A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. Danish Study Group of Diabetes in Childhood

The study aimed to identify risk markers (present at the start of the study in 1989) for the occurrence and progression of microvascular complications 6 years later (in 1995) in a Danish nationwide cohort of children and adolescents with Type 1 diabetes (average age at entry 13.7 years). Probabilities for the development of elevated albumin excretion rate (AER), retinopathy, and increased vibration perception threshold (VPT) could then be estimated from a stepwise logistic regression model. A total of 339 patients (47% of the original cohort) were studied. Sex, age, diabetes duration, insulin regimen and dose, height, weight, HbA_1c, blood pressure, and AER were recorded. In addition, information on retinopathy, neuropathy (VPT), and anti-hypertensive treatment was obtained at the end of the study. HbA_1c (normal range 4.3–5.8, mean 5.3%) and AER (upper normal limit <20 μg min⁻¹) in two, timed overnight urine collections were analysed centrally. Eye examination was performed by two-field fundus photography. Determination of VPT was assessed by biothesiometry. Increased AER (≥20 μg min⁻¹) was found in 12.8% of the patients in 1995, and risk markers for this were increased AER and high HbA_1c, in 1989 (both p<0.001). Retinopathy was present in 57.8% of patients in 1995, for which the risk markers were long duration of diabetes (p<0.0001), age (p<0.01), and high HbA_1c (p<0.0001) in 1989. Elevated VPT (>6.5 V) was found in 62.5% of patients in 1995, for which the risk markers were male sex (p<0.05), age (p<0.0001), and increased AER (p<0.05) in 1989. This study confirms that hyperglycaemia plays a major role for the development of microvascular complications in kidneys and eyes, and emphasises the need for optimal glycaemic control in children and adolescents with Type 1 diabetes.     

The impact of metabolic and blood pressure control on incidence and progression of nephropathy: A 10-year study of 385 type 2 diabetic patients

The aim of the present study was to find clinical parameters affecting incidence and progression of nephropathy in type 2 diabetic patients. A prospective study for 10 years was performed in 385 type 2 diabetic patients (diabetes diagnosis ≥30 years) attending a hospital-based outpatient clinic. Medical risk indicators like diabetes duration, HbA_1c, and blood pressure were related to the development and progression of diabetic nephropathy. The 10-year incidence of microalbuminuria was 38% (n=95) and that of macroalbuminuria was 10% (n=26). Out of 103 patients with microalbuminuria, 38 developed macroalbuminuria. In 252 normoalbuminuric patients, the mean of the HbA_1c (P<.05) levels obtained during the study were associated with a doubling of the fractional albumin clearance. In contrast, blood pressure levels, age, diabetes duration, type of diabetes treatment, BMI, and gender were not (Cox regression analysis). Among 133 patients with micro- or macroalbuminuria, 22 more than doubled their serum creatinine level, in contrast to only 6 of 252 patients without. With Cox regression analysis, systolic (P<.01), but not diastolic, blood pressure or HbA_1c levels or the abovementioned risk factors were associated with a doubling in serum creatinine. A total of 19 patients developed uremia during the study, out of whom 6 were in need of dialysis and 1 has had a renal transplantation, and 14 (74%) died. HbA_1c (P<.05) and systolic blood pressure (P<.001) levels were associated with development of uremia, but not diastolic blood pressure or the other parameters mentioned above. This study shows that poor metabolic control is associated with development and high blood pressure with progression of nephropathy in type 2 diabetic patients.     

A comparison of insulin lispro and buffered regular human insulin administered via continuous subcutaneous insulin infusion pump

This study compared glycemic control achieved with insulin lispro or buffered regular human insulin in patients with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) using an external insulin pump. In this 24-week multicenter, randomized, two-way crossover, open-label trial, 58 patients on CSII with adequate glycemic control received either insulin lispro or buffered regular human insulin for 12 weeks, followed by the alternate treatment for another 12 weeks. Efficacy and safety measures included hemoglobin A_1c (HbA_1c) at baseline and endpoint, home blood glucose monitoring, hypoglycemia, and frequency of pump catheter occlusion. Patients consumed a standard test meal on three occasions, with determinations of fasting, 1- and 2-h postprandial glucose values. Insulin lispro use was associated with a significantly lower HbA_1c than was buffered regular human insulin (7.41±0.97 vs. 7.65±0.85 mmol/l; P=.004). Fasting serum glucose values before the test meal were similar between the two therapies. The 1-h (11.16±4.29 vs. 13.20±4.68 mmol/l; P=.012) and 2-h (9.64±4.10 vs. 12.53±4.64 mmol/l; P=.001) postprandial glucose concentrations were significantly lower during treatment with insulin lispro. No differences between treatments were observed in basal or bolus insulin doses, weight gain, or the incidence and rate of hypoglycemia, hyperglycemia, or pump occlusions. When used in external pumps, insulin lispro provides better glycemic control than buffered regular human insulin with a similar adverse event profile.     

