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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

OBJECTIVE: To conduct a randomised trial of a physical activity (PA) intervention, The First Step Program (FSP) for adults with type II diabetes. DESIGN: A 16-week intervention study and 24-week follow-up assessment. PARTICIPANTS: A total of 47 overweight/obese, sedentary individuals (age=52.7±5.2 y; BMI=33.3±5.6 kg/m2) recruited through a diabetes education centre. MEASUREMENTS: Primary outcome: daily PA assessed by pedometer (steps/day). Secondary outcomes: anthropometric measures (weight, BMI, waist girth, hip girth); indicators of cardiovascular health (resting heart rate and blood pressure); glycemic control (fasting glucose, insulin, HbA1c, glucose concentration 120 min postglucose load); plasma lipid status (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides). RESULTS: Relative to the CONTROL group, FSP participants increased their PA >3000 steps/day (approximately 30 min/day) during the intervention (P

To determine if a relationship exists between blood glucose control and variability in nutrient intake from day-to-day in subjects with type 1 diabetes.Two three-day diet records and one measurement of glycated hemoglobin (HbA1c) were obtained from 272 subjects with type 1 diabetes treated with a mixture of regular and NPH insulins before breakfast and supper and using a standardized algorithm to adjust insulin dose according to the results of self-monitoring of blood glucose two to four times daily. Day-to-day variation in nutrient intake was expressed as the coefficient of variation (CV = SDx100/mean).Nutrient intakes in the study population (mean +/- SD) were energy 8.35+/-2.43 MJ, fat 81+/-30 g, protein 94+/-28 g, carbohydrate 227+/-68 g, starch 126+/-38 g and dietary fiber 20+/-6 g with diet glycemic index being 84.2+/-7.4. Neither energy, nutrient intakes nor insulin dose was significantly related to HbA1c. Day-to-day variation of carbohydrate (p = 0.0097) and starch (p = 0.0016) intakes and diet glycemic index (p = 0.033) was positively related to HbA1c, and the associations remained significant when adjusted for age, sex, duration of diabetes and BMI. Day-to-day variation in energy, protein or fat intakes was not related to HbA1c.Consistency in the amount and source of carbohydrate intake from day-to-day is associated with improved blood glucose control in people with type 1 diabetes, a result which supports continued educational efforts to achieve adherence to a diabetes diet plan. This conclusion may not apply to people on intensified insulin therapy who adjust their insulin dose based on their actual carbohydrate intake at each meal.

OBJECTIVE To determine the relationship between carbohydrate intake and the effect of acarbose on HbA1c in subjects with type 2 diabetes treated with acarbose alone, acarbose plus sulfonylurea, acarbose plus metformin, or acarbose plus insulin. RESEARCH DESIGN AND METHODS We conducted a double-blind randomized placebo-controlled study in which subjects with diabetes in four treatment strata (77 on diet alone, 83 treated with metformin, 103 treated with sulfonylurea, and 91 treated with insulin) were randomized to treatment with placebo or acarbose for 12 months. Before randomization, and 3, 6, 9, and 12 months after randomization, fasting blood was obtained for HbA1c, and 3-day diet records were collected. Subjects who completed at least 6 months of acarbose therapy and provided at least three 3-day diet records were included. RESULTS In the 114 subjects included in this analysis, carbohydrate intake varied from ∼30–60% of energy. There was no significant relationship between carbohydrate intake and change in HbAlc in any of the four treatment strata (diet: n = 26, r = 0.35, P = 0.076; metformin: n = 27, r = 0.26, P = 0.19; sulfonylurea: n = 35, r = 0.24, P = 0.16; insulin: n = 25, r = −0.27, P = 0.19). In the 80 subjects consuming 50% of energy from carbohydrate (7.55 ± 0.25% at baseline to 6.66 ± 0.23% on acarbose, P < 0.001). There was no difference in carbohydrate intake between those who dropped out of the study because of gastrointestinal side effects and those who did not, and there was no relationship between severity of symptoms and the composition of the diet. CONCLUSIONS In subjects with type 2 diabetes consuming 30–60% of energy from carbohydrate, the effect of acarbose on HbAlc and gastrointestinal symptoms was not related to carbohydrate intake. Because most people consume at least 30% of energy from carbohydrate, we conclude that no special diet is needed for acarbose to be effective in improving blood glucose control in the treatment of type 2 diabetes.

