Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease

AIM： To explore the association between hepatocellular carcinoma （HCC） and type 2 diabetes mellitus, describe the temporal relations between the onset of diabetes and the development of HCC and evaluate the possible effects of antidiabetic therapy on HCC risk,METHODS： We recruited 465 HCC patients, 618 with cirrhosis and 490 control subjects. We evaluated the odds ratio （OR） for HCC by univariate and multivariate analysis. Moreover, OR for HCC in diabetic subjects treated with insulin or sulphanylureas and with metformin were calculated.RESULTS： The prevalence of diabetes mellitus was 31.2% in HCC, 233% in cirrhotic patients and 12.7% in the Control group. By univariate and multivariate analysis, the OR for HCC in diabetic patients were respectively 3.12 （CI 2.2-4.4, P 〈 0.001） and 2.2 （CI 1.2-4.4, P = 0.01）. In 84.9% of cases, type 2 diabetes mellitus was present before the diagnosis of HCC. Moreover, we report an OR for HCC of 2.99 （CI 1.34-6.65, P = 0.007） in diabetic patients treated with insulin or sulphanylureas, and an OR of 0.33 （CI 0.1-0.7, P = 0.006） in diabetic patients treated with metformin.CONCLUSION： Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes meUitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.     

胰岛素治疗对血清中胰岛素样生长因子I水平的影响

To explore the effect of insulin therapy on serum level of insulin-like growth factor-I(IGF-I)in patients with type 2 diabetes mellitus.The results showed that serum IGF-I level increased[(126.70±51.91 vs 90.04±43.68)μg/L,P<0.01]and was positively correlated with insulin level in patients with type 2 diabetes mellitus after exogenous insulin therapy(r=0.298,P<0.05).     

胰岛素治疗对血清中胰岛素样生长因子I水平的影响

To explore the effect of insulin therapy on serum level of insulin-like growth factor-I(IGF-I)in patients with type 2 diabetes mellitus.The results showed that serum IGF-I level increased[(126.70±51.91 vs 90.04±43.68)μg/L,P<0.01]and was positively correlated with insulin level in patients with type 2 diabetes mellitus after exogenous insulin therapy(r=0.298,P<0.05).     

Comparison of acarbose and metformin as add-on therapy to insulin in uncontrolled patients with type 2 diabetes mellitus: A randomized,openlabeled,and parallel group study

正Objective To evaluate efficacy and safety of acarbose compared with metformin as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled with insulin. Methods This was a randomized,open-labeled,and parallel group study. Ninety-one type2 diabetic patients (Hb A_(1C)7. 5%-11. 0%) who were     

Application of glucosidorum tripterygii tororum as an immune intervention therapy in patients with type 1 diabetes mellitus

Objective To observe the effectiveness of glucosidorum tripterygii tororum (GTT) as an immune intervention therapy in patients with type 1 diabetes mellitus. Methods Under basic treatment with insulin, 46 patients with type 1 diabetes were randomly divided into the treatment group, in which GTT was given 10 mg thrice daily for 6-months, and the control group, 23 cases in each     

Glycemic Control for Patients With Acute Myocardial Infarction

The risk of myocardial infarction increases in patients with diabetes mellitus. The incidence of myocardial infarction is similar in patients with type 2 diabetes without history of myocardial infarction and in non-diabetic patients with history of myocardial infarction. Diabetes mellitus was considered as a coronary disease equivalent by the National Cholesterol Education Program. Strict glycemic control can improve the long-term outcome of both type 1 and type 2 diabetes mellitus. Whatever with diabetic or non-diabetic, strict glycemic control with intensive insulin therapy can reduce the mortality of critically ill patients in hospital. After myocardial infarction,     

