Pancreatic β-CELL Dysfunction in Polycystic Ovary Syndrome: the Role of Metformin

ObjectiveTo determine whether the administration of 6 months of daily metformin treatment in women with polycystic ovary syndrome (PCOS) would significantly improve pancreatic β-cell function as measured by an increase in the disposition index.MethodsWe enrolled women with PCOS from a private practice and from the Mount Sinai Hospital Endocrinology Clinic. All patients underwent frequently sampled intravenous glucose tolerance tests both on and off 500 to 1000 mg of twice daily metformin. Values of insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index were calculated for each test. The product of acute insulin response to glucose and insulin sensitivity yielded the disposition index and estimated the degree of β-cell compensation for insulin resistance.ResultsWe enrolled 14 women. We observed no significant changes in insulin sensitivity, glucose effectiveness, or acute insulin response to glucose, disposition index, or distributed glucose at time 0 before or after metformin treatment. Patients with PCOS treated with metformin remained statistically on the same hyperbolic curve, which is consistent with previously reported results of the effect of metformin on β-cell function. In contrast, the proportional change in disposition index correlated significantly with the proportional change in insulin sensitivity. Patients whose insulin sensitivity decreased after treatment showed a proportional decrease in disposition index, while patients whose insulin sensitivity increased showed a proportional increase in disposition index.ConclusionsOur findings suggest that acute insulin response to glucose does not proportionately change to match change in insulin sensitivity. Thus, there may be a β-cell defect in women with PCOS. (Endocr Pract. 2012;18:685-693)     

Metformin: Nonglycemic Effects and Potential Novel Indications

Objective: Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes because of its apparent robust effects in reducing cardiovascular risk. This review examines the current literature regarding the nonglycemic effects and potential novel indications for metformin.Methods: Review of the literature, with a focus on metformin use in Stage 3 chronic kidney disease (CKD-3) and heart failure (HF).Results: The United Kingdom Prospective Diabetes Study suggests that metformin reduces the risk of myocardial infarction, and more recent retrospective studies have shown an association between metformin use and a reduction in stroke, atrial fibrillation and all-cause mortality. The mechanism(s) explaining these putative benefits are not clear but may involve decreased energy intake (with attendant weight loss), improvement in lipids, and lowering of blood pressure; a literature review suggests that metformin lowers blood pressure when it is elevated, but not when it is normal. Metformin appears to be safe when given to patients with CKD-3. In addition, there is evidence that individuals with CKD-3, who are at increased cardiovascular risk, stand to benefit from metformin therapy. Lactic acidosis is an extremely remote and probably avoidable risk; measurement of plasma metformin levels and more frequent monitoring of renal function may be useful in selected patients with CKD-3 who are treated with metformin. Finally, there is evidence that metformin is safe in patients with HF; metformin therapy is associated with a reduction in newly incident HF and in HF mortality.Conclusion: Metformin has a dominant position in the treatment of type 2 diabetes that is deserved due to its favorable and robust effects on cardiovascular risk.Abbreviations:AMP = adenosine monophosphateBP = blood pressureCKD = chronic kidney diseaseCKD-3 = Stage 3 CKDeGFR = estimated glomerular filtration rateHDL = high-density lipoproteinHF = heart failureMAP = mean arterial pressuremVO₂ = myocardial oxygen consumptionT2DM = type 2 diabetes mellitusUKPDS = United Kingdom Prospective Diabetes Study     

Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction

ObjectiveTo determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes.MethodsPatients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing-derived indices of insulin resistance and impaired b-cell function. Patients who declined pharmacologic therapy received lifestyle modification only.ResultsOne hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or b-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and b-cell function improved by 42% and 50%, respectively (all P < .001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and b-cell function improved by 52% and 109%, respectively (all P < .001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes.ConclusionsTargeted pathophysiologic therapy based on oral glucose tolerance test-derived measures of insulin sensitivity and b-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients. (Endocr Pract. 2012;18: 342-350)     

Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: A retrospective analysis

ObjectiveTo determine whether treatment with metformin would prevent progression to glucose intolerance and type 2 diabetes in women with polycystic ovary syndrome (PCOS).MethodsWe conducted a retrospective review of medical records of women treated for PCOS during a 5-year period. Eligibility criteria included exclusion of diabetes at baseline by an oral glucose tolerance test, treatment with metformin, and a repeated oral glucose tolerance test after at least 1 year of metformin therapy. Fifty women with PCOS fulfilled the eligibility criteria.ResultsAt baseline, 11 women (22%) had impaired glucose tolerance (IGT), and 39 (78%) had normal glucose tolerance (NGT). After treatment with metformin, IGT persisted in 5 (45%) of the 11 women who had IGT at baseline, whereas 6 (55%) had reversion to NGT. During a mean treatment period of 43.3 months, 2 (5%) of the 39 women with baseline NGT had conversion to IGT, resulting in an annual conversion rate from NGT to IGT of 1.4%. In comparison with the 16% to 19% annual conversion rate reported in the literature, metformin treatment in this study resulted in an 11-fold decrease in the annual conversion rate from NGT to IGT (P = 0.01). None of the 50 women developed diabetes.ConclusionThe findings of this retrospective study suggest that long-term treatment with metformin delays or prevents the development of IGT and type 2 diabetes in women with PCOS. (Endocr Pract. 2007;13:373-379)     

Metformin-Responsive Classic Salt-Losing Congenita L Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: a Case Report

ObjectiveTo study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21- hydroxylase deficiency with suboptimal biochemical and clinical control.MethodsWe present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient.ResultsA 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged.ConclusionsMetformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome. (Endocr Pract. 2008;14:889-891)     

Metformin, but not exercise training, increases insulin responsiveness in skeletal muscle of Sprague-Dawley rats

We assessed the effects of combined metformin treatment and exercise training on body composition, on insulin concentration following glucose loading, on insulin-stimulated glucose transport in skeletal muscle, and on muscle glycogen content. Male Sprague-Dawley rats were treated for 35 days with or without metformin (320 mg/kg/day) and/or treadmill exercise training (20 min at 20 m/min, 5 days/wk). Because metformin reduces food intake, pair-fed controls were included. Metformin, training, and pair-feeding all decreased food intake, body weight, and insulin concentration following glucose loading. Metformin and training reduced intra-abdominal fat, but pair feeding did not. In isolated strips derived from soleus, epitrochlearis and extensor carpi ulnaris muscles, metformin increased insulin-stimulated transport of [3H]-2-deoxyglucose by 90%, 89% and 125%, respectively (P < 0.02) and training increased [3H]-2-deoxyglucose transport in the extensor carpi ulnaris muscle only (66%, P < 0.05). Pair-feeding did not alter [3H]-2-deoxyglucose transport. Training increased gastrocnemius muscle glycogen by 100% (P < 0.001). Metformin and pair-feeding did not alter muscle glycogen. We conclude that metformin reverses the maturation-induced impairment of insulin responsiveness in Sprague-Dawley rats by increasing insulin-stimulated glucose transport in skeletal muscle and that this effect is not secondary to reduced food intake. We also conclude that metformin and exercise training may increase insulin sensitivity by different mechanisms, with training causing increased glucose transport only in some muscles and also causing increased muscle glycogen storage.     

Metformin May Be Associated with False-Negative Cancer Detection in the Gastrointestinal Tract on Pet/Ct

ObjectiveConcurrent therapy with the antihyperglycemic drug metformin can hinder the detection of malignancy in the abdominal and pelvic portions of ¹⁸F-fluordeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging performed for the diagnosis or staging of malignancy, as well as for treatment response and radiation therapy planning. This is due to the metformin-induced increase in intestinal FDG radiotracer uptake. We aim to bring this potentially important interaction to the attention of clinicians who care for cancer patients with diabetes.MethodsWe searched MEDLINE (from 1970 to January 2014)and Google Scholar for relevant English-language articles using the following search terms: “metformin and FDG/PET, metformin and bowel uptake, metformin, and cancer, metformin and the intestine, metformin pharmacokinetics, hyperglycemia and FDG/PET.” We reviewed the reference lists of pertinent articles with respect to metformin gut physiology, impact on FDG uptake and the effect on diagnostic accuracy of abdominal-pelvic PET/CT scans with concurrent metformin therapy.ResultsWe reviewed the action of metformin in the intestine, with particular emphasis on the role of metformin in PET/CT imaging and include a discussion of clinical studies on the topic to help refine knowledge and inform practice. Finally, we discuss aspects pertinent to the management of type 2 diabetes (T2D) patients on metformin undergoing PET/CT.ConclusionsMetformin leads to intense, diffusely increased FDG uptake in the colon, and to a lesser degree, the small intestine, which limits the diagnostic capabilities of FDG PET/CT scanning and may mask gastrointestinal malignancies. We suggest that metformin be discontinued 48 hours before FDG PET/CT scanning is performed in oncology patients. More rigorous data are needed to support the widespread generalizability of this recommendation. (Endocr Pract. 2014;20:1079-1083)     

Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice

IntroductionIt was the aim of the present experiments to examine potential antidiabetic effects of the Cimicifuga racemosa extract Ze 450.MethodsZe 450 and some of its components (23-epi-26-deoxyactein, protopine and cimiracemoside C) were investigated in vitro for their effects on AMP-activated protein kinase (AMPK) compared to metformin in HepaRG cells. Ze 450 (given orally (PO) and intraperitonally (IP)), metformin (PO) and controls were given over 7 days to 68 male ob/ob mice. Glucose and insulin concentrations were measured at baseline and during an oral glucose tolerance test (OGTT).ResultsZe 450 and its components activated AMPK to the same extent as metformin. In mice, Ze 450 (PO/IP) decreased significantly average daily and cumulative weight gain, average daily food and water intake, while metformin had no effect. In contrast to metformin, PO Ze 450 virtually did not change maximum glucose levels during OGTT, however, prolonged elimination. Ze 450 administered PO and IP decreased significantly post-stimulated insulin, whereas metformin did not. HOMA-IR index of insulin resistance improved significantly after IP and PO Ze 450 and slightly after metformin. In summary, the results demonstrate that Ze 450 reduced significantly body weight, plasma glucose, improved glucose metabolism and insulin sensitivity in diabetic ob/ob mice. In vitro experiments suggest that part of the effects may be related to AMPK activation.ConclusionsZe 450 may have utility in the treatment of type 2 diabetes. However, longer term studies in additional animal models or patients with disturbed glucose tolerance or diabetes may be of use to investigate this further.     

Pseudohypoglycemia: a Cause for Unreliable Finger-Stick Glucose Measurements

ObjectiveTo identify patients with an inaccurate diagnosis of hypoglycemia and discuss predisposing factors.MethodsWe describe our patient’s clinical presentation, laboratory work-up, hospital course, and follow-up and review similar cases from the literature.ResultsA 27-year-old woman with Raynaud phenomenon was admitted because of symptomatic hypoglycemia. Physical examination showed tremulousness, sweating, and the classic Raynaud color changes of the hands during episodic symptoms. A 72-hour fast revealed finger-stick capillary glucose values ranging from 32 to 45 mg/dL on multiple occasions, while concurrent plasma glucose values were consistently 1.5 to 2 times higher. Capillary measurements of glucose performed in the arms and legs at room temperature and after warming of each extremity disclosed an increase in glucose levels from a range of 35 to 52 mg/dL at room temperature to a range of 82 to 100 mg/dL after warming, confirming a discordance between capillary and venous blood results. The diagnosis of pseudohypoglycemia was made. Pseudohypoglycemia has been reported in patients with Raynaud phenomenon, peripheral vascular disease, and shock and may result from increased glucose extraction by the tissues because of low capillary flow and increased glucose transit time.ConclusionPseudohypoglycemia should be suspected in the setting of impaired microcirculation and can be confirmed by readily available means. (Endocr Pract. 2008;14:337-339)     

Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

Background

Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model.

Methodology/Principal Findings

Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH.

Conclusions/Significance

These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.     

Impact of Prandial Plus Basal vs Basal Insulin on Glycemic Variability in Type 2 Diabetic Patients

ObjectiveTo determine whether metformin-treated patients with type 2 diabetes given an analogue mixture of basal and rapid-acting insulins (insulin lispro protamine suspension plus insulin lispro) would have less glycemic variability than patients given basal insulin glargine.MethodsTwo post hoc analyses were used to compare 7-point blood glucose profiles from 3 published studies comparing basal plus prandial premixed insulin lispro mixtures with insulin glargine in metformin-treated patients with type 2 diabetes. Glycemic variability indices used included standard deviation of mean daily blood glucose, coefficient of variation, M-value, mean amplitude of glycemic excursion, and J-index.ResultsPatients on the twice-daily insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro) plus metformin regimen had significantly lower standard deviation, M-value, and J-index than patients on the insulin glargine plus metformin regimen, but not lower coefficient of variation or mean amplitude of glycemic excursion. Patients on the 3 times daily insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin lispro) plus metformin regimen had significantly lower values for all 5 indices than patients on the insulin glargine plus metformin regimen.ConclusionUse of basal plus prandial insulin lispro mixtures at 2 or 3 meals was associated with lower glycemic variability in metformin-treated patients with type 2 diabetes. (Endocr Pract. 2009;15:343-348)     