Nutrition recommendations for type 2 diabetes (T2DM) are partly guided by the postprandial responses elicited by diets varying in carbohydrate (CHO). We aimed to explore whether long-term changes in postprandial responses on low-glycemic-index (GI) or low-CHO diets were due to acute or chronic effects in T2DM.Subjects with diet-alone-treated T2DM were randomly assigned to high-CHO/high-GI (H), high-CHO/low-GI (L), or low-CHO/high-monounsaturated-fat (M) diets for 12-months. At week-0 (Baseline) postprandial responses after H-meals (55% CHO, GI = 61) were measured from 0800 h to 1600 h. After 12 mo subjects were randomly assigned to H-meals or study diet meals (L, 57% CHO, GI = 50; M, 44% CHO, GI = 61). This yielded 5 groups: H diet with H-meals (HH, n = 34); L diet with H- (LH, n = 17) or L-meals (LL, n = 16); and M diet with H- (MH, n = 18) or M meals (MM, n = 19). Postprandial glucose fluctuations were lower in LL than all other groups (p0.001). Changes in postprandial-triglycerides differed among groups (p0.001). After 12 mo in HH and MM both fasting- and postprandial-triglycerides were similar to Baseline while in MH postprandial-triglycerides were significantly higher than at Baseline (p = 0.028). In LH, triglycerides were consistently (0.18-0.34 mmol/L) higher than Baseline throughout the day, while in LL the difference from Baseline varied across the day from 0.04 to 0.36 mmol/L (p0.001).Low-GI and low-CHO diets have both acute and chronic effects on postprandial glucose and triglycerides in T2DM subjects. Thus, the composition of the acute test-meal and the habitual diet should be considered when interpreting the nutritional implications of different postprandial responses.

We recently found that oral glucose tolerance over 1 year in type 2 diabetic patients declined to a significantly lesser degree on a low-glycaemic-index than on a reduced-carbohydrate diet. Here, we examined whether that finding was associated with an improvement in disposition index, an index of beta cell function defined as the product of insulin sensitivity and insulin secretion. Since this is a report of secondary analysis on a previously published trial, the results should be considered as hypothesis-generating.Type 2 diabetic patients treated by diet alone (n = 162) were randomised by computer to high-carbohydrate/high-glycaemic index (High-GI, n = 52), high-carbohydrate/low-glycaemic index (Low-GI, n = 56) or low-carbohydrate/high-monounsaturated-fat (Low-CHO, n = 54) diets for 1 year in a multi-centre, parallel-design clinical trial conducted at University teaching hospitals. At baseline and at 3, 6 and 12 months participants underwent 75 g OGTTs; 27 participants dropped out or were excluded. Indices of insulin sensitivity, insulin secretion and disposition index, derived from the OGTT, were compared among diets. Those assessing the outcomes were blinded to group assignment.Neither muscle insulin sensitivity index nor insulinogenic index differed significantly among diets. However, a significant time x diet interaction existed for disposition index (muscle insulin sensitivity index x insulinogenic index) (p = 0.036). After 3 months, disposition index tended to be higher on Low-CHO than on Low-GI diets, namely by 0.07 h(-1) (95% CI -0.04, 0.18). However, by 12 months this reversed and disposition index became higher on Low-GI than on Low-CHO, namely by 0.12 h(-1) (0.01, 0.23; p0.05, baseline disposition index 0.23 h(-1)). There were no important adverse effects associated with the treatments.These results suggest that, in patients with type 2 diabetes on diet alone, a Low-GI diet for 1 year increases disposition index, an index of beta cell function, compared with a Low-CHO diet.

Aims: To study the effect of acarbose, an α-glucosidase inhibitor, on glycemic control in elderly patients with type 2 diabetes. Methods: Elderly patients with type 2 diabetes treated with diet alone were randomly treated in a double-blind fashion with placebo ( n =99) or acarbose ( n =93) for 12 months. Results: After 12 months of therapy, there was a statistically significant difference in the change in glycated haemoglobin (HbA 1c ) (−0.6%) in the acarbose group versus placebo, as well as in the incremental post-prandial glucose values (−2.1 mmol h/l) and mean fasting plasma glucose (−0.7 mmol/l). Although there was no effect of acarbose on insulin release, there was a clear effect of acarbose to decrease relative insulin resistance (−0.8) (HOMA method). In addition, acarbose was generally well tolerated and safe in the elderly; most discontinuations were due to gastrointestinal side effects such as flatulence and diarrhea. There were no cases of hypoglycemia reported, and no clinically relevant changes in laboratory abnormalities or vital signs during the study. Conclusions: Acarbose improves the glycemic profile and insulin sensitivity in elderly patients with type 2 diabetes who are inadequately controlled on diet alone.

