Le carnet Bibliographique

Hou X - Wookey JP - Mc Arthur DL - Mc Latchie LM
APOPTOSE : Koyama M & Srinivasan S
PSAMMOMYS OBESUS : Shafrir E & Nesher R
DIABETE : Vaag A & Hickey MS
GLP 1: Burcelin R & Nauck MA


Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors.

Diabetologia. 1999 Feb;42(2):188-94.

Hou X, Ling Z, Quartier E, Foriers A, Schuit F, Pipeleers D, Van Schravendijk C

Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.

Most non-insulin dependent diabetic patients have amyloid deposits in their pancreatic islets. It is not known whether chronic hyperglycaemia contributes to the formation of amyloid fibrils from the islet amyloid polypeptide that is produced by the pancreatic beta cells.

Since islet amyloid exhibits islet amyloid polypeptide precursors immunoreactivity, we examined whether sustained in vitro exposure to raised glucose increases the abundance of these precursors in human beta cells.

After 6 days stimulation with 20 mmol/l glucose the cellular content of insulin but not islet amyloid polypeptide was decreased leading to an increase in the ratio of the latter over insulin (3.0 +/- 0.6 vs 1.8 +/- 0.3 after 6 mmol/l glucose culture, p < 0.05). Similar changes occurred in rat beta cells cultured for 3 days in the presence of 20 mmol/l glucose plus 3-isobutyl-1-methylxanthine. Western blot analysis of cellular islet amyloid polypeptide after prolonged exposure to high glucose indicated the presence of higher proportions of its precursor- and intermediate forms. In human beta cells cultured in 20 mmol/l glucose, the major form corresponds to an intermediate species which exhibits an immunoreactivity for the N-flanking peptide, as is also the case in islet amyloid. We concluded that prolonged in vitro exposure of beta cells to raised glucose concentrations increases the relative proportion of islet amyloid polypeptide over insulin, as well as of its precursors over the mature form of islet amyloid polypeptide.

Amylin: physiological roles in the kidney and a hypothesis for its role in hypertension.


Wookey JP. & al.
Clin Exp Pharmacol Physiol 1998 Sep;25 (9): 653-60

Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre, West Heidelberg, Victoria, Australia. wookey@austin.unimelb.edu.au

1. There are high-affinity binding sites for amylin in the renal cortex associated with proximal tubules. These appear to represent seven transmembrane (heptatopic) receptors that are known to form ternary complexes with G-proteins and activate second messenger systems.

2. Amylin stimulates sodium/water reabsorption from the basolateral side of the proximal tubules and plays a role in sodium homeostasis.

3. The transient expression of amylin-like mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. There it is thought to play a role as a growth factor for brush border epithelial cells in the developing kidney and in renal regrowth in the adult kidney.

4. In two models of hypertension, the spontaneously hypertensive rat (SHR) and one created surgically by subtotal nephrectomy, renal amylin receptors are activated. In the SHR, activation precedes the rise in blood pressure and suggests that activation of the amylin system may be an important event in the development of hypertension.

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets.

MacArthur DL, de Koning EJ, Verbeek JS, Morris JF, Clark A

Department of Human Anatomy and Genetics, University of Oxford, UK.

Diabetologia 1999 Oct; 42 (10): 1219-27

Aims/hypothesis. Amyloid fibrils are formed in islets isolated from transgenic mice expressing the gene for human islet amyloid polypeptide (IAPP) by an unknown mechanism. This model of islet amyloidosis in Type II (non-insulin-dependent) diabetes mellitus has been used to investigate the temporal and glucose dependency of fibril formation.

Methods. To determine the time course and nature of amyloid-like accumulations and the role of glucose, transgenic mouse islets were cultured for 2-12 days in medium containing glucose (4.2 mmol/l, 11.1 mmol/l or 16.7 mmol/l) or 3.3 mmol/l glucose plus non-glucose secretagogues, 10 mmol/l leucine, 10 mmol/l leucine + 0.1 mmol/l tolbutamide, 10 mmol/l alpha-ketoisocaproic acid + 10 mmol/l glutamine. The extent of fibril formation was determined by quantitative immuno-electron microscopy. Insulin and islet amyloid polypeptide secretion into the media was measured by radioimmunoassay.

Results. Extracellular amyloid fibrils immunoreactive for islet amyloid polypeptide were visible initially after 6 days of culture in 11.1 mmol/l glucose and formed 2.3 +/- 0. 8 % of the islet area after 12 days; small accumulations of intracellular fibrils and amorphous extracellular islet amyloid polypeptide-immunoreactive material were present at 6-12 days. Beta-cell secretion was increased significantly by 16.7 mmol/l glucose and by alpha-ketoisocaproic acid + glutamine. The proportion of fibrillar amyloid (amyloid area/islet area%) correlated with the amount of insulin (r = 0.55, p < 0.05) and IAPP (r = 0.5, p < 0.05) in the culture media. Evidence of cellular damage was present in less than 10 % cells and correlated with the degree of fibril deposition (r = 0.8, p < 0.0001).

