Changes in Weight and Glucose Can Protect Against Progression in Early Diabetes Independent of Improvements in ß-Cell Function.

CONTEXT: Evidence-based strategies to prevent progression of dysglycemia in newly diagnosed type 2 diabetes are needed. OBJECTIVE: To undertake a secondary analysis of the Early Diabetes Intervention Program (EDIP) in order to understand the features that were protective against worsening glycemia. DESIGN: EDIP was a randomized, placebo-controlled trial. SETTING: Two university diabetes centers. PATIENTS: A total of 219 overweight individuals with fasting glucose < 7.8 mmol/L and 2-hour oral glucose tolerance test (OGTT) glucose > 11.1 mmol/L. INTERVENTIONS: Acarbose versus placebo, on a background of dietary recommendations, with quarterly visits to assess glycemia and intervention adherence for up to 5 years. MAIN OUTCOME MEASURES: Progression of fasting glucose ≥ 7.8 mmol/L on two consecutive quarterly visits. Cox proportional hazards modeling and ANOVA were performed to evaluate determinants of progression. RESULTS: Progression-free status was associated with reductions in weight, fasting glucose, 2-hour OGTT glucose, and increases in the high-density lipoprotein/triglyceride ratio. The reduction in fasting glucose was the only effect that remained significantly associated with progression-free status in multivariable Cox modeling. The reduction in fasting glucose was in turn primarily associated with reductions in weight and in 2-hour OGTT glucose. Acarbose treatment did not explain these changes. CONCLUSIONS: In early diabetes, reductions in glucose, driven by reductions in weight, can delay progressive metabolic worsening. These observations underscore the importance of lifestyle management including weight loss as a tool to mitigate worsening of glycemia in newly diagnosed diabetes.

Profound defects in ß-cell function in screen-detected type 2 diabetes are not improved with glucose-lowering treatment in the Early Diabetes Intervention Program (EDIP).

BACKGROUND: Few studies have measured the ability of interventions to affect declining ß-cell function in screen-detected type 2 diabetes. The Early Diabetes Intervention Programme (ClinicalTrials.gov NCT01470937) was a randomized study based on the hypothesis that improving postprandial glucose excursions with acarbose would slow the progression of fasting hyperglycaemia in screen-detected type 2 diabetes. In the Early Diabetes Intervention Programme, the effect of acarbose plus lifestyle advice on progression of fasting hyperglycaemia over a 5-year period was not greater than that of placebo. However, there was an early glucose-lowering effect of the trial. The objective of the current secondary analysis was to describe ß-cell function changes in response to glucose lowering. METHODS: Participants were overweight adult subjects with screen-detected type 2 diabetes. ß-cell function was measured using hyperglycaemic clamps and oral glucose tolerance testing. The primary outcome was the change in ß-cell function from baseline to year 1, the time point where the maximal glucose-lowering effect was seen. RESULTS: At baseline, participants exhibited markedly impaired first-phase insulin response. Despite significant reductions in weight, fasting plasma glucose (PG) and 2-h PG, there was no clinically significant improvement in the first-phase insulin response. Late-phase insulin responses declined despite beneficial glycaemic effects of interventions. CONCLUSIONS: Insulin secretion is already severely impaired in early, screen-detected type 2 diabetes. Effective glucose-lowering intervention with acarbose was not sufficient to improve insulin secretion or halt the decline of ß-cell function.

Effect of acarbose to delay progression of carotid intima-media thickness in early diabetes.

BACKGROUND: The anti-diabetic agent acarbose reduces postprandial glucose excursions. We have evaluated the effect of randomized treatment with acarbose on the progression of carotid intima-media thickness (IMT) in early diabetes. METHODS: The Early Diabetes Intervention Program was a randomized trial of acarbose versus placebo in 219 participants with early diabetes characterized by glucose values over 11.1 mmol/L 2 h after a 75 g oral glucose load and a mean HbA1c of 6.3%. IMT was measured at baseline and yearly. Follow-up was discontinued if participants progressed to the study glucose endpoints; IMT readings were available for a median of 2 years, with 72 subjects followed for 5 years. RESULTS: Progressive increases in IMT were seen in both treatment groups, but progression was reduced in participants randomized to acarbose (p = 0.047). In age, sex and smoking-adjusted analyses, IMT progression was associated with greater fasting and oral glucose tolerance test-excursion glucose, fasting insulin, cholesterol and glycated low-density lipoprotein concentrations. IMT progression was reduced with study-related changes in weight, insulin and non-esterified fatty acids; these features were more strongly associated with reduced IMT progression than acarbose treatment. Despite strong associations of baseline glycemia with IMT progression, study-related changes in glucose were not important determinants of IMT progression. CONCLUSIONS: Acarbose can delay progression of carotid intima-media thickness in early diabetes defined by an oral glucose tolerance test. Glucose, weight, insulin and lipids contributed to risk of progression but reductions in glycemia were not major determinants of reduced rate of IMT progression. Vascular benefits of acarbose may be independent of its glycemic effects.

