Insulin Dose Requirements Research Articles

Higher dose requirements with insulin detemir in type 2 diabetes—Three cases and a review of the literature

We report on three type 2 diabetic patients whose daily basal insulin dose requirements were substantially reduced after switching from insulin detemir to insulin glargine. Meta-analysis of three randomised trials of basal insulin initiation confirmed this increased insulin detemir dose requirement in type 2 patients. Potential explanations are discussed.

Why does diabetes therapy often fails?

patients with type 2 diabetes (T2D) to determine if the mean daily dose in the real-world setting differs between these products. Methods: Patients with T2D (per ICD-9 code 250.x1 250.x3) were identified in the Verispan Electronic Data Warehouse (SDI, Plymouth Meeting, PA) from 7/1/2006 to 6/31/2007. Verispan data has an open architecture and does not include eligibility data, but filtering techniques were employed to eliminate cohort shrinkage. Insulin naive patients started on detemir (cases) were matched 1:1 to newly treated glargine patients (controls) for baseline characteristics that could influence dose requirements including gender, age (± 2 years), baseline antidiabetic therapy (by classes of oral agents, and exenatide), and comorbidities including cerebrovascular disease, renal failure, heart failure, heart disease/myocardial infarction, hypertension, neuropathy, and obesity. Patients were not prescribed any other insulin during the observation period. The average daily insulin dose in units was calculated as the number of units dispensed from the first to the second to last prescription in the observation period divided by the elapsed days from the first to last fill. A Wilcoxon rank sum test was used to identify differences in the average number of units per day between detemir and glargine. Changes in antidiabetic therapy by class and number of agents after insulin initiation were identified and compared between cases and controls using chi-squared tests. results: Of 2215 newly treated patients with T2D, 1581 (71.4%) were matched to a glargine patient. Mean age of this matched cohort was 59.4 years; 53.5% were female. Metformin (57.1%) and sulfonylureas (51.6%) were the most commonly used antidiabetic agents at baseline; 45% were on 1 or 2 non-insulin antidiabetic agents at baseline. The most common comorbidities were hypertension (57.6%) and heart disease/myocardial infarction (15.4%). The mean (median) of the average daily insulin dose was 35 (26) units per day for detemir and 32 (27) units per day for glargine; which was not significantly different (p=0.15). There were no differences in concomitant antidiabetic drug use from baseline to follow-up which could have influenced insulin dose requirements. conclusion: The mean daily insulin dose for detemir did not differ from glargine in patients with T2D matched on baseline characteristics that could influence insulin dose requirements.

Optimizing Treatment Success With an Amylin Analogue

Diabetes affects approximately 18 million adults in the United States. Diabetes increases the risk of microvascular and macrovascular complications, such as nerve neuropathy, retinopathy, nephropathy, and cardiovascular disease. Intensive diabetes management reduces the risk of complications but presents numerous challenges in clinical practice. In the natural course of type 2 diabetes beta cell function declines over time and may necessitate frequent medication adjustment. Oral antihyperglycemic medications may lose efficacy over time and may induce intolerable adverse events. Some medications for diabetes can cause weight gain, even if patients exercise and watch their food intake. Furthermore, patients with type 1 diabetes may experience frequent blood glucose fluctuations despite optimizing their use of insulin. Hypoglycemia is a common adverse effect of intensive diabetes management. Pramlintide as an adjunct to insulin therapy is useful for treating both type 1 and type 2 diabetes to improve control of postprandial glucose. To ensure maximal efficacy of pramlintide with minimal adverse events, it is extremely important that diabetes educators thoroughly understand pramlintide's mode of action, indications, appropriate patient selection, required insulin dose adjustments, and provide careful patient instruction.