This report describes the membership, background, activities and future plans of the Diabetes Council of Canada. The roles, goals and successes will be reviewed.

The study compared valsartan 80 mg or 160 mg o.d. with captopril 25 mg t.i.d. or placebo on plasma lipids in normotensive and treated hypertensive patients with type II diabetes and microalbuminuria. One hundred and twenty-two adult outpatients were randomised to receive either valsartan 80 mg or 160 mg, captopril 25 mg or placebo for 360 days. Changes from baseline to endpoint in plasma lipid parameters were measured. The primary criterion for tolerability was the incidence of adverse events. All treatment groups showed minor changes in lipid parameters. Triglyceride increased by 2.7% (valsartan 160 mg) to 9.1% (placebo). Total cholesterol decreased under valsartan 80 mg, while other groups showed increases of up to 0.031 mmol/l. Decreases in total cholesterol (p = 0.018), apolipoprotein B (p = 0.042) and apolipoprotein A1 (p = 0.025), were significant for the comparison of 80 mg valsartan and captopril. Valsartan 80 mg or 160 mg o.d. does not cause deleterious changes in the diabetic lipid profile and, unlike captopril, is not associated with dry cough.

The number of individuals diagnosed with diabetes mellitus is increasing. The diabetic may present with complications involving all systems of the body. While onychomycosis is often observed in diabetics, there have been no large studies on the prevalence of the condition in this patient group. We examined the prevalence of onychomycosis in diabetics attending diabetes and dermatology clinics in London, Ontario, Canada and Boston, MA, U.S.A. Diabetic subjects seen in dermatology offices were for unrelated dermatoses; those referred specifically for the management of onychomycosis were excluded from the sample. A total of 550 diabetic subjects was evaluated (283 males and 267 females), age 56.1 +/- 0.7 years (mean +/- SEM). Patients with type I diabetes constituted 34% of the sample. The racial origin was: 531 Caucasians, 17 Asians, one African-American and one American-Indian. Abnormal-appearing nails and mycological evidence of onychomycosis (mostly due to dermatophytes) were present in 253 (46%) and 144 (26%), respectively, of 550 subjects. The development of onychomycosis was significantly correlated with age (P0.0001) and male gender (P0.0001). Males were 2.99 times more likely to have onychomycosis compared with females (95% confidence interval, CI 1.94-4 61). After controlling for age and sex, the risk odds ratio for diabetic subjects to have toenail onychomycosis was 2.77 times compared with normal individuals (95% CI 2.15-3.57). After controlling for age and sex, a stepwise logistic regression demonstrated that significant predictors for onychomycosis included a family history of onychomycosis (P = 0.0001), concurrent intake of immunosuppressive therapy (P = 0.035) and peripheral vascular disease (P = 0.023). Toenail onychomycosis was present in 26% of the sample and is projected to affect approximately one-third of subjects with diabetes. Predisposing factors include increasing age, male gender, family history of onychomycosis, concurrent intake of immunosuppressive agents and peripheral vascular disease.

OBJECTIVES: To see if the long-term treatment of non-insulin dependent diabetes (NIDDM) with the α-glucosidase inhibitor acarbose affects food intake and body weight. DESIGN: Randomized, double-blind, placebo-controlled, parallel design clinical trial of 12 months duration. SUBJECTS: Subjects with NIDDM in four treatment strata: 77 on diet alone, 83 also treated with metformin, 103 also treated with sulfonylurea and 91 also treated with insulin. MEASUREMENTS: Two 3 day diet records were obtained before randomization to acarbose or placebo therapy, and additional 3 day diet records were obtained at 3, 6, 9 and 12 months after randomization. Body weight was also measured at these times. RESULTS: Of the 354 subjects randomized, 279 (79%) completed at least 9 months of therapy and, of these, 263 (94%) provided at least one diet record during the baseline period and two diet records during the treatment period. After one year, subjects on acarbose had lost 0.46±0.28 kg, which differed significantly from the 0.33±0.25 kg weight gain on placebo (P=0.027). The difference in weight change between acarbose and placebo did not differ significantly in the different treatment strata. Being in the study had significant effects on diet, including a reduction in energy intake from 1760–1700 Kcal/d (P

