Evaluation of cellular and humoral autoimmunity before the development of type 1 diabetes in a patient with idiopathic CD4 lymphocytopenia

A 64‐year‐old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet‐specific autoimmunity. Anti‐glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti‐insulinoma‐associated antigen‐2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein‐reactive CD8⁺ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non‐diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8⁺ T cells, including the islet antigen‐specific CD8⁺ T cells that might contribute to autoimmune destruction of pancreatic β‐cells.     

The broad clinical phenotype of Type 1 diabetes at presentation

Immune‐mediated (auto‐immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. Indeed, as the adult‐onset form of autoimmune diabetes may resemble Type 2 diabetes, it is imperative to test for diabetes‐associated autoantibodies to establish the correct diagnosis. The therapeutic response can be predicted by measuring the levels of autoantibodies to various islet cell autoantigens, such as islet cell antibodies (ICA), glutamate decarboxylase 65 (GAD65), insulin, tyrosine phosphatase (IA‐2) and IA‐2β, and zinc transporter 8 (ZnT8) and evaluating β‐cell function. A high risk of progression to insulin dependency is associated with particular genetic constellations, such as human leukocyte antigen risk alleles, young age at onset, the presence of multiple autoantibodies, including high titres of anti‐GAD antibodies; such patients should be offered early insulin replacement therapy, as they respond poorly to diet and oral hypoglycaemic drug therapy. Hence, considering the broad spectrum of phenotypes seen in adult‐onset diabetes, treatment targets can only be reached by identification of immune‐mediated cases, as their management differs from those with classical Type 2 diabetes.     

Life table analysis of the risk of Type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers

Summary To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2–29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p <10^–5) than HLA-identity (10% and 7%, respectively, p <0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p<0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p <10^–7). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4⁺ subjects had the highest risk (70% after 8 years, predictive value 58%, p <10^–7) compared with islet cell antibody-positive DR3,4^– (37% and 20%, respectively) and islet cell antibody-negative DR3,4⁺ (5% and 3.6%, respectively). Furthermore, islet cell antibody-positive DR3,4⁺ siblings progressed to diabetes at a younger age (risk 84% by age 22 years vs 20% in islet cell antibody-positive DR3,4^– siblings, p <0.005). Siblings with moderate islet cell antibody levels who carry the DR3,4 antigens have been identified as a subgroup with increased risk and more rapid progression to Type 1 diabetes.     

Effect of sitagliptin on glucose control in type 2 diabetes mellitus after Roux‐en‐Y gastric bypass surgery

The present study was a 4‐week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl‐peptidase‐4 inhibitor, in persistent or recurring type 2 diabetes after Roux‐en‐Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self‐monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon‐like peptide‐1 and β‐cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m²), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β‐cell function did not differ between the placebo and sitagliptin groups at pre‐intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β‐cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose‐lowering effect, with no identified improvement in β‐cell function.     

Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus

Summary The differential diagnosis between Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes is complicated since no specific markers are available for either disease. In this study, 244 consecutive patients were diagnosed with diabetes mellitus during two years in Malmö (230000 inhabitants), corresponding to an incidence rate of 53·100000^–1·year^–1. Age, body mass index, HbA_1c, C-peptide, and levels of islet cell antibodies were determined at the clinical onset, and related to the classification at diagnosis and at follow-up (n=233) after a median time of 31 (range 1–49) months. After diagnosis, 42 of 244 (17%) were started on insulin while 202 of 244 (83%) were not. Islet cell antibodies were present in 25 of 42 (60%), and in 18 of 183 (10%), respectively. In the non-insulin treated group, patients with islet cell antibodies had lower body mass index (p<0.001), higher HbA_1c (p<0.004), and lower C-peptide (p<0.001) than patients without. At follow-up, 11 of 18 (61%) islet cell positive patients were changed to insulin treatment, as were six other patients. Insulin was discontinued in five initially insulin-treated but islet cell antibody negative patients. The sensitivity, specificity and predictive value for insulin treatment at follow-up were for islet cell antibody positivity; 72%, 96% and 84%, respectively, and for low C-peptide value; 60%, 96%, and 80%, respectively. Islet cell antibodies and low C-peptide at diagnosis of diabetes mellitus are concluded to be useful markers to predict insulin dependence.     