十例永久性新生儿糖尿病的分子遗传学诊断及个体化治疗

目的明确永久性新生儿糖尿病患者的分子遗传学诊断,并评价个体化治疗的效果。方法对北京协和医院2007年8月至2012年8月收治的1岁内起病的10例永久性新生儿糖尿病患者,用聚合酶链反应（PCR）直接测序法对编码胰岛p细胞ATP敏感性钾通道（K_ATP）的Kit6．2亚单位和SUR1亚单位的KCNJ11和ABCC8基因进行检测,以明确分子遗传学诊断;对于由编码KATP通道基因突变导致的永久性新生儿糖尿病患者,由皮下胰岛素注射治疗转换为口服格列苯脲治疗并观察疗效。结果10例永久性新生儿糖尿病患儿中,发现KCNJ11突变3例,均为已知基因突变;ABCC8突变4例,2例为已知基因突变,另外2例的突变位点尚无文献报道。对于已明确是由编码K_ATP通道基因突变致病的7例患儿,由皮下胰岛素注射治疗转换为口服格列苯脲治疗;共4例转换成功,包括3例KCNJ11突变和1例ABCC8突变患儿,格列苯脲的平均剂量为0．18mg·kg-1·d-1,成功者接受治疗转换时的病程相对较短（2．0—3．6年）。治疗转换成功的患者血糖控制均良好,且未出现低血糖等副作用。结论编码胰岛p细胞K椰通道的Kir6．2亚单位和SUR1亚单位的KCNJ11和ABCC8基因突变是我国永久性新生儿糖尿病患者常见致病原因,口服磺脲类药物的个体化治疗方案在此类患者中常具有较好疗效和安全性。     

Endocrinology

6.1 Diabetes mellitus 2007165 Evaluation of the first-phase insulin release and insulin sensitivity in patients with newly-diagnosed type 2 diabetes. JIA Weiping(贾伟平), et al. Dept Endocrinol & Metab, 6th People′s Hosp, Shanghai Jiaotong Univ, Shanghai 200233. Chin J Endocrinol Metab 2007;23(2):100-103. Objective To evaluate the first-phase insulin release and insulin sensitivity in patients with newly-diagnosed type 2 diabetes. Methods A total of 332 patients with newly-diagnosed type 2 diabetes were classified into two groups of normal or abnormal islet function according to arginine stimulation test, and their results were evaluated. Results(1)Body weight, body mass index (BMI), waist circumference, hip circumference, femoral circumference, fasting serum true insulin and triglyceride in normal islet function group were significantly higher than those in abnormal group (all P<0.01). (2) After adjusting gender, age, BMI and waist to hip ratio, increment of true insulin (△TI) and insulin resistant index (HOMA-IR) in normal group were significantly higher than those in abnormal group (both P<0.01). (3)The proportion of patients of normal insulin releasing function with insulin resistance, patients of normal insulin releasing function without insulin resistance, patients of impaired insulin releasing function with insulin resistance and patients of impaired insulin releasing function without insulin resistance were 35.11%, 5.02%, 29.78% and 30.09%, respectively. Conclusion The patients with type 2 diabetes could be divided into three categories being simple islet function abnormality, simple insulin resistance and islet function abnormality combined with insulin resistance. Both diagnosis and therapy project should be based on such pathophysiological assessment.     

Evaluation of first phase insulin secretion by a nateglinide-intravenous glucose insulin release test in newly diagnosed type 2 diabetics

Objective To evaluate the function of the first phase of insulin secretion of pancreatic B cells in newly diagnosed type 2 diabetics using nateglinide-intravenous glucose insulin release test (NG-IVGIRT). Methods NG-IVGIRT and intravenous glucose insulin release test (IVGIRT) were done in 8 patients with newly diagnosed type 2 diabetes mellitus and NG-IVGIRT was done in 8 normal people. Insulin and glucose of blood were deter-     

胰岛素治疗对血清中胰岛素样生长因子I水平的影响

探讨胰岛素治疗对2型糖尿病患者血清中胰岛素样生长因子I(IGF-I)水平的影响以及两者之间的关系.结果 发现2型糖尿病患者外源性胰岛素治疗可增加血清中的IGF-I水平[(126.70±51.91对90.04±43.68)μg/L,P<0.01],并且IGF-I水平与胰岛素水平呈正相关(r=0.298,P<0.05).

