Residual effects of a short-term intensified insulin therapy in type 2 diabetic patients with oral drug failure.

The present study was designed to evaluate the long-term effects of a short course of insulin therapy on glycaemic control in type 2 diabetic patients after failure with oral therapy. Twenty type 2 diabetic patients poorly controlled with maximal doses of sulfonylurea were given intensified insulin treatment for 12-14 days adjusted so as to achieve near normoglycaemia. They were then restarted on their previous oral medication to which one bedtime injection of NPH insulin was added if the mean diurnal glucose profile exceeded 10 mM (n = 8). At the follow up evaluation (n = 18), 6 +/- 1 months later, fasting glucose (12.3 +/- 1.1 to 8.3 +/- 0.6 mM) and HbA1c (10.2 +/- 0.5 to 8.5 +/- 0.5%) levels were significantly improved in the patients receiving a combined therapy. In the group maintained on sulfonylurea alone, fasting glucose (13.2 +/- 0.7 to 6.9 +/- 0.7 mM) and HbA1c (9.6 +/- 0.6 to 6.9 +/- 0.6%) were also significantly improved in 5 patients who had lost weight (-6 +/- 1 kg) whereas none of these parameters were significantly different from the preinsulin value in the 6 patients whose weight remained unchanged. In conclusion, the current results do not provide any evidence that short-term insulin therapy is able to reinduce the efficacy of a previously ineffective sulfonylurea treatment, on a long term basis.     

Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary failure to sulfonylureas

According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for treating diabetic patients with secondary failure to sulfonylureas. From its revival in the early 1980s, combination therapy has been shown to have a positive effect on blood glucose control although initially published clinical studies, generally open and uncontrolled, have been widely criticized. Several recent well-designed studies confirmed these favorable results, with better glucose profiles and/or decreased insulin needs, which were shown to persist after 1 year or more. Most of the studies investigating the mechanism of action indicate that the effect is mainly due to stimulation of the residual insulin secretion with minimal or no effect on insulin sensitivity. The risk of hypoglycemic episodes is rather small when insulin doses are adapted at the beginning of the combined therapy. Effects on lipid metabolism are minimal and controversial. Thus, insulin-sulfonylurea treatment may be a safe and effective solution in type 2 diabetic patients with secondary failure to sulfonylureas, particularly in those with significant residual endogenous insulin secretion. The additional cost of such combined therapy should be weighed against the potential advantages of better metabolic control.     

Blood glucose control and insulin secretion improved with combined therapy in type 2 diabetic patients with secondary failure to oral hypoglycaemic agents

The influence of combined therapy using insulin and oral hypoglycaemic agents on blood glucose control and on insulin secretion in Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents was evaluated. Type 2 diabetic patients (n = 180) (98 normal-weight, 82 over-weight), at least 3 years from diagnosis, and having poor blood glucose control on oral hypoglycaemic agents for at least 3 months (fasting plasma glucose greater than 10.0 mmol l-1) despite intensive efforts at improvement, were included in the study. A single daily insulin injection (human ultralente), at a dose of 0.22 +/- 0.07 U kg-1 d-1 in normal-weight and 0.33 +/- 0.10 U kg-1 d-1 in over-weight patients, was added to the previous dietary and drug treatment for 6 months. A progressive and significant (2p less than 0.001) reduction of the mean daily blood glucose was observed during the first 3 months of combined therapy (from 13.2 +/- 3.2 to 8.1 +/- 2.1 mmol l-1 in normal-weight and from 13.4 +/- 3.1 to 8.8 +/- 2.3 mmol l-1 in over-weight patients), with no further significant changes thereafter. A significant increase (2p less than 0.001) in the mean daily C-peptide concentration (from 0.50 +/- 0.30 to 0.71 +/- 0.29 nmol l-1 in normal-weight and from 0.78 +/- 0.36 to 1.00 +/- 0.41 nmol l-1 in over-weight patients) took place during combined therapy. No changes of body weight (+ 1.5 +/- 1.2 kg in normal-weight and + 1.0 +/- 1.0 kg in over-weight patients) were observed.     

Nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas

Eighteen patients with non-insulin-dependent (type 2) diabetes mellitus of normal body weight [body mass index (BMI) <25 kg/m²] without signs of autoimmunity [negative for islet cell antibodies (ICA)], with secondary failure of sulphonylureas, defined as persistent hyperglycaemia in spite of maximal doses of sulphonylureas, were evaluated for C-peptide release under basal conditions and 6 min after i.v. glucagon, for glycosylated haemoglobin (HbA_1c), and for fasting and mean daily blood glucose levels. They entered a 6-month, single-blind study in which they were randomly assigned to one of three treatments: (1) insulin plus nicotinamide (group 1, 0.5 g, three tablets/day); (2) insulin plus placebo (group 2, 3 tablets/day); (3) current sulphonylureas plus nicotinamide (group 3, 0.5 g, three tablets/day). They were re-evaluated for C-peptide, HbA_1c, and fasting and mean daily blood glucose levels after 6 months. Compared with group 2, C-peptide release increased in both groups 1 and 3, while HbA_1c, fasting and mean daily blood glucose levels improved in the three groups to the same extent. With multiple regression analysis, nicotinamide administration was the only significant factor for the improvement of C-peptide release. These data indicate that nicotinamide improves C-peptide release in type 2 diabetic patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin. Received: 26 September 1997 / Accepted in revised form: 27 November 1997     

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).     

34例持续6年胰岛素强化治疗的2型糖尿病患者随访观察

对34例2型糖尿病患者的6年胰岛素强化治疗的观察结果显示:每年的HbA1C均值均＜7.0％,无1例发生严重低血糖事件;未见糖尿病微血管并发症的发生和进展;β细胞功能得到改善;评价患者生活质量的DQOL量表得分没有显著改变(P＞0.05).2型糖尿病患者接受长期胰岛素强化治疗可以获得良好安全长期血糖控制,对生活质量没有造成不良影响.     

Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents.

Twenty non-insulin-dependent diabetic patients on insulin therapy for more than 2 months due to secondary failure to oral hypoglycemic agents (OHA) were additionally treated with gliclazide, 80 mg b.i.d., for 1 month and 160 mg b.i.d. for a further 2 months, while reducing insulin dose gradually according to glycemic control. At the end of the first month, fasting blood glucose had decreased from 12.8 +/- 0.7 to 9 +/- 0.8 mM (mean +/- standard error; P < 0.005) and thereafter remained stable. Insulin requirements decreased from 34.2 +/- 2.5 to 18.3 +/- 3.2 U/day (P < 0.001). Three patients were able to cease insulin treatment altogether. A direct correlation was found between final insulin dose and previous duration of infusion monotherapy (r = 0.52; P < 0.05). C-peptide/glucose score (fasting C-peptide/fasting BG x 100) increased from 0.11 +/- 0.03 to 0.21 +/- 0.05 (P < 0.05). We conclude that combined therapy reduces insulin requirement by increasing endogenous secretion, which may mainly affect hepatic glucose production as indicated by greater improvement in fasting vs. post-prandial blood glucose. This therapy could avoid hyperinsulinemia, which has been reported to be involved in macrovascular complications, and the additional haemovascular properties of gliclazide could make it more effective in such a combination.     

磺脲类降糖药继发性失效的2型糖尿病患者血浆胰淀素水平

在各30例的正常对照组，2型糖尿病患者磺脲类药物治疗有效组和继发性失效组进行口服75g葡萄糖耐量试验，测定各时间点血糖，胰岛素和胰淀素水平，结果提示高糖刺激的胰淀素分泌量的增加可能与2型糖尿病的发病和碘脲类降糖药继发性失效有关。     

口服降糖药联合胰岛素治疗2型糖尿病磺酰脲类药物继发性失效的疗效

探讨316例口服降糖药联合中效胰岛素（NPH）治疗2型糖尿病磺酰脲类药物继发性失效的疗效。患者分成四组：A组为NPH＋二甲双胍（Met）＋阿卡波糖（Acar）组,B组为NPH＋Met组,C组为NPH＋Acar组,D组为NPH＋Met＋格列齐特（Glic）组,每组79例,记录治疗前后临床指标。结果显示D组控制空腹血糖最好,A组控制餐后血糖最佳。     

Characteristics of non-insulin-dependent diabetic patients with secondary failure to oral antidiabetic therapy

