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Objective: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes.Research Design and Methods: Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models.Results: Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-cell responses.Conclusions: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses. [ABSTRACT FROM AUTHOR]

Objective: We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSThis was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed.RESULTSAt randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect.CONCLUSIONSDespite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve. [ABSTRACT FROM AUTHOR]

Objective: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes.Research Design and Methods: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors.Results: GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs.Conclusions: Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function. [ABSTRACT FROM AUTHOR]

The article reviews the Daniel Porte who understanding the role of defective insulin secretion and action in obesity and type 2 diabetes.

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE Cross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients. RESEARCH DESIGN AND METHODS Twenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits. RESULTS Of the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab2T2), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses. CONCLUSIONS These pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline. [ABSTRACT FROM AUTHOR]

Abstract: Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials. [Copyright &y& Elsevier]

OBJECTIVE-Islet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with β-cell function. RESEARCH DESIGN AND METHODS- Adult phenotypic type 2 diabetic patients (n = 36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma-associated protein-2 autoantibody, and zinc transporter autoantibody). RESULTS- We identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab-T-, Ab+T-, Ab-T+, and Ab+T+). The Ab-T+ type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab+T+ type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses. CONCLUSIONS- We have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab-T+ and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated. [ABSTRACT FROM AUTHOR]

Latent autoimmune diabetes in adults or type 1.5 diabetes is considered to be a T-cell-mediated autoimmune disease. However, identification of patients is based commonly on autoantibody (Ab) detection. To determine whether measuring T-cell reactivity to islet proteins compared with measuring Abs improves detection of autoimmune diabetes and how β-cell function correlates with T-cell reactivity compared with Ab positivity, we assessed the T-cell proliferative responses and Ab responses (islet cell autoantibodies, insulin autoantibodies, insulinoma-associated protein-2 autoantibodies, and GAD Abs) to islet proteins of 36 phenotypic type 2 diabetic patients. To be considered Ab+ or T-cell+, patients were required to be positive for a minimum of two consecutive time points. β-Cell function was measured with fasting and glucagon-stimulated C-peptide. Independent of T-cell reactivity, Ab+ and Ab- patients had comparable fasting and glucagon-stimulated C-peptide. Independent of Ab status, T-cell+ patients demonstrated significantly lower glucagon-stimulated (P < 0.003) C-peptide compared with T-cell- patients. These data suggest that measuring T-cell responses to multiple islet proteins in phenotypic type 2 diabetic patients improves identification of patients with autoimmune diabetes and delineates those who have a more severe β-cell lesion compared with Ab assessment alone. Diabetes 56:2110-2115, 2007 [ABSTRACT FROM AUTHOR]

Diabetes is classified clinically into two types: type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune diabetes, whereas, in contrast, type 2 diabetes is nonautoimmune. However, there is a group of phenotypic adult type 2 diabetic patients ( approximately 10%) who have islet autoantibodies similar to type 1 diabetes. These patients are said to have latent autoimmune diabetes in adults (LADA) or type 1.5 diabetes. T-cells reacting with islet proteins have been demonstrated in type 1 and type 1.5 diabetic patients. In contrast, classic autoantibody-negative type 2 diabetic patients are also negative for T-cell responses to islet proteins. Therefore, we questioned whether type 1 and type 1.5 diabetes are similar or different autoimmune diseases. We have investigated the immunological and metabolic differences between type 1, type 1.5, and classic type 2 diabetic patients. We have identified autoantibody differences, differences in islet proteins recognized by T-cells, and differences in insulin resistance. We have also identified a small group of patients who have T-cells responsive to islet proteins but who are autoantibody negative. These patients appear to be similar to type 1.5 patients in having decreased stimulated C-peptide values. These immunological differences between type 1 and type 1.5 diabetes suggest at least partially distinct disease processes. [ABSTRACT FROM AUTHOR]

Intensive therapy for type 1 diabetes results in greater weight gain than conventional therapy. Many factors may predispose to this greater weight gain, including improved glycemic control, genetic susceptibility to obesity, and hypoglycemia. To study this, relationships among family history of type 2 diabetes, frequency of severe hypoglycemia, β-cell autoantibodies, and weight gain were examined in 1,168 subjects aged ≥18 years at baseline randomized to intensive and conventional therapy groups in the Diabetes Control and Complications Trial. With intensive therapy, subjects with a family history of type 2 diabetes had greater central weight gain and dyslipidemia characterized by higher triglyceride levels and greater cholesterol in VLDLs and intermediate-density lipoproteins compared with subjects with no family history. Neither the frequency of severe hypoglycemia nor positivity to GAD65 and insulinoma-associated protein 2 antibodies was associated with increased weight gain with either intensive or conventional therapy. These data support the hypothesis that increased weight gain with intensive therapy might be explained, in part, by genetic traits. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a cell-mediated autoimmune disease characterized by autoantibody and peripheral blood mononuclear cell (PBMC) reactivity to islet cell proteins. Type 2 diabetes is not an autoimmune disease but rather results from both insulin resistance and a nonautoimmune insulin secretory defect. There is, however, a group of phenotypic type 2 diabetic patients who have islet autoantibodies that are similar to those of type 1 diabetic patients. In this study, we investigated, using cellular immunoblotting, whether type 2 diabetic patients positive for islet autoantibodies have PBMC responses to islet proteins. We observed that autoantibody negative (Ab-) type 2 diabetic patients (n = 9) and normal control subjects (n = 12) demonstrated PBMCs responsive to 0-3 molecular weight regions. In contrast, autoantibody positive (Ab+) type 2 diabetic patients (n = 11) demonstrated PBMC responses to 3-18 molecular weight regions, similar to that of type 1 diabetic patients (responsive to 4-18 molecular weight regions). PBMCs from over 90% of the Ab+ type 2 and type 1 diabetic patients were observed to proliferate to islet proteins in the vicinity of 97 kDa. In contrast, 65-90% of type 1 diabetic patients had responsive PBMCs for islet proteins in most of the molecular weight regions, whereas <60% of the Ab+ type 2 diabetic patients had PBMCs responsive to the same molecular weight proteins. Ab+ type 2 diabetic patients appear to be heterogeneous with respect to cellular reactivity to islet proteins. Some subjects demonstrate PBMC responses similar to those of "classic" type 1 diabetic patients, whereas others have PBMC responses potentially distinct from type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