Islet cell and other organ-specific autoantibodies in all children developing Type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children

Summary The majority (about 90%) of children developing Type 1 (insulin-dependent) diabetes mellitus do not have a first-degree relative with the disease. Nearly all (389/405, 96%) children (0–14 years) in Sweden, who developed diabetes during one year, were therefore studied to compare islet cell, thyroid peroxidase, thyroglobulin, and gastric H⁺, K⁺-ATPase antibodies with 321 age, sex, and geographically matched, but non-related, control children. Islet cell (cytoplasmic) antibodies were found in 81% (316/389) of the patients and in 3% (9/321) of the control children (p<0.001). The median islet cell antibody levels were 70 (range 3–8200) Juvenile Diabetes Foundation (JDF) Units in the islet cell antibody positive patients, and 27 (range 17–1200) JDF Units in the control children (NS). Autoantibodies against thyroid peroxidase (8%), thyroglobulin (6%), and gastric H⁺, K⁺- ATPase (3%) were all increased in the patients compared with the control children, being 2% (p<0.001), 2% (p<0.01), and 0.3% (p<0.01), respectively. During an observation time of 20–34 months, two of the nine islet cell antibody positive control children developed Type 1 diabetes, after 8 and 25 months respectively, while the others remained healthy and became islet cell antibody negative. None of the islet cell antibody negative control children developed diabetes during the same time of observation. This first investigation of an unselected population of diabetic children and matched control children shows: that islet cell antibodies are strongly associated with newly diagnosed childhood diabetes, that other autoantibodies are more frequent among diabetic children than control children, and that the frequency of islet cell antibodies in the background population of children is higher than previously documented, and could also be transient, underlining that factors additional to islet cell antibodies are necessary for the later development of Type 1 diabetes.The names of the co-workers are listed in the Acknowledgement section     

Analysis of pathogenesis of juvenile new-onset diabetes

Background: Measurement of anti‐islet autoantibodies at the time of disease onset contributes greatly to the differentiation of Type 1A diabetes with HLA Class II subtyping also contributing. Methods: Blood samples were obtained from 900 patients with age from 1 month to 25 years (median age 11.1 years) within 2 weeks of diabetes onset to test anti‐islet autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma antigen (IA‐2AA), the zinc transporter‐8 (ZnT8AA), and islet‐cell antibodies (ICA). Polymorphisms of the HLA Class II gene were typed in 547 randomly selected patients. Results: Of the 900 subjects analyzed, 145 (16.1%) were negative for all five anti‐islet autoantibodies, and autoantibody negativity significantly increased with age: 10.2% (38/372) among children <10 years of age, 14.2% (46/325) in those 10–14 years of age, and 30.1% (61/203) in those >14 years of age (P < 0.001). The prevalence of IA‐2AA was the highest among young children. The prevalence of GADA increased with age while the prevalence of IAA was inversely correlated with age. At diagnosis, the subjects with negative antibodies had a higher body mass index (P < 0.001) and less high risk HLA genotype DR3‐DQ2/DR4‐DQ8 (P < 0.01). Conclusion: A large percentage of children and youths negative for all anti‐islet autoantibodies at the onset of diabetes are likely to have the non‐immune form, especially those without DR3/DR4 and obese patients. Among autoantibody‐positive Type 1A patients, IAA and GADA showed a reciprocal prevalence, suggesting differential disease pathogenesis.     

Islet transplantation in type 1 diabetes: hype,hope and reality – a clinician's perspective

The β‐cell replacement by islet transplantation is an attractive approach for normalizing blood glucose without hypoglycaemia in patient with type 1 diabetes mellitus (T1D). A pioneer study by the Edmonton group more than a decade ago showed that alloislet transplantation may result in insulin independence for at least 1 year after transplantation. This breakthrough excited researchers, physicians and patients, who felt that the ultimate goal of cure for T1D was at hand. Longer follow‐up of patients who underwent islet transplantation showed less favourable results, with only approximately 10% of the patients remaining insulin‐free 5 years after transplantation. In the last few years, progress has been made, and the success rate of islet transplantation has steadily increased. Important hurdles, however, related to limited tissue supply and need for life‐long immunosuppressive drugs have yet to be overcome. Herein, we review recent achievements in islet transplantation and the challenges that still need to be addressed before this procedure can become a standard therapy for T1D. Copyright © 2013 John Wiley & Sons, Ltd.     