Current therapeutic options for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) focus on regimens that primarily lower fasting blood glucose concentrations. In several short-term studies, the alpha-glucosidase inhibitor, acarbose, has been reported to significantly lower post-prandial plasma glucose levels as well as HbA1c. The primary objective of this present study was to assess the long-term efficacy of adjunctive acarbose therapy to improve metabolic control. Over a 1-y period, acarbose or placebo was administered to 4 groups of patients: those managed by diet only, diet and sulfonylurea, diet and biguanide, and diet and insulin. In all treatment groups, the addition of acarbose resulted in significant reductions in postprandial blood glucose levels. Additionally, HbA1C was significantly lower after 12 months of acarbose therapy, compared with placebo, in all groups except the diet and insulin group. The addition of acarbose consequently expands the armamentarium available to clinicians for the optimization of glycemic control in patients with NIDDM.

alpha-Glucosidase inhibitors such as acarbose improve blood glucose control in diabetes by delaying or reducing carbohydrate absorption. The fermentation of malabsorbed carbohydrate in the colon is associated with the production of gas, leading to flatulence, and short chain fatty acids such as acetate, which may have systemic effects. To see if acarbose raised fasting serum acetate in diabetic patients, we studied 85 subjects selected from the 267 who had completed a 1-year, double-blind, placebo-controlled, parallel design study of the effects of acarbose in the treatment of diabetes. At baseline, there was no significant difference between the 44 subjects subsequently randomized to placebo and the 41 randomized to acarbose, respectively, in fasting serum acetate (80 +/- 5 vs 71 +/- 4 mumoll-1) or glycosylated haemoglobin (HbA1C; 7.2 +/- 0.3 vs 7.4 +/- 0.3%). Compared to placebo, acarbose treatment significantly increased fasting serum acetate by 11 +/- 4 vs 2 +/- 3 mumoll-1 (p0.02) and reduced HbA1C by -0.59 +/- 0.16 vs -0.13 +/- 0.20% (p0.02). Acarbose treatment had no significant effect on serum cholesterol or non-esterified fatty acids, but was associated with a significant increase in flatulence. There was no relationship between changes in serum acetate and changes in HbA1C, serum cholesterol or symptoms. We conclude, in subjects with diabetes who tolerate therapy for a 1-year period, that acarbose treatment increases serum acetate. The magnitude of change in acetate was unrelated to side-effects or changes in blood glucose control or serum lipids.

Controlled trials have shown that a diet with a low glycemic index improves blood glucose and lipid control in patients with diabetes. To study the distribution and determinants of diet glycemic index, we obtained two 3-d diet records from 342 free-living subjects with non-insulin-dependent diabetes. Mean +/- SD 24-h intakes were as follows: energy, 7170 +/- 1890 kJ; fat, 33.6 +/- 6.5% of energy; protein, 20.1 +/- 3.2% of energy; available carbohydrate, 45.3 +/- 7.2% of energy; and dietary fiber, 17.2 +/- 6.4 g. Diet glycemic index values (85.4 +/- 4.55, range, 70-97.8) were normally distributed. Diet glycemic index was inversely associated with intake of simple sugars, whether expressed in grams (r = -0.426), percent of energy (r = -0.446), or percent of carbohydrate (r = -0.453, P < 0.001). By step-wise-multiple-linear regression, grams carbohydrate and percent protein were also independently related to diet glycemic index. Differences in diet glycemic index between men and women, and between subjects on different types of diabetes therapy were explained by differences in intake of simple sugars.

