Brigid Gregg

Natural history of β-cell adaptation and failure in type 2 diabetes

Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis.

Metformin; a review of its history and future: from lilac to longevity

Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses.

Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21 Cip

Aims/hypothesisThe ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Protein kinase B (Akt) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt (caAktTg) show enhanced beta cell proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21Cip). In the present study, we sought to assess the mechanisms responsible for augmented p21Cip levels in caAktTg mice and test the role of p21Cip in the proliferative responses induced by activation of Akt signalling.MethodsTo gain a greater understanding of the relationship between Akt and p21Cip, we evaluated the mechanisms involved in the modulation of p21Cip by Akt and the in vivo role of reduced p21Cip in proliferative responses induced by Akt.ResultsOur experiments showed that Akt signalling regulates p21Cip transcription and protein stability. caAktTg/p21Cip+/− mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAktTg mice. Glucose tolerance tests revealed improved glucose tolerance in caAktTg/p21Cip+/− mice compared with caAktTg. These changes resulted from increased proliferation, survival and beta cell mass in caAktTg/p21Cip+/− compared with caAktTg mice.Conclusions/interpretationOur data indicate that increased p21Cip levels in caAktTg mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21Cip could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.

Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors

Aims/hypothesisDeveloping beta cells are vulnerable to nutrient environmental signals. Early developmental processes that alter the number of pancreatic progenitors can determine the number of beta cells present at birth. Metformin, the most widely used oral agent for treating diabetes, alters intracellular energy status in part by increasing AMP-activated protein kinase (AMPK) signalling. This study examined the effect of metformin on developing pancreas and beta cells.MethodsPancreatic rudiments from CD-1 mice at embryonic day 13.0 (E13.0) were cultured with metformin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an AMPK activator) or vehicle control in vitro. In another set of studies, pregnant C57BL/6 mice were treated with metformin throughout gestation. Embryonic (E14.0) and neonatal pancreases were then analysed for their morphometry.ResultsIn vitro metformin treatment led to an increase in the proliferation and number of pancreatic duodenal homeobox 1-positive (PDX1+) progenitors. These results were reproduced by in vitro culture of embryonic pancreas rudiments with AICAR, suggesting that AMPK activation was involved. Similarly, metformin administration to pregnant dams induced an increase in both PDX1+ and neurogenin 3-positive progenitors in the embryonic pancreas at E14.0 and these changes resulted in an increased beta cell fraction in neonates.Conclusions/interpretationThese results indicate that exposure to metformin during gestation modulates the early steps of beta cell development (prior to E14.0) towards an increase in the number of pancreatic and endocrine progenitors. These changes ultimately result in a higher beta cell fraction at birth. These findings are of clinical importance given that metformin is currently used for the treatment of gestational diabetes.

C-peptide levels in pediatric type 2 diabetes in the Pediatric Diabetes Consortium T2D Clinic Registry

To describe C‐peptide levels in a large cohort of children with type 2 diabetes T2D and examine associations with demographic and clinical factors.

Vitamin D status in youth with type 1 and type 2 diabetes enrolled in the Pediatric Diabetes Consortium (PDC) is not worse than in youth without diabetes

To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels.

Fractalkine signaling in regulation of insulin secretion.

Fractalkine is a chemokine, which has been shown to play important roles in metabolic disease in both animal models and humans. Fractalkine is a key player in the accumulation of atherosclerotic plaques, and fractalkine receptor (CX3CR1) mutations have been implicated in obesity. Serum fractalkine levels have been found to be elevated in type 2 diabetic patients, but the role of fractalkine signaling on the pancreatic β cell was unclear. Recently published findings in April 2013 issue of the journal Cell by Lee and Olefsky et al. have implicated fractalkine in β-cell insulin secretion. They demonstrate that Cx3cr1 knockout mice have impaired glucose tolerance resulting from decreased insulin secretion. In addition, fractalkine administration improved glucose tolerance and induced insulin secretion. This modulation of insulin secretion was proposed to result from an increase in intracellular calcium and potentiation of insulin secretion, which occurs in a Gαi and MEK-dependent manner. They also found that Cx3cr1 knockout animals had transcriptional repression of genes important for β-cell function, specifically NeuroD, via induction of ICER-1. One important issue that remains unresolved is how CX3CR1 signaling regulates the potentiation of calcium influx and the distal events in insulin exocytosis. Finally, testing the effects of fractalkine treatment on proliferation and survival in vivo during regenerative conditions would be critical to determine the potential use of this chemokine in diabetes. While these exciting results open the possibility for new therapeutics, there are some concerns about a potential risk for exacerbation of atherosclerosis.

Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring

Pancreatic β-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic β-cell mass at birth. We hypothesized that adult offspring would have improved metabolic parameters as a long-term outcome of metformin exposure. Virgin dams were given 5 mg/mL metformin in their water from E0.5 to delivery at E18.5. Body weight, glucose tolerance, insulin tolerance and glucose stimulated insulin secretion were analyzed in the offspring. When male offspring of dams given metformin during gestation were tested as adults they had improved glucose tolerance and enhanced insulin secretion in vivo as did their islets in vitro. Enhanced insulin secretion was accompanied by changes in intracellular free calcium responses to glucose and potassium chloride, possibly mediated by increased L channel expression. Female offspring exhibited improved glucose tolerance at advanced ages. In conclusion, in this model in utero metformin exposure leads to improved offspring metabolism in a gender-specific manner. These findings suggest that metformin applied during gestation may be an option for reprogramming metabolism in at risk groups.