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Aims After initiation of treatment in Type 1 diabetes, a period with lower insulin requirement often follows, reflecting increased insulin sensitivity and improved insulin secretion. We explored if efficiency of proinsulin processing is associated with the remission phenomenon. Methods Seventy-eight patients with new-onset Type 1 diabetes were followed prospectively for 3 years. Daily insulin dosage, HbA1c, plasma glucose, proinsulin, C-peptide, glucagon concentrations and islet antibodies were determined at diagnosis and after 3, 6, 9, 12, 18, 24, 30 and 36 months. We studied remission, defined as an insulin dose ≤ 0.3 U kg-1 24 h-1 and HbA1c within the normal range, in relation to the above-mentioned variables. Results A rise and subsequent decline in plasma proinsulin and C-peptide concentrations was observed. Forty-five per cent of the patients experienced remission at one or more times, characterized by higher proinsulin and C-peptide levels, and lower proinsulin / C-peptide ratios, indicating more efficient proinsulin processing, compared with those not in remission. Nonremission also tended to be associated with higher glucagon values. Patients entering remission were more often men, had higher BMI at diagnosis, but did not differ at baseline with respect to islet antibody titres compared with patients with no remission. Conclusions Remissions after diagnosis of Type 1 diabeteswere associated with lower proinsulin / C-peptide ratios, suggesting more efficient proinsulin processing, and tended to have lower glucagon release than non-remissions. This indicates that, in remission, the residual islets maintain a secretion of insulin and glucagon of benefit for control of hepatic glucose production. [ABSTRACT FROM AUTHOR]

Hyperproinsulinemia is associated with obesity and type 2 diabetes. We explored the after-meal dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in patients treated with bileopancreatic diversion with duodenal switch (BPD-DS) surgery compared with normal-weight controls [body mass index (BMI)±SD, 23.2 ± 2.4 kg/m2]. Ten previously morbidly obese (BMI±SD, 53.5 ± 3.8 kg/m2) patients free from diabetes who had undergone BPD-DS (BMI±SD, 29.0 ± 5.2 kg/m2) 2 years earlier were recruited. A standardised meal (2400 kJ) was ingested, and glucose, proinsulin, insulin, free fatty acids and triglycerides (TGs) were determined during 180 min. Follow-up characteristics yearly on glucose, lipids, creatinine and uric acid over 3 years after BPD-DS are presented. Fasting glucose and insulin were lower, 0.4 mmol/L and 4.6 pmol/L, respectively, in the BPD-DS group despite higher BMI. Fasting proinsulin was similar in both groups. Postprandial area under the curve (AUC) for glucose, proinsulin and insulin did not differ between the two groups ( p = 0.106–734). Postprandial changes in glucose, proinsulin and insulin were essentially similar but absolute concentrations of proinsulin and insulin were lower in the later phases in the BPD-DS group ( p = 0.052–0.001). Postprandial AUC for TGs was lower in the BPD-DS group ( p = 0.005). Postprandial changes in TGs were lowered in the intermediate phase ( p = 0.07–0.08) and in the late phase (0.002). Follow-up data showed markedly lowered creatinine and uric acid after BPD-DS. BPD-DS surgery induces a large weight loss and lowers, close to normal, postprandial responses of glucose, proinsulin and insulin but with marked lowering of TGs. [ABSTRACT FROM AUTHOR]

Background: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined the early effects on glucose and lipid metabolism and on certain adipose tissue and inflammatory markers during treatment for 28 days. Methods: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in the first week, 500 mg twice daily during week 2 and 1000 mg twice daily during weeks 3 and 4. Results: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared to baseline. Insulin sensitivity, as derived from the OGTT by Gutt’s index, was increased. Reductions in fasting plasma glucose, total cholesterol and low-density lipoprotein cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt’s index, and showed strong trends for PAI-1 and leptin. Conclusions: The data demonstrate that in type 2 diabetes, metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue. [ABSTRACT FROM AUTHOR]

Presents the study "Temporary Preservation of β-Cell Function by Diazoxide Treatment in Childhood Type 1 Diabetes." Reason behind the partial preservation of β-cell function in childhood type 1 diabetes; Definition of type 1 diabetes; Effect of diazoxide treatment on patients with type 1 diabetes; Results of the study.