Improvement of metabolic parameters and vascular function by metformin in obese non-diabetic rats

AimsMetformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin.Main methods16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed.Key findings18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats.SignificanceMetformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.     

二甲双胍联合炔雌醇环丙孕酮片治疗对多囊卵巢综合征患者临床疗效及糖脂代谢的影响

摘要 目的：研究二甲双胍联合炔雌醇环丙孕酮片治疗多囊卵巢综合征（polycystic ovarian syndrome,PCOS）患者的临床疗效及对患者糖脂代谢的影响。方法：选取2018年1月~2020年12月在我院接受治疗的60例PCOS患者作为研究对象,随机数表法均分为对照组和研究组：对照组患者接受炔雌醇环丙孕酮片治疗,而研究组患者接受二甲双胍联合炔雌醇环丙孕酮片治疗。比较两组患者治疗后排卵和妊娠情况,并比较治疗前后性激素水平和糖脂代谢的变化。结果：研究组治疗总有效率为83.33%,显著高于对照组63.33%的治疗总有效率（P<0.05）。治疗前,两组患者血清卵泡刺激素（Follicle Stimulating Hormone, FSH）、黄体生成素（Luteinizing hormone, LH）、雌二醇（Estradiol, E2）、睾酮（Testosterone, T）等性激素水平,空腹血糖（fasting plasma glucose, FPG）、空腹胰岛素（Fasting serum lisulin, FINS）、口服葡萄糖耐量试验（oral glucose tolerance test, OGTT）2 h血糖和胰岛素等糖代谢指标以及甘油三酯（Triglycerides, TG）、胆固醇（Total cholesterol, TC）、高密度脂蛋白（High density lipoprotein, HDL）和低密度脂蛋白（Low density lipoprotein, LDL）等脂代谢指标脂代谢指标比较均无显著差异（P>0.05）;治疗后,所有患者血清FSH、LH、T、E2、TG、LDL、TC、FPG、FINS、OGTT 2h PG和OGTT 2h INS均较治疗前显著降低（P<0.05）,而HDL较治疗前升高（P<0.05）;研究组患者治疗后血清FSH、LH、T、E2、TG、LDL、TC、FPG、FINS、OGTT 2h PG和OGTT 2h INS均较显著低于对照组患者（P<0.05）,而HDL显著高于对照组患者（P<0.05）。结论：二甲双胍联合炔雌醇环丙孕酮片治疗多囊卵巢综合征临床效果显著,可有效改善患者糖脂代谢水平。     

Metformin Safety in the Management of Gestational Diabetes

ObjectiveThe use of metformin in pregnant women is still controversial, despite the increasing reports on metformin’s safety and effectiveness. We aimed to evaluate the maternal and neonatal safety of metformin in subjects with gestational diabetes mellitus (GDM).MethodsWe retrospectively reviewed the clinical records of 186 pregnancies complicated with GDM surveilled at Hospital de Santa Maria, Lisboa, between 2011 and 2012. The maternal and neonatal outcomes of 32 females who took metformin during pregnancy were compared with 121 females controlled with diet and 33 insulintreated females.ResultsOf the 186 GDM subjects, 32 (17.2%) received metformin during pregnancy. No statistical differences between the diet and metformin groups were found with regard to the rates of abortion, prematurity, preeclampsia, macrosomy, small-for-gestational-age (SGA) or largefor- gestational-age (LGA) newborns, cesarean deliveries, neonatal intensive care unit (NICU) admissions, and birth malformations or neonatal injuries. Similarly, there were no differences between the metformin and insulin groups with regard to the referred outcomes. No abortions or perinatal deaths were recorded in the metformin group. Ten out of 32 metformin patients required additional insulin.ConclusionThis retrospective study suggests that metformin is a safe alternative or additional treatment to insulin in females with GDM. Metformin was not associated with a higher risk of maternal or neonatal complications when compared to the insulin or diet groups. (Endocr Pract. 2014;20:1022-1031)     

