Incretin-based therapies: GLP-1, glucose homeostasis, and diabetes
The first paper selected this month is a review of incretin-based therapies. These therapies fall into two groups: 1. Incretin mimetics, which are injectable peptide preparations with actions similar to natural incretin hormones and 2. Incretin enhancers which can be taken orally. The incretin enhancers inhibit the normal degradation of incretin hormones in the body and, thereby, increase their plasma concentrations and biological actions. The scientific basis for the development of incretin-based drugs, and the clinical experience gathered to date is the topic of the review. The authors state that incretin hormones have a very important role in the regulation of postprandial glucose levels (1). The systemic physiological roles for Glucagon-like peptide-1 (GLP-1) are effects on pancreatic islets and on the digestive tract. There are indications for a role of GLP-1 in glucose homeostasis beyond the above-mentioned effects, suggesting that GLP-1 might contribute to increased postprandial glucose disposition via increased muscle glucose utilization, and/or inhibition of hepatic glucose output. This is discussed in the second paper (2).

Fetuin-A
Diabetes does not develop in all obese individuals and there is a strong genetic contribution to risk. Mechanisms responsible for individual differences in clinical phenotype of diabetes remain largely unknown. Recent research has, however, identified proteins secreted from adipose tissue that regulate glucose metabolism, termed adipocytokines. Study of these proteins has provided new insights into the biology of glucose regulation and has identified novel candidate therapeutic targets. In contrast to adipocytokines, fetuin-A (alpha2-Heremans-Schmid glycoprotein [Ahsg]) is produced in hepatocytes and secreted into serum, where it is found in high concentrations. In vitro, fetuin-A reversibly binds the insulin receptor tyrosine kinase in muscle and fat and decreases downstream signal cascades, which results in insulin resistance in these target tissues. Furthermore, in cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. Fetuin-A also seems to be independently associated with incident diabetes in older individuals. Future studies should evaluate whether these results may be generalized to middle-aged individuals in whom the incidence rate is highest. If confirmed in future studies, fetuin-A may ultimately prove useful as a target for therapeutics and its study may provide novel insights into glucose metabolism in humans (3).

SGLT 2 inhibitors
The sodium glucose co-transporter type 2 (SGLT2) is a member of a larger group of sodium substrate co-transporters i.e. the solute carrier family 5A (SLC5A) gene family, of which there are 12 human genes expressed in tissues ranging from epithelia to the central nervous system. Six of these gene products, named SLGTs, actively transport sugars coupled to sodium ion transport as a driving force. SGLT2 located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, and this normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke renal excretion of glucose have been discovered. SGLT2 inhibitors may prove to be beneficial in the treatment of type 2 diabetes as monotherapy or in combination with other oral or parenteral agents or insulins (4).

AST-120 (Kremezin®) in early stage chronic kidney disease
AST-120 (Kremezin®) is an oral adsorbent that has been reported to have a preventive effect on the progression of diabetic nephropathy. Data from a very small-scaled prospective randomized study in type 2 diabetic patients suggest that administration of AST-120 initiated in early stages of overt diabetic nephropathy exerts large renoprotective effects in type 2 diabetic patients. Only 16 patients had been randomized and even fewer were available for follow-up; therefore, this has to be considered to be very preliminary data that calls for larger clinical studies to clarify whether AST-120 is a potential therapeutic principle for patients with type 2 diabetes with renal dysfunction (5).

PPAR-alpha: therapeutic role in diabetes-related cardiovascular disease?
The Peroxisome proliferator-activated receptor (PPAR) family is a popular therapeutic target because of its multiple roles in lipid and glucose metabolism, and in vascular biology. PPARs are ligand-activated transcription factors. PPAR-alpha which is found predominantly in the liver, skeletal muscle, and the heart has been shown to have an important role in lipid and glucose metabolism and development of atherosclerosis. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. However, fibrates do not presently have a role as monotherapy for the reduction of cardiovascular disease in diabetes. It is, however, possible that the main role for fibrates in patients with diabetes in the future will be in combination with statins. This question will be answered by the ongoing NIH sponsored Action to Control Cardiovascular Risk In Diabetes trial (6).

