Hypothalamus-pituitary-thyroid feedback control: implications of mathematical modeling and consequences for thyrotropin (TSH) and free thyroxine (FT4) reference ranges.

The components of thyrotropic feedback control are well established in mainstream physiology and endocrinology, but their relation to the whole system's integrated behavior remains only partly understood. Most modeling research seeks to derive a generalized model for universal application across all individuals. We show how parameterizable models, based on the principles of control theory, tailored to the individual, can fill these gaps. We develop a system network describing the closed-loop behavior of the hypothalamus-pituitary (HP)-thyroid interaction and the set point targeted by the control system at equilibrium. The stability of this system is defined by using loop gain conditions. Defined points of homeostasis of the hypothalamus-pituitary-thyroid (HPT) feedback loop found at the intersections of the HP and thyroid transfer functions at the boundaries of normal reference ranges were evaluated by loop gain calculations. At equilibrium, the feedback control approaches a point defined in both dimensions by a [TSH]-[FT4] coordinate for which the loop gain is greater than unity. This model describes the emergence of homeostasis of the HPT axis from characteristic curves of HP and thyroid, thus supporting the validity of the translation between physiological knowledge and clinical reference ranges.

Protection from diabetes development by single-chain antibody-mediated delivery of a NF-κB inhibitor specifically to ß-cells in vivo.

Recently, we reported the generation of single-chain antibodies (SCAs) highly specific for rodent and human ß-cells. Our current report describes the generation of a fusion protein of one of these SCAs (SCA B1) with a NF-κB essential modifier (NEMO)-binding domain (NBD) peptide, thereby creating a selective inhibitor of NF-κB activation in ß-cells. The SCA B1-NBD fusion protein was cloned in the pIRES-EGFP, expressed in bacteria, and purified by metal affinity chromatography; the newly generated complex was then administered intravenously to rodents and evaluated for its ability to protect ß-cells against cytokines in vitro and diabetogenic agents in vivo. First, it was shown clearly that our SCA B1-NBD fusion protein binds highly selective to CD rat ß-cells in vivo. Second, we observed that SCA B1-mediated in vivo delivery of the NBD peptide completely blocked IL-1ß + IFNγ- and TNFα + IFNγ-mediated induction of NF-κB as well as islet dysfunction in culture. Finally, repeated intravenous injection of SCA B1-NBD prior to multiple low-dose administration of streptozotocin in CD mice not only induced a striking resistance to diabetes development but also preserved ß-cell mass. In conclusion, our data show for the first time that a SCA B1-NBD fusion peptide reliably protects ß-cells against cytokines in vitro and allows protection from diabetes development in CD mice in vivo.

Usefulness of Serum Free Thyroxine Concentration to Predict Ventricular Arrhythmia Risk in Euthyroid Patients With Structural Heart Disease.

The aim of the present study was to determine whether free thyroxine (FT4) and calculated thyroid parameters predict the incidence of ventricular arrhythmias in euthyroid heart failure patients with implantable cardioverter-defibrillators (ICD). In this open-label prospective cohort study, 115 consecutive euthyroid patients (mean age 62.9 ± 1.3 years; 87% male; ischemic cardiomyopathy 63%) scheduled for primary prevention ICD implantation or exchange were enrolled. Serum concentrations of thyrotropin (thyroid-stimulating hormone) and FT4 were measured 1 day before device operation. Primary and secondary end points were defined as occurrence of appropriate ICD therapy (AIT) and cardiovascular death, respectively. During a mean follow-up of 1,191 ± 35 days, 24 patients (21%) experienced AIT, and cardiovascular death was observed in 10 patients (9%). Patients with AIT had higher FT4 concentrations compared with those without AIT (18.9 ± 0.48 vs 16.2 ± 0.22 pmol/L, p <0.001). FT4 was an independent predictor of AIT in an adjusted Cox regression (hazard ratio = 1.47, p <0.001). Kaplan-Meier analysis demonstrated that Jostel's thyroid-stimulating hormone index, reflecting the central component of the hypothalamus-pituitary-thyroid loop, and SPINA-GT as surrogate markers for thyroid's secretory capacity predicted AIT incidences. None of the indices predicted cardiovascular death. In conclusion, FT4 concentration predicts an increased incidence of ventricular arrhythmias in euthyroid patients receiving ICDs for primary prevention. Our data suggest that both impending primary hyperthyroidism and an increased thyroid homeostasis set point may increase the rate of AIT in this patient population.