Effectiveness and Long-Term Safety of Thiazolidinediones and Metformin in Renal Transplant Recipients

ObjectiveTo investigate the long-term safety and effectiveness of thiazolidinediones and metformin in renal transplant recipients with posttransplant diabetes mellitus (PTDM) or preexisting diabetes mellitus (DM).MethodsRetrospective chart review was performed for renal transplant recipients with PTDM or preexisting DM followed up during the years 2000-2006. Data collected included baseline characteristics; glomerular filtration rate (GFR); creatinine; hemoglobin A_1c; and development of congestive heart failure, edema, and liver function abnormalities. GFR was calculated using the Modification of Diet in Renal Disease study equation calculator.ResultsThirty-two patients comprised the metformin group (PTDM = 21, preexisting DM = 11), and 46 patients were included in the TZD group (PTDM = 33, preexisting DM = 13). Only 24 patients taking metformin and 31 patients taking TZDs were included for effectiveness analysis since the others required additional medications to control their DM. Mean follow-up was 16.4 months (range, 1-55 months) for patients treated with metformin and 37.1 months (range, 6-72 months) for patients treated with TZDs. GFR was decreased from baseline in all patients, but the only significant change was in patients with preexisting DM. While there was a significant change in creatinine levels in the metformin group, only 5 patients had to discontinue the drug because of this elevation (3 in preexisting DM group, 2 in PTDM group). Change in hemoglobin A_1c from baseline was not significant in either study group. Development of congestive heart failure or liver function abnormalities was not observed.ConclusionsMetformin appears to be safe in the renal transplant population for a mean duration of 16 months, although caution should be exercised using close monitoring in patients with preexisting DM. TZDs appear to be safe for a mean duration of 37 months after renal transplant. (Endocr Pract. 2008;14:979-984)     

Lack of Correlation Between 1,5-Anhydroglucitol Assay and Oral Glucose Tolerance Test in Patients with Cystic Fibrosis

ObjectiveTo determine whether the 1,5-anhydroglucitol (1,5-AG) assay, which reflects serum glucose levels during the preceding 2 weeks, could be used as an alternative to the current standard screening test for cystic fibrosis-related diabetes (CFRD)—the oral glucose tolerance test (OGTT).MethodsSerum 1,5-AG, hemoglobin A1c (A1C), fructosamine, and glucose at various time intervals during the OGTT were measured in 10 patients, 19 to 36 years old, with cystic fibrosis. Correlation coefficients were calculated to compare 1,5-AG with A1C, fructosamine, and serum glucose levels during the OGTT, and the mean 1,5- AG, A1C, and fructosamine for normal glucose tolerance, impaired glucose tolerance (IGT), and CFRD were compared statistically.ResultsOn the basis of the 120-minute OGTT, 1 of the 10 study subjects had CFRD and 4 had IGT. The mean 1,5-AG for patients with normal glucose tolerance was not significantly different from that for patients with IGT (P = .063). The 1,5-AG value was not significantly correlated with serum glucose during the OGTT, A1C, or fructosamine.ConclusionIn this pilot study, we found no significant correlation between 1,5-AG and glucose values during the OGTT or between 1,5-AG and other glycemic markers.Hence, the utility of the 1,5-AG assay for screening for CFRD in the population of patients with cystic fibrosis may be limited. (Endocr Pract. 2010;16:167-170)     

Metformin protects against insulin resistance induced by high uric acid in cardiomyocytes via AMPK signalling pathways in vitro and in vivo