Immunological Responses to Exogenous Insulin

Regardless of purity and origin, therapeutic insulins continue to be immunogenic in humans. However, severe immunological complications occur rarely, and less severe events affect a small minority of patients. Insulin autoantibodies (IAAs) may be detectable in insulin-naive individuals who have a high likelihood of developing type 1 diabetes or in patients who have had viral disorders, have been treated with various drugs, or have autoimmune disorders or paraneoplastic syndromes. This suggests that under certain circumstances, immune tolerance to insulin can be overcome. Factors that can lead to more or less susceptibility to humoral responses to exogenous insulin include the recipient's immune response genes, age, the presence of sufficient circulating autologous insulin, and the site of insulin delivery. Little proof exists, however, that the development of insulin antibodies (IAs) to exogenous insulin therapy affects integrated glucose control, insulin dose requirements, and incidence of hypoglycemia, or contributes to beta-cell failure or to long-term complications of diabetes. Studies in which pregnant women with diabetes were monitored for glycemic control argue against a connection between IAs and fetal risk. Although studies have shown increased levels of immune complexes in patients with diabetic microangiopathic complications, these immune complexes often do not contain insulin or IAs, and insulin administration does not contribute to their formation. The majority of studies have shown no relationship between IAs and diabetic angiopathic complications, including nephropathy, retinopathy, and neuropathy. With the advent of novel insulin formulations and delivery systems, such as insulin pumps and inhaled insulin, examination of these issues is increasingly relevant.

Assessing treatment satisfaction in patients treated with pramlintide as an adjunct to insulin therapy

ABSTRACTObjective: This study was designed to assess treatment satisfaction in patients using pramlintide who had not previously achieved glycemic targets with insulin therapy alone. Assessment included the association between treatment satisfaction and clinical outcomes (changes in post-prandial glucose [PPG], glycosylated hemoglobin [HbA1c], weight, and insulin requirements).Research design and methods: In this open-label study 240 participants with type 1 diabetes and 160 participants with type 2 diabetes added pramlintide to their established insulin regimen. Mealtime insulin doses were subsequently adjusted to optimize glycemic control.Main outcome measures: Seven-point glucose profiles, weight, and insulin requirements were obtained at baseline and months 1, 3, and 6; HbA1c levels were obtained at baseline and months 3 and 6. Participants completed a treatment satisfaction questionnaire (TSQ) at months 1, 3, and 6.Results: Participants rated the study treatment regimen including pramlintide significantly ( p < 0.001) superior to their pre-study regimens in terms of ‘glucose control’, ‘eating-weight control’, and ‘general benefits’ at all three TSQ administrations. Regression analysis of treatment satisfaction at 6 months revealed several independent predictors ( p < 0.05). Participants who were able to reach the maximum dosage of pramlintide per protocol, and those who experienced more reduction in PPG and insulin requirements during the study, reported higher satisfaction with glucose control and general benefits; those who lost more weight reported higher treatment satisfaction on all three TSQ measurements.Conclusions: Greater satisfaction with the study regimen was reported on all treatment satisfaction factors at all three TSQ administrations, with all advantages representing large treatment effects. Treatment satisfaction was higher for patients who experienced better clinical outcomes (decreases in weight, insulin dose requirements, and PPG levels). Study limitations include the fact this was an open-label study.

Weight gain and insulin requirement in type 2 diabetic patients during the first year after initiating insulin therapy dependent on baseline BMI

