnosed with diabetes compared with none in the control group (P < 0.01). Hirsutism was present in 34 (29.8%) women with preterm birth versus 12 (9.4%) in the control group (P < 0.01). CONCLUSIONS: The prevalences of PCOS, diabetes and hirsutism are increased among women with a history of preterm birth. This indicates that endocrine and/or metabolic factors may be involved in the pathogenesis of preterm birth. Women experiencing preterm delivery may have an increased risk of developing diabetes and PCOS later in life.

Breast size increment during pregnancy and breastfeeding in mothers with polycystic ovary syndrome: a follow-up study of a randomised controlled trial on metformin versus placebo.

OBJECTIVE: To study the significance of breast size increment in pregnancy, and the impact of metformin during pregnancy on breastfeeding in women with polycystic ovary syndrome (PCOS). DESIGN: A follow-up study of a randomised controlled trial (the PregMet study). SETTING: Eleven secondary care centres. POPULATION: Women with PCOS during pregnancy and postpartum. METHODS: Women with PCOS were randomised to treatment with metformin or placebo from the first trimester to delivery. Questionnaires were sent to 240 participants 1 year postpartum: 186 responded. MAIN OUTCOME MEASURES: Pre-pregnancy and late-pregnancy brassiere size and breastfeeding patterns were registered, and androgen levels were measured in the mothers. RESULTS: No difference in breast size increment and breastfeeding were found between the placebo and metformin groups. Breast size increment correlated positively with the duration of both exclusive and partial breastfeeding, whereas body mass index (BMI) correlated negatively with the duration of partial breastfeeding. Dehydroepiandrostenedione-sulphate (DHEAS), testosterone and free testosterone index (FTI) in pregnancy did not correlate with breast size increment or duration of breastfeeding. Women with no change in breast size were more obese, had higher blood pressure, serum triglycerides and fasting insulin levels, and had a shorter duration of breastfeeding compared with those with breast size increment. CONCLUSIONS: Metformin and androgens had no impact on breastfeeding. Women with PCOS who had no breast size increment in pregnancy seem to be more metabolically disturbed and less able to breastfeed.

Short-term continuous glucose monitoring: effects on glucose and treatment satisfaction in patients with type 1 diabetes mellitus; a randomized controlled trial.

Objective: To assess whether 4 week's use of a continuous glucose monitoring (CGM) system improves glucose control, treatment satisfaction or health status, as compared to intensified conventional finger-prick measurements (ICFM) in patients with type 1 diabetes mellitus (DM1). Method: Thirty patients suffering from DM1 for more than three years and treated with either insulin pumps or multiple daily insulin injections, were included in a randomised controlled cross-over trial. They were Caucasians of both genders, between 18 and 50 years, and had moderately well controlled diabetes. The participants performed either ICFM or CGM for 4 weeks, followed by an 8 week's observation period. Thereafter they were crossed over to the opposite intervention. HbA(1c) , hypoglycaemic episodes, treatment satisfaction and health status were assessed at all meetings, although HbA(1c) was the primary endpoint. Results: At inclusion mean HbA(1c) was 7.8 ± 0.9 %. The mean change in HbA(1c) was -0.2 ± 0.1% and -0.2 ± 0.1% for the CGM and the ICFM periods, accordingly (p = 0.91). The mean changes in HbA(1c) during the combined treatment and observation periods were -0.1 ± 0.1% and -0.2 ± 0.1% for the CGM and the ICFM period, accordingly (p = 0.86). The frequency of severe hypoglycaemic episodes, treatment satisfaction and health status was also equal between the two interventions. No adverse events were observed.

Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study.

BACKGROUND: To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS: A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS: Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS: Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00159575.

Metformin influence on hormone levels at birth, in PCOS mothers and their newborns.

BACKGROUND: Polycystic ovary syndrome (PCOS) tends to run in families and excess intrauterine androgen exposure has been suggested as one possible cause of PCOS. We wanted to study the relationship between maternal and offspring sex hormone levels and the possible effects of metformin treatment in PCOS pregnancies. METHODS: We performed a post hoc analysis of a trial in which 40 pregnant women with PCOS were randomized in the first trimester, to use either metformin 850 mg twice daily or placebo until delivery. Maternal venous blood and umbilical arterial and venous blood samples were collected at delivery. Outcome measures were levels of androgens, estrogens and sex hormone binding globulin (SHBG). RESULTS: (i) In newborns, SHBG levels were higher in the metformin group. All other hormones, both in mothers and offspring, were unaffected by metformin treatment. (ii) Mothers, who gave birth to boys, had higher estrone and estradiol levels compared with those who gave birth to girls. (iii) Male newborns had higher levels of testosterone, androstanediol glucuronide and estradiol compared with females. (iv) Positive correlations were found between maternal and newborn levels of androstenedione, dihydrotestosterone and estradiol. CONCLUSIONS: Intrauterine metformin exposure seems to result in elevated SHBG levels in newborns. However, at birth, maternal and newborn androgen and estrogen levels are unaffected by metformin use in pregnancy. Although androgen and estrogen levels are higher in male newborns compared with females, maternal and newborn androgen and estrogen levels are highly correlated at birth.