Diabetic retinopathy, visual acuity, and medical risk indicators. A continuous 10-year follow-up study in Type 1 diabetic patients under routine care

The objective of this study was to describe incidence and progression of diabetic retinopathy in relation to medical risk indicators as well as visual acuity outcome after a continuous follow-up period of 10 years in a Type 1 diabetic population treated under routine care. The incidence and progression of retinopathy and their association to HbA_1c, blood pressure, urinary albumin, serum creatinine levels, and insulin dosage were studied prospectively in 452 Type 1 diabetic patients. The degree of retinopathy was classified as no retinopathy, background, or sight-threatening retinopathy, i.e. clinically significant macular edema, severe nonproliferative, or proliferative retinopathy. Impaired visual acuity was defined as a visual acuity <0.5 and blindness as a visual acuity ≤0.1 in the best eye. In patients still alive at follow-up (n=344), 61% (69/114) developed any retinopathy, 45% (51/114) background retinopathy, and 16% (18/114) sight-threatening retinopathy. Progression from background to sight-threatening retinopathy occurred in 56% (73/131). In 2% (6/335), visual acuity dropped to <0.5 and in less than 1% (3/340) to ≤0.1. Patients who developed any retinopathy and patients who progressed to sight-threatening retinopathy had higher mean HbA_1c levels over time compared to those who remained stable (P<.001 in both cases). Patients who developed any retinopathy had higher levels of mean diastolic blood pressure (P=.036), whereas no differences were seen in systolic blood pressure levels between the groups. Cox regression analysis, including all patients, showed mean HbA_1c to be an independent risk indicator for both development and progression of retinopathy, whereas mean diastolic blood pressure was only a risk indicator for the incidence of retinopathy. Metabolic control is an important risk indicator for both development and progression of retinopathy, whereas diastolic blood pressure is important for the development of retinopathy in Type 1 diabetes. The number of patients who became blind during 10 years of follow-up was low.     

Insulin lispro is as effective as regular insulin in optimising metabolic control and preserving beta-cell function at onset of type 1 diabetes mellitus

The aim of the study was to examine the effects of intensive insulin therapy using lispro on metabolic control, immunogenicity and β-cell function of newly diagnosed type 1 diabetic subjects in comparison with intensive insulin therapy using regular insulin. An open study was conducted in 45 newly diagnosed type 1 diabetic subjects. Patients were randomly assigned to intensive insulin therapy using insulin lispro (lispro) (lispro, n=22; 22.8 years) or intensive insulin therapy using regular insulin (regular) (regular, n=23; 24.4 years): three to five injections of subcutaneous rapid-acting insulin before meals and Neutral Protamine Hagedorn (NPH) before dinner/bed-time. GAD, IA2, insulin antibodies, basal and stimulated plasma C-peptide and HbA_1c were measured initially and at months 1, 4, 8 and 12. Daily blood glucose profiles tended to be lower in the lispro group, particularly values after breakfast, without reaching statistical significance. There were no differences in terms of HbA_1c throughout the study. The proportion of subjects achieving an HbA_1c<6% at the end of the study was similar in both groups (regular 73.9%, lispro 68.0%). The number of mild hypoglycemic episodes tended to be lower with lispro, but not significantly. β-Cell function was not significantly different in both groups. During follow-up there were no differences in antibodies, including IAAb. In summary, insulin lispro used in intensive insulin therapy is as effective as regular insulin in optimizing metabolic control and preserving β-cell function at diagnosis of type 1 diabetes.     

Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin

Transitioning safely to insulin therapy when oral antidiabetic agents fail to provide adequate glycemic control is a critical aspect of care for the patient with type 2 diabetes mellitus (T2DM). We evaluated the clinical effectiveness of starting patients on a relatively simple regimen of once-daily injections of either biphasic insulin aspart 70/30 (10 min before dinner), NPH insulin (at 10 p.m.), or biphasic human insulin 70/30 (30 min before dinner) in combination with metformin. Enrolled patients had T2DM and inadequate glycemic control (AlC≥7.5%) on a previous regimen of metformin as monotherapy or in combination with a sulphonylurea. One hundred and forty (140) patients received metformin monotherapy for 4 weeks followed by 12 weeks of combination treatment with metformin and once-daily insulin injections. AlC levels decreased from baseline by 1.1–1.3% for patients in each of the three treatment groups. Overall, FPG values decreased from baseline by 31% (biphasic insulin aspart), 37% (NPH insulin), and 28% (biphasic human insulin). Subjects whose final FPG level was <126 mg/dl experienced the largest decreases in AlC values (−2.3%, −1.9%, −1.8%, respectively). All three treatment regimens were well tolerated. The results indicate that patients with T2DM can safely and effectively begin insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin.     

The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM)

To determine whether a difference in HbA_1c could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA_1c levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.

A prospective trial was conducted in five medical centers in 153 men of 60 ± 6 years of age who had a known diagnosis of diabetes for 7.8 ± 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10).

An average HbA_1c separation of 2.07% was achieved with INT, having HbA_1c at or below 7.3% (p = 0.001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0.008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms.

Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.     

Comparison of efficacy, secondary failure rate, and complications of sulfonylureas

The data from three clinical trials are presented, comparing the efficacy of different sulfonylureas in the treatment of type II diabetes. In a multicenter study, gliclazide^* improved control in 49% of patients who had failed on other drugs. When five groups of type II diabetic patients were treated concurrently with five randomly allocated different sulfonylureas over 1 year, the percentage of patients achieving normal HbA₁ levels was best with gliclazide (80%) and glibenclamide (74%), when compared with chlorpropamide (17%), glipizide (40%), and gliquidone (40%). Secondary failure rate over 5 years was assessed in 248 type II diabetic patients randomly allocated to three different sulfonylureas and found to be lowest with gliclazide (7%) compared with glibenclamide (17.9%): p < 0.1 and glipizide (25.6%: p < 0.005. The incidence of hypoglycemia was significantly higher with glibenclamide than with gliclazide (p < 0.05. The differences in efficacy and secondary failure rate between sulfonylureas may be related to the mechanism of insulin release from the β-cell and the more physiological action of gliclazide could partly explain this. These trials suggest that gliclazide is a potent sulfonylurea with a low rate of secondary failure and a low incidence of side effects and may be a better choice in long-term sulfonylurea therapy.     

Energy consumption for the formation of hemoglobin A1c: a reappraisal and implication on the poor-control diabetes mellitus patients

Diabetes mellitus (DM) is a frequent disorder affecting individuals of all ages. Glycohemoglobin has a key role in the assessment of glycemic control in diabetic patients. Several studies have clearly shown that improved glycemic control is strongly associated with decreased development and/or progression of diabetic complications. The chemical reaction of glycosylation in formation of hemoglobin A_1c (HbA_1c) has been described for decades. Here, the author performed a reappraisal on the bonding energy based on quantum chemical analysis. The author calculated the bonding energy of the reaction and found that the reaction is a type of “energy-consuming reaction.” In addition, the author gives further implication of the findings on the poor-control DM patients. The author hereby proposed that the nature of energy-consuming reaction in formation of hemoglobin A_1c (HbA_1c) is a main underlying for the energy loosing in poorly controlled DM patients. Gathering of the energy from the nearby cellular compartment during formation of HbA_1c might be an important pathological process.     

Therapy after single oral agent failure: adding a second oral agent or an insulin mixture?

AIM: to compare the glycemic response to an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily plus metformin (Mix25+M) with glibenclamide plus metformin (G+M), in patients with type 2 diabetes inadequately controlled with a single oral agent. METHODS: 597 patients treated in a randomized, open-label, 16-week parallel study. Variables evaluated: hemoglobin A1C (A1C), patient symptoms, hypoglycemia rate (episodes/patient/30 days), and incidence (% patients experiencing > or =1 episode). For a subset of patients (N=120), fasting, 1-h, and 2-h postprandial plasma glucose (FPG, 1-h ppPG, 2-h ppPG) in response to a standardized test meal (STM) and self-monitored blood glucose (BG) profiles were measured. RESULTS: improved A1C at endpoint for both groups, and A1C changes from baseline to endpoint were not significantly different between treatments (Mix25+M, -1.87+/-1.35% vs. G+M, -1.98+/-1.28%; p=0.288). Among patients completing STM; endpoint 2-h ppPG was significantly lower with Mix25+M (9.05+/-3.32 mmol/l vs. 12.31+/-3.65 mmol/l; p<0.001), as was 2-h ppPG excursion (2-h ppPGex)(0.38+/-3.23 mmol/l vs. 2.88+/-1.98 mmol/l; p<0.001). Percentage of patients achieving postprandial BG targets (<10 mmol/l) at endpoint was significantly greater with Mix25+M (80% vs. 48%; p<0.001). Although, overall hypoglycemia rates were similar, percentage of patients experiencing and rate of nocturnal hypoglycemia was less with Mix25+M (1% vs. 5%; p<0.01, and 0.01 vs. 0.08 episodes/pt/30 d; p=0.007). Patients reported less polyuria with Mix25+M (p<0.001). CONCLUSION: in patients with type 2 diabetes failing on metformin or a sulfonylurea, Mix25+M provided similar overall glycemic control, lower ppPG, reduced nocturnal hypoglycemia, and fewer hyperglycemic symptoms compared to G+M.     