Aims/hypothesis. We aimed to study the effects of two KATP channel openers (KCO), diazoxide and the more potent compound NNC 55-0118, on beta-cell suppression and/or toxicity induced by alloxan, sodium nitroprusside and IL-1β. Methods. Islets from rats were exposed to 0.3 mmol/l diazoxide or NNC 55-0118 for 30 min and either alloxan (0.5 mmol/l), sodium nitroprusside (0.5 mmol/l) or IL-1β (12.5 or 25 U/ml) were added and the incubation continued for 30 min. Islets were then washed and incubated for 24 h before examination. Results. After exposure to alloxan, islets showed reduced glucose oxidation rate and impaired glucose-stimulated insulin release. NNC 55-0118 counteracted the effects of alloxan, while diazoxide was less effective. After treatment with sodium nitroprusside, islet glucose oxidation rates were reduced and this was prevented by pretreatment with NNC 55-0118. In short-term experiments the potassium channel openers (KCOs) did not influence the IL-1β effect on insulin secretion. However, long-term addition (24 h) of NNC 55-0118 counteracted IL-1β induced inhibition of the glucose oxidation rate. It was shown, using the fluorescent probe JC-1, that the mitochondrial membrane potential was reduced by the potassium channel openers (KCOs), most strongly by NNC 55-0118. Nevertheless culture with KCOs for 72 h did not cause irreversible damage to the islets. Conclusion/interpretation. Potassium channel openers (KCOs), in particular NNC 55-0118, prevented the toxic effects of alloxan and sodium nitroprusside. IL-1β mediated suppression was reduced by NNC 55-0118 provided the long-term addition of the potassium channel opener (KCO). The protective mechanism of potassium channel openers (KCOs) might involve a decrease of the mitochondrial membrane potential. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is the result of a chronic inflammatory process that causes elimination of insulin-producing beta-cells, resulting in insulin deficiency and hyperglycemia. The destruction is thought to be mediated by an autoimmune process involving cytotoxic T cells recognizing beta-cell autoantigens in the context of MHC class I-peptide complexes. Autoantibodies against insulin, glutamic acid decarboxylase (GAD) and and ICA 512 protein tyrosine phosphatase are frequently found. At the clinical onset of diabetes, some beta-cells remain and after initiation of insulin treatment, most patients enter a period of remission, a phenomenon that may reflect diminished autoimmune activity in the islets. There is evidence to suggest that a further loss of beta-cells can be curtailed, and that patients, who maintain endogenous insulin production, have better glycemic control and less risk of complications. This is the basis for our current research. We are characterizing the remission phenomenon in epidemiological studies in order to identify determinants of beta-cell survival. In randomized, prospective multicenter trials, we are evaluating the benefit of beta-cell secretory rest for rescue of insulin production in patients at onset of clinical disease. In experimental studies, we are investigating expression and regulation of the key molecules of an autoimmune process in the islets. Further, selective beta-cell damage is induced in rat islets and measures to enhance beta-cell resistance and repair are being examined. We have recently identified a remarkable, beta-cell protective effect of K[sub ATP]-channel opening. [ABSTRACT FROM AUTHOR]