The general and ophthalmologic eligibility criteria were applied in the course of formal screening of selected members of clinic populations at the six treatment centers between August 1980 and November 1981. Patients eligible on the grounds of the history and general physical examination underwent a detailed ophthalmologic examination and determination of C-peptide status. Initial rates of recruitment were slow, which occasioned modifications of the eligibility criteria and a prolongation of the recruitment phase. All six clinics approached their goal of at least six patients in each of the continuous subcutaneous insulin infusion (CSII) and conventional insulin treatment (CIT) groups, with a final total of 70 randomized subjects. The method of paired randomization was acceptable, but led to some delay during periods of slow recruitment activity. Data from two patients who chose to drop out of the study shortly after randomization are included in the baseline characteristics. There was no difference between treatment groups with respect to age or duration of known diabetes, body weight, systolic blood pressure, proportion of cigarette smokers, retinopathy level as assigned by analysis of stereofundus photographs, or microaneurysm counts performed on fluorescein angiograms. A trend toward milder retinopathy in the CIT group proved to be statistically insignificant. Subsequent assessment of stereofundus photographs at the Fundus Photograph Reading Center indicated that six patients were misclassified by treatment center ophthalmologists with respect to ophthalmologic eligibility. We conclude that recruitment goals were met and randomization was successful.

Control of glycemia by means of continuous subcutaneous infusion of insulin (CSII) was examined in insulin-dependent diabetes mellitus (IDDM). A battery-powered portable infusion pump was employed to deliver insulin at a constant basal rate designed to maintain plasma glucose within the normal range in the postabsorptive state, and empirically determined supplementary infusions of insulin were delivered before meals by the same system with the objective of maintaining excursions of plasma glucose within the normal range during absorption of a meal. The effects of CSII were compared with those of optimized conventional treatment using twice daily injections of mixed intermediate-acting and crystalline insulins in the same groups of volunteers in short term (1 wk) studies in hospital and in longer term (1 to 7 mo) studies with unrestricted activity under normal conditions after leaving hospital. The control of glycemia obtained with CSII in hospital was closely approximated by optimized conventional treatment under these conditions. In studies in hospital, continued infusion of insulin by the CSII program at basal rates with omission of meals and with vigorous exercise did not result in hypoglycemia. Abrupt cessation of CSII for 12 h overnight resulted in moderate ketoacidosis, which was rapidly corrected on resumption of insulin infusion. After the subjects were discharged from hospital, their mean postabsorptive plasma glucose concentrations and mean excursions of plasma glucose after ingestion of meals were maintained within normal limits with CSII but not with optimized conventional therapy. The control of glycemia with CSII was associated with significant reduction of daily dose of insulin by comparison with conventional treatment. During CSII, plasma free immunoreactive insulin (IRI) concentrations were in the normal range in the postabsorptive state. The supplementary doses of insulin before meals with the CSII program were shown to be essential for control of glycemia and were associated with dose-related increments of plasma free IRI, which were detectable within 15 min of delivery, rose to peaks at between 60 and 90 min, and declined to baseline at between 3 and 4 h. It is concluded that the management of IDDM by CSII is effective and safe and provides normalization of mean diurnal plasma glucose concentration through prolonged unrestricted activities under everyday conditions. The treatment can be maintained by the unaided subject and permits the undertaking of long term studies of its effects on the complications of diabetes mellitus.

Administration of cyclosporine resulted in reduced insulin requirements and improved glycemic control in patients with insulin-dependent diabetes mellitus of recent onset, but the drug was less effective in young children. Renal toxic effects and other problems related to therapy resolved after discontinuation of the drug. Sustained remission seemed dependent on continued administration of cyclosporine. Although short-term control of diabetes may be achieved in some patients, more studies are needed to determine whether cyclosporine can be given safely as maintenance therapy to maintain glycemic control and prevent the long-term consequences of the disease.

Continuous subcutaneous insulin infusion (CSII) has been compared with conventional insulin injection treatment (CIT) supplemented by self-monitoring of capillary blood glucose (SMBG) in 18 nonobese adults with insulin-dependent diabetes mellitus (IDDM). Mean daily insulin dosage and rates of hypoglycemia were similar during CSII (duration of treatment 36 ± 2 wk mean ± SE) and CIT (31 ± 1.6 wk). On the basis of fasting C-peptide concentrations and postintravenous glucagon increments of < 0.1 pmol/ml, subjects were classified C-peptide negative (CP NEG) (N = 11), or C-peptide positive (CP POS) (N = 7). Relative to CIT, CP NEG subjects on CSII had significant decreases in premeal/bedtime and postmeal plasma glucose concentrations and glycosylated hemoglobin (percent of total). CP POS patients during each of CSII and CIT showed glycemic responses equivalent to those of CP NEG patients on CSII. In neither group could results be explained on the basis of improved beta cell function. Thus, therapeutic advantage of CSII was not apparent in IDDM adults retaining significant C-peptide activity.