马来酸罗格列酮对2型糖尿病患者的长期疗效与安全性的观察

目的观察罗格列酮对2型糖尿病（T2DM）患者的长期疗效及安全性。方法采用自身治疗前后对照的方法，42例合用磺脲类、双胍类和α糖苷酶抑制剂药物治疗3个月以上血糖控制不良的T2DM患者加服马来酸罗格列酮，随访36个月，观察治疗前后血糖、HbA1c、FIns、HOMAIR、ISI、血清高敏C反应蛋白（hsC-RP）、Hb、谷丙转氨酶（GPT）、谷草转氨酶（GOT）、谷氨酰转移酶（γ-GT）等的变化。结果马来酸罗格列酮治疗组FPG、2hPG、HbA1c、FIns、hsCRP均较治疗前明显下降（P〈0．01），且与时间成正比，约治疗9个月后疗效趋于稳定，GPT、GOT、γ-GT较治疗前明显下降（P〈0．05）；所见的不良反应为下肢水肿，发生率为4．8％，经对症处理后消失。结论马来酸罗格列酮能有效降低长期口服降糖药物控制不佳的T2DM患者的血糖水平，对因脂肪肝而致的肝脏酶谱的增高有治疗作用，有良好的安全性。     

Efficacy of glimepiride/metformin fixed‐dose combination vs metformin uptitration in type 2 diabetic patients inadequately controlled on low‐dose metformin monotherapy: A randomized,open label,parallel group,multicenter study in Korea

Aims/Introduction

To compare the efficacy and safety of early combination therapy with glimepiride/metformin to metformin uptitration in reducing glycated hemoglobin (HbA1c) levels in Korean type 2 diabetic patients inadequately controlled on low-dose metformin monotherapy.

Materials and Methods

In a randomized, open label, parallel group, multicenter study, 209 Korean type 2 diabetic patients (HbA1c 7.0–10.0%, on metformin 500–1,000 mg/day) received glimepiride/metformin fixed-dose combination (G/M FDC) or metformin uptitration treatment (Met UP). The primary end-point was the change in HbA1c from baseline to week 24.

Results

G/M FDC therapy provided significantly greater adjusted mean decreases vs Met UP therapy in HbA1c (−1.2 vs −0.8%, P < 0.0001), and fasting plasma glucose (−35.7 vs −18.6 mg/dL, P < 0.0001). A significantly greater proportion of patients with G/M FDC therapy achieved HbA1c < 7% (74.7 vs 46.6%, P < 0.0001) at the end of the study. More patients experienced hypoglycemia with G/M FDC therapy compared with Met UP therapy (41 vs 5.6%, P < 0.0001), but there was no serious hypoglycemia in any group. A modest increase in mean bodyweight occurred in the patients who were treated with G/M FDC therapy (1.0 kg), whereas a slight decrease was observed in the patients who were treated with Met UP therapy (−0.7 kg).

Conclusion

The present study showed that glimepiride/metformin fixed-dose combination therapy was more effective in glycemic control than metformin uptitration, and was well tolerated in type 2 diabetic patients inadequately controlled by low-dose metformin monotherapy in Korea. This trial was registered with ClinicalTrial.gov (no. {"type":"clinical-trial","attrs":{"text":"NCT00612144","term_id":"NCT00612144"}}NCT00612144).     

A 16-week open-label, multicenter pilot study assessing insulin pump therapy in patients with type 2 diabetes suboptimally controlled with multiple daily injections

Background

We assessed the efficacy, safety, and patient-reported outcomes (PROs) of insulin pump therapy in patients with type 2 diabetes mellitus (T2DM) who were suboptimally controlled with a multiple daily injection (MDI) regimen.

