John Dupre

CYCLOSPORIN PREVENTS DIABETES IN BB WISTAR RATS

Cyclosporin (U.S.A.N. cyclosporine) was used prophylactically to suppress the development of insulin-dependent diabetes mellitus in BB Wistar rats. In this rat strain diabetes spontaneously develops between 60 and 120 days of age and this condition resembles human type 1 diabetes. In 30 (75%) out of 40 control rats glycosuria and hyperglycaemia developed and these rats became insulin-dependent. Their pancreases showed partial to complete destruction of the islets of Langerhans by lymphocytic infiltration. None of the 40 cyclosporin-treated rats became diabetic and their pancreases were histologically normal. Serum cyclosporin was monitored in a subgroup and the dosage was adjusted accordingly; neither hepatotoxicity nor nephrotoxicity was seen in the treated animals.

Glucagon-Like Peptide I Reduces Postprandial Glycemic Excursions in IDDM

Effects of human glucagon-like peptide I (GLP-I)(7–36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 ± 1.4 years; body mass index, 24.7 ± 0.7 kg/m2; duration of diabetes, 3.2 ± 0.8 years; insulin dose, 0.41 ± 0.05 U · kg−1· day−1; meal-stimulated CP, 1.0 ± 0.2 nmol/l [means ± SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol · kg−1 · min−1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol · kg−1 · min−1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol · kg−1 · min−1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0–60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying. This effect of the peptide on blood glucose levels after meals may have therapeutic implications in both IDDM and non-insulin-dependent diabetes.

Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR)

Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for β cell autoimmunity, clinical type 1 diabetes, or both. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) is an international, randomized, double-blind, controlled intervention trial designed to answer the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of type 1 diabetes later in childhood. In our pilot study, weaning to a highly hydrolyzed formula decreased by ≈ 50% the cumulative incidence of one or more diabetes-associated autoantibodies by a mean age of 4.7 y. This finding was confirmed in a recent follow-up analysis to 10 y of age. Currently, the full-scale TRIGR takes place in 77 centers in 15 countries. The TRIGR initially recruited 5606 newborn infants with a family member affected by type 1 diabetes and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. All recruited mothers were encouraged to breastfeed. The intervention lasted for 6-8 mo with a minimum study formula exposure time of 2 mo, and hydrolyzed casein and standard cow milk-based weaning formulas were compared. Eighty percent of the participants were exposed to the study formula. The overall retention rate over the first 5 y was 87%, and protocol compliance was 94%. The randomization code will be opened when the last recruited child turns 10 y of age (ie, in 2017).

Follow-up of cyclosporin A treatment in type 1 (insulin-dependent) diabetes mellitus : lack of long-term effects

SummaryIn the Canadian/European randomized controlled study on cyclosporin A (CsA) in recent onset Type 1 (insulin-dependent) diabetes, treatment with the immunosuppressive drug had increased and maintained Beta-cell function and clinical remission during the first 12 months. Following discontinuation of the study drug and double-blinding after a mean of 13.8 months former CsA patients doubled the daily insulin dose within 6 months reaching the level of former placebo patients. The difference in Beta-cell function between the two groups was also lost. Metabolic control (HbA1c) was transiently worse in the former CsA group. Adverse effects of cyclosporin A on systolic blood pressure, haemoglobin levels, serum potassium and creatinine levels also remitted during that time. We conclude that treatment with cyclosporin A for a mean of 13.8 months had no long-lasting effect on the course of Type 1 diabetes persisting beyond drug discontinuation.

The Effects of Erythromycin in Patients Treated with Cyclosporine

Excerpt The clinical introduction of cyclosporine heralded a new class of immunoregulatory drugs with specific inhibitory effects on T-cell functions and elaborated products (1, 2). Cyclosporines ...

Determinants of Clinical Remission in Recent-Onset IDDM

Objective— To assess the relationship of SI and insulin secretion (C-peptide levels) to remission status in recent-onset IDDM. Research Design and Methods— We followed 22 newly diagnosed patients, of whom 16 received immunomodulatory treatment with low-dose (5 mg·kg−1·day−1) CsA and/or short-term (72 h) methylprednisolone and 6 received standard insulin treatment, at 3-mo intervals for 12 mo. Insulin secretion was assessed by C-peptide levels and AIRglu, which was determined as the area under the insulin response curve, above the fasting level, from 0–10 min after a 0.3 g·kg−1·i.v. glucose xbolus. SI was assessed by the minimal model technique applied to a frequently sampled IVGTT. Clinical remission was defined in those patients who maintained normal range GHb and capillary blood glucose levels <7.8 mM premeal without insulin therapy for a minimum of 14 days. Results— The rate of clinical remission was not different with immunomodulatory treatment; nor were the metabolic parameters of plasma C-peptide levels, AIRglu, and S1 different in the treatment groups. The mean plasma C-peptide level improved significantly at 3 mo and was maintained to 12 mo. AIRglu was grossly subnormal throughout, but a significant improvement was seen at 3 and 6 mo. Mean SI was normalized at 3 and 6 mo but not maintained beyond 9 mo. The maximum rate of clinical remission was seen at 6 mo. Conclusions— Clinical remission in recent-onset IDDM patients is associated with improvement in both insulin secretion and SI. Although the improvement in basal C-peptide persisted, AIRglu increased only transiently and declined as loss of remission occurred in most patients. Loss of remission to an insulin-requiring state is associated with a decrease in SI.

