Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope.

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

Cardiovascular risk in diabetes: a brief review.

Cardiovascular disease (CVD) is the major cause of the morbidity and mortality associated with diabetes in the US. A 2- to 3-fold incidence of CVD occurs in both type 1 and type 2 diabetic individuals over that in age- and gender-matched non-diabetic persons. Recent encouraging data demonstrating a decline in CVD mortality in the general US population do not reflect such a decline in the diabetic population, particularly in women. Increased risk for CVD is related to duration of diabetes and hyperglycemia, as well as hypertension, dyslipidemia, insulin resistance, gender, coagulation abnormalities, and other factors. Health care providers need to advocate for an uncompromising, multi-component attack on all modifiable risk factors for CVD, including glucose control, in the person with diabetes mellitus. This review focuses on known modifiable risk factors for CVD associated with diabetes, potential targets for primary and secondary prevention.

Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures.

The purpose of this study was to explore possible calculations using oral glucose tolerance test (OGTT) values in order to develop a simple measure of insulin sensitivity. We devised a formula for an insulin sensitivity index, ISI(0,120), that uses the fasting (0 min) and 120 min post-oral glucose (OGTT) insulin and glucose concentrations. It appears to be generalizable across a spectrum of glucose tolerance and obesity. Most importantly, our data show that ISI(0,120) correlates well, when applied prospectively in comparative studies, with the insulin sensitivity index obtained from the euglycemic hyperinsulinemic clamp (r = 0.63, P < 0.001). This correlation was demonstrably superior to other indices of insulin sensitivity such as the HOMA formula presented by Matthews, and performed comparably to the computerized HOMA index. Measurement of insulin sensitivity has traditionally been possible only in research settings because of the invasiveness and expense of the methods used. Clinical investigators have therefore sought more practical methods to obtain an index of insulin sensitivity. Such an index should approximate insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp (M). We present ISI(0,120), a simple yet sensitive measure of insulin sensitivity which is adaptable for use in clinical settings as well as large epidemiologic studies.

History of gestational diabetes, insulin resistance and coronary risk.

The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20-42 years), postpartum (3-18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease.

Aberrant parasympathetic and hemodynamic function distinguishes a subgroup of psychologically distressed individuals with asymptomatic type-I diabetes mellitus.

In a previous study, a subgroup of asymptomatic insulin-dependent diabetic individuals (termed IDDM-2) were identified on the basis of diminished parasympathetic cardiac input and elevated heart rate at rest. When compared to another group of asymptomatic IDDM participants (termed IDDM-1), and a nondiabetic healthy control group, the IDDM-2 group displayed elevated blood pressure, supported by elevated total peripheral resistance. Measures of psychological regulation were also taken in this study, and form the basis of this article, which examined whether these IDDM-2 patients differed from the other two groups on these measures. The possible role of glycemic control, IDDM duration, and number of somatic complaints among group differences in psychological regulation was also examined. The IDDM-2 group reported increased psychological distress, as reflected by increased dysphoric or depressive symptoms, trait anxiety, perceived stress, and cynical hostility, as well as decreased optimism and interpersonal, but not family, social support. Glycemic control did not account for any of the group differences in psychological regulation. However, group differences in dysphoria and anxiety were accounted for by differences in somatic complaints, whereas differences in interpersonal social support were accounted for by IDDM duration. Moreover, none of the variables investigated accounted for the diminished optimism of the IDDM-2 group. Therefore, in individuals with IDDM, who would otherwise be considered, after medical examination, as no different from other asymptomatic IDDM individuals, the combination of diminished parasympathetic cardiac input and elevated heart rate was associated with aberrant alterations of both hemodynamic and psychological functioning; the increased psychological distress in these individuals may be influenced, in part, by increased diabetes duration and number of somatic symptoms.

Nephropathy and hypertension in diabetes.

The treatment of the patient with diabetes, with or without hypertension, is complex and challenging. Hyperglycemic treatment should ideally not only control blood glucose, but also prevent the chronic complications and associated metabolic derangements that can lead to increased morbidity and mortality. Hypertensive treatment should not only decrease blood pressure, but also reduce the risk of macrovascular and microvascular disease. The use of antihypertensive agents that improve insulin resistance, dyslipidemia, glycemic control, and nephropathy is preferred whenever possible. The real key to success in the care of the hypertensive diabetic patient is adequate screening and appropriate, early treatment. Currently, there is ample evidence to support the use of intensive management with the goal of near-normalization of blood glucose levels in most patients with diabetes. Similarly, aggressive treatment of hypertension is the current standard. Accomplishing these goals helps to prevent the development of chronic diabetic complications, including nephropathy. ESRD need not be the inevitable outcome for individuals with early diabetic nephropathy. Interventions currently available that are targeted at the known modifiable risk factors underlying the development and progression of diabetic nephropathy offer the best hope for reducing the incidence and severity of this complication. Prevention of the complications of diabetes, including nephropathy, must be the goal for the future on behalf of all those who now have diabetes.