Methods

In this subanalysis of a 16-week multicenter study, 21 insulin-pump-naïve patients [age 57 ± 13 years, hemoglobin A1c (A1C) 8.4 ± 1.0%, body weight 98 ± 20 kg, total daily insulin dose 99 ± 65 U, mean ± standard deviation] treated at baseline with MDI therapy with or without oral antidiabetic agents discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin was titrated to achieve the best possible glycemic control with the simplest possible dosing regimen. Outcome measures included A1C, fasting and postprandial glucose, body weight, incidence of hypoglycemia, and PROs.

Results

Glycemic control improved significantly after 16 weeks: A1C 7.3 ± 1.0% (−1.1 ± 1.2%, p < .001), fasting glucose 133 ± 33mg/dl (−32 ± 74 mg/dl, p < .005), and postprandial glucose 153 ± 35 mg/dl (−38 ± 46 mg/dl, p < .001). At week 16, the mean daily basal, bolus, and total insulin doses were 66 ± 36, 56 ± 40, and 122 ± 72 U (1.2 U/kg), respectively, and 90% of patients were treated with two or fewer daily basal rates. Body weight increased by 2.8 ± 2.6 kg (p < .001). Mild hypoglycemia was experienced by 81% of patients at least once during the course of the study with no episodes of severe hypoglycemia. There were significant improvements in PRO measures.

Conclusions

Insulin pump therapy using a relatively simple dosing regimen safely improved glucose control and PROs in patients with T2DM who were unable to achieve glycemic targets with MDI therapy. Controlled trials are needed to further assess the clinical benefits and cost-effectiveness of insulin pumps in this patient population.     

Homocysteine and endogenous markers of renal function in type 2 diabetic patients without coronary heart disease

The aim of this study was to assess parameters of renal function and other determinants of plasma homocysteine in type 2 diabetic patients without coronary heart disease (CHD). Fasting plasma homocysteine, serum cystatin C and serum creatinine were determined in 183 (75 men, 108 women) Type 2 diabetic patients without clinical evidence of CHD. Creatinine clearance was calculated and parameters such as blood pressure, body mass index (BMI), and glycated haemoglobin (HbA_1c) were assessed. The urine albumin:creatinine ratio was used to classify patients as normo-, micro- or macroalbuminuric. One hundred and ten patients were normoalbuminuric, 67 patients were microalbuminuric and six patients were macroalbuminuric. There was no statistically significant difference in plasma homocysteine concentration between patients with normoalbuminuria and microalbuminuria. There was a trend towards increasing plasma homocysteine with decreasing glomerular filtration rate (GFR) (r=−0.46; P<0.0001). There was statistically significant correlation between plasma homocysteine and age (r=0.37), serum cystatin C (r=0.47), and serum creatinine (r=0.56). Plasma homocysteine concentration was significantly higher in patients with BMI<30 kg/m² and showed significant inverse correlation with weight (r=−0.16; P=0.03) and body mass index (r=−0.24; P=0.001). Homocysteine and serum creatinine were significantly higher in males than females and higher in smokers than non smokers but was not associated with glycemic control and duration of diabetes. In conclusion, elevated homocysteine concentration in patients with type 2 DM without CHD is related to age, gender, smoking, BMI and GFR. Follow up studies will provide further information on the association between hyperhomocysteinemia and the development of cardiovascular disease.     

Is β-cell failure in type 2 diabetes mellitus reversible?

BACKGROUND:

In the UK Prospective Diabetes Study (UKPDS), many subjects maintained glycemic goal (HbA_1c < 7.0%) at 9 years, showing that β-cell function was preserved and that the initial decline in β-cell function recovered with sulphonylureas. Moreover, obese subjects using high daily doses of insulin for several years rarely require insulin or oral hypoglycemic agents to maintain their glycemic goal following weight loss achieved by gastric bypass surgery. Thus, declining β-cell function during the course of type 2 diabetes mellitus (T2DM) is neither universal nor permanent.

OBJECTIVE:

To assess β-cell function in morbidly obese subjects before insulin withdrawal and on attaining the glycemic goal with weight loss and oral agents.

MATERIALS AND METHODS:

Serum C-peptide (CPEP) and glucose (G) concentrations were determined up to 180 min during an oral glucose tolerance test (OGTT) with 75 glucose in 10 obese men with T2DM, before insulin withdrawal, and on achieving the glycemic goal with metformin, glimepiride, and weight loss. Ten age-matched healthy men participated as controls. Cumulative responses (CR) of CPEP and G were calculated by adding differences between the level at each time-period during OGTT and fasting (F) concentration. β-Cell function was expressed as the FCPEP as well as the insulinogenic index (CRCPEP/CRG). Insulin sensitivity was determined as FCEP × FG.