PURPOSE: Secondary failure to treatment with oral antidiabetic agents frequently occurs in patients with non-insulin-dependent diabetes mellitus. In the search for causes of such failures, we examined patient- and disease-related factors in nonresponders and in responders to treatment with oral antidiabetic agents. PATIENTS AND METHODS: The study population consisted of three groups: (1) 34 nonresponders to treatment with sulfonylureas; (2) 25 patients who still responded to treatment with sulfonylureas; and (3) 10 age-matched healthy control subjects. In addition to patient-related factors such as adherence to diet and knowledge of diabetes, we examined insulin response to a test meal and hepatic and peripheral insulin sensitivity during a euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3-]glucose. RESULTS: Patient-related factors such as daily nutrient intake, activity score, knowledge of diabetes, and "stress level" were similar in both groups. However, nonresponders had a higher rate of basal hepatic glucose production (4.60 +/- 0.14 versus 3.63 +/- 0.26 mg/minute/kg of lean body weight; p less than 0.001), which was less suppressed by euglycemic hyperinsulinemia (about 100 microU/mL) than was that of the responders (p less than 0.001). In addition, total insulin-stimulated glucose metabolism was reduced (5.07 +/- 0.22 versus 7.09 +/- 0.56 mg/kg.LBM.minute; p less than 0.001), and this was mainly accounted for by a reduction in non-oxidative glucose metabolism (glycogen synthesis and anaerobic glycolysis) (1.78 +/- 0.22 versus 3.54 +/- 0.49 mg/kg.LBM.minute; p less than 0.001). The severity of hepatic and peripheral insulin resistance correlated with the plasma glucose concentration but was unrelated to insulin secretion. In a multiple linear regression analysis, glucose overproduction in the liver (26.1%), impaired peripheral glucose metabolism (17.3%), and insulin deficiency (12.6%) could explain only 56% of the causes of secondary drug failure. CONCLUSION: Secondary failure to treatment with oral hypoglycemic agents is determined by the disease itself rather than by patient-related factors. Treatment of secondary drug failure should therefore aim at ameliorating both hepatic and peripheral insulin resistance.     

Exogenous insulin therapy slows weight loss in type 2 diabetic patients

The impact of exogenous insulin therapy on the ability of obese, noninsulin dependent diabetic patients to lose weight was studied. Weight loss data from seven insulin-requiring type 2 diabetic patients, 11 sulfonylurea-treated type 2 diabetic patients and 12 non-diabetic controls on very-low-calorie diets were analyzed. Upon starting the diet, insulin doses were reduced by 50 percent and given once daily as intermediate-acting insulin. Doses were adjusted to maintain capillary blood glucoses between 6.7 and 10 mM. Sulfonylureas were stopped upon initiation of the diet. Patients were seen weekly for determination of their dietary compliance, medical status, glucose control, activity level and amount of weight loss. The insulin-treated subjects lost significantly less weight per week, whether expressed as kilograms, change in body mass index or percent of initial body weight lost. Treatment of obese type 2 diabetic patients with insulin retards their ability to lose weight independent of caloric intake.     

The combination of insulin and sulphonylurea in the treatment of secondary drug failure in patients with type II diabetes

Thirteen patients (6 females and 7 males) who were secondary failures on oral drug therapy were randomly allocated to either 2 months of treatment with insulin + glibenclamide or insulin + placebo. Thereafter the treatment schedules of the two groups were switched over for another two months. The combination of insulin and glibenclamide was more effective in lowering the fasting blood glucose (P = 0.026) and 24 h urine glucose (P = 0.042) than the combination of insulin and placebo. The combination therapy with insulin and glibenclamide revealed higher basal (P = 0.021) and glucagon-stimulated C-peptide concentrations (P = 0.037) than therapy with insulin and placebo. However, insulin binding to erythrocytes did not differ between the two study periods. The results indicate that the addition of glibenclamide to insulin in type II diabetics poorly controlled by oral antidiabetics alone may slightly improve diabetic control. The mechanism of this action is due at least partly to sulphonylurea-induced stimulation of endogenous insulin secretion. The effectiveness of the combination treatment during long-term therapy still remains to be proven, however.     

