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Emilia Ottosson-Laakso

Causes and consequences of hyperglycemia and glycosuria

Type 2 diabetes is one of the world’s major challenges today. Over 400 million people around the globe are diagnosed with diabetes and the consequences to the individual patient and health care systems are significant. Diabetes is a chronic disease and the standard treatment including lifestyle changes, metformin and insulin is in many cases not effective enough. New anti-diabetic drugs have been developed aiming to lower blood glucose by inhibition of the glucose re-uptake via the sodium glucose co-transporter 2 (SGLT2) from urine, leading to excessive glycosuria. The potential effects of this treatment on the prevention of glucose intolerance have not been addressed in previous studies. The SGTL2-inhibitors mimic a condition where mutations in the SLC5A2 gene, which encodes the SGLT2 transporter, give rise to glycosuria. In study 1 we investigated the effect of chronic glycosuria on glucose tolerance over time in a family with mutations in the SLC5A2 gene and found that despite their life-long “SGLT2-inhibition” there was no effect of chronic glycosuria on the development of glucose intolerance.
There is a strong genetic component of diabetes that has been investigated using linkage studies and genome-wide association studies but only a small part of the estimated heritability has been explained by these findings. In families with high incidence of diabetes we can search for part of the missing heritability in the form of rare, family specific mutations. We show in study 2 that a previous linkage on chromosome 9 in families enriched with type 2 diabetes might in part be explained by rare variants in the multiple PDZ domain containing protein (MPDZ) gene. Knock down of the gene in an insulin secreting rat beta cell line resulted in impaired glucose-stimulated insulin secretion.
A vital part of glucose homeostasis is the regulation of blood glucose by insulin. The ultimate characteristic of type 2 diabetes is the failure of the pancreas to produce insulin in response to increased glucose demands. Studies of gene expression in islets of Langerhans may provide an answer to why this occurs. Study 3 compared the global gene expression in islets from human type 2 diabetic and non-diabetic donors. Over 1500 genes were differentially expressed in diabetic islets, e.g. the RAS guanyl releasing protein 1 (RASGRP1) was negatively associated with diabetes and positively associated with insulin secretion. Of the genes associated with diabetes we found that the expression of 35 genes was influenced by genetic variants and silencing of the gene tetraspanin 33 (TSPAN33), 5’-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6) and p21 protein activated kinase 7 (PAK7) in a rat beta cell line resulted in reduced glucose-stimulated insulin secretion.
Glucose is a potent regulator of gene expression and the regulation of genes by elevated glucose might further impair insulin secretion. In study 4 we aimed to separate the causes from the consequences of hyperglycemia on islet gene expression by global transcriptome analysis of islets exposed to short-term glucose (18.9 mmol/l glucose for 24 hours). We then compared the changes in gene-expression seen in patients with chronic hyperglycemia (diabetes) with genes regulated by short-term glucose exposure with the assumption that genes whose expression change after short-time hyperglycemia may reflect consequences rather than causes of hyperglycemia. This resulted in about 400 genes likely to be pathogenically involved in the development of hyperglycemia. For example the ERO1-Like Beta (ERO1LB) gene was down-regulated in islets from diabetic donors and correlated positively with insulin secretion whereas the transmembrane protein 132C (TMEM132C) gene that was up-regulated in islets from diabetic donors and correlated negatively with insulin secretion.

More information

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00