Breastfeeding patterns of mothers with type 1 diabetes: results from an infant feeding trial

Both the initiation and maintenance of breastfeeding have been reported to be negatively affected by maternal type 1 diabetes (T1D). The aim of this study was to prospectively examine the breastfeeding patterns among mothers with and without T1D participating in a large international randomized infant feeding trial (TRIGR).

Subcutaneous Glucagon-Like Peptide I Combined With Insulin Normalizes Postcibal Glycemic Excursions in IDDM

OBJECTIVE To determine whether a subcutaneous injection of truncated glucagon-like peptide 1 (tGLP-I)(7–36) amide that delays gastric emptying transiently can prevent postcibal hyperglycemia in IDDM without causing hypoglycemia when administered with insulin. RESEARCH DESIGN AND METHODS The postcibal increase in plasma human pancreatic polypeptide (HPP) was used as a presumptive indicator of arrival of nutrient in the small intestine. Studies in seven normal human volunteers established the dose of tGLP-I that delayed the postcibal rise in HPP by 30 min. This dose was tested in six patients with IDDM with a range of residual endogenous insulin secretion. The patients received a standard liquid test meal with or without subcutaneous tGLP-I and their usual dose of regular insulin before the meal. Blood samples collected at timed intervals were assayed for plasma concentrations of glucose, C-peptide (CP), immunoreactive insulin (IR1), HPP, and glucagon (GLN). RESULTS In normal subjects after administration of tGLP-I, postcibal plasma glucose concentration at 20 min fell below fasting levels in a dose-dependent manner. At 10 and 20 min, transient increments in plasma CP and IRI, and decrements in GLN, occurred. Subsequently, through 60 min, the excursions of plasma HPP, CP, and IRI were negatively correlated to the dose of tGLP-I. In subjects with IDDM, the selected dose of tGLP-I given with insulin before the meal delayed the plasma HPP response for 30 min and confined excursions of plasma glucose within the range observed in normal subjects receiving saline injections, whereas administration of insulin with saline injections in IDDM was followed by supranormal increases of plasma glucose. In IDDM, this dose of subcutaneous tGLP-I had no effect on plasma CP, IRI, or GLN. CONCLUSIONS In normal subjects, transient hypoglycemia after injections of tGLP-I with a meal was associated with transient stimulation of insulin secretion and inhibition of glucagon secretion. These actions together with delayed gastric emptying may account for the hypoglycemia, but other unidentified mechanisms cannot be excluded. In the subjects with IDDM, the selected relatively low dose of tGLP-I delayed excursions of plasma HPP as in normal subjects, but did not reduce the plasma glucose below the fasting level and had no effect on plasma CP, IRI, or GLN. However, injection of tGLP-I reduced the postcibal glycemic excursion and confined it within the normal range. Thus, in IDDM, a pharmacological dose of subcutaneous tGLP-I that presumably delays gastric emptying by ∼30 min can normalize glycemic excursions after a meal when given in combination with insulin. Because this cannot be achieved with regular insulin alone without risk of hypoglycemia, this combination of glucoregulatory peptides has therapeutic potential in insulin-requiring diabetes.

Insulin Resistance in Latent Autoimmune Diabetes of Adulthood

Abstract: Insulin resistance in patients with latent autoimmune diabetes of adulthood (LADA) was determined by homeostasis model assessment (HOMA). LADA was identified by a clinical phenotype of type 2 diabetes with antibodies to GAD65 and/or IA‐2/ICA512. All patients were managed with insulin therapy. Insulin resistance in LADA was lower than in antibody‐negative type 2 diabetes, higher than in normal humans and in recent‐onset type 1 diabetes, and similar to that in long‐term type 1 diabetes. Mean values for HOMA varied linearly with mean values for BMI, which accounted for much of the insulin resistance in these forms of diabetes. LADA resembles long‐term type 1 diabetes with respect to insulin resistance and BMI, but occurs at an older age.

Metabolic Changes in Alzheimer's Disease

Patients with Alzheimers disease (AD) and matched controls fasted for 24 hours, and serial glucose, pyruvate, lactate, β‐hydroxybutyrate, acetoacetate, insulin, and glucagon levels were measured. Patients with AD showed a glucose insulin correlation pattern over the 24 hours that differed from the control group. These differences may be secondary to weight loss or to other metabolic or nutritional factors affecting the AD patients.