IGFBP-1 in the prediction and development of type 2 diabetes
Insulin-like growth factor binding protein-1 (IGFBP-1) is secreted by the liver and has an inhibitory effect on the actions of insulin-like growth factor (IGF) -1 and IGF-2 in peripheral tissues. IGFBP-1 synthesis is regulated by insulin and other factors that are altered in conditions associated with abnormal glucose regulation. The suppression of IGFBP-1 production by insulin is achieved within the physiological range of insulin concentrations. Low circulating concentrations of IGFBP-1 are associated with the metabolic syndrome and cardiovascular disease. In a prospective population study individuals with low IGFBP-1 had increased risk of cardiovascular disease mortality. In a case-controlled study of the Stockholm Diabetes Prevention Program (SDPP), low fasting IGFBP-1 concentrations predicted the development of abnormal glucose regulation 10 years later. When IGFBP-1 was used in combination with glucose, waist, height and pro-insulin levels, individuals in the highest quartile were observed to have a 40-fold increased risk of developing diabetes. In individuals developing diabetes mellitus during a 10-year interval, fasting IGFBP-1 concentrations increased to levels greater than expected for the fasting insulin concentration and change in waist measurement. The higher fasting IGFBP-1 levels in this group of individuals with type 2 diabetes were inversely related to the change in IGF-1 levels and correlated positively with glucose values two hours after a glucose challenge. Factors responsible for the increase in IGFBP-1 in diabetes and its role in catabolism and glucose intolerance will be further investigated in future studies (7).

The glucose-lowering agent sodium tungstate
Sodium tungstate is an oral glucose-lowering and anti-obesity agent. This compound has a low toxicity profile in animals and humans, and is currently undergoing phase II clinical trials. Tungstate normalizes carbohydrate metabolism in the liver, stimulates insulin secretion, and regenerates pancreatic beta cells in neonatal streptozotocin-induced diabetic rats. In streptozotocin-induced diabetic rats tungstate also increases production and translocation into the diaphragm of the insulin-responsive glucose transporter GLUT4. It has now been shown that tungstate treatment increases the potential role for glucose transport in muscle cells by two mechanisms. Compounds like tungstate (currently in phase II clinical trials) which exert their action through the improvement of glucose uptake in skeletal muscle via an increase in levels of the myogenic regulatory gene MEF2, and GLUT4 translocation are excellent candidates for restoring the impaired muscle glucose metabolism that is characteristic of diabetes mellitus (8).

The endocannabinoid system in obesity and type 2 diabetes
The last paper selected this month is a review discussing the endocannabinoid system. It is of particular interest that blocking one of the cannabinoid receptors (CB1) is effective in reducing not only body weight, but also hyperglycaemia and dyslipidaemia. Future studies will help to reinforce the concept of the weight loss-independent beneficial metabolic effects of CB1 antagonists and profile the ideal patients to be treated with these compounds (9).

References

  1. Holst JJ, Deacon CF, Vilsbøll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med. 2008;14:161-8.
  2. Ionut V, Zheng D, Stefanovski D, Bergman RN. Exenatide can reduce glucose independent of islet hormones or gastric emptying. Am J Physiol Endocrinol Metab. 2008;295:E269-77.
  3. Ix JH, Wassel CL, Kanaya AM, Vittinghoff E, Johnson KC, Koster A, et al.; Health ABC Study. Fetuin-A and incident diabetes mellitus in older persons. JAMA. 2008;300:182-8.
  4. Jabbour SA, Goldstein BJ. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract. 2008;62:1279-84.
  5. Konishi K, Nakano S, Tsuda S, Nakagawa A, Kigoshi T, Koya D. AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res Clin Pract. 2008;81:310-5.
  6. Cheng AYY, Leiter LA. PPAR-alpha: therapeutic role in diabetes-related cardiovascular disease. Diabetes Obes Metab. 2008;10:691-8.
  7. Lewitt MS, Hilding A, Ostenson CG, Efendic S, Brismar K, Hall K. Insulin-like growth factor-binding protein-1 in the prediction and development of type 2 diabetes in middle-aged Swedish men. Diabetologia. 2008;51:1135-45.
  8. Girón MD, Sevillano N, Vargas AM, Domínguez J, Guinovart JJ, Salto R. The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D. Diabetologia. 2008;51:1285-95.
  9. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008;51:1356-67.