The aim of this study was to determine differences, if any, in weight gain and increased insulin requirements in insulin-treated type 2 diabetic patients with a normal and an elevated body mass index (BMI). A total of 192 patients with newly insulinized type 2 diabetes were included in the study. The patients were divided into three groups: those with BMI <26 (n = 102), BMI 26-30 (n = 50) and those with BMI >30 (n = 40). At the beginning of insulin therapy and 12 months later, we compared HbA1c, BMI and required insulin doses in each group and evaluated weight gain and the increase in insulin requirement during the observation period. Moreover, we investigated the influence of additional metformin therapy on weight gain and insulin requirement. Body weight increased in the group with normal BMI from 68.8 +/- 9.2 to 70.8 +/- 9.4 kg (+2.9%) and in the other groups from 79.0 +/- 9.3 to 81.2 +/- 8.4 (+2.8%) and from 96.2 +/- 11.2 to 99.1 +/- 16.5 kg (+3.0%) respectively. The differences between the groups were not significant. The insulin requirement increased by 22% in the normal-weighted group and by 23% in both groups with overweight. The reduction in mean HbA1c was similar in the three groups (22, 18 and 22%). Under additional metformin therapy, the increment of insulin requirement of all patients (n = 40) was significantly lower (11 vs. 26%, p < 0.01), and there was no significant difference between the groups with different BMIs. During the same period, the gain in body weight and the decrease of HbA1c were not significantly different in the patients with and without metformin independent on the BMI. The risk for weight gain and increase in insulin requirement is similar in insulin-treated type 2 diabetic patients with normal and elevated BMI. Additional metformin therapy reduces insulin requirement in patients with and without overweight.

Improvement of glycemic control after a 3–5 day insulin infusion in type 2-diabetic patients with insulin resistance can be maintained with glitazone therapy

Insulin resistance is a common problem in obese patients with type 2 diabetes. In a prospective randomized study, we investigated the improvement of metabolic control after a 3-5 day period of intravenous insulin infusion in poorly insulin-treated, overweight type 2-diabetic patients with and without additional glitazone therapy. Twenty-eight overweight patients (BMI > 28) with poorly insulin-treated type 2 diabetes (HbA1c > 8%) requiring > 80 IU insulin/day received a continuous insulin infusion for 3-5 days (initially 4-6 IU insulin/hour). Thereafter, 14 of the patients also received pioglitazone (15 mg/day). The two groups were compared for HbA1c, mean blood glucose (MBG), body weight, cholesterol, triglycerides and insulin requirement (IU/day) three months before insulin infusion, during infusion, and at three and six months after the infusion. Glycemic control was immediately improved under insulin infusion in both groups: MBG was reduced from 188 +/- 32 mg/dl at baseline to 142 +/- 28 mg/dl at the end of insulin infusion (p < 0.05). In the group receiving pioglitazone, the mean HbA1c three months after the insulin infusion was 16% lower and after six months 17% lower than baseline values (p < 0.02). Concomitantly, the required insulin dose decreased significantly by 15% after three months and 18% after six months (p < 0.02). Two patients (14%) were non-responders (< 10% reduction of required insulin dose). In the group without pioglitazone the mean HbA1c level three months after insulin infusion was 10% lower (p < 0.05) than at baseline; at six months the HbA1c value was the same as that before the infusion. The required insulin dose was 10% lower after three months and only 3% lower after six months (NS). Four patients (28%) were non-responders. Short-term insulin infusion therapy is effective in improving metabolic control and, concomitantly, in reducing insulin requirement in poorly insulin-treated type 2-diabetic patients; however, these effects are mostly limited to three months. With additional glitazone treatment after the insulin infusion, the improvement in metabolic control and the reduced insulin requirement can be maintained for more than six months.

