Neonatal Diabetes due to a Mutation in the Distal PTF1A Enhancer: A Case Report and Literature Review

: Biallelic variants in the pancreas-specific transcription factor 1A (PTF1A) gene are a rare cause of permanent neonatal diabetes. We report a case of neonatal diabetes with unique clinical manifestations. The clinical diagnosis of the affected infant was confirmed by insufficient endocrine and exocrine pancreas activity; however, the pancreas was normal in imaging. Molecular analyses identified a novel homozygous single nucleotide variant (Chr10, g.23508441T > G), affecting a highly conserved nucleotide within a distal enhancer of the PTF1A gene. The literature review showed that most of these patients had IUGR and imaging evidence of pancreatic agenesis or hypoplasia. We suggest that pancreatic imaging and evaluation of exocrine pancreas function can help early confirmation of the diagnosis in patients with permanent neonatal diabetes.

Glucocorticoid receptor antagonist alters corticosterone and receptor sensitive mRNAs in the hypoxic neonatal rat

Hypoxia, a common stressor with preterm birth, increases morbidity and mortality associated with prematurity. Glucocorticoids (GC) are administered to the preterm infant to improve oxygenation; prolonged use of GCs remains controversial. We evaluated a selective glucocorticoid receptor (GR) antagonist (CORT113176) in our neonatal rat model of human prematurity to assess how fasting and hypoxia-induced increases in neonatal corticosterone affects endogenous hormones and endocrine pancreas function. Neonatal rat pups at postnatal day (PD) 2, PD8, and PD15 were pretreated with CORT113176 and, after 60 min of separation and fasting, exposed to hypoxia (8% O2) or control (normoxia) for 30 or 60 minutes while fasting was continued. Plasma corticosterone, ACTH, glucose, and insulin were measured and fasting HOMA-IR (index of insulin resistance) calculated. Glucocorticoid and insulin receptor sensitive gene mRNAs were analyzed in liver, muscle, and adipose to evaluate target tissue biomarkers. CORT113176 pretreatment augmented baseline and hypoxia-induced increases in corticosterone and attenuated hypoxia-induced increases in insulin resistance at PD2. Normoxic and hypoxic stress increased the hepatic GR sensitive gene mRNAs, Gilz and Per1; this was eliminated by pretreatment with CORT113176. CORT113176 pretreatment decreased baseline insulin receptor sensitive gene mRNAs Akt2, Irs1, Pik3r1, and Srebp1c at PD2. We show that CORT113176 variably augments the stress-induced increases in corticosterone concentrations (attenuation of negative feedback) and that GR is critical for hepatic responses to stress in the hypoxic neonate. We also propose that measurement of Gilz and Per1 mRNA expression may be useful to evaluate the effectiveness of GR antagonism.

Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

Aims Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

Diagnostic value of research methods in diagnostics of chronic pancreatitis

Chronic pancreatitis remains an unsolved problem for clinicians. One of the biggest dilemmas is to establish a clear diagnosis. Diagnosis can be particularly elusive in patients with early chronic pancreatitis. Many studies have been undertaken to improve diagnostics in chronic pancreatitis, but this has been significantly limited by the lack of a gold standard. The evaluation of patients with suspected chronic pancreatitis should follow a progressively non-invasive to more invasive approach. Computed tomography is the best primary imaging modality to obtain as it has good sensitivity for severe chronic pancreatitis and may exclude the need for other diagnostic tests. When ambiguous results are obtained, a magnetic resonance cholangiopancreatography may require for a more detailed evaluation of both the pancreatic parenchyma and ducts. If the diagnosis remains in doubt, endoscopic ultrasound with or without pancreas function testing becomes the preferred method. Endoscopic retrograde cholangiopancreatography remains a last line diagnostic test and generally should be used only for diagnostic purposes. Future researches in the field of diagnosis of early-stage chronic pancreatitis should purpose optimizing current diagnostic tools. A definitive diagnosis of chronic pancreatitis may not be made simply by clinical history, imaging or function testing alone, but rather by the data gathered by a combination of these diagnostic tools.

Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells

The pancreas is comprised of exocrine and endocrine compartments releasing digestive enzymes into the duodenum and regulating blood glucose levels by insulin and glucagon release. Tissue homeostasis is depending on transcription factor networks, involving Ptf1α, Ngn3, Nkx6.1, and Sox9, which are already activated during organogenesis. However, proper organ function is challenged by diets of high sugar and fat content, increasing the risk of type 2 diabetes and other disorders. A detailed understanding of processes that are important for homeostasis and are impaired during type 2 diabetes is lacking. Here, we show that Zeb1—a transcription factor known for its pivotal role in epithelial-mesenchymal transition, cell plasticity, and metastasis in cancer—is expressed at low levels in epithelial cells of the pancreas and is crucial for organogenesis and pancreas function. Loss of Zeb1 in these cells result in an increase of islet mass, impaired glucose tolerance, and sensitizes to develop liver and pancreas steatosis during diabetes and obesity. Interestingly, moderate overexpression of Zeb1 results in severe pancreas agenesis and lethality after birth, due to islet insufficiency and lack of acinar structures. We show that Zeb1 induction interferes with proper differentiation, cell survival, and proliferation during pancreas formation, due to deregulated expression of endocrine-specific transcription factors. In summary, our analysis suggests a novel role of Zeb1 for homeostasis in epithelial cells that is indispensable for pancreas morphogenesis and proper organ function involving a tight regulation of Zeb1 expression.