Progressive deterioration of insulin secretion in Japanese type 2 diabetic patients in comparison with those who carry the S20G mutation of the islet amyloid polypeptide gene: A long‐term follow‐up study

Aims/Introduction: In order to clarify the enhanced β‐cell dysfunction in type 2 diabetic patients carrying the S20G mutation of the islet amyloid polypeptide gene (S20G‐patients), we first estimated the decline of insulin secretion in Japanese type 2 diabetic patients without the S20G mutation (non‐S20G‐T2D‐patients) by long‐term observation, and then compared it with that of the S20G‐patients. Materials and Methods: We followed 70 non‐S20G‐T2D‐patients (body mass index <30 kg/m²) for more than 10 years and six S20G‐patients for more than 5 years. We measured fasting C‐peptide (F‐CP) every 1–2 years and carried out a glucagon test at least once during the follow‐up period. F‐CP and a 5‐min value of C‐peptide after glucagon injection (5′‐CP) were used as the indices of insulin secretion. We excluded patients who had renal dysfunction and/or anti‐insulin antibodies in the insulin‐treated patients. The individual annual declines were calculated from the slopes of the regression lines between C‐peptide levels and duration (years after diagnosis). Results: The mean individual annual declines of both F‐CP and 5′‐CP were significantly greater in the S20G‐patients than the non‐S20G‐T2D‐patients (F‐CP; 0.047 ± 0.026 vs 0.011 ± 0.037 nmol/L/year, P = 0.025, 5′‐CP; 0.139 ± 0.055 vs 0.022 ± 0.012 nmol/L/year, P = 0.008). Conclusions: We established the annual decline of insulin secretion in the Japanese type 2 diabetic patients by the long‐term observation. The results show that the decline of insulin secretion is more rapid in the S20G‐patients than the non‐S20G‐T2D‐patients. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00102.x, 2011)     

Increased reduction in fasting C-peptide is associated with islet cell antibodies in Type 1 (insulin-dependent) diabetic patients

Summary A cohort of 82 patients with Type 1 (insulin-dependent) diabetes was followed prospectively for 24 months, and 54 of them for 30 months, to study the relationship between fasting levels of immunoreactive C-peptide and titres of islet cell antibodies. After diagnosis, fasting C-peptide rose temporarily for 1–6 months of insulin therapy and declined continuously thereafter. While islet cell antibodies were present among 55% of the newly diagnosed patients, only 31% remained positive at 30 months. Their antibody titres decreased from 181 at diagnosis to 13. Only 3 patients (4%) who were islet cell antibody negative at diagnosis became positive later. The median C-peptide values among the persistently islet cell antibody positive patients decreased from 0.11 pmol/ml at 18 months, to 0.09 pmol/ml at 24 months, to 0.06 pmol/ml at 30 months compared to 0.18 (p=0.04), 0.15 (p=0.05) and 0.16 (p< 0.003) pmol/ml, respectively, for the islet cell antibody negative patients. The median slope for the latter was –0.09 compared to –0.19 for the islet cell antibody positive patients (p=0.01). These differences were reflected in increasing dosages of insulin, since patients remaining antibody-positive for 30 months were given 1.3–1.4 times more insulin (p=0.01–0.004) than the antibody negative patients. This study demonstrates that islet cell antibodies may be a useful marker for predicting an increased rate by which endogenous B cell function is lost in Type 1 diabetes.     

Effects of chronic administration of alogliptin on the development of diabetes and β-cell function in high fat diet/streptozotocin diabetic mice

Aim: Alogliptin is a potent and highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor. The aim of this study was to determine its effects on glucose control and pancreas islet function and to identify the underlying molecular mechanisms after chronic administration, in a non‐genetic mouse model of type 2 diabetes. Methods: Alogliptin (5, 15 and 45 mg/kg) was orally administered to high fat diet/streptozotocin (HFD/STZ) diabetic mice daily for 10 weeks. Postprandial and 6‐h fasting blood glucose levels, blood A1C level, oral glucose tolerance and pancreas insulin content were measured during or after the treatment period. Alogliptin plasma concentration was determined by an LC/MS/MS method. Islet morphology and architectural changes were evaluated with immunohistochemical analysis. Islet endocrine secretion ability was assessed by measuring insulin release from isolated islets which were challenged with 16 mM glucose and 30 mM potassium chloride, respectively. Gene expression profiles of the pancreas were analysed using the mouse diabetes RT² Profiler PCR array which contains 84 genes related to the onset, development and progression of diabetes. Results: Alogliptin showed dose‐dependent reduction of postprandial and fasting blood glucose levels and blood A1C levels. Glucose clearance ability and pancreas insulin content were both increased. Alogliptin significantly restored the β‐cell mass and islet morphology, thus preserving islet function of insulin secretion. Expression of 10 genes including Ins1 was significantly changed in the pancreas of diabetic mice. Chronic alogliptin treatment completely or partially reversed the abnormalities in gene expression. Conclusions: Chronic treatment of alogliptin improved glucose control and facilitated restoration of islet architecture and function in HFD/STZ diabetic mice. The gene expression profiles suggest that the underlying molecular mechanisms of β‐cell protection by alogliptin may involve alleviating endoplasmic reticulum burden and mitochondria oxidative stress, increasing β‐cell differentiation and proliferation, enhancing islet architecture remodelling and preserving islet function.     