Objectives: To describe the course of clinical remission in adult patients (16-50 years of age) with type 1 diabetes and to identify factors predictive of the occurrence and length of remission.Design: A retrospective cohort study.Subjects: Sixty-two consecutive patients (43 men and 19 women) with new onset IDDM, 27 +/- 8 years at diagnosis and treated with multiple insulin injections from the beginning.Setting: Department of Medicine, Uppsala University Hospital and Orebro Medical Centre, Sweden.Main Outcome Measures: Length and occurrence of remission (defined as maintenance of HbA1c < or = 6.5% and an insulin dosage of < or = 0.4 U kg-1 day-1 for a minimum of 1 month) in relation to nine biochemical and clinical factors at diagnosis.Results: Sixty-one per cent of the patients entered remission. The duration of remission was longer in males than females (10 +/- 12 vs. 2 +/- 3 months; P < 0.01). Male gender, normal serum bicarbonate at onset and a short time of classic symptoms before onset were predictive markers (P < 0.01; P < 0.05 and P < 0.01, respectively) for longer duration of remission. Low serum bicarbonate levels at onset were associated with lower occurrence of remission. Blood glucose, body mass index (BMI), and age at diagnosis did not influence the occurrence or the duration of remission.Conclusions: In most adult patients with new onset of type 1 diabetes remission is induced when using multiple insulin injection therapy. Male patients seem particularly prone to remission, and the length and extent of beta-cell strain prior to diagnosis strongly influences its course. [ABSTRACT FROM AUTHOR]

GAD is a major islet cell autoantigen in human type 1 diabetes mellitus. Autoantibodies are preferentially directed against the 65-kD isoform of the enzyme which is the only form expressed in human islets of Langerhans. The NOD mouse is a spontaneous model of type 1 diabetes, frequently employed in studies dealing with the immunopathogenesis of the disease. In the present study the reactivity of sera from 34 prediabetic and 15 diabetic NOD mice was tested against GAD protein present in islets of Langerhans and cerebellum, and against recombinant, .semi-purified GAD-65 and GAD-67. A rabbit antiserum (K2) raised against GAD-67 could readily recognize the recombinant GAD-67 and the isoform present in rat and mouse islets and mouse brain. A MoAb (GAD-6) specific for the GAD-65 isoform reacted against the recombinant GAD-65 and the isoform present in rat islets and mouse brain, whereas no reactivity was observed when using mouse islets. However, when testing the NOD mice sera by immunohistochemistry, immunoprecipitation and Western blot, no reactivity against any of the isoforms of GAD could be detected. Using reverse transcription polymerase chain reaction (PCR), GAD-67 mRNA could be detected in mouse and rat islets and in mouse brain. GAD-65 mRNA could also be detected in rat islets and mouse brain, but apparently a much lower copy number is present in mouse islets. These findings stress important differences in the immune response occurring in the animal model NOD mouse compared with human type 1 diabetes, and emphasize that human and animal type 1 diabetes possibly represent the final outcome of several different etiological factors. [ABSTRACT FROM AUTHOR]

Abstract: Potassium channel openers (KCOs) decrease insulin secretion from β-cells. Some KCOs also protect against damage to β-cell function and type 1 diabetes in animal models. Previously we have found that the KCO NNC 55-0118 counteracted islet cell dysfunction, and this was associated with a lowering of the mitochondrial membrane potential (Δψ). Presently we aimed to explore whether inhibition of insulin secretion per se or rather inhibition of mitochondrial function correlates to counteraction of β-cell suppression. For this we used two novel KCOs (NNC 55-0321 and NNC 55-0462), which at certain concentrations have different actions regarding insulin secretion and the Δψ, with NNC 55-0321 being a potent inhibitor of Δψ and NNC 55-0462 being a potent inhibitor of insulin secretion. At 10μM NNC 55-0321, but not with NNC 55-0462, the islet ATP content and ATP/ADP ratio was acutely decreased. This was accompanied by a complete protection against streptozotocin-induced suppression of islet insulin secretion using the former KCO. In cardiac research KCOs have been used to induce an ischemic preconditioning (IPC) response. In line with an IPC-like mechanism we found that NNC 55-0321 induced an initial free oxygen radical formation, PKC-ɛ isoform activation and a subsequent phosphorylation of the survival promoting factor Akt. Thus, KCOs may elicit mitochondrial events that resemble classical IPC seen in cardiomyocytes, and this could explain the enhanced islet cell function observed. KCOs with this property may be particularly interesting compounds to study as a rescue therapy during acute episodes of β-cell suppression/destruction. [Copyright &y& Elsevier]