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy

The aim of this randomized placebo-controlled study was to evaluate the safety and efficacy of pioglitazone administered alone or in combination with metformin in reducing insulin dosage requirements for improved glycaemic control in patients with type 2 diabetes previously poorly controlled with combination therapy. In this multicentre, double-blind study, 222 patients with haemoglobin A1c (HbA(1c))>8.0% at screening treated with combination therapy initially were given titrated insulin therapy (to fasting plasma glucose <140 mg/dl) and then were randomly assigned to 20-week treatment with pioglitazone or placebo in combination with insulin, with or without concurrent metformin therapy. More than 98% of patients were taking metformin prior to and during the study. Pioglitazone significantly reduced (p < 0.05) insulin dose requirements 2 weeks after treatment initiation. At study end relative to baseline, pioglitazone reduced daily insulin dosages by 12.0 units (p < 0.001), a 21.5% (12.0/55.8 units at baseline) group mean average reduction. Relative to placebo, pioglitazone reduced daily insulin dosages by 12.7 units [95% confidence interval [CI]: -17.5, -8.0], while improving mean HbA(1c) levels [adjusted mean HbA(1c) change: pioglitazone, -1.6% vs. placebo, -1.4% (not statistically different)]. Pioglitazone also significantly increased high-density lipoprotein cholesterol levels [adjusted mean difference: +4.5 (95% CI: 2.6-6.5) mg/dl], decreased triglyceride levels [-43.9 (-69.2, -18.6) mg/dl], shifted low-density lipoprotein (LDL) particle concentrations from small [pattern B, -13.6% (-17.7%, -9.5%)] to large [pattern A, +15.1% (10.8%, 19.5%)] and increased mean LDL particle size [+3.8 (2.6, 4.9) A]. More pioglitazone-treated patients experienced oedema (9.0 vs. 4.5%) and weight gain (9.1 vs. 2.7%) than placebo patients. Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.

Weight Gain and Metabolic Control in Newly Insulin-treated Patients With Type 2 Diabetes With Different Insulin Regimens

ABSTRACT OBJECTIVE Weight gain with insulin therapy is a well-known side effect of the pharmacologic management of type 2 diabetes, but appears to occur less frequently when an insulin analogue is used.The aim of the study was to determine differences in weight gain and insulin requirement in patients on different insulin therapy regimens. METHODS We retrospectively evaluated 154 patients with type 2 diabetes newly treated with insulin due to failure of secondary sulfonylurea treatment. The indication was secondary sulfonylurea failure with A1C > 7.5% (2 measurements). All patients had participated in a 5-day diabetes education program and were permitted to select their own insulin regimen from the following choices: 1) conventional insulin therapy (an insulin mix containing 25 or 30% regular insulin or insulin lispro and 70 or 75% NPH insulin injected twice daily); 2) the combination of insulin (insulin mix or NPH insulin, injected once daily) and sulfonylurea (glimepiride or gliclazide); or 3) prandial insulin therapy consisting of regular or lispro insulin as short-acting insulin 3 times daily and bedtime NPH insulin. The following parameters were compared at the start of insulin therapy and after 12 months: weight, body mass index (BMI), glycosylated hemoglobin (A1C), cholesterol, triglycerides (TG), insulin requirement and the influence of metformin on the insulin requirement. In addition, we measured basal C-peptide at the start of insulin therapy and evaluated the incidence of hypoglycemia during the observation period. RESULTS Weight gain was similar in the 3 groups: 2.6%, 2.7% and 2.5%, respectively; mean weight gain was 2.1 kg (2.6%). A1C decreased by − 2.2% (23%), -1.8% (19%) and − 1.8% (18%), respectively. The group who received the insulin and sulfonylurea combination required a much lower initial insulin dose than the other groups. The increase in the required insulin dose over 12 months was similar in the 3 groups: 8% in patients receiving insulin and sulfonylurea, 10% in those receiving the conventional insulin regimen and 8% in the group receiving prandial insulin substitution. Mean total cholesterol levels did not decrease significantly from baseline in the 3 groups (decrease: -4%, -3% and − 5%, respectively), and there were no significant difference between the groups. TG levels decreased to a similar extent: 20, 18 and 17%, respectively.The patients in each group who also took metformin experienced a 22% lower increase in their mean insulin requirement than did those who used insulin without metformin. CONCLUSION Weight gain in insulin-treated patients with type 2 diabetes was similar with different insulin regimens; the mean increase at 1 year was 2.6%. The 3 patient groups experienced similar metabolic control and similar increases in insulin requirements. The additional intake of metformin was associated with a 22% lower increase in the required insulin dose.