Optogenetic stimulation of cholinergic fibers for the modulation of insulin and glycemia

Previous studies have demonstrated stimulation of endocrine pancreas function by vagal nerve electrical stimulation. While this increases insulin secretion, expected concomitant reductions in circulating glucose do not occur. A complicating factor is the non-specific nature of electrical nerve stimulation. Optogenetic tools, however, provide the potential for cell-type specific neural stimulation using genetic targeting and/or spatially shaped excitation light. Here, we demonstrate light-activated stimulation of the endocrine pancreas by targeting parasympathetic (cholinergic) axons. In a mouse model expressing ChannelRhodopsin2 (ChR2) in cholinergic cells, serum insulin and glucose were measured in response to (1) ultrasound image-guided optical stimulation of axon terminals in the pancreas or (2) optical stimulation of axons of the cervical vagus nerve. Measurements were made in basal-glucose and glucose-stimulated conditions. Significant increases in plasma insulin occurred relative to controls under both pancreas and cervical vagal stimulation, while a rapid reduction in glycemic levels were observed under pancreatic stimulation. Additionally, ultrasound-based measurements of blood flow in the pancreas were increased under pancreatic stimulation. Together, these results demonstrate the utility of in-vivo optogenetics for studying the neural regulation of endocrine pancreas function and suggest its therapeutic potential for the control of insulin secretion and glucose homeostasis.

Bilateral Corneal Arcus In Canine

Background: The cornea is a component of the animal’s eye that is transparent in appearance because of the arrangement of collagen fibrils and the absence of vascularization and pigmentation. Corneal degeneration can result in a lesion known as corneal arcus, which presents as loss of transparency. It is characterized by a dense white opacity with defined borders. This lesion can be caused by lipid keratopathy, occurring as cholesterol and triglyceride deposits in the corneal stroma. In this case, analysis of the serum lipid profile and evaluation of thyroid and pancreas function are recommended. This study aimed to report on a case of occurrence of corneal arcus in a canine.Case: A 6-year-old dog, of no defined breed, weighing 13.250 kg was attended at the Veterinary Hospital of the Universidade Federal de Alagoas with a 5-day history of constipation. Under ultrasound, fecaloma was observed; however, the finding that drew attention was the presence of an eye alteration presenting as bilateral opacity in the form of a vertical arc in the corneal regions, with whitish crystalline appearance. The lesion did not exhibit roughness or vascularization and had well-defined borders. The animal showed no discomfort or visual acuity changes. The tutor reported that the marks had already been on the animal’s eye when it was adopted four years age, and that it showed a slow progressive growth. Given that there were no clinical signs of metabolic or hormonal diseases that could be a primary cause for the formation of the corneal lesion, lipid or calcium deposition in the corneal stroma was suspected, possibly due to diet or idiopathic cause. Blood samples were collected for a blood count and to determine triglyceride, calcium, and cholesterol levels. Based on the test results (all within the normal range), history, and a physical examination (with no evidence of metabolic and/or endocrine diseases), a diagnosis of corneal arcus was made. Excessive lipids in the diet was suggested as the cause of lesions, given that the dog’s diet had consisted of rice with a beef broth tablet, once a day, which over the years may have contributed to both the formation of the corneal lesions and to the enteric disorder (fecaloma). Dietary correction was indicated for both disorders, consisting of commercial dog food of adequate nutritional value. Keratectomy was not indicated for the corneal lesions, as they did not appear to be compromising the field of vision. Instead, we opted for follow-up to monitor the growth of lesions.Discussion: As no clinical evidence of metabolic or hormonal disease was verified, the primary cause for the formation of the corneal lesions was assumed to be lipid or calcium deposits in the corneal stroma, due to diet or even idiopathic cause. The dog was fed boiled rice and industrialized meat broth tablet, providing inadequate nutrition for the past four years or so, possibly leading to hyperlipidemia and/or hypercalcemia, with consequent deposition in the cornea, causing the arc lesion. Triglyceride, cholesterol, and calcium levels were measured, and were within normal range, probably because the blood collection was performed after the control of the post-enterotomy diet. Therefore, it was not possible to correlate the corneal changes with hyperlipidemia or hypercalcemia. The animal did not present with impaired vision as the lesions were located in the peripheral regions of the cornea, bilaterally. Therefore, it was decided to not to perform keratectomy.