Steroid Profiling as an Additional Tool to Confirm One-Sided Hormone Overproduction in Primary Aldosteronism: A Case Report.

Primary aldosteronism (PA) is the leading cause of secondary hypertension. The source of aldosterone hypersecretion is often due to a unilateral aldosterone-producing adenoma, and unilateral laparoscopic adrenalectomy is recommended in such patients. Before surgery, confirmation of unilateral hypersecretion is necessary. This is optimally performed by adrenal venous sampling (AVS). However, AVS is not always successful e.g., due to difficulties in the cannulation of the right adrenal vein. Here we present the case of a 53-year-old female patient with primary aldosteronism, a left-sided adrenal mass and an inconspicuous right adrenal. AVS was performed, but cannulation of the right adrenal vein failed. Therefore, aldosterone hypersecretion also of the right adrenal could not be excluded despite higher aldosterone concentrations in the left renal and adrenal vein. To increase the certainty that the left sided adrenal mass was the source of aldosterone hypersecretion, steroid profiling was performed in a sample from the inferior vena cava. This revealed markedly elevated levels of 18-oxocortisol, 18-hydroxycortisol, 11-deoxycorticosterone, and 11-deoxycortisol, a steroid profile that strongly suggested that the left sided adrenal mass was an aldosterone producing adenoma, most likely due to a somatic KCNJ5 mutation. Following unilateral adrenalectomy, CYP11B2 immunohistochemistry, and genetics analysis of the resected adrenal confirmed a solitary aldosterone-producing adenoma with intense aldosterone synthase expression, which harbored a previously described KCNJ5 Phe154Cys mutation. Biochemical and clinical cure was confirmed 6 months postoperatively.

The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome.

BACKGROUND: Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies. OBJECTIVES: Primary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis.Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication. DESIGN: The approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes.The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00591032.

Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling.

Calpains are a family of non-lysosomal cytoplasmatic cysteine proteases. Since calpain 10 (CAPN10), a member of the calpain family of proteases, has been found to represent a putative diabetes susceptibility gene, it was argued that calpains may be involved in the development of type 2 diabetes. The functional role of calpains in insulin signaling and/or insulin action is, however, not clear. We investigated the effects of the calpains 1 and 2 inhibitor PD151746 on insulin signaling and insulin action in human hepatoma G2 cells (HepG2). HepG2 cells were incubated without (-PD) or with (+PD) 5.33 micromol/l PD151746 for different times and then stimulated with 100 nmol/l insulin for 0 (t(0)), 5 (t(5)), 15 (t(15)), 30 (t(30)), 45 (t(45)), and 60 (t(60)) min. After solubilization of the cells, insulin receptor kinase activity, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated phosphatidylinositol-3 kinase (PI3-kinase), PI3-kinase activity, Thr(308) phosphorlyation of Akt, amount of protein tyrosine phosphatase-epsilon (PTPepsilon), and glycogen synthase activity were determined. Incubation with PD151746 resulted in a significant reduction of insulin-stimulated glycogen synthesis compared with cells not pre-incubated with the calpain inhibitor (-PD: t(0), 4.90 +/- 1.20%; t(5), 5.90 +/- 1.02%; t(15), 5.29 +/- 0.95%; t(30), 5.60 +/- 1.10%; t(45), 5.52 +/- 0.90%; t(60), 5.67 +/- 0.97%;+PD: t(0), 4.56 +/- 1.10%; t(5), 6.16 +/- 1.05%; t(15), 7.52 +/- 1.09%; t(30), 7.68 +/- 1.10%; t(45), 8.28 +/- 0.89%; t(60), 7.69 +/- 0.98%; P < 0.05). Incubation with PD151746 significantly increased the protein amount of PTPepsilon in the cells after 12 h (-PD: t(1), 0.85 +/- 0.18 RU (Relative unit); t(8), 0.87 +/- 0.18 RU; t(12), 0.9 +/- 0.13 RU; +PD: t(1), 0.92 +/- 0.21 RU; t(8), 1.1 +/- 0.15 RU; t(12), 1.34 +/- 0.16 RU; P < 0.05). Calpain inhibition with PD151746 had no effect on the insulin stimulation of the investigated insulin signaling parameters. These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway.