The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors.

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.

Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. Department of Veterans Affairs Implantable Insulin Pump Study Group.

OBJECTIVE: To determine whether implantable insulin pump (IIP) therapy and multiple daily insulin (MDI) injections could equally attain improved blood glucose control, and to compare the 2 treatments with respect to reducing daily blood glucose fluctuations, reducing serious hypoglycemic insulin reactions, and improving patients' quality of life. DESIGN: Randomized clinical trial. SETTING: Seven Veterans Affairs medical centers. PATIENTS: One hundred twenty-one male type II diabetic patients between the ages of 40 and 69 years, receiving at least 1 injection of insulin per day and having hemoglobin A1c (HbA1c) levels of 8% or above. INTERVENTION: Intensive therapy (IIP or MDI) for 1 year. MAIN OUTCOME MEASURES: Hemoglobin A1c and blood glucose levels. RESULTS: Blood glucose levels declined to 7.96+/-1.08 mmol/L (143.4+/-19.5 mg/dL) and 8.30+/-1.52 mmol/L (149.6+/-27.4 mg/dL) (mean +/- SD) for IIP and MDI, respectively (P=.57). Hemoglobin A1c levels improved in both groups (time effect P<.001), to means of 7.54%+/-0.83% (MDI) vs 7.34%+/-0.79% (IIP). IIP reduced blood glucose fluctuations compared with MDI (P<.001), and reduced the incidence of mild clinical hypoglycemia by 68% (P<.001); IIP also eliminated the weight gain associated with MDI therapy and yielded better overall quality-of-life (P=.03) and impact-of-disease subscale scores (P=.05). Adverse events included 25% of subjects with episodes of insulin underdelivery due to microprecipitates of insulin within the pump. CONCLUSIONS: Intensive insulin therapy with IIP and MDI is effective in controlling non-insulin-dependent diabetes mellitus. IIP has significant advantages in reducing glycemic variability, clinical hypoglycemia, and weight gain, while improving aspects of quality of life.

Marked deterioration in glycemic control with change in brand of lactulose syrup.

Lactulose is a poorly absorbed synthetic disaccharide frequently used in the treatment of portasystemic encephalopathy. Because lactulose syrup contains small amounts of absorbable sugars, it may cause hyperglycemia in diabetic individuals, but is usually well tolerated. We report the case of a patient with diet-controlled diabetes and cirrhosis who experienced a marked deterioration in glycemic control, requiring insulin use, when he began using a different brand of lactulose syrup. The hyperglycemia resolved and insulin was discontinued after use of the original brand of lactulose syrup was resumed.

A nurse-coordinated intervention for primary care patients with non-insulin-dependent diabetes mellitus: impact on glycemic control and health-related quality of life.

OBJECTIVE: To examine the impact of a nurse-coordinated intervention delivered to patients with non-insulin-dependent diabetes mellitus between office visits to primary care physicians. DESIGN: Randomized, controlled trial. SETTING: Veterans Affairs general medical clinic. PATIENTS: 275 veterans who had NIDDM and were receiving primary care from general internists. INTERVENTION: Nurse-initiated contacts were made by telephone at least monthly to provide patient education (with special emphasis on regimens and significant signs and symptoms of hyperglycemia and hypoglycemia), reinforce compliance with regimens, monitor patients' health status, facilitate resolution of identified problems, and facilitate access to primary care. MEASUREMENTS: Glycemic control was assessed using glycosylated hemoglobin (GHb) and fasting blood sugar (FBS) levels. Health-related quality of life (HRQOL) was measured with the Medical Outcomes Study SF-36, and diabetes-related symptoms were assessed using patients' self-reports of signs and symptoms of hyper- and hypoglycemia during the previous month. MAIN RESULTS: At one year, between-group differences favored intervention patients for FBS (174.1 mg/dL vs 193.1 mg/dL, p = 0.011) and GHb (10.5% vs 11.1%, p = 0.046). Statistically significant differences were not observed for either SF-36 scores (p = 0.66) or diabetes-related symptoms (p = 0.23). CONCLUSIONS: The intervention, designed to be a pragmatic, low-intensity adjunct to care delivered by physicians, modestly improved glycemic control but not HRQOL or diabetes-related symptoms.