Anti-Müllerian hormone concentrations in androgen-suppressed women with polycystic ovary syndrome.

BACKGROUND: Current data suggest that excessive androgen exposure can lead to the development of polycystic ovaries and polycystic ovary syndrome (PCOS). Anti-Müllerian hormone (AMH) levels reflect the number of small antral follicles in the ovaries and are elevated in PCOS. We hypothesized that protracted reduction of circulating androgens and/or insulin resistance would reduce circulating AMH concentrations in women with PCOS. METHODS: A prospective, randomized, double-blind 26 week long study was undertaken in 50 women with PCOS. They all received diet and lifestyle counselling, and metformin 850 mg three times daily. Concomitantly, they were randomized to either dexamethasone 0.25 mg daily (n = 25) or placebo (n = 25). Thirty-eight women completed the study. AMH (primary outcome) and other hormone levels were measured at inclusion and after 8 and 26 weeks of treatment. RESULTS: At baseline in univariate regression analyses, AMH levels associated positively with testosterone levels (P = 0.041) and ovarian volume (P = 0.002). In multivariate regression analyses, AMH associated positively with testosterone P = 0.004), and negatively with dehydroepiandrosterone sulphate (DHEAS) (P = 0.001) and C-peptide levels (P = 0.020). Circulating AMH concentrations were unaffected by 6 months of lifestyle counselling with metformin and placebo treatment. AMH levels were also unaffected by 6 months of androgen suppression with dexamethasone in addition. CONCLUSIONS: AMH levels in untreated PCOS women associated positively with testosterone, and negatively with DHEAS and C-peptide levels. Six months of androgen suppression by either metformin or low-dose dexamethasone treatment failed to influence circulating AMH levels.

Association of size at birth with adolescent hormone levels, body size and age at menarche: relevance for breast cancer risk.

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7-15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life.

Metformin has no major effects on glucose homeostasis in pregnant women with PCOS: results of a randomized double-blind study.

OBJECTIVE: Previous non-randomized and uncontrolled studies indicate major metformin effects on glucose homeostasis in pregnant women with polycystic ovary syndrome (PCOS). We investigated metformin effects on glucose homeostasis in a prospective controlled study. MATERIAL AND METHODS: Forty pregnant women with PCOS and without known diabetes mellitus were included in the first trimester and randomized to either metformin 850 mg twice daily or placebo. Outcome measures were fasting glucose and insulin at inclusion and changes to pregnancy weeks 19, 32 and 36 and 2 h glucose levels during a 75 g oral glucose tolerance test (OGTT) carried out at inclusion and pregnancy weeks 19 and 32. Insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta) were calculated using the homeostasis assessment model. RESULTS: At inclusion, 2 h glucose levels during OGTT were higher in the placebo group (7.14 versus 6.03 mmol/L; p = 0.012). Accordingly, 6 out of 22 in the metformin group versus 2 out of 18 women in the placebo group (p = 0.21) had gestational diabetes mellitus at inclusion. At gestational weeks 19 and 32, 2-h plasma glucose levels were equal between the groups. The total proportion of women with gestational diabetes did not differ between the groups, nor did any of the other indices of glucose metabolism and insulin resistance. CONCLUSIONS: Metformin seems to be without major effects on glucose homeostasis in pregnant women with PCOS.

Maternal testosterone levels during pregnancy are associated with offspring size at birth.