Microvascular dysfunction in rheumatoid arthritis assessed by laser Doppler anemometry: relationship to soluble adhesion molecules and extraarticular manifestations.

In search of a noninvasive diagnostic test for rheumatoid vasculitis (RV), this study addressed the questions whether changes in capillary blood cell velocity (CBV) detected by laser Doppler anemometry in patients with rheumatoid arthritis (RA) were correlated with the levels of soluble adhesion molecules and whether cutaneous flow abnormalities may reflect extraarticular manifestations in RA. In 31 RA patients and 20 patients with osteoarthritis (OA), CBV was measured in the skin above the left ring finger at rest and after 3-min arterial occlusion. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) were assessed by enzyme linked immunosorbent assay. Peak CBV was reduced in RA patients compared to OA patients (0.42 +/- 0.07 mm/s vs. 0.70 +/- 0.13 mm/s; P = 0.013). Both CBV during rest and reactive hyperemia were not correlated with the levels of soluble adhesion molecules. There were no significant differences in resting or peak CBV between RA patients with or without extraarticular manifestations. The lack of an inverse correlation between the levels of soluble adhesion molecules and CBV during rest and reactive hyperemia contradicts the assumption that inflammatory vascular damage indicated by increased levels of soluble adhesion molecules was the main reason for the impairment of microcirculation. The present results do not suggest that cutaneous flow abnormalities may reflect extraarticular manifestations in RA.

[Therapeutic management of acral manifestations of systemic sclerosis]. / Therapeutisches Management akraler Manifestationen der systemischen Sklerose.

Acral manifestations of systemic sclerosis include Raynaud's phenomenon, calcinosis cutis, and sclerodactyly. In the later stages of the disease, contractures of the skin and joints as well as obliterative vasculopathy leading to digital ulcers and necrotic lesions may occur. Patients with acral manifestations of systemic sclerosis are ideally treated by a team that includes a rheumatologist, dermatologist, hand surgeon, physiotherapist, and, eventually, a psychologist. Calcium channel antagonists, alpha(1)-adrenergic blockade with prazosin, and prostacyclin analogs were proven to be effective in the treatment of scleroderma-related Raynaud's phenomenon. Losartan, an angiotensin II receptor inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor, have been beneficial for systemic sclerosis-associated Raynaud's phenomenon in pilot studies. Parenteral prostacyclin analogs, e. g., iloprost, can be recommended as first-line treatment of ischemic digital ulcers. When prostacyclin analogs fail, the phosphodiesterase type 5 inhibitor sildenafil can be tried to improve ulcer healing. Bosentan, an endothelin receptor antagonist, may prevent new digital ulcers. At present, there are no medical agents agreed to be generally effective in the reduction of calcinotic deposits or cutaneous fibrosis, although some drugs have been identified as potentially beneficial. Surgical treatment of acral manifestations consists of excision or curettage of symptomatic calcific deposits, digital sympathectomy, arterial reconstruction, and amputation in rare cases. Flexion contractures of the proximal interphalangeal joints, with secondary hyperextension of the metacarpophalangeal joints, can be treated by arthrodesis of the proximal interphalangeal joints and resection arthroplasty or prostheses at the metacarpophalangeal joints to improve hand function.

Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming.

The hypothalamus-pituitary-thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

[Endosonography -- an additional diagnostic possibility in the differentiation between the two common types of primary hyperaldosteronism]. / Endosonographie -- eine zusätzliche diagnostische Möglichkeit bei der Differenzierung der beiden häufigsten Formen des primären Hyperaldosteronismus.