The relationship between glycemic control and health-related quality of life in patients with non-insulin-dependent diabetes mellitus.

The relationship between glycemic control and health-related quality of life was examined in patients with non-insulin-dependent diabetes mellitus (NIDDM). Within the context of a randomized controlled trial, 275 patients with NIDDM receiving primary care from a Veteran's Administration general medical clinic were enrolled and monitored for 1 year. Glycemic control (glycosylated hemoglobin levels) and health-related quality of life (Medical Outcomes Study Short-Form 36-item Health Survey [SF-36]) were assessed at baseline and at 1 year. Multivariate regression modeling using baseline and change scores during a 1-year period did not find a linear or curvilinear relationship between glycosylated hemoglobin and SF-36 scores (P = .15); this was true even after controlling for five covariates identified a priori (insulin use, number of diabetic complications, duration of diabetes, education, number of hyper-, or hypoglycemic episodes during the preceding month). Health services researchers and clinicians alike need to be aware that these two important outcomes may not be directly related. This lack of association could contribute to the high noncompliance rates observed among patients prescribed complex diabetic regimens. Unless patients perceive a benefit from following such regimens, good glycemic control may continue to be an elusive therapeutic goal, especially in patients with long-standing disease.

A telephone-delivered intervention for patients with NIDDM. Effect on coronary risk factors.

OBJECTIVE: To examine whether a telephone-delivered intervention (TDI), designed to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM), improved coronary risk factors in high-risk patients. RESEARCH DESIGN AND METHODS: This randomized controlled trial involved 275 veterans with NIDDM followed in a general medical clinic. Intervention (TDI) patients were telephoned at least monthly by a nurse. Calls emphasized compliance with the medical regimen (diet, medications, and exercise), encouraged behavioral changes, and facilitated referrals to a dietitian or smoking cessation clinic. Control patients received no such calls. Baseline and 12-month follow-up measurements included fasting lipid profiles, weight, smoking status (self-reported; cessation verified by measurement of exhaled CO), adherence to diet and exercise (self-reported), appointments, and medications (hospital computerized data base). RESULTS: After 12 months, equal numbers of obese patients in the two groups reported adhering to a diabetic diet and exercising, although more obese TDI patients had seen a dietitian (30 vs. 7%, P = 0.003). Weight loss was not seen in either group (-0.9 +/- 5.3 vs. -0.1 +/- 3.6 kg, P = 0.202). Hyperlipidemic TDI patients were more likely to see a dietitian (31 vs. 6%, P = 0.003) and receive lipid-lowering medications (22 vs. 9%, P = 0.096), but serum cholesterol reduction was similar between groups (-11.7 +/- 33.4 vs. -4.3 +/- 32.7 mg/dl, P = 0.270); comparable results were seen for high-density lipoprotein, low-density lipoprotein, and triglyceride levels. More TDI group smokers reported quitting (26 vs. 0%, P = 0.033), but the difference was not significant for CO-verified abstention (10 vs. 0%, P = 0.231). CONCLUSIONS: The TDI improved self-reported adherence to regimens that might reduce coronary risk, but had little effect on objective measures of risk.

Granulocyte deformability and F-actin content: relationship to diabetes mellitus and retinopathy.

Capillary closure in diabetic retinopathy may be initiated by lumenal occlusion by granulocytes. To determine whether subjects with diabetes mellitus have less deformable granulocytes than healthy subjects, granulocyte deformability was measured by mean entry time into a model capillary system in 16 diabetic-nondiabetic pairs. Granulocyte F-(filamentous) actin content between groups was compared, under basal conditions and after cellular stimulation. The relationship of granulocyte deformability to several diabetes-related variables was examined. Diabetic granulocytes were only 9% +/- 22% less deformable than normal granulocytes (p = 0.16). Deformability was increased in subjects with retinopathy and those with the worst glycemic control (r = 0.61, p = 0.026); both findings were in the opposite direction from that predicted. Basal and stimulated granulocyte F-actin content did not differ between the two groups (p > 0.2 for all assays). Although granulocytes may be important in the pathogenesis of diabetic retinopathy, granulocyte deformability (measured by mean entry time) and F-actin content are not significantly different between healthy patients and those with diabetes.