OBJECTIVE: Animal studies have indicated that maternal androgen levels influence the intrauterine environment and development of the offspring. Human data are missing. We therefore investigated the possible association between maternal androgens and offspring size at birth in humans. DESIGN: A random sample of parous Caucasian women (n=147) was followed prospectively through pregnancy. METHODS: Maternal serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone and sex hormone-binding globulin (SHBG) were measured at gestational weeks 17 and 33. The main outcome measures were weight and length at birth. Associations between maternal androgen levels and offspring birth weight and length were investigated using multiple linear regression modeling adjusted for potential confounding by maternal height, pre-pregnancy body mass index, smoking, parity, offspring gender and gestational age at birth. RESULTS: Elevated maternal testosterone levels at week 17 and 33 were both associated with lower birth weights and lengths. Accordingly, at week 17, an increase in maternal testosterone levels from the 25th to the 75th percentile was associated with a decrease in birth weight by 160 g (95% confidence interval (CI); 29-290 g), while at week 33 that estimate was 115 g (95% CI; 21-207 g). No similar associations were observed for DHEAS, androstenedione or SHBG. CONCLUSIONS: Elevated maternal testosterone levels during human pregnancy are associated with growth restriction in utero. Our results support animal studies, which have indicated that maternal androgen levels influence intrauterine offspring environment and development.

Preoperative octreotide therapy and surgery in acromegaly: associations between glucose homeostasis and treatment response.

In acromegaly, high GH/IGF-1 levels associate with abnormal glucose metabolism. Somatostatin analogs (SSAs) reduce GH and IGF-1 but inhibit insulin secretion. We studied glucose homeostasis in de novo patients with acromegaly and changes in glucose metabolism after treatment with SSA and surgery. In this post hoc analysis from a randomized controlled trial, 55 de novo patients with acromegaly, not using antidiabetic medication, were included. Before surgery, 26 patients received SSAs for 6 months. HbA1c, fasting glucose, and oral glucose tolerance test were performed at baseline, after SSA pretreatment and at 3 months postoperative. Area under curve of glucose (AUC-G) was calculated. Glucose homeostasis was compared to baseline levels of GH and IGF-1, change after SSA pretreatment, and remission both after SSA pretreatment and 3 months postoperative. In de novo patients, IGF-1/GH levels did not associate with baseline glucose parameters. After SSA pretreatment, changes in GH/IGF-1 correlated positively to change in HbA1c levels (both p < 0.03). HbA1c, fasting glucose, and AUC-G increased significantly during SSA pretreatment in patients not achieving hormonal control (all p < 0.05) but did not change significantly in patients with normalized hormone levels. At 3 months postoperative, HbA1c, fasting glucose, and AUC-G were significantly reduced in both cured and not cured patients (all p < 0.05). To conclude, in de novo patients with acromegaly, disease activity did not correlate with glucose homeostasis. Surgical treatment of acromegaly improved glucose metabolism in both cured and not cured patients, while SSA pretreatment led to deterioration in glucose homeostasis in patients not achieving biochemical control.

Evidence for dissociation of insulin- and weight-reducing effects of metformin in non-diabetic male patients with coronary heart disease.

Metformin effects on insulin resistance and insulin/glucose relationships during an oral glucose tolerance test (OGTT) were investigated in 60 non-diabetic male patients previously treated with coronary artery bypass surgery or angioplasty in an open, 12 week prospective study. During a 4 week run-in period, all patients were treated with diet and lifestyle advice and lovastatin 40 mg daily. Lovastatin treatment was continued in all the patient throughout the study. After randomization, the metformin group got additional treatment with metformin up to 2000 mg/day. Fasting plasma glucose levels and glucose area during OGTT remained unaffected by metformin treatment. Insulin resistance, assessed as the insulin area/glucose area ratio during OGTT decreased by 24% (P = 0.028) in the whole group and by 30% in obese subjects (P = 0.049). Notably, the reduction in body weight by metformin treatment did not correlate with amelioration of insulin resistance or changes in lipid levels. However, changes in insulin resistance correlated with changes in lipid levels. Hence, metformin effects on insulin resistance and body weight appear to be mediated, at least partly, by different mechanisms, while metformin effects on insulin resistance and lipid metabolism are associated in non-diabetic subjects.

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial.

OBJECTIVE: Randomised studies have demonstrated a beneficial effect of pre-surgical treatment with somatostatin analogues (SSA) in acromegaly when evaluated early postoperatively. The objective of this study was to evaluate the long-term surgical cure rates. METHODS: Newly diagnosed patients were randomised to direct surgery (n=30) or 6-month pretreatment with octreotide LAR (n=32). The patients were evaluated 1 and 5 years postoperatively. Cure was defined as normal IGF1 levels and by normal IGF1 level combined with nadir GH <2 mU/l in an oral glucose tolerance test, all without additional post-operative treatment. A meta-analysis using the other published randomised study with long-term analyses on preoperative SSA treatment was performed. RESULTS: The proportion of patients receiving post-operative acromegaly treatment was equal in the two groups. When using the combined criteria for cure, 10/26 (38%) macroadenomas were cured in the pretreatment group compared with 6/25 (24%) in the direct surgery group 1 year postoperatively (P=0.27), and 9/22 (41%) vs 6/22 (27%) macroadenomas, respectively, 5 years postoperatively (P=0.34). In the meta-analysis, 16/45 (36%) macroadenomas were cured using combined criteria in the pretreatment group vs 8/45 (18%) in the direct surgery group after 6-12 months (P=0.06), and 15/41 (37%) vs 8/42 (19%), respectively, in the long-term (P=0.08). CONCLUSION: This study does not prove a beneficial effect of SSA pre-surgical treatment, but in the meta-analysis a trend towards significance can be claimed. A potential favourable, clinically relevant response cannot be excluded.

