New-Onset Diabetes Mellitus in the Kidney Recipient: Diagnosis and Management Strategies

Advancing care has markedly improved survival after kidney transplantation, leaving patients susceptible to the effects of chronic transplant-associated morbidities. New-onset diabetes mellitus (NODM) is common in kidney recipients, threatening health and longevity by predisposing to microvascular and cardiovascular disease and by reducing graft survival. A strong rationale therefore exists for the aggressive treatment of NODM in kidney recipients to limit these complications. Screening for diabetes should be systematic and should span the pre- and posttransplantation periods. Once NODM is diagnosed in the kidney transplant patient, a comprehensive plan of therapy should be used to achieve treatment targets. As in the general population, treatment includes lifestyle modification and drug therapy as needed, but transplant-specific factors add complexity to the care of kidney recipients. Among these, minimizing immunosuppression-related toxicity without compromising graft outcomes is of paramount importance. Preexisting allograft functional impairment and the potential for significant interactions with immunosuppressive agents mandate that the expanding armamentarium of hypoglycemic agents be used with care. A team-oriented treatment approach that capitalizes on the collective expertise of transplant physicians, diabetologists, nurse-educators, and dieticians will optimize both glycemic control and the overall health of hyperglycemic kidney recipients

Dose distribution and up-titration patterns of metformin monotherapy in patients with type 2 diabetes.

Aims:To assess the dose distribution among users of metformin monotherapy as well as the patterns of up-titration following initiation of therapy in people with type 2 diabetes mellitus (T2DM). Materials and Methods:This was a retrospective cohort study of adults with T2DM in the United Kingdom (UK). Metformin dose distribution was assessed at 0, 6 and 12 months in people initiating metformin monotherapy (new users) and cross-sectionally in people with ongoing metformin monotherapy (prevalent users). Patterns and predictors of up-titration were also analysed in new users. Dose distributions and treatment patterns were assessed descriptively; predictors of up-titration were determined using multivariable logistic regressions. Results:Totals of 6174 new users and 8733 prevalent users were included. New users initiated metformin at >0 mg to ≤500 mg (25%), >500 mg to ≤1000 mg (47%), >1000 mg to ≤1500 mg (17%) or >1500 mg to ≤2000 mg (12%) daily. This distribution did not vary over time. Prevalent users of metformin received doses of >0 mg to ≤500 mg (14%), >500 mg to ≤1000 mg (40%), >1000 mg to ≤1500 mg (15%), >1500 mg to ≤2000 mg (29%) or >2000 mg (1%) daily. Among new users of metformin, 6.7% and 10.8% had been up-titrated at 6 and 12 months, respectively, despite the majority having glycated haemoglobin >53 mmol/mol. Predictors of up-titration included younger age and higher HbA1c. Conclusions:A majority of T2DM patients taking metformin received a dose ≤1000 mg/day. Up-titration of metformin is infrequent in the first year postinitiation

The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice

Heterozygous mutations in the gene encoding the pancreatic homeodomain transcription factor pancreatic duodenal homeobox 1 (PDX1) are associated with maturity onset diabetes of the young, type 4 (MODY4) and type 2 diabetes. Pdx1 governs the early embryonic development of the pancreas and the later differentiation of the insulin-producing islet β cells of the endocrine compartment. We derived a Pdx1 hypomorphic allele that reveals a role for Pdx1 in the specification of endocrine progenitors. Mice homozygous for this allele displayed a selective reduction in endocrine lineages associated with decreased numbers of endocrine progenitors and a marked reduction in levels of mRNA encoding the proendocrine transcription factor neurogenin 3 (Ngn3). During development, Pdx1 occupies an evolutionarily conserved enhancer region of Ngn3 and interacts with the transcription factor one cut homeobox 1 (Hnf6) to activate this enhancer. Furthermore, mRNA levels of all 4 members of the transcription factor network that regulates Ngn3 expression, SRY-box containing gene 9 (Sox9), Hnf6, Hnf1b, and forkhead box A2 (Foxa2), were decreased in homozygous mice. Pdx1 also occupied regulatory sequences in Foxa2 and Hnf1b. Thus, Pdx1 contributes to specification of endocrine progenitors both by regulating expression of Ngn3 directly and by participating in a cross-regulatory transcription factor network during early pancreas development. These results provide insights that may be applicable to β cell replacement strategies involving the guided differentiation of ES cells or other progenitor cell types into the β cell lineage, and they suggest a molecular mechanism whereby human PDX1 mutations cause diabetes