Hypertension in patients with diabetes mellitus.

Diabetes mellitus and hypertension each confer increased cardiovascular risk. That risk is much greater when the diseases coexist and is further magnified by their frequent association with dyslipidemia and central obesity. Insulin resistance appears to be an important common component to these four entities, whether or not the relationship is truly cause and effect. Increased renal tubule absorption of sodium and increased sympathetic nervous system stimulation from insulin have been said to be the mechanisms by which elevated levels of insulin cause hypertension. However, animal experiments suggest that these are short-term effects only and that long-term insulin may actually increase peripheral blood flow and reduce blood pressure. Experiments in humans suggest that the insulin resistant state in obese patients and type II diabetics is associated with a decrease of the usual vasodilatory effect of insulin. Antihypertensive drugs have differing effects on insulin resistance. Angiotensin converting enzyme inhibitors, alpha-adrenergic blockers, and dihydropyridines appear to improve insulin sensitivity. Other calcium channel blockers appear to be neutral, as is furosemide. Thiazide diuretics, spironolactone, and beta-adrenergic blockers impair insulin sensitivity. The drugs that increase insulin sensitivity also tend to improve dyslipidemia or remain lipid neutral. In contrast, those drugs that tend to impair insulin sensitivity also tend to worsen dyslipidemia.

Effects of an anti-CD5 immunoconjugate (CD5-plus) in recent onset type I diabetes mellitus: a preliminary investigation. The CD5 Diabetes Project Team.

Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting beta cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus. This agent is composed of the murine IgG1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. Beta-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline beta-cell function as measured by the AUC was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonmydriatic fundus photography in screening for treatable diabetic retinopathy.

Diabetic retinopathy is a complication of both insulin-dependent (type I) and non-insulin-dependent (type II) diabetes. The American Diabetes Association and others recommend screening for retinopathy, beginning 5 years after onset of symptoms for patients with type I diabetes and at the time of diagnosis for patients with type II diabetes. Ideally, diabetic patients are evaluated at recommended intervals by an ophthalmologist. Realistically, however, this is often not feasible, for reasons both of cost and availability. There is evidence that many diabetic patients are being referred too late for intervention, perhaps in part due to lax screening and detection, often the responsibility of internists and other primary care physicians. Data supports the need for a cheap, widely available, easy-to-use, effective screening tool for detecting treatable diabetic retinopathy. To this end, several studies have evaluated nonmydriatic fundus photography, and compared it with more-established methods of detecting diabetic retinal disease. The real question to be considered is whether nonmydriatic fundus photography will help to detect early treatable retinopathy better than the average physician using ophthalmoscopy. Several studies support its usefulness in this regard, and are discussed in this review. Questions remain, however, and further study is warranted in evaluating its potential role.

Case report: adrenal myelolipoma--rationale for a noninvasive diagnosis.

Myelolipomas are nonfunctioning, benign tumors of the adrenal gland composed of fat and normal bone marrow elements in varying proportions. Although rare, they should be included in the differential diagnosis of the incidentally discovered adrenal mass. The authors describe a patient with a myelolipoma diagnosed by characteristic radiological findings in whom the use of invasive procedures or surgical exploration was unnecessary.

Endocrine manifestations of human immunodeficiency virus (HIV) infection.

Endocrine manifestations of HIV infection include both pathological changes and disturbances in function. Mechanisms include direct infection of glands by HIV or opportunistic organisms, infiltration by neoplasms, side effects of drugs, and production of humoral factors that may alter metabolism. The adrenal gland is most often affected, but virtually every endocrine system may be involved. Dysfunction is often subtle, with symptoms overlapping those of the HIV infection itself. Endocrine manifestations may be found at any time in the course of the disease, from the asymptomatic HIV-positive stage through full-blown AIDS. Optimal management of these patients may include a careful search for, and appropriate treatment of, associated endocrine abnormalities.

Case report: hypothyroidism due to pneumocystis carinii thyroiditis in a patient with acquired immunodeficiency syndrome.

Pneumocystis carinii is the most common cause of opportunistic pulmonary infection in AIDS patients and disseminated disease is being recognized with increasing frequency. We describe a patient with cavitary pulmonary disease, lymphadenopathy, thyroiditis, and associated hypothyroidism, all a result of P. carinii. The organism was easily demonstrated in a fine-needle aspirate specimen of the thyroid. This is the second reported case of clinically apparent Pneumocystis thyroiditis and the first reported case of hypothyroidism due to an opportunistic infection in a patient with AIDS. Clinicians should be aware of this entity and request a Grocott-Gomori methenamine-silver nitrate stain of appropriate cytology specimens to make the diagnosis.