In 68 newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) whose treatment included cyclosporin (CyA) the prevalence and mean titre of islet cell cytoplasmic antibodies (ICA) fell faster than they did in the 56 who received only insulin. However, in the CyA-treated patients the prevalence or titre of ICA at diagnosis did not correlate with beta-cell function as measured by glucagon-stimulated C-peptide levels; improvement and recovery of beta-cell function after 30 days of CyA therapy occurred despite the continued presence of ICA; and CyA-induced remission of IDDM (ie, glucagon stimulated plasma C-peptide levels greater than 0.6 pmol/ml) was not predicted by nor coincident with disappearance of ICA. Therefore, although CyA therapy was associated with a higher than expected frequency of remission and faster disappearance of ICA, the two observations were not temporally and may not be causally related. ICA should not be used to identify the target population for or to predict response to immunosuppressive therapy. The contribution of ICA to the pathogenesis of beta-cell destruction in IDDM needs serious re-examination.

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.

The results of epidemiological and clinical studies of diabetes in man and of studies of experimental diabetes in animals provide strong evidence: (1) that insulin-dependent diabetes mellitus is due to absolute or severe deficiency of insulin; (2) that replacement treatment with insulin is potentially capable of normalizing the metabolic abnormalities; and (3) that normalization of the metabolic abnormalities can be expected to prevent or ameliorate the complications of the disease. However, consideration of the problems involved in replacement treatment with insulin raises practical and physiological questions regarding the appropriate patterns and routes of delivery of the hormone. Studies with glucose-controlled automatic infusion systems delivering into systemic or portal vessels point to the question whether the homeostatic mechanism can be viewed as one dominated by the responses of the endocrine pancreas to glucose. Nevertheless, empirical studies with non-glucose-controlled portable programmed infusion systems delivering insulin by intravenous, subcutaneous, or intraperitoneal routes have suggested that these techniques can produce near-normoglycemia under everyday conditions in a high proportion of insulin-dependent diabetic subjects. The blood levels of biologically active insulin resulting from these treatments are not higher, and may be lower, than those with conventional depot injection therapy. It appears also that the results of intensive depot injection therapy making use of 3 or 4 injections day-1 of crystalline and intermediate-acting insulins can approximate the effects of insulin infusion treatment. It is argued that the intensive insulin treatment regimens with continuous or intermittent use of the subcutaneous route of delivery can be viewed as options in the management of insulin-dependent diabetes mellitus when adequate supervision and monitoring is available, and that clinical systems fulfilling these conditions must be provided.

The advantages of a multicenter trial can easily be lost if results from individual centers cannot be safely combined for statistical analysis. One objective of the Kroc Study was to develop methods that would allow valid amalgamation of results from laboratories at the six clinical centers and a central biochemical laboratory at the University of Newcastle upon Tyne. Responsibilities of the local laboratories, in addition to measurement of plasma glucose, creatinine, and glycosylated hemoglobin, were to obtain and prepare samples for measurement of plasma glucose, glycosylated hemoglobin, and serum lipids at the central laboratory, of C-peptide at the University of Chicago, and to collect and prepare samples for measurement of urinary albumin excretion at Guy's Hospital. The central laboratory was additionally to provide a system to ensure the comparability of plasma glucose determinations between and within centers, and to advise on common procedures for sample handling. Major problems were encountered with sample labeling, dispatch, and transport to the central laboratory. Although central determinations of plasma glucose and serum lipids were still possible in transported specimens, central assay of glycosylated hemoglobin proved inaccurate and useless. Compliance with the plasma glucose quality control program was variable among centers. Although the difference between the centers recording the highest and lowest values was 24.6% of the mean estimate of plasma glucose level, correlation between local and central plasma glucose determinations was good (r = 0.99, see pages 22-26).(ABSTRACT TRUNCATED AT 250 WORDS)