New prospects for immunotherapy at diagnosis of type 1 diabetes

Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring β‐cell mass and function. Recent clinical trials of non‐specific and of antigen‐specific immune therapies have demonstrated the feasibility of modulation of islet‐specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin‐secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non‐genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to β‐cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of β‐cell‐destruction 1 - 3 . Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen‐specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non‐antigen‐specific immunoregulation (anti‐CD3) and to anti‐inflammatory (anti‐IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C‐peptide secretion as evidence of a therapeutic effect on restoration of β‐cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals.     

The natural history of pre-Type 1 (insulin-dependent) diabetes mellitus in patients with autoimmune endocrine diseases

Summary An 11-year prospective study was carried out in 180 non-diabetic patients with organ-specific autoimmune diseases to evaluate islet cell antibodies in predicting Type 1 (insulin-dependent) diabetes mellitus. Islet cell antibodies were characterised according to titres, persistence, complement-fixing ability, and pattern. During follow-up, 14 of 46 patients with islet cell antibodies persistently greater than 5 Juvenile Diabetes Foundation Units (JDF-U) (30.4%), none of 23 with islet cell antibodies between 2.5 and 5JDF-U or fluctuating, and 3 of 109 without islet cell antibodies (2.7%), developed diabetes. The cumulative risk of developing diabetes was 70%, 0%, and 4%, respectively. All the patients who developed diabetes were females. Eight progressed to insulin-dependence acutely, four showed a transient period of non-insulin-dependence, while two were still insulin-free. No difference was found in titres of islet cell antibodies for the risk of diabetes. Complement-fixing islet cell antibodies enhanced the cumulative risk for the disease in patients with conventional islet cell antibodies at low-middle (2.5–40 JDF-U), but not at high (80 JDF-U) titres. Forty-two patients with islet cell antibodies were investigated for the whole or the selective pattern. In the presence of the whole pattern the cumulative risk for diabetes rose to 100%, while with the selective pattern it declined to 34%. The whole pattern was found in 83% of patients who developed Type 1 diabetes acutely. In patients with organ-specific autoimmune diseases, the whole islet cell antibody pattern greatly enhances the prediction for diabetes.     

HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden

Aims/hypothesis The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients.Subjects and methods Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15–34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743.Results Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003).Conclusions/interpretation Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes.     

Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes

Aim: Recent studies indicate that type 2 diabetes is associated with an increased secretion of both hepatic and intestinal lipoproteins, leading to the accumulation of atherogenic triglyceride (TG)‐rich lipoproteins. Sitagliptin is a selective inhibitor of dipeptidyl peptidase‐4 that has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes presumably through incretin hormone‐mediated improvements in islet function. The objective of the present study is to examine the effects of treatment with sitagliptin on postprandial lipid and incretin hormone levels as well as glucose homeostasis in patients with type 2 diabetes. Methods: Thirty‐six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m²) were recruited in this double‐blind cross‐over study using sitagliptin 100 mg/day or placebo for a 6‐week period each, with a 4‐week washout period between the two phases. At the end of each phase of treatment, patients underwent an oral lipid tolerance test providing 35 g of fat per m² of body surface area and blood samples were taken over an 8‐h period. Results: Sitagliptin therapy significantly decreased the postprandial area under the curves (AUCs) for plasma apolipoprotein (apo)B (?5.1%, p = 0.002), apoB‐48 (?7.8%, p = 0.03), TG (?9.4%, p = 0.006), very low‐density lipoprotein (VLDL)‐cholesterol (?9.3%, p = 0.001), free fatty acids (FFAs) (?7.6%, p = 0.005) and glucose (?9.7%, p < 0.0001). Furthermore, the postprandial AUCs for plasma intact glucagon‐like peptide‐1 (+67.8%, p < 0.0001) and glucose‐dependent insulinotropic polypeptide (+67.3%, p < 0.0001) were significantly increased following treatment with sitagliptin, whereas the AUC for plasma glucagon was reduced by ?9.7% (p = 0.001) with no significant changes in the AUCs for plasma insulin and C‐peptide. Sitagliptin therapy also improved homeostasis model assessment (HOMA) index for insulin resistance (?14.6%, p = 0.01) and β‐cell function (+32.3%, p = 0.007). Conclusions: Treatment with sitagliptin for 6 weeks reduced postprandial plasma levels of TG‐rich lipoproteins of both intestinal and hepatic origin, most likely by increasing incretin hormone levels, reducing circulating plasma FFA concentrations and improving insulin sensitivity and β‐cell function.     