Conclusion/interpretation. These data suggest that islet amyloid polypeptide amyloid is formed primarily at extracellular sites in isolated transgenic mouse islets and progressive fibril formation correlates with beta-cell secretion.

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.

Nature 1998 May 28;393(6683):333-9

McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM

Receptor Systems and Cell Biology Units, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, UK.

Calcitonin-gene-related peptide (CGRP) and adrenomedullin are related peptides with distinct pharmacological profiles. Here we show that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-transmembrane-domain proteins, which we have called receptor-activity-modifying proteins or RAMPs, are expressed. RAMPs are required to transport CRLR to the plasma membrane. RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor. RAMP2-transported receptors are core-glycosylated and are adrenomedullin receptors.



Accelerated loss of islet beta cells in sucrose-fed Goto-Kakizaki rats, a genetic model of non insulin-dependent diabetes mellitus.

Koyama M, Wada R, Sakuraba H, Mizukami H, Yagihashi S

Am J Pathol. 1998 Aug; 153 (2): 537-45.

Department of Pathology, Hirosaki University School of Medicine, Japan.

The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of beta cells in the pancreatic islets with fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model.

Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison.

The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean beta-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of beta cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet beta cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of beta cells measured by 5-bromo-2'-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group.

The present study thus indicated that sucrose feeding promoted the apoptosis of beta cells in GK rats through increased oxidative stress without altering their proliferative activity.


Serum from patients with type 2 diabetes with neuropathy induces complement-independent, calcium-dependent apoptosis in cultured neuronal cells.

Srinivasan S, Stevens MJ, Sheng H, Hall KE, Wiley JW

J Clin Invest. 1998 Oct 1;102(7):1454-62.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center and the Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan 48105, USA.

We hypothesized that sera from type 2 diabetic patients with neuropathy contains an autoimmune immunoglobulin that promotes complement-independent, calcium-dependent apoptosis in neuronal cell lines. Neuronal cells were cultured in the presence of complement-inactivated sera obtained from patients with type 2 diabetes with and without neuropathy and healthy adult control patients.

Serum from diabetic patients with neuropathy was associated with a significantly greater induction of apoptosis, compared to serum from diabetic patients without neuropathy and controls. In the presence of calcium channel antagonists, induction of apoptosis was reduced by approximately 50%.

Pretreatment of neuronal cells with serum from diabetic patients with neuropathy was associated with a significant increase in elevated K+-evoked cytosolic calcium concentration. Serum-induced enhancement in cytosolic calcium and calcium current density was blocked by treatment with trypsin and filtration of the serum using a 100,000-kd molecular weight filter. Treatment with an anti-human IgG antibody was associated with intense fluorescence on the surface of neuronal cells exposed to sera from patients with type 2 diabetes mellitus with neuropathy.

We conclude that sera from type 2 diabetic patients with neuropathy contains an autoimmune immunoglobulin that induces complement-independent, calcium-dependent apoptosis in neuronal cells.

Psammomys obesus

Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome.

Shafrir E, Ziv E

J Basic Clin Physiol Pharmacol. 1998; 9 (2-4): 347-85

Diabetes Research Unit, Hadassah University Hospital, Jerusalem, Israel.

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats.

Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia.

The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity.

It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.


Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes.

Nesher R, Gross DJ, Donath MY, Cerasi E, Kaiser N

Diabetes. 1999 Apr; 48 (4): 731-7.
Department of Endocrinology and Metabolism, the Hebrew University-Hadassah Medical Center, Jerusalem, Israel. nesherr@cc.huji.ac.il
The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function.

A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients.


On the pathophysiology of late onset non-insulin dependent diabetes mellitus. Current controversies and new insights.

Vaag A

Hvidore Hospital, Klampenborg.

Dan Med Bull. 1999 Jun; 46 (3): 197-234.

The development of late onset non-insulin dependent diabetes mellitus (NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut incretin hormones (defective glucagon like peptide 1 (GLP1) secretion) on the other side. Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a genetic predisposition to NIDDM, higher concordance rates for abnormal glucose tolerance including NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different NIDDM susceptibillity genes at the sites of Insulin Receptor Substrate 1 (IRS1), the beta-3 adrenergic receptor, and the sulfonylurea receptor. However, the latter susceptibility genes only explain a minor proportion of NIDDM in the general population, and the quantitative extent to which genetic versus non-genetic factors contribute to NIDDM is presently unsolved.

Environmental components include both an early intrauterine component associated with low birth weight, and later postnatal components including low physical activity, high fat diet, and the subsequent development of obesity and elevated plasma and tissue free fatty acid levels. Our finding of lower birth weights in monozygotic twins compared with their non-diabetic genetically identical co-twins excludes the possibility that the association between NIDDM and low birth weight as demonstrated in several studies may solely be explained by a coincidence between a certain gene causing both a low birth weight and an increased risk of NIDDM.