BACKGROUND: Primary aldosteronism is an important and one of the few potentially curable forms of secondary hypertension. The distinction between aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IHA) may be difficult, but establishing the correct diagnosis is essential because surgery is only effective in patients with adrenal adenoma. CASE REPORT: The case of a 65-year-old man with long-term hypertension due to an APA is reported. The routine laboratory tests displayed an elevated plasma aldosterone/renin quotient as well as an elevated 24-h urinary excretion of aldosterone and its metabolites. The serum aldosterone concentration did not decrease normally in the saline suppression test. The posture testing demonstrated an increase in aldosterone. These facts might lead to the conclusion of an IHA. Magnetic resonance imaging (MRI) of the adrenal glands revealed no abnormalities. Because of the unusual combination of laboratory findings and radiologic results an endosonographic examination of the adrenal glands was performed which yielded a unilateral adrenal adenoma. With establishing this diagnosis, curative surgery became possible. CONCLUSION: This case demonstrates that in the differential diagnosis of primary aldosteronism, endosonography is more important than previously discussed. It may be helpful in the differentiation of an unusual constellation of laboratory and radiologic findings.

Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research.

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thyroid dysfunctions. Advances in mathematical and simulative modeling of pituitary-thyroid feedback control have improved our understanding of physiological mechanisms governing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel's TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes.

We investigated whether the effect of troglitazone on glucose disposal is associated with altered insulin signaling. Nondiabetic first-degree relatives of type 2 diabetic patients (age 30 +/- 2 years, BMI 30 +/- 1 kg/m(2); n = 20) were randomized in a double-blind manner to 3 months of troglitazone (200 mg/day) or placebo treatment. Before and after treatment, 3-h euglycemic-hyperinsulinemic glucose clamps (40 mU. m(-2). min(-1)) were performed, and muscle biopsies were obtained immediately before and after the clamps. In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. After troglitazone treatment, insulin-stimulated glucose disposal was increased compared with pretreatment and placebo (279 +/- 37 vs. 211 +/- 26 and 200 +/- 25 mg. m(-2). min(-1); both P < 0.05). IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). PKB Thr(308) phosphorylation also tended to be higher, but this was not statistically significant. Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle.

Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling.

BACKGROUND: Although hyperthyroidism predisposes to atrial fibrillation, previous trials have suggested decreased triiodothyronine (T3) concentrations to be associated with postoperative atrial fibrillation (POAF). Therapy with thyroid hormones (TH), however, did not reduce the risk of POAF. This study reevaluates the relation between thyroid hormone status, atrial electromechanical function and POAF. METHODS: Thirty-nine patients with sinus rhythm and no history of atrial fibrillation or thyroid disease undergoing cardiac surgery were prospectively enrolled. Serum concentrations of thyrotropin, free (F) and total (T) thyroxine (T4) and T3, reverse (r)T3, 3-iodothyronamine (3-T1AM) and 3,5-diiodothyronine (3,5-T2) were measured preoperatively, complemented by evaluation of echocardiographic and electrophysiological parameters of cardiac function. Holter-ECG and telemetry were used to screen for POAF for 10 days following cardiac surgery. RESULTS: Seven of 17 patients who developed POAF demonstrated nonthyroidal illness syndrome (NTIS; defined as low T3 and/or low T4 syndrome), compared to 2 of 22 (p < 0.05) patients who maintained sinus rhythm. In patients with POAF, serum FT3 concentrations were significantly decreased, but still within their reference ranges. 3,5-T2 concentrations directly correlated with rT3 concentrations and inversely correlated with FT3 concentrations. Furthermore, 3,5-T2 concentrations were significantly elevated in patients with NTIS and in subjects who eventually developed POAF. In multivariable logistic regression FT3, 3,5-T2, total atrial conduction time, left atrial volume index and Fas ligand were independent predictors of POAF. CONCLUSION: This study confirms reduced FT3 concentrations in patients with POAF and is the first to report on elevated 3,5-T2 concentrations in cardiac NTIS. The pathogenesis of NTIS therefore seems to involve more differentiated allostatic mechanisms.