Intraperitoneal Alginate-Encapsulated Neonatal Porcine Islets in a Placebo-Controlled Study With 16 Diabetic Cynomolgus Primates

Background A nonhuman primate model of diabetes is valuable for assessing porcine pancreatic islet transplants that might have clinical benefits in humans. Methods Neonatal porcine islets, microencapsulated in alginate–polyornithine–alginate, were injected intraperitoneally (10,000 IEQs/kg islets) into eight adult male cynomolgus monkeys rendered diabetic with streptozotocin. Eight diabetic controls were given an equivalent dose of empty placebo capsules. All subjects received a repeat transplant 3 months after the first. Results The transplant was well tolerated and no adverse or hypoglycemic events occurred. There were two deaths from nontransplant treatment or diabetic complications unrelated to the transplants. After transplantation, the average insulin dose was reduced in the islet-treated group and increased in the control group. At 12 weeks after the first transplant there was a mean 36% (95% CI: 6% to 65%, P = .02) drop in daily insulin dose compared with the control group. After 24 weeks the difference increased to a mean of 43% (95% CI: 12% to 75%, P = .01) without significant differences in blood glucose values between the two groups. Individual responses after islet transplant varied and one monkey was weaned off insulin by 36 weeks. At terminal autopsy, organs appeared normal and there was no visible peritoneal reaction. No animal had polymerase chain reaction (PCR)-amplified signals of porcine endogenous retrovirus or exogenous virus infections in blood or tissues. Conclusion Repeated intraperitoneal transplantation of microencapsulated neonatal porcine islets is a safe procedure in diabetic primates. It was shown to result in a significant reduction in insulin dose requirement in the majority of animals studied, whereas insulin requirement increased in controls.

Effect of a Levonorgestrel Intrauterine System on Women With Type 1 Diabetes: A Randomized Trial

Women with diabetes need safe, effective contraception. Although intrauterine devices provide superior contraception, concerns remain that progestin absorbed systemically from the levonorgestrel-releasing device may impair carbohydrate metabolism. To examine the effect of the levonorgestrel-releasing intrauterine system on glucose metabolism in diabetic women. We randomly assigned 62 women with uncomplicated insulin-dependent diabetes mellitus to either a levonorgestrel-releasing or a copper T 380A intrauterine device. The primary outcome to assess glucose metabolism was glycosylated hemoglobin; fasting serum-glucose levels and daily insulin dose requirements over 12 months of observation were examined as well. Outcome data were available for 29 women using the levonorgestrel-releasing and 30 using the copper device. At 12 months, mean glycosylated levels were similar for women of the 2 groups (6.3%, standard deviation [SD] +/- 1.5 compared with 6.3%, SD +/- 1.3, respectively). The same was true for mean fasting-serum glucose levels (7.4 mM, SD +/- 4.2 compared with 7.5 mM, SD +/- 4.2) and daily insulin doses (35.1 units, SD +/- 12.8 compared with 36.4 units, SD +/- 9.0). No important differences were noted at either 6 weeks or 6 months. The levonorgestrel-releasing device had no adverse effect on glucose metabolism, even at the 6-week observation when systemic levels of levonorgestrel would have been higher than at later observations. Concern about a potential adverse effect of this contraceptive on glucose control is unwarranted, and its use in women with diabetes should be liberalized. I.