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

Summary First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a M_r 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n=6) and low (n=30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type 1 diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the M_r 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years.     

Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women

Abstract. Fagerberg B, Kellis D, Bergström G, Behre CJ (Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden). Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64‐year‐old women. J Intern Med 2011; 269 : 636–643. Objectives. To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and β‐cell function during 5.5 years of follow‐up. Methods. In a population‐based cohort of 64‐year‐old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high‐sensitivity C‐reactive protein. After 5.5 years of follow‐up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re‐examined and incidence of diabetes was assessed. Results. A total of 69 new cases of diabetes were detected during follow‐up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L^?1 was associated with an odds ratio of 3.6 (95% confidence interval 1.4–8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow‐up. Conclusions. Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.     

The association of calcium channel blockers with β‐cell function in type 2 diabetic patients: A cross‐sectional study

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β‐cell function has not been well studied. To investigate this question, the authors performed a cross‐sectional study involving 882 hypertensive T2DM patients. To assess β‐cell function, patients were given 75g glucose orally and C‐peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa‐β was computed by Homeostasis Model Assessment model to evaluate β‐cell function using fasting C‐peptide and glucose levels in the plasma. Multivariable‐adjusted analysis was performed to evaluate the association of antihypertensive drugs with C‐peptide levels, HbA1c, and Homa‐β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate‐adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92‐0.98], P = 0.002). Our data further illustrated that the C‐peptide levels before and 1, 2, and 3 hours of OGTT were 1.10‐, 1.18‐, 1.19‐, and 1.15‐fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C‐peptide levels; P ≤ 0.024 for C‐peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non‐CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C‐peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β‐cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β‐cell function.     

Insulin autoantibodies are associated with islet cell antibodies; their relation to insulin antibodies and B-cell function in diabetic children

Summary Blood was drawn from 74 children, 3–16 years old, at diagnosis of Type 1 (insulin-dependent) diabetes and before the first insulin injection. Insulin autoantibodies were detected with a polyethylen-glycol-method in 27/74 (36.4%) and with an immuno-electrophoretic method in 6/74 (8.1%). Islet cell cytoplasmic antibodies detected by indirect immuno-fluorescence were found in 49/74 patients (66.2%), who included as many as 23 of the 27 patients with insulin autoantibodies determined with the polyethylen-glycol-method (p<0.01). The proportion of insulin autoantibody-positive patients who developed insulin antibodies during the first 9 months of insulin treatment was not significantly greater (51.8%) than that of insulin autoantibody-negative patients (44.6%), but patients with both islet cell antibodies and insulin autoantibodies at diagnosis produced more insulin antibodies during the first 9 months (p<0.05). There was no difference in fasting or meal stimulated serum C-peptide after 3, 9 or 18 months as related to occurrence of insulin autoantibodies and/or islet cell antibodies. The correlation between insulin autoantibodies and islet cell antibodies indicates that both types of autoantibodies reflect the same immunological process, although the lack of correlation to C-peptide may indicate that they play a minor causal role. In addition, the results show that patients with an active autoimmune process evidently tend to produce more insulin antibodies during the first months of insulin treatment, but the islet cell antibodies and insulin autoantibodies-positive patients had at least as good residual B-cell function as patients without autoantibodies at diagnosis. If insulin antibodies produced as a response to exogenous insulin do have a negative effect on B-cell function our present results suggest that such mechanisms are of minor importance.