Prevalence of Low Bone Density and Comorbid Hypogonadism in Patients With Chronic Pancreatitis.

OBJECTIVES: Patients with chronic pancreatitis (CP) are at increased risk of low bone mineral density (BMD), although the prevalence of low BMD in patients with CP in the United States is lacking. We aimed to determine the prevalence of low BMD and identify potential risk factors, including hypogonadism and use of opioid medications, in subjects with CP in the United States. METHODS: This was a prospective, observational study. Subjects with CP underwent dual-energy x-ray absorptiometry scan. Blood was assayed for vitamin D, sex hormones, and a metabolic panel. History was obtained for fractures, menopause, hypogonadal symptoms, and opioid medication doses. Low BMD was defined by both World Health Organization and the International Society for Clinical Densitometry criteria. RESULTS: Depending on criteria used, 37% to 55% of our cohort had low BMD. Subjects with low and normal BMD had similar vitamin D levels. Hypogonadism was present in 27% of nonmenopausal subjects and was associated with reduced lumbar spine BMD in subjects 30 years or older. CONCLUSIONS: Patients with CP are at increased risk of low BMD, which is likely multifactorial. Hypogonadism, possibly related to opioid pain medications, may be an independent risk factor for low BMD in CP.

Post-transplant diabetes: diagnosis and management.

Post-transplant diabetes mellitus (PTDM) is common after most types of solid organ transplantation, though the actual incidence is as yet unknown because of the use of different diagnostic criteria. PTDM is the result of individual risk factors as well as risk factors associated with the transplant itself, particularly immunosuppressants. Previously called New Onset Diabetes, in many cases inadequate screening for diabetes before transplant cannot assure that the diabetes is new after transplant. The most recent international consensus guidelines suggest diagnosis should be delayed until the patient is taking maintenance doses of immunosuppressants even if they require treatment in the immediate hospitalization. Criteria for diagnosis follow those of the American Diabetes Association and the World Health Organization, although hemoglobin A1C should not be used as the only screening test at least until one year after transplant because of its insensitivity for significant glucose intolerance in the transplant patient and setting. Management of PTDM is best done in a team setting, with an emphasis on glycemic control, dyslipidemia, and hypertension, and taking into consideration immunosuppressant regimens and potential drug side effects and interactions. While PTDM has been associated with changes in outcomes, these have and may continue to improve with improved diabetes care in and out of the hospital, and other changes in post-transplant care.

Exploiting Expression of Hippo Effector, Yap, for Expansion of Functional Islet Mass.

Loss of pancreas ß-cell function is the precipitating factor in all forms of diabetes. Cell replacement therapies, such as islet transplantation, remain the best hope for a cure; however, widespread implementation of this method is hampered by availability of donor tissue. Thus, strategies that expand functional ß-cell mass are crucial for widespread usage in diabetes cell replacement therapy. Here, we investigate the regulation of the Hippo-target protein, Yes-associated protein (Yap), during development of the endocrine pancreas and its function after reactivation in human cadaveric islets. Our results demonstrate that Yap expression is extinguished at the mRNA level after neurogenin-3-dependent specification of the pancreas endocrine lineage, correlating with proliferation decreases in these cells. Interestingly, when a constitutively active form of Yap was expressed in human cadaver islets robust increases in proliferation were noted within insulin-producing ß-cells. Importantly, proliferation in these cells occurs without negatively affecting ß-cell differentiation or functional status. Finally, we show that the proproliferative mammalian target of rapamycin pathway is activated after Yap expression, providing at least one explanation for the observed increases in ß-cell proliferation. Together, these results provide a foundation for manipulating Yap activity as a novel approach to expand functional islet mass for diabetes regenerative therapy.

WS6 induces both alpha and beta cell proliferation without affecting differentiation or viability.

Agents that stimulate human pancreatic beta cell proliferation are needed to improve diabetes mellitus treatment. Recently, a small molecule, WS6, was observed to stimulate human beta cell proliferation. However, little is known about its other effects on human islets. To better understand the role of WS6 as a possible beta cell regenerative therapy, we carried out in-depth phenotypic analysis of WS6-treated human islets, exploring its effects on non-beta cell proliferation, beta cell differentiation, and islet cell viability. WS6 not only stimulated beta cell proliferation in cultured human islets (in agreement with previous reports), but also human alpha cell proliferation, indicating that WS6 is not a beta cell-specific mitogen. WS6 did not change the proportion of insulin-positive beta cells or the expression of beta cell-specific transcription factors, suggesting that WS6 does not alter beta cell differentiation, and WS6 had no effect on human islet cell apoptosis or viability. In conclusion, WS6 stimulates proliferation of both human beta and alpha cells while maintaining cellular viability and the beta cell differentiated phenotype. These findings expand the literature on WS6 and support the suggestion that WS6 may help increase human islet mass needed for successful treatment of diabetes.

Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation.