Type 1.5 diabetes or LADA comprises approximately 10% of Caucasian adult phenotypic type 2 diabetes patients. Whereas, the presence of autoantibodies (Ab) and T cells (T) reactive to islet proteins suggest an autoimmune pathogenesis, classic type 2 patients are negative for both. LADA patients are usually defined as Ab+, but it has also been observed that most Ab+ patients simultaneously demonstrate T cell responses to islet proteins. We, however, have recently identified a group of phenotypic T2DM patients who are T cell positive but autoantibody negative. Our aim was to determine whether T cell-positive (T+) autoantibody-negative (Ab-) phenotypic type 2 diabetic patients become Ab+ with time or whether they remain antibody negative and constitute a separate subset of autoimmune diabetes. This data was taken from a prospective study where phenotypic type 2 patients have been evaluated every 3 months for up to 36 months. Patients were classified as phenotypic type 2 by their physicians. We assessed each patient's T cell responses to islet proteins (using cellular immunoblotting) and autoantibody responses (IAA/IA-2/GAD) during each follow-up visit. At baseline we identified 13 patients that were T+Ab- and an additional 12 patients were identified during follow-up. Of the T+Ab- patients, 17/25 (68%) did not seroconvert and remained Ab- during a median follow-up duration of 21 months (range 3-36). Only 8/25 (32%) developed Ab reactivity during a median follow-up period of 30 months (range 12-36). Of the T+Ab- patients who seroconverted, only one out of the eight patients remained persistently positive for both GAD and IA-2 antibodies during follow-up. The remaining 7 patients (87.5%) demonstrated transient autoantibody positivity. Of these 7 patients, one was positive for IA-2 at one time point, 4 were positive for either GAD (3 patients) or IA-2 (1 patient) at two time points, and 2 were positive for both GAD and IA-2 at one or two time points respectively. This Ab positivity, however, was not corrected for by multiple testing. Although some T+Ab- patients seroconverted to autoantibody positivity during follow-up, the majority (68%) remained autoantibody negative. Most T+Ab- diabetic patients belong to a unique subgroup of autoimmune-mediated diabetes that would not be detected using autoantibodies alone. [ABSTRACT FROM AUTHOR]

Editorial. Explains the therapeutic importance of subsets of type 2 diabetes. Significance of a type 1 and type 2 diabetes family history; Details on type 2 diabetes; Importance of the identification of subsets of type 2 diabetes.

Recent advances in understanding the etiology of obesity, metabolic syndrome, and type 2 diabetes (T2D) have established involvement of the immune system. These developments highlight the potential of immunomodulatory therapies for treatment of these conditions. Here, we discuss current and new immunotherapeutic strategies for the treatment of T2D, the need for stratification of patients based on immune and autoimmune status, and biomarkers for evaluating treatment efficiency. The time has come to re-evaluate the clinical management of T2D patients using metabolic parameters alone, and to realize that patients should be stratified based on their immune and/or autoimmune status prior to initiation of therapy to realize fully the potential of immunomodulatory strategies for T2D. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Both type 1 (T1D) and type 2 diabetes (T2D) are increasing in incidence in children; often an admixture of T1D and T2D features are present at diagnosis. We examined the relationship between diabetes autoantibodies (DAA), human leukocyte antigen (HLA), and clinical course in subjects grouped by clinical diabetes type. Methods: Subjects 8–18years old with T1D, T2D, and mixed clinical features (T1.5D), were studied at diagnosis. DAA were measured in all subjects; a subset of subjects underwent HLA genotyping. Clinical course was followed in 84% of subjects for 47.9+8.7 months. Results: Eighty-nine percent of T1.5D subjects were positive for at least one DAA; 88% of HLA-typed subjects had risk HLA genotypes. Two subjects initially treated with oral agents were subsequently treated with insulin (50%); one had risk HLA, and the other was DAA positive. Thirty-three percent of T2D subjects were DAA positive and 93% were treated with oral agents at diagnosis. Three subjects were subsequently treated with insulin (21%); of these, two were DAA positive, and one had risk HLA. No subject who remained on diet therapy or oral agents had a combination of DAA-positivity and risk HLA genotype. Conclusions: Children clinically classified with T1.5D or T2D have a high frequency of autoimmune markers and T1D-associated HLA alleles which appears to indicate a more aggressive diabetes disease process, as has been shown for DAA-positive adults with phenotypic T2D. [Copyright &y& Elsevier]