Tripeptide amide L-pyroglutamyl-histidyl-L-prolineamide (L-PHP-thyrotropin-releasing hormone, TRH) promotes insulin-producing cell proliferation.

A very small tripeptide amide L-pyroglutamyl-L-histidyl-L-prolineamide (L-PHP, Thyrotropin-Releasing Hormone, TRH), was first identified in the brain hypothalamus area. Further studies found that L-PHP was expressed in pancreas. The biological role of pancreatic L-PHP is still not clear. Growing evidence indicates that L-PHP expression in the pancreas may play a pivotal role for pancreatic development in the early prenatal period. However, the role of L-PHP in adult pancreas still needs to be explored. L-PHP activation of pancreatic ß cell Ca2+ flow and stimulation of ß-cell insulin synthesis and release suggest that L-PHP involved in glucose metabolism may directly act on the ß cell separate from any effects via the central nervous system (CNS). Knockout L-PHP animal models have shown that loss of L-PHP expression causes hyperglycemia, which cannot be reversed by administration of thyroid hormone, suggesting that the absence of L-PHP itself is the cause. L-PHP receptor type-1 has been identified in pancreas which provides a possibility for L-PHP autocrine and paracrine regulation in pancreatic function. During pancreatic damage in adult pancreas, L-PHP may protect beta cell from apoptosis and initiate its regeneration through signal pathways of growth hormone in ß cells. L-PHP has recently been discovered to affect a broad array of gene expression in the pancreas including growth factor genes. Signal pathways linked between L-PHP and EGF receptor phosphorylation suggest that L-PHP may be an important factor for adult ß-cell regeneration, which could involve adult stem cell differentiation. These effects suggest that L-PHP may benefit pancreatic ß cells and diabetic therapy in clinic.

Thyrotropin-releasing hormone (TRH) reverses hyperglycemia in rat.

Hyperglycemia in thyrotropin-releasing hormone (TRH) null mice indicates that TRH is involved in the regulation of glucose homeostasis. Further, TRH levels in the pancreas peak during the stages of late embryonic and early neonatal beta cell development. These observations are consistent in linking TRH to islet cell proliferation and differentiation. In this study, we examined the effect of TRH administration in damaged pancreatic rat (streptozotocin, STZ) to determine whether TRH could improve damaged pancreatic beta cells function. We hypothesize that TRH is able to reverse STZ-induced hyperglycemia by increasing pancreatic islet insulin content, preventing apoptosis, and potentially induce islet regeneration. It was found that following intra-peritoneal (ip) injection, TRH (10 microg/kg body weight (bwt)) reverses STZ (65 mg/kg bwt)-induced hyperglycemia (TRH given 3 days after STZ injection). Increased circulating insulin levels and insulin content in extracted pancreas suggests that TRH reversed STZ-induced hyperglycemia through improving pancreatic islet beta cell function. Further studies show a significantly lower level of apoptosis in islets treated with TRH as well as the presence of proliferation marker nestin and Brdu, suggesting that the TRH has the potential to prevent apoptosis and stimulate islet proliferation.

Thyrotropin releasing hormone (TRH) may preserve pancreatic islet cell function: potential role in the treatment of diabetes mellitus.

Thyrotropin Releasing Hormone (TRH), first identified in the hypothalamus as a regulator of the Pituitary-Thyroid axis, has also been found in the beta-cell of the pancreas co-localised with insulin. The significance of this association is emphasised by the report that the TRH knock-out (KO) mouse is hyperglycemic. These findings have led to speculation that TRH may have a physiologic role in the regulation of carbohydrate metabolism. To understand better the role of TRH in the pancreas, TRH was administered to rats rendered diabetic from streptozotocin damage to the islets of Langerhans. This resulted in almost complete normalisation of the profound hyperglycemia. TRH is capable of reversing Diabetes Mellitus (DM) in an experimental animal model, possibly by promoting neogenesis of beta cells through induction of adult stem cells in the pancreas. These studies point to a potential therapeutic role for TRH in the treatment of DM in man.

Effect of growth hormone replacement on BMD in adult-onset growth hormone deficiency.

UNLABELLED: To determine if replacement of GH improves BMD in adult-onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%. INTRODUCTION: Growth hormone (GH) deficiency (GHD) acquired in adulthood results in diminished BMD; the evidence that replacement of GH improves BMD is not conclusive. We therefore performed a randomized, placebo-controlled trial to determine whether GH replacement would increase lumbar spine BMD in a combined group of men and women with adult-onset GHD. MATERIALS AND METHODS: We randomized 67 men and women to receive GH (n=33) or placebo (n=34) for 2 yr. The GH dose was initially 2 microg/kg body weight/d, increased gradually to a maximum of 12 microg/kg/d and adjusted to maintain a normal IGF-I concentration for age and sex. BMD was assessed before treatment and at 6, 12, 18, and 24 mo of treatment. Fifty-four subjects completed the protocol. RESULTS: BMD of the lumbar spine in the entire group increased by 2.9 +/- 3.9% above baseline in the GH-treated subjects, which was significantly (p=0.037) greater than the 1.4 +/- 4.5% increase in the placebo-treated subjects. In a secondary analysis, spine BMD in GH-treated men increased 3.8 +/- 4.3% above baseline, which was significantly (p=0.001) greater than that in placebo-treated men (0.4 +/- 4.7%), but the change in GH-treated women was not significantly different from that in placebo-treated women. Treatment with GH did not increase total hip BMD more than placebo treatment after 2 yr. CONCLUSIONS: We conclude that GH replacement in men who have adult-onset GHD improves their spine BMD, but we cannot draw any conclusions about the effect of GH replacement on spine BMD in women with adult-onset GHD.

Preliminary study of the relationship between thyroid status and cognitive and neuropsychiatric functioning in euthyroid patients with Alzheimer dementia.

OBJECTIVE: To investigate whether variations within normal ranges of thyroid functioning are related to cognitive and neuropsychiatric functioning in Alzheimer disease (AD). BACKGROUND: Mild alterations of thyroid hormone levels, even in the normal range, are associated with changes in mood and cognitive functioning in older, nondemented adults, and lower concentrations of thyroid hormones have been shown to be associated with an increased risk for cognitive decline. Less is known about the relationship between thyroid hormone levels and cognitive and neuropsychiatric dysfunction in AD. METHOD: Twenty-eight euthyroid patients with AD on donepezil underwent evaluation of thyroid status, including measures of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and cognitive and neuropsychiatric assessment with the Alzheimer's Disease Assessment Scale, Neuropsychiatric Inventory, and Visual Analog Mood Scales. RESULTS: Correlational analyses indicated statistically significant associations between FT4 concentrations and self-reported feelings of fear and fatigue. Fear and fatigue were negatively correlated with FT4. There were no significant relationships between thyroid hormones and cognition and other depressive and anxiety symptoms. CONCLUSIONS: Results of this preliminary study support a relationship between thyroid status and neuropsychiatric symptoms in euthyroid individuals with AD, with lower concentrations of FT4 associated with fear and fatigue.