Antibody Response to Inhaled Insulin in Patients with Type 1 or Type 2 Diabetes. An Analysis of Initial Phase II and III Inhaled Insulin (Exubera) Trials and a Two-Year Extension Trial

To compare antibody responses to inhaled human insulin vs. sc human insulin and to determine whether insulin antibody binding is associated with adverse clinical consequences. Insulin antibody data from initial phase II/III trials were analyzed comparing the efficacy and safety of inhaled insulin with various agents, including sc insulin. Additionally, data from a 24-month extension of the phase III studies were examined. Data were pooled into the following three groups based on insulin treatment status at baseline: patients with type 1 diabetes, and patients with type 2 diabetes using insulin and not using insulin at baseline. Ig class analysis was also performed on randomly selected sera from type 1 patients at the end of the initial trials. In the initial trials, greater insulin antibody binding was observed in patients receiving inhaled insulin vs. sc insulin. The greatest antibody responses to inhaled insulin were observed in patients with type 1 diabetes [nonparametric comparison of medians at the end of the study, 22.0% binding (unadjusted 95% confidence interval: 19.5, 24.5)], and the lowest responses were observed in non-insulin-using patients with type 2 diabetes in which there was no difference in median values at the end of the study. There were no correlations between antibody binding and glycemic control (measured using glycosylated hemoglobin), insulin dose requirements, hypoglycemic events, or pulmonary function (measured by changes in forced expiratory volume in 1 sec and diffusion capacity of carbon monoxide). Antibody responses were IgG in type. Differences in antibody levels observed in patients with type 1 vs. type 2 diabetes were maintained over the 24-month extension trials. Peak antibody levels across all groups were generally observed after 6-12 months of insulin therapy. Inhaled insulin therapy was not associated with a greater incidence of allergy or other hypersensitivity reactions. Inhaled insulin was observed to produce a larger antibody response than sc insulin. Insulin antibody binding has not been associated with adverse clinical consequences in trials to date.

Efficacy of Glimepiride in Patients with Poorly Controlled Insulin-treated Type 2 Diabetes Mellitus

We retrospectively investigated the effects of adding glimepiride in patients with type 2 diabetes showing suboptimal control by insulin therapy. Of 63 patients with poorly controlled insulin-treated type 2 diabetes (baseline HbA1c, 8.4 +/- 0.6%), 32 were treated with insulin alone and 31 were given glimepiride in addition to insulin. HbA1c values, daily insulin dose, body weight, blood pressure, plasma lipid concentrations, and the number of hypoglycemic events were recorded at weeks 0, 12, 24, 36, 48, 60, and 72. HbA1c decreased by 1.1%, from 8.5 +/- 0.6% to 7.4 +/- 0.8% (P<0.0001) in patients treated with insulin plus glimepiride at 12 weeks, and improved glycemic control continued throughout the study. Required insulin dose was reduced significantly in patients treated with insulin plus glimepiride (from 29.4 +/- 14.5 to 22.3 +/- 12.1 units/day, P = 0.0187). Body weight increased significantly in patients treated with insulin plus glimepiride (from 57.0 +/- 8.7 to 59.5 +/- 9.2 kg, P = 0.0232). Adding glimepiride showed little effect on blood pressure, plasma total cholesterol, triglyceride, or HDL-cholesterol. Serum C peptide concentrations increased significantly in patients treated with insulin plus glimepiride (from 1.01 +/- 0.71 to 1.28 +/- 0.65 ng/ml, P = 0.0367). The number of hypoglycemic events did not differ between groups. Adding glimepiride to insulin therapy resulted in sustained improvement of glycemic control in patients with poorly controlled type 2 diabetes.

Will pulmonary insulin delivery help improve type 1 and type 2 diabetes care?

Will pulmonary insulin delivery help improve type 1 and type 2 diabetes care?

Subcutaneous Insulin Therapy in the Hospital Setting: Issues, Concerns, and Implementation