Different isozymes of mouse 11 beta-hydroxylase produce mineralocorticoids and glucocorticoids.

We have isolated and characterized two isozymes of mouse steroid 11 beta-hydroxylase (11 beta-OHase), designated 11 beta-OHase and aldosterone synthase (AS). Physical mapping of overlapping cosmid and phage isolates defined two genes (designated Cyp11b-1 and Cyp11b-2 in the standard nomenclature for cytochrome P450 genes) that are oriented in the same direction and separated by approximately 8 kilobase pairs of DNA. The two genes are highly homologous in their coding regions, with 84% nucleotide identity and 86% predicted amino acid identity. In regions where the sequences of the rat 11 beta-OHase and AS genes diverged most widely, the mouse sequences also differed significantly, thereby identifying putative mouse 11 beta-OHase and AS genes. Both genes were mapped to chromosome 15 by analyzing restriction fragment length variations in a panel of DNA samples from an interspecific cross. To determine the functional properties of the 11 beta-OHase and AS proteins, we transfected COS-7 cells with plasmids that expressed the proteins encoded by the 11 beta-OHase and AS genes. When expressed in transfected COS-7 cells, the 11 beta-OHase protein converted deoxycorticosterone to corticosterone but did not produce aldosterone. Consistent with its postulated role in mineralocorticoid biosynthesis, the product of the AS gene efficiently synthesized aldosterone. We next studied the expression of these two isozymes in Y1 adrenocortical tumor cells and in the intact mouse adrenal gland. Although Y1 cells otherwise resemble zona fasciculata cells and express the 11 beta-OHase gene at high levels, transcripts encoded by the AS gene were detected at levels approximately 10-fold lower than the 11 beta-OHase transcripts.(ABSTRACT TRUNCATED AT 250 WORDS)

Economic impact of diabetes mellitus in the elderly.

Diabetes mellitus is a prevalent disease in Americans aged 65 years and older. It leads to significant morbidity, mortality, and utilization of health care services. Using extant data, we estimated that health care services provided to elderly persons with diabetes cost $5.16 billion annually, nearly 80% of which were attributed to hospital costs. Treatment for cardiovascular disease as a complication of diabetes accounted for the largest proportion of these costs. In addition to admissions for uncomplicated diabetes, substantial portions of inpatient costs were attributed to renal and neurologic diseases. Expenditures per capita for medical care were 50% higher in the elderly diabetic population than in an elderly nondiabetic population. The average yearly expenditure per diabetic patient was estimated to be $4265, $900 of which were out-of-pocket expenses. We conclude that increased vigilance to prevent or delay the incidence of morbidity leading to hospital admissions must take priority in caring for patients with DM. Intensifying outpatient care may offer the opportunity to accomplish this goal.

Analysis of the promoter region of the gene encoding mouse cholesterol side-chain cleavage enzyme.

The cholesterol side-chain cleavage enzyme (SCC) catalyzes the initial and rate-limiting step in the synthesis of steroid hormones. The mouse gene encoding SCC was cloned and the nucleotide sequence of its 5'-flanking region determined. This sequence includes an AP-1 motif at -319 and two motifs, AGGTCA at -70 and AGCCTTG at -40, that match elements proposed to be important in the expression of steroid 21-hydroxylase. When transfected into mouse Y1 adrenocortical tumor cells, 1.5 kilobase pairs of 5'-flanking region of the SCC gene directed high levels of expression of a growth hormone reporter gene; treatment of the transfected Y1 cells with 8-bromo-cAMP increased this expression by 5-fold. In contrast, transfected mouse MA-10 Leydig cells showed appreciably lower expression, suggesting that SCC expression in Leydig cells requires additional elements not contained in the 5'-flanking region of the SCC gene used in these experiments. Deletion experiments showed that 424 base pairs of 5'-flanking sequences were sufficient for regulated expression in Y1 cells and mapped two regulatory regions: one from -424 to -327 and a second from -219 to -77. DNase I footprinting and gel mobility shift analyses of these 424 base pairs defined several interactions between nuclear proteins and the SCC promoter, including footprints centered over the AP-1 motif, over a sequence at -120, and over the sequences (-70 and -40) that resemble 21-hydroxylase promoter elements. Finally, site-selected mutagenesis of the potential elements at -40, -70, or -120 decreased SCC promoter activity in transfected Y1 adrenocortical cells, thus establishing their importance in SCC expression.