High uric acid (HUA) is associated with insulin resistance (IR) in cardiomyocytes. We investigated whether metformin protects against HUA-induced IR in cardiomyocytes. We exposed primary cardiomyocytes to HUA, and cellular glucose uptake was quantified by measuring the uptake of 2-NBDG, a fluorescent glucose analog. Western blot was used to examine the levels of signalling protein. Membrane of glucose transporter type 4 (GLUT4) was analysed by immunofluorescence. We monitored the impact of metformin on HUA-induced IR and in myocardial tissue of an acute hyperuricaemia mouse model established by potassium oxonate treatment. Treatment with metformin protected against HUA-reduced glucose uptake induced by insulin in cardiomyocytes. HUA directly inhibited the phosphorylation of Akt and the translocation of GLUT4 induced by insulin, which was blocked by metformin. Metformin promoted phosphorylation of AMP-activated protein kinase (AMPK) and restored the insulin-stimulated glucose uptake in HUA-induced IR cardiomyocytes. As a result of these effects, in a mouse model of acute hyperuricaemia, metformin improved insulin tolerance and glucose tolerance, accompanied by increased AMPK phosphorylation, Akt phosphorylation and translocation of GLUT4 in myocardial tissues. As expected, AICAR, another AMPK activator, had similar effects to metformin, demonstrating the important role of AMPK activation in protecting against IR induced by HUA in cardiomyocytes. Metformin protects against IR induced by HUA in cardiomyocytes and improves insulin tolerance and glucose tolerance in an acute hyperuricaemic mouse model, along with the activation of AMPK. Consequently, metformin may be an important potential new treatment strategy for hyperuricaemia-related cardiovascular disease.     

Pilot Study to Evaluate the Effect of Short-Term Improvement in Vitamin D Status on Glucose Tolerance in Patients With Type 2 Diabetes Mellitus

ObjectiveTo study the effect of improvement in vitamin D status on glucose tolerance in Asian Indian patients with moderately controlled type 2 diabetes mellitus (T2DM).MethodsThis randomized, double-blind, placebocontrolled pilot study was conducted in 28 Asian Indian patients with T2DM. Study participants were randomly assigned to a vitamin D-treated group (group D) or a placebo group (group P). Serum 25-hydroxyvitamin D, hemoglobin A1c, and serum fructosamine levels were measured, and an oral glucose tolerance test (OGTT) was performed in all patients at baseline and 4 weeks after intervention. During the OGTT, plasma glucose and serum insulin levels were measured at 0, 30, 60, 90, and 120 minutes. The unpaired t test was used to compare the groups at baseline and to compare the differences in changes from baseline to 4 weeks between the 2 study groups.ResultsGroup D and group P were similar with respect to their fasting plasma glucose and serum insulin concentrations, post-OGTT plasma glucose and serum insulin levels, and hemoglobin A1c and fructosamine values at baseline. Serum 25-hydroxyvitamin D levels increased significantly in group D at 4 weeks. No significant differences were found between the groups at baseline and 4 weeks with respect to serum fructosamine, fasting plasma glucose and serum insulin, post-OGTT plasma glucose and serum insulin levels, and homeostasis model assessment of insulin resistance.ConclusionIn this study, short-term improvement in vitamin D status was not associated with improvement in glucose tolerance, insulin secretion, or insulin sensitivity in Asian Indian patients with moderately controlled T2DM.(Endocr Pract. 2010;16:600-608)     

An Outpatient-Based Clinical Program for Type 2 Diabetes Prevention

ObjectiveTo review first-year results of a clinic-based type 2 diabetes prevention program.MethodsFrom January through December 2007, patients with a diagnosis of prediabetes participated in the Diet-Exercise-Activity-Lifestyle program for instruction in lifestyle changes. Physical therapy assessments were retospectively reviewed to search for symptoms or findings of physical impairments. Changes in weight and 2-hour glucose tolerance test results were assessed at 6 months. Patient satisfaction with the program was evaluated.ResultsNinety-two patients qualified for the program. Mean baseline fasting glucose concentration was 108 mg/dL, and 2-hour glucose concentration was 134 mg/dL. Mean age was 62 years, and 66% were women. Review of physical therapy assessments demonstrated gait/balance disturbances in 47% of patients, peripheral neuropathy in 43%, and musculoskeletal problems in 63%. Among 47 patients who had 6-month follow-up visits, 72% lost weight. Fasting glucose levels improved in 58% in persons with impaired fasting glucose, and 2-hour glucose values decreased in patients who had impaired glucose tolerance. Seventy-eight percent graded the program as either “very good” or “excellent.”ConclusionsPrograms geared toward type 2 diabetes prevention can be feasibly implemented on an outpatient basis. Preliminary data suggest that improvements in weight and glucose values can be achieved. As the prevalence of prediabetes increases, health care systems must gain further experience with effective outpatient diabetes prevention strategies. (Endocr Pract 2010;16:21-29)