Jay M. Sosenko

HYPERGLYCEMIA AND PLASMA LIPID LEVELS: A PROSPECTIVE STUDY OF YOUNG INSULIN-DEPENDENT DIABETIC PATIENTS

We explored the relation of plasma lipid levels to the degree of blood glucose control in young, insulin-dependent diabetic patients. Levels of total plasma cholesterol and triglyceride, of their lipoprotein subfractions, and of hemoglobin A, and fasting blood glucose were measured repeatedly over a one-year period in 105 patients. Lipid levels were also measured in 74 nondiabetic siblings. Increasingly poor control of diabetes, reflected by levels of hemoglobin A1 or of fasting blood glucose, was associated with statistically significant increases in total cholesterol (P less than or equal to 0.01), total triglyceride (P less than or equal to 0.007), and lipoprotein subfractions except for high-density lipoprotein cholesterol. Diabetic patients in best control had lipid levels similar to those in their nondiabetic siblings. These data on the relation of plasma lipid levels to diabetic control lend credence to the hypothesis that poor control of blood glucose is conducive to accelerated atherosclerosis in diabetes mellitus.

Pancreatic islet autoantibodies as predictors of type 1 diabetes in the diabetes prevention trial-type 1

OBJECTIVE There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+). RESULTS In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Fall in C-Peptide During First 2 Years From Diagnosis: Evidence of at Least Two Distinct Phases From Composite Type 1 Diabetes TrialNet Data

Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was −0.0245 pmol/mL/month (95% CI −0.0271 to −0.0215) through the first 12 months and −0.0079 (−0.0113 to −0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials.

Impaired vibratory perception and diabetic foot ulceration

We have studied risk factors for diabetic foot ulceration by comparing diabetic patients who had active foot ulcers (n = 86) with diabetic patients who had no history of foot ulcers (n = 49). Whereas there was a strong association of diabetic foot ulceration with abnormal vibratory perception (Odds Ratio = 10.77; p < 0.001, which increased with worsening vibratory perception), there was little association with abnormality of the ankle‐pressure index (Odds Ratio = 2.84, p = n.s.). Although foot ulceration and limited joint mobility were associated (Odds Ratio = 3.57, p < 0.001), this relation was not significant when allowances for abnormal vibratory perception and diabetes duration were made. These data suggest that sensory neuropathy is of greater aetiological importance than peripheral vascular disease in the development of diabetic foot ulceration. The measurement of the vibratory perception threshold is clinically useful in identifying those diabetic patients at high risk of foot ulceration.

Fall in C-peptide During First 2 Years From Diagnosis Evidence of at Least Two Distinct Phases From Composite TrialNet Data

Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was −0.0245 pmol/mL/month (95% CI −0.0271 to −0.0215) through the first 12 months and −0.0079 (−0.0113 to −0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials.

Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.

Comparison of Quantitative Sensory-Threshold Measures for Their Association With Foot Ulceration in Diabetic Patients

We compared the accuracy of cutaneous pressure perception-threshold measurements with that of other sensory-threshold measurements for detecting diabetic foot ulcer patients. Three hundred fourteen non-insulindependent diabetic patients were studied, of whom 91 had either a current foot ulcer or a history of foot ulceration. Foot ulcer patients had much higher pressure perception thresholds at the hallux than those without foot ulcers (mean ± SE 4.63 ± 0.05 vs. 3.54 ± 0.04 U, P < 0.001). The magnitude of association was higher than that for vibration thresholds and markedlygreater than those for cool and warm thresholds. Pressure thresholds were highly accurate for identifying foot ulcer patients. At a threshold level of 4.21 U, the sensitivity was 0.84, with a specificity of 0.96. At similar sensitivities for vibration and thermal thresholds, specificities were lower. Foot ulceration and cutaneous pressure perception threshold are strongly associated. Pressure-threshold measurements are extremely accurate and perform atleast as well as other quantitative sensory tests in identifying foot ulcer patients. Assessment of the foot pressure threshold may have promise as a simple and inexpensive method for detecting diabetic patients at risk for footulcers.

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic diabetic neuropathy. 3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies. View this table: Table 1 Classification for diabetic neuropathies Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …

Blood pressure, insulin, and glycemia in nondiabetic subjects

The relation of blood pressure to fasting (basal) insulin and glycosylated hemoglobin (hemoglobin A1) was examined in 248 nondiabetic subjects (137 women and 111 men). None of the subjects was taking antihypertensive medication. There were statistically significant associations of systolic and diastolic blood pressure with insulin levels (r = 0.24, p less than 0.01; r = 0.30, p less than 0.01) and hemoglobin A1 levels (r = 0.28, p less than 0.001; r = 0.22, p less than 0.05) in women. These blood pressure indexes were also related to insulin levels in men (r = 0.23, p less than 0.05; r = 0.02, p less than 0.05). In a multiple regression analysis, the association between blood pressure and insulin level was diminished with an allowance for adiposity; however, it remained statistically significant. These data indicate that blood pressure is related to insulin levels in nondiabetic subjects and suggest that insulin may be a physiologic determinant of blood pressure.

Glycosylated Hemoglobins: Increased Glycosylation of Hemoglobin A in Diabetic Patients

The components of the hemoglobin-A1 fraction —hemoglobins A1a-c—arise from nonenzymatic glycosylation of hemoglobin A at the β-chain N-terminal amino groups and can be resolved from hemoglobin A by cation exchange chromatography. Glycosylation can also occur at the α-chain N-terminals as well as the E-amino groups of lysine residues of both α- and β-chains; this results in glycosylated species appearing in the hemoglobin-A fraction. In this study, we determined the extent of hemoglobin-A glycosylation using a colorimetric chemical method specific for the detection of ketoamine-linked hexoses in proteins. We demonstrate increased glycosylation of the main hemoglobin-A fraction in diabetic patients, which correlates significantly (r = 0.72, P < 0.001) with the hemoglobin-A, percentage determined by column chromatography in the corresponding hemolysates. This finding provides the basis for the application of this chemical procedure to the measurement of total glycosylation of hemoglobin.