New-onset diabetes after transplantation (NODAT) is a common comorbidity after renal transplantation. Though metformin is the first-line agent for the treatment of type 2 diabetes, in renal transplant recipients, metformin is frequently avoided due to concerns about renal dysfunction and risk for lactic acidosis. Therefore, alternative first-line agents for the treatment of NODAT in renal transplant recipients are needed. Sitagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, has a low incidence of hypoglycemia, is weight neutral, and, in a small study, did not affect immunosuppressant levels. However, long-term sitagliptin use for the treatment of NODAT in kidney transplant recipients has not been studied. We retrospectively analyzed renal transplant recipients diagnosed with NODAT and treated with sitagliptin to assess safety and efficacy. Twenty-two patients were started on sitagliptin alone. After 12 months of followup, 19/22 patients remained on sitagliptin alone with a significant improvement in hemoglobin A1c. Renal function and immunosuppressant levels remained stable. Analysis of long-term followup (32.5 ± 17.8 months) revealed that 17/22 patients remained on sitagliptin (mean hemoglobin A1c < 7%) with 9/17 patients remaining on sitagliptin alone. Transplant-specific adverse events were rare. Sitagliptin appears safe and efficacious for the treatment of NODAT in kidney transplant recipients.

TGF-ß superfamily member Nodal stimulates human ß-cell proliferation while maintaining cellular viability.

In an effort to expand human islets and enhance allogeneic islet transplant for the treatment of type 1 diabetes, identifying signaling pathways that stimulate human ß-cell proliferation is paramount. TGF-ß superfamily members, in particular activin-A, are likely involved in islet development and may contribute to ß-cell proliferation. Nodal, another TGF-ß member, is present in both embryonic and adult rodent islets. Nodal, along with its coreceptor, Cripto, are pro-proliferative factors in certain cell types. Although Nodal stimulates apoptosis of rat insulinoma cells (INS-1), Nodal and Cripto signaling have not been studied in the context of human islets. The current study investigated the effects of Nodal and Cripto on human ß-cell proliferation, differentiation, and viability. In the human pancreas and isolated human islets, we observed Nodal mRNA and protein expression, with protein expression observed in ß and α-cells. Cripto expression was absent from human islets. Furthermore, in cultured human islets, exogenous Nodal stimulated modest ß-cell proliferation and inhibited α-cell proliferation with no effect on cellular viability, apoptosis, or differentiation. Nodal stimulated the phosphorylation of mothers against decapentaplegic (SMAD)-2, with no effect on AKT or MAPK signaling, suggesting phosphorylated SMAD signaling was involved in ß-cell proliferation. Cripto had no effect on human islet cell proliferation, differentiation, or viability. In conclusion, Nodal stimulates human ß-cell proliferation while maintaining cellular viability. Nodal signaling warrants further exploration to better understand and enhance human ß-cell proliferative capacity.

Hippo signaling regulates pancreas development through inactivation of Yap.

The mammalian pancreas is required for normal metabolism, with defects in this vital organ commonly observed in cancer and diabetes. Development must therefore be tightly controlled in order to produce a pancreas of correct size, cell type composition, and physiologic function. Through negative regulation of Yap-dependent proliferation, the Hippo kinase cascade is a critical regulator of organ growth. To investigate the role of Hippo signaling in pancreas biology, we deleted Hippo pathway components in the developing mouse pancreas. Unexpectedly, the pancreas from Hippo-deficient offspring was reduced in size, with defects evident throughout the organ. Increases in the dephosphorylated nuclear form of Yap are apparent throughout the exocrine compartment and correlate with increases in levels of cell proliferation. However, the mutant exocrine tissue displays extensive disorganization leading to pancreatitis-like autodigestion. Interestingly, our results suggest that Hippo signaling does not directly regulate the pancreas endocrine compartment as Yap expression is lost following endocrine specification through a Hippo-independent mechanism. Altogether, our results demonstrate that Hippo signaling plays a crucial role in pancreas development and provide novel routes to a better understanding of pathological conditions that affect this organ.

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

BACKGROUND: Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia. METHODS: Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed. RESULTS: Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). CONCLUSIONS: rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).

Diabetes and cardiovascular disease following kidney transplantation.

Kidney transplantation is being performed more frequently for individuals with end stage renal disease (ESRD) due to improved survival and quality of life compared to long-term dialysis. Though rates decrease after transplant, cardiovascular disease (CVD) remains the most common cause of death after kidney transplant. New-onset diabetes after transplant (NODAT), a common complication following kidney transplantation, and pre-transplant diabetes both significantly increase the risk for CVD. Several other risk factors for CVD in kidney transplant recipients have been identified; however, optimal therapy for controlling the risk factors of CVD after kidney transplantation, including NODAT and pre-transplant diabetes, is not well defined. In the following review we will discuss the role of traditional and non-traditional risk factors in CVD after kidney transplant and the mechanisms involved therein. We will also examine the current literature regarding treatment of these risk factors for the prevention of CVD. Finally, we will review the current recommendations for pre- and post-transplant cardiovascular evaluation and management.

Type 1 diabetes: role of intestinal microbiome in humans and mice.

Type 1 diabetes is a disease involving autoimmune destruction of pancreatic beta cells in genetically predisposed individuals. Identifying factors that trigger initiation and progression of autoimmunity may provide opportunities for directed prophylactic and therapeutic measures to prevent and/or treat type 1 diabetes. The human intestinal microbiome is a complex, symbiotic ecological community that influences human health and development, including the development and maintenance of the human immune system. The role of the intestinal microbiome in autoimmunity has garnered significant attention, and evidence suggests a particular role for intestinal microbiome alterations in autoimmune disease development, including type 1 diabetes. This review will examine the role of the intestinal microbiome in the development and function of the immune system and how this relates to the development of autoimmunity. Data from animal and human studies linking alterations in the intestinal microbiome and intestinal integrity with type 1 diabetes will be closely examined. Finally, we will examine the interactions between the intestinal microbiome and dietary exposures and how these interactions may further influence autoimmunity and type 1 diabetes development.