RESULTS:

FCPEP was decreased, though still present, prior to insulin withdrawal. Moreover, on attaining the glycemic goal over 6-9 months, FCPEP, CRPEP/CRG, and FCPEP × FG improved markedly (P < 0.001).

CONCLUSION:

Decline in β-cell function in morbidly obese T2DM may not be progressive and is reversible on improving insulin sensitivity and on eliminating the inhibition by exogenous insulin.     

Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial

BACKGROUND: Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain. OBJECTIVE: To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes. DESIGN: Randomized, controlled trial. SETTING: Four outpatient clinics at central hospitals. PATIENTS: 96 patients (mean age, 58 +/- 1 years; mean body mass index, 29 +/- 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% +/- 0.2%; mean fasting plasma glucose level, 11.9 +/- 0.3 mmol/L [214 +/- 5 mg/dL]). INTERVENTION: Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements. MEASUREMENTS: Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control. RESULTS: At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 +/- 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 +/- 0.7 kg, 3.6 +/- 1.2 kg, and 4.6 +/- 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% +/- 0.4% to 7.2% +/- 0.2% [difference, -2.5 +/- 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups. CONCLUSIONS: Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.     

Plasma relaxin concentration is related to beta-cell function and insulin sensitivity in women with type 2 diabetes mellitus

The aim of the study was to assess whether HbA_1c levels reflected mean blood glucose (MBG) levels in Type 2 diabetes. Despite the good correlation between HbA_1c and MBG, one-third of the patients had consistently higher HbA_1c or lower HbA_1c levels than that expected under the hypothesis that HbA_1c is solely determined by MBG, suggesting the existence of different haemoglobin glycation phenotypes. The use of HbA_1c alone for glycemic control monitoring in these patients could be insufficient to clearly trace their risk of complications.     

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.     

Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus

In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 +/- 0.48 v 9.46 +/- 0.47 mmol/L, P <.001) and the combined SU and metformin therapy group (14.09 +/- 0.51 v 10.57 +/- 0.85 mmol/L, P =.001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 +/- 0.09 v 0.34 +/- 0.07 mmol/L, P =.02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 +/- 19 v 446 +/- 18 ng/mL, P =.02) and the combined SU and metformin therapy group (496 +/- 29 v 456 +/- 31 ng/mL, P =.05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.     

Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control.

The effect of metformin treatment was studied in 13 patients with noninsulin-dependent diabetes mellitus (NIDDM), whose fasting plasma glucose concentration was greater than 10 mmol/L with maximal sulfonylurea doses. Patients were studied before and 3 months after receiving 2.5 g/day metformin. The fasting plasma glucose concentration (12.4 +/- 0.8 vs. 8.8 +/- 0.7 mmol/L), mean hourly postprandial plasma glucose concentration from 0800-1600 h (14.0 +/- 1 vs. 9.4 +/- 0.9 mmol/L), and glycosylated hemoglobin level (12.3 +/- 0.6% vs. 9.0 +/- 0.6%) were all significantly (P less than 0.005-0.001) lower after the administration of metformin. The improvement in glycemic control was associated with a 24% increase (P less than 0.05) in insulin-stimulated glucose uptake during glucose clamp studies and a 16% decrease in basal hepatic glucose production (P less than 0.05). Mean hourly concentrations of plasma insulin (411 +/- 73 vs. 364 +/- 73 pmol/L) and FFA concentrations (440 +/- 31 vs. 390 +/- 40 mumol/L) were also lower after 3 months of metformin treatment. However, neither insulin binding nor insulin internalization by isolated monocytes changed in response to metformin. Finally, plasma triglyceride, very low density lipoprotein triglyceride, and very low density lipoprotein cholesterol were significantly decreased (P less than 0.01-0.001), and high density lipoprotein cholesterol was significantly increased (P less than 0.001) after metformin treatment. Thus, the addition of metformin to sulfonylurea-treated patients with NIDDM not in good glycemic control significantly lowered fasting and postprandial plasma glucose concentrations, presumably due to the combination of enhanced glucose uptake and decreased hepatic glucose production. Since the dyslipidemia present in these patients also improved, the results suggest that metformin may be of significant clinical utility in patients with NIDDM not well controlled with sulfonylurea compounds.