The effect of exercise and metformin treatment on circulating free DNA in pregnancy.

INTRODUCTION: Some pregnancy complications are characterized by increased levels of cell-free fetal (cffDNA) and maternal DNA (cfmDNA), the latter may also be elevated during physical strain. This study aims at assessing the impact of exercise and metformin intervention in pregnancy, and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis. METHODS: Consecutive women from two previous randomized controlled trials in pregnancy were included. Women came from a trial with organized exercise vs. standard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women. Levels of cffDNA, cfmDNA and cell-free total DNA (cftDNA) were measured by qPCR. RESULTS: Training in pregnancy did not affect the levels of cffDNA, cfmDNA or cftDNA. PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 (mean ± SD: 301 ± 162 versus 570 ± 337, p = 0.012, 345 ± 173 versus 635 ± 370, p = 0.019); otherwise the levels were comparable to PCOS-controls. Metformin-treated PCOS-women had higher cffDNA at inclusion, in the 1st trimester; later on in pregnancy the levels in the metformin and placebo groups were equal. A comparison of pregnant women in the exercise study (TRIP) to placebo-treated pregnant PCOS-women, showed the levels of cffDNA, cfmDNA or cftDNA during mid-pregnancy (weeks 18-36) to be equal. DISCUSSION: Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA, but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women.

Gestational diabetes mellitus among Norwegian women with polycystic ovary syndrome: prevalence and risk factors according to the WHO and the modified IADPSG criteria.

OBJECTIVE: The consequences of the recently proposed International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria for gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) are not known. We compared the prevalence rates and risk factors for GDM in PCOS women according to both the WHO and the modified IADPSG criteria. DESIGN: Post hoc analyses from a randomized, multicenter study were used. METHODS: Fasting and 2-h plasma glucose levels were measured using a 75 g oral glucose tolerance test. GDM was diagnosed according to both the WHO and the modified IADPSG criteria. RESULTS: The prevalence rates of GDM according to the WHO and the modified IADPSG criteria were 9.2 and 15.0% at week 12, 18.7 and 18.7% at week 19, and 25.6 and 24.2% at week 32. Shorter stature and increased insulin levels were correlated with WHO-GDM, but not with modified IADPSG-GDM at weeks 12 and 19. Less weight gain in pregnancy predicted GDM according to both sets of criteria. GDM diagnosis was correlated with less maternal weight loss the first year post-partum. CONCLUSIONS: No difference was found in the prevalence of GDM between the two sets of criteria used. Less weight gain in pregnancy was associated with GDM, independent of the diagnostic criteria used. Reduced weight loss the first year post-partum in women with GDM raises the question of whether GDM diagnosis per se or the fact that these women lose less weight after pregnancy predicts later diabetes mellitus.

Metformin treatment in pregnant women with polycystic ovary syndrome--is reduced complication rate mediated by changes in the uteroplacental circulation?

OBJECTIVES: To study a possible effect of metformin on the uteroplacental circulation. METHODS: Forty pregnant women with polycystic ovary syndrome (PCOS) were enrolled in a randomized, double-blind, placebo-controlled trial of metformin (1700 mg/day) during pregnancy. Doppler ultrasound examinations of the uterine arteries were performed at 12, 19, 24, 32 and 36 gestational weeks and of the umbilical artery at 19, 24, 32 and 36 gestational weeks. RESULTS: There was a greater mean bilateral uterine artery pulsatility index (PI) at 12 weeks (1.95 vs. 1.58, P = 0.02), and a greater reduction in mean PI from 12 to 19 weeks (P = 0.03) in metformin-treated women. There were no differences in mean PI values between groups at 19, 24, 32 or 36 gestational weeks. Pregnancy complications, such as preterm delivery before 32 weeks, severe pre-eclampsia or serious postpartum events, occurred only in the placebo group (7 of 22 vs. 0 of 18, P = 0.01). There were no associations between uterine artery Doppler measurements and pregnancy complications. We found no differences between groups in mean umbilical artery PI at 19, 24, 32 or 36 gestational weeks. CONCLUSIONS: In this small randomized trial, metformin treatment in pregnancy reduced uterine artery impedance between 12 and 19 weeks of gestation, and this was associated with reduced complication rate. Published by John Wiley & Sons, Ltd.