Young first degree relatives of patients with NIDDM are characterized by hyperinsulinaemia and peripheral insulin resistance, which in turn may be explained by a decreased insulin activation of the enzyme glycogen synthase in skeletal muscle. Therefore, a defective skeletal muscle glycogen synthase activation may represent an early phenotypic expression of a genetic defect contributing to an increased risk of later development of NIDDM. However, elderly insulin resistant non-diabetic co-twins (64 years old) of twins with overt NIDDM does not--in contrast to their NIDDM co-twins--have a significantly decreased insulin activation of glycogen synthase in skeletal muscle. This demonstrates that the defective muscle glycogen synthase insulin activation has an appearant non-genetic component, and that this key defect of metabolism can be escaped or postponed even in non-diabetic subjects with a presumeably 100% genetic predisposition to NIDDM. The insulin activation of glycogen synthase in skeletal muscle is compensated or appearantly normalised in NIDDM patients when studied during their ambient fasting hyperglycaemia and a subsequent isoglycaemic (hyperglycaemic) physiologic insulin infusion. This indicates that the prevailing hyperglycaemia in NIDDM subjects compensates for the defective insulin activation of glycogen synthase present in those subjects when studied during eulycaemia. Our data and those of others also indicates that hyperglycaemia in NIDDM compensates for the defects in insulin secretion, the disproportionately elevated hepatic glucose production, and to some extent for the increased lipid oxidation and the decreased glucose oxidation present in NIDDM patients.

Accordingly, NIDDM subjects exhibit all of those defects of metabolism when studied during "experimental decompensation" when the ambient hyperglycaemia is normalized by a prior and later withdrawn intravenous insulin infusion. However, shortly after the withdrawal of the intravenous insulin infusion, the plasma glucose concentration increased spontaneously in the NIDDM patients.


A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?

Hickey MS, Pories WJ, MacDonald KG Jr, Cory KA, Dohm GL, Swanson MS, Israel RG, Barakat HA, Considine RV, Caro JF, Houmard JA

Ann Surg 1998 May; 227(5): 637-43; discussion 643-4
Department of Exercise and Sport Science, Colorado State University, Ft. Collins, USA.

SUMMARY BACKGROUND DATA: We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy.

Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year.

This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor.

METHODS: Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity.

RESULTS: Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group.

CONCLUSIONS: Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut.

GLP -1

Encapsulated, genetically engineered cells, secreting glucagon-like peptide-1 for the treatment of non-insulin-dependent diabetes mellitus.

Burcelin R, Rolland E, Dolci W, Germain S, Carrel V, Thorens B

Ann N Y Acad Sci. 1999 Jun 18;875:277-85.

Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland.


Non-insulin-dependent, or type II, diabetes mellitus is characterized by a progressive impairment of glucose-induced insulin secretion by pancreatic beta cells and by a relative decreased sensitivity of target tissues to the action of this hormone. About one third of type II diabetic patients are treated with oral hypoglycemic agents to stimulate insulin secretion. These drugs however risk inducing hypoglycemia and, over time, lose their efficacy.

An alternative treatment is the use of glucagon-like peptide-1 (GLP-1), a gut peptidic hormone with a strong insulinotropic activity. Its activity depends of the presence of normal blood glucose concentrations and therefore does not risk inducing hypoglycemia. GLP-1 can correct hyperglycemia in diabetic patients, even in those no longer responding to hypoglycemic agents. Because it is a peptide, GLP-1 must be administered by injection; this may prevent its wide therapeutic use. Here we propose to use cell lines genetically engineered to secrete a mutant form of GLP-1 which has a longer half-life in vivo but which is as potent as the wild-type peptide. The genetically engineered cells are then encapsulated in semi-permeable hollow fibers for implantation in diabetic hosts for constant, long-term, in situ delivery of the peptide. This approach may be a novel therapy for type II diabetes.

Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective.

Nauck MA

Acta Diabetol. 1998 Oct; 35(3): 117-29. Review.

Department of Medicine, Ruhr-University, Knappschafts-Krankenhaus, Bochum, Germany.

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone from the lower gastrointestinal tract, partially explaining the augmented insulin response after oral compared to intravenous glucose administration in normal humans. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, and reduces food intake upon intracerebroventricular administration in animals.

Therefore, GLP-1 offers some interesting perspective for the treatment of type 2, and perhaps also for type 1 diabetic patients. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in type-2 diabetic patients.

In contrast, GLP-1 glucose-dependently stimulates insulin secretion in type-2 diabetic patients and exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately three to four times physiological postprandial levels fully normalizes fasting hyperglycaemia and reduces postprandial glycaemic increments. Due to rapid proteolytic cleavage, which results in an inactive or even antagonistic fragment. GLP-1 [9-36 amide], and to rapid elimination, the half-life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections of the natural peptide hormone. Current research aims to characterize GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Given the large amount of GLP-1 present in L cells, it also appears worthwhile to search for more agents that could 'mobilize' this endogenous pool of GLP-1.

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