Abstract：

To explore the effect of insulin therapy on serum level of insulin-like growth factor-I(IGF-I)in patients with type 2 diabetes mellitus.The results showed that serum IGF-I level increased[(126.70±51.91 vs 90.04±43.68)μg/L,P<0.01]and was positively correlated with insulin level in patients with type 2 diabetes mellitus after exogenous insulin therapy(r=0.298,P<0.05).     

Neonatal hyperglycaemia and abnormal development of the pancreas

Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions occurring in around 1 per 300,000 live births. In TNDM, growth-retarded infants develop diabetes in the first few weeks of life, only to go into remission after a few months with possible relapse to permanent diabetes usually around adolescence or in adulthood. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. The very recently elucidated mutations in KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunits of the pancreatic K(ATP) channel involved in regulation of insulin secretion, account for a third to a half of the PNDM cases. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provides a tool for distinguishing transient from permanent neonatal diabetes mellitus in the neonatal period. Some patients (those with mutations in KCNJ11 and ABCC8) may be transferred from insulin therapy to sulphonylureas.     

Glyburide or insulin for metabolic control in non-insulin-dependent diabetes mellitus. A randomized, double-blind study

STUDY OBJECTIVE: To compare the relative efficacy, risks, and benefits of insulin with glyburide in achieving normoglycemia in non-insulin-dependent diabetes mellitus. DESIGN: Randomized, double-blind, placebo-controlled trial with a 9-month treatment period. SETTING: University hospital. PATIENTS: Thirty-one patients with non-insulin-dependent diabetes mellitus who did not have normal glucose control with diet alone. INTERVENTIONS: Once-per-day NPH insulin and placebo glyburide, or glyburide and once-per-day placebo insulin injection. Active drug and placebo adjusted in parallel to achieve fasting plasma glucose level less than 6.4 mmol/L (115 mg/dL) without hypoglycemia. MEASUREMENTS and MAIN RESULTS: Insulin and glyburide produced similar improvement in fasting blood glucose levels and hemoglobin A1c concentrations, similar frequencies of mild symptomatic hypoglycemia, and similar weight gain despite dietary reinforcement. Triglyceride and cholesterol levels decreased and high-density lipoprotein cholesterol and ratios of high-density lipoprotein to total cholesterol increased in both groups, with a significantly greater improvement in high-density lipoprotein cholesterol and ratio of high-density lipoprotein total cholesterol in patients treated with insulin. CONCLUSIONS: Therapy with glyburide or once-per-day NPH insulin provides a similar degree of glucose control in patients with non-insulin-dependent diabetes mellitus. Insulin may have a relative advantage in that it is associated with higher levels of high-density lipoprotein cholesterol and a higher ratio of high-density lipoprotein to total cholesterol.     

Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus

BACKGROUND: Long-term studies on the comparative efficacy and relative potency of glipizide and glyburide are sparse and controversial. METHODS: In a randomized prospective trial, we compared the effectiveness and relative potency of glipizide and glyburide over a 15-month period in 18 patients with type 2 diabetes mellitus (DM2) (9 on glyburide and 9 on glipizide) who were unresponsive to diet therapy. Glycemic control was assessed using 4 methods: 1) quarterly fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose after a standard breakfast; 2) insulin and glucose response to Sustacal (test meal) challenge every 3 to 6 months; 3) quarterly hemoglobin A1c; and 4) intravenous glucose tolerance testing every 6 months to measure first and second phase insulin secretion. Patient characteristics were similar in each treatment group. RESULTS: Similar doses of glipizide (11 mg/day) or glyburide (10 mg/day) resulted in comparable reduction of FPG and hemoglobin A1c and increase in first phase insulin response to intravenous glucose tolerance testing. There was greater reduction in FPG and 2-hour postprandial plasma glucose with glipizide than with glyburide in 6 months. Contrary to the Physicians' Desk Reference, but consistent with another short-term study, our long-term study demonstrated that glipizide and glyburide are equipotent at similar doses in controlling hyperglycemia in DM2. CONCLUSIONS: Glipizide and glyburide are effective in controlling hyperglycemia with similar doses in DM2. Glipizide exhibits greater reduction in FPG and 2PPG at 6 months. Additional studies are needed to validate equipotency of these drugs.     

Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births

Until early 2000, permanent and transient neonatal diabetes mellitus (NDM), defined as diabetes with onset within 6?weeks from birth that requires insulin therapy for at least 2?weeks, were considered exceedingly rare conditions, with a global incidence of 1:500,000-1:400,000 live births. The new definition of NDM recently adopted, that includes patients with diabetes onset within 6?months of age, has prompted studies that have set the incidence of the permanent form alone between 1:210,000 and 1:260,000 live births. Aim of the present work was to ascertain the incidence of NDM (i.e. permanent?+?transient form) in Italy for years 2005-2010. Patients referred to the Italian reference laboratory for NDM between years 2005 and 2010 and screened for mutations in common NDM genes (KCNJ11, ABCC8, and INS) and for uniparental isodisomy of chromosome 6 (UDP6) were reviewed. A questionnaire aimed at identifying NDM cases investigated in other laboratories was sent to 54 Italian reference centers for pediatric diabetes. Twenty-seven patients with NDM born between 2005 and 2010 were referred to the reference laboratory. In this group, a mutation of either KCNJ11, ABCC8 or INS was found in 18 patients, and a case with UDP6 was identified. Questionnaires revealed 4 additional cases with transient neonatal diabetes due to UDP6. Incidence of NDM was calculated at 1:90,000 (CI: 1:63,000-1:132,000) live births. Thus, with the definition currently in use, about 6 new cases with NDM are expected to be born in Italy each year.     

Is There a Role for Oral Antihyperglycemics in Gestational Diabetes and Type 2 Diabetes during Pregnancy?

Diabetes mellitus is a heterogeneous disorder of glucose intolerance that is generally classified into the following categories: type 1 and type 2 diabetes and gestational diabetes (GDM). Currently, the number of pregnancies complicated by type 2 diabetes and GDM exceed those affected by type 1 diabetes. Numerous studies have established a direct relationship between maternal glycemic control and neonatal outcomes for all types of diabetes. Therefore, modern treatment protocols during pregnancy emphasize strict glycemic control by a combination of diet and medication. Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Since GDM and type 2 diabetes are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral antihyperglycemic agents that target these defects is of potential interest. However, because of concerns regarding transplacental passage and, therefore, the possibility of fetal teratogenesis and prolonged neonatal hypoglycemia, these agents are not currently recommended in pregnancy. There are no randomized controlled trials on which to draw conclusions regarding the teratogenicity of these oral agents. However, most retrospective studies and the published clinical experience have not demonstrated an increased risk of malformed infants among women treated with oral antihyperglycemic agents. Rather, the data indicate that the increased risk for major congenital anomalies appears to be related to maternal glycemic control prior to and during conception. These studies and currently available data on the use of both metformin and sulfonylureas in pregnancy have also failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities. To date, there has only been one randomized controlled trial to test the effectiveness and safety of sulfonylurea therapy (glyburide [glibenclamide]) in the management of women with GDM. Both the insulin- and glyburide-treated women were able to achieve satisfactory glucose control and had similar perinatal outcomes. Glyburide was not detected in the cord serum of any infant in the glyburide group. In summary, based on the currently available data, it appears that glyburide could be safely and effectively utilized in the management of GDM. However, more intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary. It is important to emphasize that it is the level of metabolic control achieved and not the mode of therapy that is crucial to improving outcomes in these pregnancies.     

