Diabetes 60:391-397, 2011.

Accumulating evidence during the last several decades has suggested that glucagon is of key importance for diabetes hyperglycemia. Thus, patients with type 2 diabetes have hyperglucagonemia and increased hepatic glucose output, and the hyperglycemia seems to be caused by a defective suppression of glucagon during hyperglycemia (1). A recent experimental study by Lee and collaborators examined the role of glucagon in mice with type 1 diabetes induced by streptozotin (2). They approached this aim by using a mouse model with genetic deletion of the glucagon receptors. This model has been characterized before and shown to be associated with reduced fasting and prandial glycemia (3). The authors challenged these mice with a high dose of streptozotocin, a beta cell toxin completely destroying beta cell function. Wild type mice became severely diabetic after this challenge with massive hyperglycemia. However, the mice with the glucagon receptor knockout remained in good health with low glucose and had normal glucose tolerance after a glucose challenge, even in the absence of any insulin response.

The study therefore shows that in the presence of glucagon deficiency, complete lack of insulin does not result in hyperglycemia, which suggests that a main function of insulin is to restrain the hepatic action of glucagon. The mechanism by which glucose tolerance remains normal after streptocotozin administration in glucagon receptor knockout mice remains now to be studied. The authors hypothesize that leptin or insulin-like growth factors may contribute, although no evidence for this is presented. Nevertheless, the main conclusion of the study strengthens the hypothesis that glucagon is a major player behind hyperglycemia in diabetes.

Bo Ahrén – Sweden

1. Dunning BE, Gerich JE 2007 The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev 28:253-283.
2. Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH 2011 Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60:391-397.
3. Gelling RW, Du XQ, Dichmann DS, et al. 2003 Lower blood glucose, hyperglycagonemia, and pancfreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100:1438-1443.

J Clin Endocrinol Metab 96:737-745 (2011)

The incretin effect is defined as the augmented insulin secretion after oral versus intrave-nous glucose administration and is due to the release from the gut of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) after oral glucose; these incretin hormones augment glucose-stimulated insulin secretion (1). The incretin function is of key importance for normal glucose levels after oral glucose. It has also been shown that the incretin effect is impaired in type 2 diabetes (2). This is mainly due to impaired action on insulin secretion by the incretin hormone GIP in type 2 diabetes (3) and a reduced incretin hormone secretion may also contribute in some patients (4).

The new study by Dr Bagger and co-authors presents novel information on the regulation of the incretin function under normal conditions and in type 2 diabetes (5). They challenged healthy volunteers and patients with type 2 diabetes with 25g, 50g and 125g oral glucose. They found in healthy subjects that the incretin effect (defined as the difference in insulin response after oral vs intravenous glucose) was increased by increased glucose and that the increase was such that in spite of the larger glucose challenge at 125g, the glucose peak was not higher due to augmented insulin secretion. They also showed that this increased incretin function was impaired in type 2 diabetes. Thus, these patients with diabetes had impaired increase in incretin function after increasing glucose load, resulting in hyperglycemia. The authors also showed that GIP and GLP-1 secretion was increased by the higher glucose load to the same extent as in healthy subjects and therefore, the main conclusion was that patients with type 2 diabetes had defective islet effects of the incretin hormones.

The study therefore presents new data on incretin physiology and pathophysiology and in particular shows that defective islet response to incretin hormones may explain the hyperglycemia following increased glucose load.

Bo Ahrén – Sweden

1) Holst JJ, Vilsbøll T, Deacon CF 2009 The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297:127-136
2) Nauck M, Stockmann F, Ebert R, Creutzfeldt W 1986 Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46-52
3) Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W 1993 Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest 91:301-307.
4) Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ 2011 Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54:10-18.
5) Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T 2011 Im-paired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 96:737-745

Metformin, discovered in the 1920s appeared on the market in 1957. It belongs to one of the major families of products acting on insulin resistance in patients suffering from type 2 diabetes.

The target of its action is the mitochondrion¹, more specifically complex 1, the entry point of NADH reduction which allows preservation of the proton gradient required for ATP production at the level of the mitochondrial membrane. However, the molecular target of metformin within complex 1 remains unknown.

Metformin is considered to have as a dominant cell action the activation of AMP kinase (AMPK) to which the inhibition of hepatic neoglucogenesis by metformin is attributed. Finally, metformin acts selectively on the liver; a transport protein from the Organic Cation Transporter (OCT), family,OCT1, being in control of the entry of metformin into hepatocytes.^2,3

Figure. Metformin mechanisms of action.

A work that has just been published in J Clin Invest⁴ questions the role of AMPK in the action of metformin on hepatic neoglucogenesis. Metformin continues to block hepatic glucose production.² This is observed in the presence and absence of catalytic AMPK subunits in mouse hepatocyte primary cultures at concentrations comparable to those obtained under treatment in humans. It is a fast effect, noticeable as soon as the 4th hour. The inhibition of hepatic production takes place irrespective of the presence or absence of glucose in AMPK-deficient hepatocytes, the absence of phosphorylation of CRTC2, central mediator of neoglucogenesis in the liver, and without modification of the levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase, conversely strongly altered in the absence of LKB1. These data indicate that the basal regulation of CRTC2 phosphorylation is dependent on LKB1, but independent of AMPK. CRTC2 phosphorylation is abolished in the absence of AMPK or LKB1, but without abolishing the action of metformin, both on glucose production and on the inhibition of glucose-6-phosphatase. Comparable results were obtained in vivo; metformin improved insulin sensitivity both in deficient and control mice. Furthermore, the deficient mice are normoglycemic, respond normally to glucose, and have blood insulin levels comparable to those of control mice, indicating a normal insulin sensitivity.

The effect of metformin in deficient mice thus seems independent of the effect of AMPK and CRTC2 phosphorylation observed in control mice. In this model, it is independent of the genes controlling neoglucogenesis, suggesting more an inhibitor effect on neoglucogenic fluxes than an effect on neoglucogenesis transcription genes.⁵

C. Boitard – France

1- El-Mir MY et al. J Clin Biochem. 2001;275:223.
2- Wang DS et al. J Pharmacol Exp Ther. 2002;302:510.
3- Shu Y et al. J Clin Invest. 2007;117:1422.
4- Foretz M et al. J Clin Invest. 2010,120:2355.
5- Miller RA et Bimbaum J. J Clin Invest.2010;120:2267.

Source:

Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B.
J Clin Invest. 2010 Jul 1;120(7):2355-69. doi: 10.1172/JCI40671. Epub 2010 Jun 23.

Dear Colleagues,

As Chairman of IGIS, I am happy to announce that we have recently created an IGIS web site; I invite you to visit it at www.igis.com.

At this site users will have access to extensive information on IGIS, including the history and structure of IGIS, and the past and future programs of the Servier-IGIS symposia (11 so far). Furthermore, they will have access to the annual symposia synopses (IGIS Digest) as well as links to the abstracts of the presented papers

I hope you will like this web site. Our aim has been to present IGIS to a wider public of professionals, and to allow fruitful exchanges with colleagues and students. I see the IGIS web site as an additional tool for our ultimate aim: to encourage research in the dynamic field of insulin secretion and islet research.

I wish you very enjoyable browsing!

Best regards

Erol Cerasi, MD, PhD