The addition of glipizide to insulin therapy in type-II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of a significant residual insulin secretion

The present study aimed at 1) investigating the effect of a combined insulin + glipizide treatment on the metabolic control (HbA1c levels) and insulin requirements (Biostator assessment) in ten non-obese Type-II diabetic patients with recent secondary failure to sulfonylureas; and 2) characterizing the relative contributions of changes in endogenous insulin secretion (C-peptide response) and insulin sensitivity (insulin-induced glucose disposal in clamped conditions) to this effect. The patients were treated in a randomized cross-over order with either insulin alone or insulin + glipizide (3 X 10 mg/day) during two periods averaging 6 weeks each. Mean HbA1c levels were similar in both experimental conditions (8.2 +/- 0.6 vs 7.9 +/- 0.6%, NS). In fact, during the combined therapy, HbA1c levels decreased in five subjects (from 8.6 +/- 0.7 to 7.1 +/- 0.5%; 'responder'), but not in the five others ('non-responders'); the 20-h Biostator insulin infusion was significantly decreased in the responders (29%; P less than 0.05), but not in the non-responders. Basal (0.271 +/- 0.086 vs 0.086 +/- 0.017 nmol/l; P less than 0.05) and post-glucagon (0.468 +/- 0.121 vs 0.180 +/- 0.060 nmol/l; P less than 0.05) C-peptide plasma levels were significantly higher in the responders than in the non-responders; in addition, glipizide significantly increased basal C-peptide concentrations in the responders only (+68%; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens

Despite the development of alternative therapies in recent years, insulin injections remain essential treatment for type 2 diabetes once oral therapy alone becomes inadequate. However, neither patients nor physicians are proactive enough with regard to starting insulin, despite the well-known benefits of early insulin initiation and aggressive dose titration. Barriers to starting insulin therapy are being overcome by developments in insulin and delivery device technology and are the subject of this review. A literature search spanning the last 25 years was carried out to identify publications addressing issues of insulin initiation, how insulin analogs can help overcome barriers to initiation, and the advantages of pen-type insulin delivery systems. Seventy-five publications were identified. These references illustrate that the drawbacks associated with regular exogenous human insulins (soluble and NPH) are improved with modern insulin analogs. The more rapid absorption of prandial insulin analogs compared with human insulin eliminates the need for an injection-meal-interval, increasing convenience, while basal analogs have no discernible peak in activity. Modern insulin delivery devices also have advantages over the traditional vial and syringe. Currently available insulin pens are either durable (insulin cartridge is replaceable; e.g., HumaPen, Eli Lilly [Indianapolis, IN]; NovoPen series, Novo Nordisk [Bagsvaerd, Denmark]) or disposable (prefilled; e.g., FlexPen, Novo Nordisk; SoloSTAR, sanofi-aventis [Paris, France]), with features to aid ease-of-use. These include a large dose selector, dial-up and dial-down facility, and audible clicks when selecting the dose. The potential for dosing errors is thus reduced with pen-type devices, with other benefits including a discreet appearance, ease of learning, and greater user confidence. Collectively, these features contribute to overwhelming patient preference when compared with vials and syringes. Despite the greater cost of insulin pens relative to vials and syringes, improvements in treatment adherence with pens-and hence glycemic control-may offset these costs in the long term.     

有或无糖尿病家族史的初诊2型糖尿病患者胰岛素泵强化治疗前后早期胰岛素分泌功能的比较

目的：观察有或无糖尿病家族史的初诊2型糖尿病（T2DM）患者胰岛素泵强化治疗前后胰岛素第一时相分泌功能的变化,探讨遗传背景对早期胰岛素分泌功能的影响。方法选取2008年7月1日至2011年12月1日初诊T2DM患者158例,其中有家族史组（FH＋DM）81例,无家族史组（FH-DM）77例,分别给予胰岛素泵治疗10 d,于治疗前和停泵2 d后用左旋精氨酸（L-ARG）刺激法测胰岛素值。两组间比较采用t检验,多个变量间的分析采用多元逐步回归分析。结果（1）胰岛素分泌峰值：治疗前,FH＋DM、FH-DM组胰岛素峰值倍数分别为5.0±2.5、5.2±2.5。强化治疗后,胰岛素峰值倍数分别增加了14.3％和16.1％。（2）胰岛素净分泌量：治疗前FH＋DM组2 min胰岛素值和胰岛素第一时相净分泌量均明显低于FH-DM组。治疗后,两组胰岛素第一时相净分泌量分别为20.41 mU/L、22.39 mU/L（ P＜0.05）;2组胰岛素第一时相净分泌量均较治疗前降低,分别降低了18.4％和20％。（3）稳态模型胰岛素抵抗指数：FH＋DM组与FH-DM组患者治疗10 d后比治疗前降低（分别为4.26比2.02和5.14比2.15,均P＜0.05）。结论胰岛素泵强化治疗对无家族史的初诊T2DM患者胰岛第一时相分泌功能改善作用更明显。     