[Sulfonylurea-induced hypoglycemia. An iatrogenic and potentially fatal condition]. / Sulfonylureaindusert hypoglykemi. En iatrogen og potensielt dødelig tilstand.

Sulfonylureas are the most frequently used peroral antidiabetic drugs in Norway. Five cases of serious sulfonylurea-induced hypoglycemia are described. In one of these cases glibenklamid-induced hypoglycemia was thought to be the direct cause of death. A review of the literature indicates that glibenclamide induces more frequent and serious hypoglycemias than other sulfonylureas do. The author discusses the possible mechanisms behind these differences, and the conditions predisposing to sulfonylurea-induced hypoglycemia. It is recommended to check blood glucose whenever a patient's diagnosis has not been adequately clarified.

[Should insulin treatment be avoided? Blood sugar is not everything in type 2 diabetes]. / Bør insulinbehandling unngås? Blodsukkeret betyr ikke alt hos type 2-diabetikere.

Cardiovascular disease is frequent and is the main cause of death in type 2-diabetic patients. Hyperinsulinaemia is a risk factor for cardiovascular disease, and insulin accelerates many of the processes leading to atherosclerosis. Studies in type 2-diabetic patients show that high insulin levels correlate with cardiovascular disease and overall mortality. A recent pilot study showed that intensive versus traditional insulin treatment increased the incidence of cardiovascular disease. Therefore treatment regimens that reduce insulin levels should be preferred, at least when equal glucose levels are achieved. In this perspective metformin is the drug of choice. Insulin treatment should be considered only when combined treatment with metformin and sulfonylurea is contraindicated or leads to insufficient blood glucose control. Special caution should be shown with insulin treatment in patients with cardiovascular disease.

Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment.

OBJECTIVES: Metformin treatment increases circulating homocysteine levels. We studied whether administration of folate reduces serum total homocysteine levels in patients on long-term metformin treatment. DESIGN: A prospective, randomized, double-blind, placebo-controlled study lasting for 12 weeks and taking place in a university hospital setting. SUBJECTS: Thirty patients treated with a metformin dose of at least 1000 mg day-1 for a minimum of 1 year were included. At baseline serum total homocysteine levels were within the reference range. One patient who withdrew and one who died were excluded from the statistical evaluation. Twenty-six of the remaining patients suffered from NIDDM, the other two from hyperlipidaemia. INTERVENTION: Patients were randomized into two groups at week 0. The folate group received 0.25 mg day-1 of folate in addition to 60 mg day-1 of Fe2+, while the placebo group received only 60 mg day-1 of Fe2+. MAIN OUTCOME MEASURES: Fasting homocysteine, cysteine, cysteinylglycine, vitamin B12 and folate were measured at week 0, 4 and 12. Changes from week 0 to week 4 and from week 0 to week 12 were calculated. RESULTS: Folate administration reduced serum levels of total homocysteine in the folate group as compared with the placebo group by 13.9% (P < 0.01) and 21.7% (P < 0.001) at week 4 and 12, respectively. In the folate group versus the placebo group serum levels of vitamin B12 increased by 9.9% (P = 0.010) and 9.6% (P = 0.043) while folate levels increased by 96.9 and 89.9% at week 4 and 12, respectively. CONCLUSION: The present study indicates that the homocysteine-increasing effect of metformin can be counteracted by folate administration.

[Metformin reevaluated--time for rehabilitation?]. / Metformin revurdert--tid for rehabilitering?

The consumption of metformin in Norway is low. Most probably this is caused by poorly based impressions of small effects and frequent and serious side effects. A review of the literature shows that metformin and sulfonylurea lower average blood glucose values equally well, both in obese and non-obese type 2 diabetic patients. In sulfonylurea failure, addition of metformin lowers the glucose values to the same extent as a shift to insulin monotherapy does. Metformin is anti-hyperglycaemic only, and therefore does not cause hypoglycaemia. The risk of drug-related deaths is no higher with metformin than with sulfonylurea. Metformin improves the lipid profile, and has other effects which could lower risk of cardiovascular complications. The place of metformin in the treatment of type 2 diabetic patients should be reconsidered.