Second degree AV block and severely impaired contractility in cardiac myxedema: a case report.

The heart is a major target organ for thyroid hormone action. Severe overt hypothyroidism can result in diastolic hypertension, lowered cardiac output, impaired left ventricular contractility and diastolic relaxation, pericardial effusion and bradycardia. However, the function of the atrial pacemaker is usually normal and the degree by which the heart rate slows down is often modest. Here we report the case of a 20 year old male Caucasian with severe overt hypothyroidism. He presented with syncopation due to second degree atrioventricular block type Mobitz 2 and heart failure with reduced ejection fraction (38 %). Laboratory testing revealed a severe overt hypothyroidism with markedly elevated TSH (>100 mIU/L) and reduced fT3 and fT4 levels. The condition was caused by hypothyroid Graves' disease (Graves' disease with Hashimoto component). Although magnetic resonance imaging of the heart demonstrated decreased cardiac contractility and pericardial effusion, suggesting peri-myocarditis, plasma levels for BNP and troponin I were low. A possible infectious cause was unlikely, since testing for cardiotropic viruses was negative. The patient was treated with intravenous levothyroxine and after peripheral euthyroidism had been achieved, left ventricular ejection fraction returned to normal and pericardial effusion dissolved. Additionally, bradycardiac episodes abated, although intermittent second degree AV block was still occasionally present during the night. In conclusion, overt hypothyroidism may be associated by cardiac myxedema affecting both electrophysiology and contractility, observations that underscore the necessity of thyroid testing in different phenotypes of heart failure.

[The HIV protease inhibitor-induced insulin resistance syndrome]. / Das HIV-Proteasehemmer-induzierte Insulinresistenzsyndrom.

BACKGROUND: HIV protease inhibitors improve the morbidity and mortality of HIV infection, however, this therapy also initiates insulin resistance that is associated with an increasing development of disturbances in glucose and lipid metabolism. Similar to the common insulin resistance syndrome, treated patients also suffer from an increased cardiovascular risk. PATHOGENESIS: Studies based on animal or cell models suggest that HIV protease inhibitors induce short-term effects on GLUT4 glucose transport and longterm effects on insulin signal transduction. CONCLUSION: Therapy with HIV protease inhibitors should include regular monitoring of metabolic alterations and cardiovascular damage. Particularly patients with genetic or traditional risk factors for type 2 diabetes should be monitored frequently.

The treatment of type 2 diabetes.

BACKGROUND: 5% to 8% of adults have type 2 diabetes, a disease that is usually asymptomatic at first. The goals of management are timely diagnosis and the prevention of complications. METHODS: Selective review of the literature, including guidelines from Germany and abroad. RESULTS: High caloric intake and lack of exercise are the main contributing causes of type 2 diabetes and the principal targets of intervention. If lifestyle changes do not yield adequate improvement, then drug treatment should be initiated (or intensified) and managed on the basis of the HbA1c fraction. Guidelines recommend an HbA1c target range of 6.5% to 7.5%; the individual target value should be chosen in consideration of patient-specific factors and established in collaboration with the patient. Metformin is recommended for initial drug treatment. If metformin is contraindicated, poorly tolerated, or inadequately effective, many therapeutic alternatives and supplements are available. Clinical trials have shown that sulfonylureas and insulin are beneficial with respect to patient-relevant endpoints, but comparable data from clinical trials are not yet available for any other antidiabetic drug (except metformin). For individual patients, other drugs may have advantages such as a lower risk of hypoglycemia, less weight gain, oral administration, and/or applicability in the setting of renal insufficiency. The treatment is individually oriented, depending on the patient's age, disease stage, body weight, comorbidities, work situation, adherence, and personal priorities. Combining more than two antidiabetic drugs is not recommended. CONCLUSION: Although there are many treatment options, individualized long-term treatment still presents a challenge in many cases.