A program designed to achieve normal plasma glucose concentrations before meals was tested in 83 insulin-dependent diabetic women during 110 pregnancies. The women rigidly controlled their carbohydrate intake but not their total energy intake, and twice daily they injected a combination of short-acting (Toronto) and intermediate-acting (NPH or Lente) insulin. Obstetric care was highly individualized and was aimed at avoiding or minimizing the impact of complications, such as hypertension, on the fetus and ensuring fetal lung maturity before delivery. The mean plasma glucose levels before meals (+/- standard error of the mean) were 136 +/- 9, 117 +/- 5 and 101 +/- 2 mg/dl during the first, second and third trimesters respectively. Obstetric complications included hypertensive disease of pregnancy (in 30.0%) and hydramnios (in 16.4%). The mean gestational age (+/- standard deviation [SD]) was 38.1 +/- 1.8 weeks, the cesarean section rate 45.4% and the mean stay in hospital for diabetes control before delivery (+/- SD) 15.7 +/- 9.6 days. The perinatal mortality rate was 0.9%. Neonatal problems included congenital anomalies in 3.6%, somatomegaly in 24.6%, hypoglycemia in 26.5%, hypocalcemia in 17.3% and hyperbilirubinemia in 39.4%. There were nine cases (8.2%) of the respiratory distress syndrome, four (3.6%) of which were severe. These findings lend support to the importance of a policy aimed at achieving normoglycemia and fetal lung maturity before delivery, goals that are attainable without lengthy antenatal hospitalization.

Eighteen lean adult volunteers with insulin-requiring diabetes mellitus attempted to achieve normoglycemia using continuous subcutaneous insulin infusion (CSII) or conventional insulin therapy (CIT) in a randomized crossover trial of 68 +/- 2.5 weeks (mean +/- SEM) duration. As reported (Diabetes Care 8: 447-55, 1985) the group with absent to low beta-cell function (C-peptide negative, n = 11) attained mean post-absorptive normoglycemia only during CSII vs CIT (p less than 0.05). Only following CSII was this without change in post-absorptive serum triglyceride concentrations (-4 +/- 5.6 vs 12 +/- 4.7 mg/dl; -0.04 +/- 0.6 vs 0.14 +/- 0.05 mM, p less than 0.05) or body weight (0.01 +/- 0.02 vs 0.05 +/- 0.01 kg/week, p less than 0.05). In the group with glucagon stimulated serum C-peptide 100-400 pmol/L (C-peptide positive) responses to CSII or CIT were equal. As total daily insulin dosage (0.05 +/- 0.04 U/kg/day) was the same under all conditions, to explain the efficacy of CSII, glucoregulatory hormone responses were examined. Pre- and post-test breakfast serum free immunoreactive insulin and plasma glucagon concentrations were essentially unaffected by C-peptide or treatment status. Erythrocyte 125I-insulin binding was decreased in the C-peptide negative group only during CSII (8.6 +/- 0.5 vs 10.1 +/- 0.7%, p less than 0.005); C-peptide positive group receptor binding was consistently low (8.2 +/- 0.8, 8.4 +/- 0.9%). During CIT using intermediate-acting insulin post-lunch peripheral venous insulin failed to rise (p less than 0.05), but in the C-peptide positive group, on the basis of C-peptide responses to breakfast an undetected rise and fall of portal venous insulin was assumed to coincide with each meal. Thus, only during CIT in the C-peptide negative group, which received on average 6.4/wk/subject fewer pre-meal regular insulin boluses (p less than 0.01), was the frequency of meal-related change in portal insulinemia decreased. Consistent meal-related fluctuations in portal insulinemia inherent in CSII hepatocytes sensitized by a post-receptor mechanism to the suppressive effects of insulin on glucose output and thus were indirectly responsible for the observed improvement in glycemic control and lipid metabolism in the C-peptide negative group.

The recognition of secretion as a physiological regulator of the exocrine secretions of the pancreas in 1902 led to generalization of the concept of hormonal control of digestive sections,1 and excited interest in such mechanisms as possible mediators of the functions of the pancreas in control of glycemia.2 According to the “incretin” hypothesis, hormones released from the gastrointestinal tract in response to ingestion of nutrients serve to activate the glucoregulatory function of the pancreas.3 With the later identification of insulin as a hormonal effector of these functions, the hypothesis was adapted by suggesting that incretin stimulates insulin secretion. A variety of experiments with crude extracts of gastrointestinal tissues yielded conflicting results4, and following the recognition of direct effects of glucose on the release of insulin interest in incretin waned. However in the early 1960’s it was recognized that the glycemic stimulus to insulin secretion cannot account for differences in blood insulin levels after enteral and parenteral administration of glucose, which are also accompanied by apparent differences in glucose disposa1.5,6 These observations revived the hormonal hypothesis for stimulation of the beta cells by gastrointestinal factors, and a renewed search for candidate peptides that might fill this role was undertaken. Studies of these phenomena have yielded evidence related to the pathophysiology of disorders of intermediary metabolism in diabetes, with indications of differences between Type I and Type II diabetes in this context. However, before discussing the identification of incretins it is necessary to consider the question whether the hypothetical enteroinsular axis is necessary or sufficient to account for differences in glucose homeostasis observed with enteral and parenteral administration of the sugar, and whether mechanisms other than those simply dependent on portal perfusion of the liver and/or the recognized effects of insulin must be invoked.