Beneficial effects of a glyburide/metformin combination preparation in type 2 diabetes mellitus

BACKGROUND: Type 2 diabetes mellitus is characterized by both insulin deficiency and insulin resistance. Effective treatment often requires therapy directed at both abnormalities. Patients on monotherapy might benefit from a combination agent such as glyburide/metformin, which increases insulin secretion and reduces insulin resistance. METHODS: All patients taking a glyburide/metformin preparation at the Carl T. Hayden VAMC were identified from pharmacy records. Patients with documented hemoglobin A values within 31 weeks prior and between 3 and 33 weeks after initiation of therapy (92 subjects) were examined. RESULTS: Glyburide/metformin combination therapy reduced hemoglobin A levels from 0.087 to 0.083 (P < 0.06). Significant reductions were seen in those patients with initial levels higher than 0.08 (0.094 to 0.087; P < 0.01). No significant reductions were seen in those patients with initial levels lower than 0.08. CONCLUSIONS: In patients on monotherapy or on dual oral therapy with inadequate control, changing to a glyburide/metformin combination preparation may improve glucose control.     

Management of diabetes mellitus in infants

Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older children regarding its causes, clinical characteristics, treatment options and needs in terms of education and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have been elucidated, including monogenic β-cell defects and chromosome 6q24 abnormalities. In patients with KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effective treatment option. Type 1 diabetes mellitus in infants is characterized by a more rapid disease onset, poorer residual β-cell function and lower rate of partial remission than in older children. Insulin therapy in infants with type 1 diabetes mellitus or other monogenic causes of diabetes mellitus is a challenge, and novel data highlight the value of continuous subcutaneous insulin infusion in this very young patient population. Infants are entirely dependent on caregivers for insulin therapy, nutrition and glucose monitoring, which emphasizes the need for appropriate education and psychosocial support of parents. To achieve optimal long-term metabolic control with low rates of acute and chronic complications, continuous and structured diabetes care should be provided by a multidisciplinary health-care team.     

Permanent neonatal diabetes mellitus: same mutation, different glycemic control with sulfonylurea therapy on long-term follow-up

Permanent neonatal diabetes mellitus (PNDM) is a rare condition presenting before six months of age. Mutations in the genes encoding the ATP-sensitive potassium (KATP) channel are the most common causes. Sulfonylurea (SU) therapy leads to dramatic improvement in diabetes control and quality of life in most patients who carry these mutations. Here, we report the long-term follow-up results of two siblings with PNDM who were treated with insulin until ABCC8 gene mutation was identified, and were successfully transferred to oral SU therapy. After 3.5 years of follow-up on SU, one patient had a very good response, while the other one had a poor response. Bad compliance to diet was thought to be the most probable reason for poor glycemic control in this patient. In conclusion, molecular genetic diagnosis in all patients with PNDM is recommended. Compliance to treatment should be an important aspect of the follow-up of these patients.     

Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case-control study

OBJECTIVES: Limited data are available on metformin therapy in gestational diabetes. The aim of the study was to compare maternal and neonatal outcomes in patients with gestational diabetes mellitus (GDM) treated with metformin with those treated with insulin, or diet alone. STUDY DESIGN AND METHODS: We conducted a retrospective study that included 45 GDM women treated with metformin, 45 women treated with insulin and 83 women with no pharmacological treatment. Subjects were matched for pre-pregnancy body mass index (BMI) and age. RESULTS: There were no differences between the metformin-treated group and the other two groups in terms of maternal outcomes (total weight gain during pregnancy or after the diagnosis of GDM, pre-pregnancy hypertension, pregnancy induced hypertension, pre-eclampsia etc.). In the diagnostic 2-hour oral glucose tolerance test, glucose values were slightly, but significantly, higher in the insulin group than in the metformin group (p < 0.003). Eighteen percent of mothers treated with metformin needed supplementary insulin therapy. No differences between the metformin-treated group and the other two groups (insulin, diet only) were observed in relation to mean birth weights, prevalence of macrosomia, or gestational weeks at delivery. The incidence of neonatal hypoglycemia was higher in the insulin group than in the metformin group (p = 0.03). There were no differences between the groups in other neonatal outcomes (small for gestational age, Apgar scores, umbilical artery pH or base excess, etc.). CONCLUSION: These retrospective data suggest that metformin is effective in controlling gestational diabetes and is not associated with a higher risk of maternal or neonatal complications compared with insulin.     

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)