Clinical expression and insulin sensitivity in type 2 diabetic patients with heterozygous mutations for haemochromatosis

BACKGROUND: Elevated iron metabolism indices as well as liver enzymes abnormalities have been reported in type 2 diabetic patients. The aim of this study was to determine the clinical and biological characteristics of overweight or obese type 2 diabetic subjects, with and without heterozygosity for HFE gene mutation (C282Y or H63D). We also assessed their insulin sensitivity and B cell function. METHODS: 90 patients (age and diabetes duration: 61 +/- 11 and 12 +/- 8 years [mean +/- 1 SD]) were included. BMI was 32 +/- 6 kg/m(2). HbA(1c) was 8.9 +/- 1.8%. HFE genotyping was performed by PCR and restriction enzyme cleavage. Insulin sensitivity and B cell function were measured by the Homeostasis Model Assessment (HOMA). RESULTS: Heterozygosity for C282Y (wt/C282Y) or H63D (wt/H63D) allele was found in 11 and 12 subjects respectively. There were no major differences in clinical status and iron parameters according to the single allelic presence of C282Y or H63D. However, systolic blood pressure [BP] was lower when such mutation was present. Insulin sensitivity and B cell function (HOMA) were comparable. When the cohort was divided according to gender, we found higher serum iron in females with than in those without HFE mutation (91 +/- 27 vs 73 +/- 25 microgram/dl;P=0.049), while a transferrin saturation index above 45% was observed in 36% of females with a mutation (vs 7% in wt/wt;P=0.06). When analysis was performed according to the presence of each particular mutation, we observed a transferrin saturation index higher than 45% in 60% of wt/C282Y patients vs 21% in the wt/wt group (P=0.008). A significantly lower BP was also identified in wt/C282Y patients. Cholesterol-HDL was 38 +/- 11 vs 46 +/- 12 mg/dl in wt/C282Y and wt/wt subjects, respectively (P=0.045). There were no differences in iron status, BP or lipids between wt/wt and wt/H63D subjects. CONCLUSION: Type 2 diabetic patients, in particular females, with mono-allelic C282Y mutation, had slightly increased iron parameters. Systolic BP and cholesterol-HDL were also lower in wt/C282Y subjects. No difference in insulin sensitivity or B cell function was observed in the presence of mono-allelic HFE mutations.     

Cellular and humoural autoimmunity markers in Type 2 (non-insulin-dependent) diabetic patients with secondary drug failure

Summary In some cases patients with Type 2 (non-insulin-dependent) diabetes mellitus fail to respond to treatment with oral hypoglycaemic agents. These patients may respond in the same way as Type 1 (insulin-dependent) diabetic patients. Cellular immune aggression (defined as the capacity of peripheral mononuclear cells to inhibit stimulated insulin secretion by dispersed rat islet cells), insulin autoantibodies, C-peptide response and HLA antigens were determined in 31 Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents and in 22 control subjects. Nine (29.03%) of the 31 Type 2 diabetic patients showed positive cellular immune aggression (2 SD below control group) and 22 (70.97%) presented no cellular immune aggression. There was a relationship between positive cellular immune aggression and each of the following parameters: age, body mass index and microangiopathy. No correlation was found between positive cellular immune aggression and glycaemia, HbA₁, blood lipids or atherosclerosis. Patients with positive cellular immune aggression showed a significantly lower glucagon-stimulated C-peptide response vs those with no cellular immune aggression. Within a sub-group of patients who had never been treated with insulin, insulin autoantibodies were present in four of six patients with positive cellular immune aggression. DR2 antigen was found with decreased frequency in patients whereas no DR3/DR4 heterozygotes were observed. Our data support the hypothesis that a group of Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents presented autoimmunity towards pancreatic Beta cells.