The incidence of death due to heart disease in diabetics treated with phenformin was double that of other groups in the University Group Diabetes Program of the U.S.A.1 Despite some insights into the actions of oral hypoglycemic agents this observation has not been explained. The human diabetic myocardium contains large amounts of glycogen, consumes glucose at rates comparable to those of normal hearts, may experience high serum insulin levels, and is subject to ischemic disease. We have compared the effects of phenformin with insulin on tissue glycogen levels in a model of coexisting hyperinsulinemia and hyperglycemia in which glucose was infused at a rate 6 times greater than that needed to satisfy energy needs.

In November 1982 a “pilot” (uncontrolled) clinical trial of the effects of the administration of ciclosporin to volunteer subjects with recent onset Type I diabetes mellitus was initiated. The rationale and preliminary findings in this study have been published earlier [1]. In this presentation we summarize further experience in this ongoing trial.

The general and ophthalmologic eligibility criteria were applied in the course of formal screening of selected members of clinic populations at the six treatment centers between August 1980 and November 1981. Patients eligible on the grounds of the history and general physical examination underwent a detailed ophthalmologic examination and determination of C-peptide status. Initial rates of recruitment were slow, which occasioned modifications of the eligibility criteria and a prolongation of the recruitment phase. All six clinics approached their goal of at least six patients in each of the continuous subcutaneous insulin infusion (CSII) and conventional insulin treatment (CIT) groups, with a final total of 70 randomized subjects. The method of paired randomization was acceptable, but led to some delay during periods of slow recruitment activity. Data from two patients who chose to drop out of the study shortly after randomization are included in the baseline characteristics. There was no difference between treatment groups with respect to age or duration of known diabetes, body weight, systolic blood pressure, proportion of cigarette smokers, retinopathy level as assigned by analysis of stereofundus photographs, or microaneurysm counts performed on fluorescein angiograms. A trend toward milder retinopathy in the CIT group proved to be statistically insignificant. Subsequent assessment of stereofundus photographs at the Fundus Photograph Reading Center indicated that six patients were misclassified by treatment center ophthalmologists with respect to ophthalmologic eligibility. We conclude that recruitment goals were met and randomization was successful.

In this brief review of regulatory function of gastroenteropancreatic peptides in control of intermediary metabolism in normal and diabetic states, with and without mediation by insulin and/or glucagon, a variety of possible mechanisms have been described. It is apparent that the pharmacologic actions of the peptides identified in various locations provide models for multiple routes of delivery and modes of action of effectors in this control system. Examples already exist of each of the hypothetical mechanisms illustrated in the scheme in Figure 4. It is clear that a great deal of study will be necessary in identification of the active agents and assessment of their importance in the physiology of intermediary metabolism. With respect to the possible pathophysiologic roles of regulatory peptides of the gastroenteropancreatic system other than insulin and glucagon, a number of considerations of Type I and Type II diabetes have been raised. The balance of the evidence suggests that Type I diabetes may be viewed as an insulin deficiency syndrome, so that physiological replacement with insulin may be expected to result in correction of the metabolic abnormalities. Nevertheless, the difficulty of physiologic replacement treatment, which may call for portal delivery of insulin, is well recognized, and abnormalities secondary to insulin deficiency even in "well-treated" Type I diabetes may be compounded by the effects of gastroenteropancreatic peptides other than insulin, exerted through the various mechanisms discussed. In Type II diabetes mellitus, current understanding of the pathophysiology is much less complete and no convincing description of the etiology exists. The various metabolic actions of the gastroenteropancreatic peptides, and their interactions with other endocrine, paracrine and nervous regulatory mechanisms, represent a dauntingly complex control system. The elucidation of this system can provide fertile ground for the development and testing of hypotheses for the pathophysiology of disordered metabolism in Type II diabetes mellitus.