To summarize issues and recommendations regarding subcutaneous insulin therapy in various clinical settings in the hospital. The inpatient insulin regimen must be tailored to the specific clinical circumstance of the individual patient. Because nutritional intake is not necessarily provided as discrete meals in the hospital, the insulin dose requirement can be subclassified into "basal" and "nutritional" needs. In addition, the insulin requirement is generally increased in the presence of acute illness and stress. Thus, components of the insulin requirement are divided into basal, nutritional, and correction insulin. When the physician writes insulin orders, the basal and nutritional components are written as programmed or scheduled insulin, and the correction-dose insulin is written as an algorithm to supplement the scheduled insulin. Total insulin requirements may vary widely. Practical guidelines and suggestions are presented for selection of appropriate insulins, the delivery route, and the logical apportionment to programmed and correction insulin doses for hospitalized patients who are eating or not eating. Moreover, the role of bedside blood glucose monitoring in the hospital setting is discussed. Strict glycemic management in hospitalized patients has been shown to improve outcomes. Development and implementation of specific strategies for insulin delivery and improved methods for blood glucose monitoring should help to achieve target blood glucose levels safely.

Mathematical modelling approach to the treatment of insulin-dependant diabetes disease

Medical scientists have various ways of handling cases of insulin-dependent diabetes diseases of which one of the most popularly used methods is carrying out experiments on the patient. However, each time a case is presented, the need for fresh experiment to determine the treatment procedure will arise. To therefore reduce the time in experimentation as well as to save life of the patient by using accurate information of the patient's state of health, the need for mathematical model arises. A mathematical model that can be used to estimate the level of the plasma insulin and glucose levels at all times is presented. The required insulin dose to be given to the patient so as to correct the disease with the subsequent doses of glucose intake without necessarily arousing the disease again is also determined using this model. The effect of the pancreatic release of the insulin and the peripheral response of the cells to the available insulin were demonstrated. Also it was shown that the reduction in body cell usage of plasma glucose results mainly to the increase in time of clearance of glucose in the blood plasma. Equally demonstrated is the consequence of improper diagnosis of the level of severity of the disease before recommending certain dose of the insulin to be given to the patient as a corrective measure. Solutions to the modeled equations were obtained by linearising the non-linear equations and then solving analytically. (Global Journal of Pure and Applied Sciences: 2002 8(3): 339-346)

Combined metformin and insulin therapy for patients with type 2 diabetes mellitus

Objective This study was undertaken to assess the effects of combined treatment with insulin and metformin in patients with type 2 diabetes mellitus in whom dietary measures, weight control, and oral antihyperglycemic therapy had failed. Background Insulin resistance in peripheral tissues, increased hepatic gluconeogenesis, and impaired insulin secretion are the underlying factors in the development of type 2 diabetes. Metformin is a biguanide antihyperglycemic agent that increases peripheral insulin sensitivity, reduces hepatic gluconeogenesis, and decreases intestinal glucose absorption. Methods Thirty-one patients (24 women, 7 men; mean age, 61.8 years; mean body mass index [BMI], 28.0 kg/m 2) were enrolled in this randomized, double-blind, 2-way, crossover, placebo-controlled study. Patients with type 2 diabetes who were treated previously with insulin or oral hypoglycemic agents and who had a glycosylated hemoglobin (HbA 1c) level >9% or a fasting blood glucose level >8 mmol/L were included. Patients who were being treated with oral agents were switched to insulin therapy and required to maintain stable blood glucose control for 2 months prior to randomization. Patients received insulin plus either metformin 1700 mg/d or placebo for 5 months, followed by a 2-month washout period, and were then crossed over to the other treatment arm for 5 months of additional treatment (total treatment period: 12 months). Results Thirty patients completed the study; 1 patient withdrew early because of hypoglycemia. Compared with placebo, metformin produced significant reductions from overall baseline in mean daily insulin dose requirement (−8.69 units [17.2%], P < 0.001), HbA 1c level (−0.74 [9.9%], P = 0.005), serum fructosamine level (−44.40 μmol/L, P = 0.026), 24-hour blood glucose profile ( P = 0.008), and total cholesterol level (−0.42 mmol/L, P = 0.005). No treatment effects were observed on body weight, blood pressure, serum highdensity lipoprotein cholesterol levels, or serum triglyceride levels. There was no correlation between BMI and reduction in HbA 1c. No major side effects were reported. Conclusions Combination therapy with metformin and insulin improves glycemic control and reduces insulin requirements, with no major side effects, in patients with type 2 diabetes and may improve the risk profile in this patient population.

