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.

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.

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.