An overnight insulin infusion algorithm provides morning normoglycemia and can be used to predict insulin requirements in noninsulin-dependent diabetes mellitus.

Initial insulin requirements in noninsulin-dependent diabetes mellitus (NIDDM) are difficult to estimate because of individual variability in insulin sensitivity and secretion. We evaluated a simple, nurse-managed algorithm for overnight delivery of insulin, for its ability to provide morning near-normoglycemia and as a means to predict initial insulin requirements in NIDDM. Twenty-seven patients with poorly controlled NIDDM were studied on 30 occasions. A 12-h iv insulin infusion was begun at 2000 h, and bedside blood glucose concentrations were measured at hourly intervals. The rate of insulin infusion was adjusted according to blood glucose levels. We estimated the preprandial insulin dose requirement for the following day in 16 patients based on overnight insulin requirements to maintain normoglycemia. Preprandial insulin doses were adjusted for prevailing blood glucose concentrations. At 2000 h, the mean (+/-SEM) blood glucose concentration was 265.7 +/- 10.8; at 0300 h, it was 122.8 +/- 3.4; and at 0700 h, it was 123.8 +/- 5.1 mg/dL. On the next day, mean blood glucose levels (before and 2 h after a meal) were: breakfast, 102.5 +/- 5.9 and 177.3 +/- 19.2; lunch, 138.9 +/- 15.5 and 136.3 +/- 11.4; dinner, 105.7 +/- 7.2 and 178.1 +/- 15.7 mg/dL. There was no significant difference between mean calculated and administered total insulin dosage the next day (84.2 +/- 7.0 vs. 78.2 +/- 8.2 U). Thus, a weight-based algorithm for iv insulin infusion induced near-normoglycemia in NIDDM and successfully predicted the insulin dose requirement. We conclude that initiating insulin therapy in NIDDM patients can be achieved rapidly and efficiently based on a nurse-managed overnight insulin infusion.

Diabetes mellitus in patients with liver cirrhosis

In spite of the high prevalence of diabetes mellitus (DM) in patients with liver cirrhosis (LC) few studies have focused on the clinical implications of this association. We investigated the clinical and pancreatic-endocrine features of 34 patients who developed DM after LC (Group I). Results were compared with 34 carefully matched patients with only Type II DM (Group II). A standard meal test was performed in 26 patients with normal renal function from each group to assess β-cell function. Group I patients, less frequently had retinopathy (14.7% vs. 45.5%, P < 0.05) and a family history of diabetes (23.5% vs. 58.8%, P < 0.01). Group I patients also showed signs of enhanced insulin resistance, reflected by higher insulin dose requirements in insulin-treated patients (0.87 ± 0.10 vs. 0.62 ± 0.05 IU/kg/day, P < 0.01) and increased basal C-peptide values (0.88 ± 0.06 vs. 0.68 ± 0.07 pmol/l, P < 0.05, respectively) than those in Group II. These results suggest that several clinical features, probably related to the hepatopathy, define DM occurring in patients with LC.

Antidiabetic agents and lactation.

If the dose of insulin and adequate carbohydrate intake is ensured, most diabetic mothers taking insulin will be able to breastfeed satisfactorily. Compared to the dose before pregnancy, the required insulin dose probably will be substantially reduced during breastfeeding. The American Academy of Pediatrics recommends tolbutamide as the preferred oral hypoglycemic agent during the breastfeeding period; however, the infant should be monitored closely for signs of jaundice. The mother should be monitored using a method specific for glucose, since lacturia may interfere with nonspecific methods of urine glucose measurement. It is important to monitor for ketones in the mother because acetone is excreted in breastmilk and may adversely affect the infant's liver.