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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hormone insulin remains the cornerstone of diabetic therapy since it is required for almost all cases of Type 1 and many cases of Type 2 diabetes. Since the discovery of insulin in 1921, much has been learned about its chemistry, structure and action as well as its production in the beta cell. Insulin is formed through a series of precursors, beginning with preproinsulin, the protein encoded in the insulin gene. These precursors direct the prohormone into the secretory pathway and ultimately into the secretory granules where it is converted into insulin and C-peptide. These products are stored and secreted together in a highly regulated manner in response to glucose and other stimuli. This review focuses on the recently discovered prohormone convertases, PC2 and PC3 (PC1), the enzymes responsible for the endoproteolytic processing of proinsulin to insulin and C-peptide in the beta cell as well as for the selective processing of proglucagon to glucagon in the alpha cell or GLP1 in intestinal L-cells. PC2 and PC3 are calcium-dependent serine proteases related to the bacterial enzyme subtilisin. They cleave selectively at Lys-Arg or Arg-Arg sites in precursors, generating products with C-terminal basic residues that are then removed by carboxypeptidase E, an exopeptidase. All 3 enzymes are expressed mainly in secretory granules of neuroendocrine cells throughout the body and in the brain. Inherited defects affecting the prohormone-processing enzymes have recently been found in association with unusual syndromes of obesity and other metabolic disorders.
Diabetes Metab 1996 Apr
PMID:The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals. 879 89

A strong relationship between long term metabolic control and low frequency of chronic diabetes complications was shown in the Diabetes Control Complication Trial (DCCT). However, the subcutaneous intensive insulin therapy required to achieve the glycemic goals defined by the DCCT led to an unacceptable frequency of severe hypoglycemia and a significant weight gain. This limits the benefits of this therapy and excludes groups of patients such as young children, the elderly or hypoglycemia prone patients. The intensive therapy and self blood glucose monitoring (SMBG) necessary to limit hypoglycemia represent a heavy burden for the patients and their family. Improvements in parenteral insulin therapy are possible by either modifying subcutaneous insulin characteristics (analogs, adjunction of peptides such as amylin, GLP1, IGF1), or by developing better routes of administration and making SMBG easier, which is a key to intensive insulin therapy success. The ultimate goal remains the development of an automated, glucose controlled device.
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PMID:Current status and future prospects of parenteral insulin regimens, strategies and delivery systems for diabetes treatment. 1083 97

Several factors are determinant for postprandial blood glucose. Knowing and analysing these factors will help to optimize diabetes management. First, meal introduces the concept of food glycemic index. Blood glucose peak following a meal is modulated by gut hormones incretin effect, essentially GIP and GLP1. At the hepatic level, 30% of absorbed glucose is extracted by the liver which reduces its endogenous production in parallel. A reduction in hepatic glucose production blockade--through an excess in glucagon or free fatty acids in portal flow--will result in postprandial hyperglycemia. Finally, insulin secretion pattern is less influent than the hepatic insulin resistant state itself in determining this hyperglycemia.
Diabetes Metab 2000 Jun
PMID:[Physiopathology of postprandial hyperglycemia]. 1097 43

Post-prandial hyperglycemia (PPHG) is an independent risk factor for the development of macrovascular complications. It is now recognized that normalizing post-prandial blood glucose is more difficult than normalizing fasting glucose. Many factors affect the post-prandial blood glucose excursion. The glycemic index of the meal depends on the nature of the ingested food and starch composition. Gastric emptying is influenced by various factors including gut hormones such as GIP and GLP1, which potentiate insulin secretion, especially in its acute first phase, now referred to as an incretin effect. They also modulate glucagon secretion. Post-prandial hyperglycemia is limited by uptake of glucose by the liver and by inhibition of endogenous glucose production in this organ. In healthy controls, hepatic glucose production is halved after a meal, whereas in glucose-intolerant individuals and type 2 diabetics this inhibition is impaired (20-30% versus 50%). The persistence of endogenous glucose production during the post-prandial phase appears to be the main culprit in the PPHG. This reduced decrease in endogenous glucose in glucose intolerant and type 2 diabetic patients depends not only on the first acute phase of insulin secretion, but above all on the non-suppressed glucagon level during the post-prandial phase. Glucagon levels fall in healthy control subjects during the post-prandial phase. Although peripheral glucose uptake by insulin-dependent tissues is altered in type 2 diabetic patients, it does not appear to be the major cause of the PPHG as there are patients with insulin resistance but without post-prandial hyperglycemia.
Diabetes Metab 2000 Sep
PMID:Post-prandial hyperglycemia. post-prandial hyperglycemia and diabetes. 1101 Dec 18

The urinary excretion of insulinotropic glucagon-like peptide 1 (GLP-1) was investigated as an indicator of renal tubular integrity in 10 healthy subjects and in 3 groups of type 2 diabetic patients with different degrees of urinary albumin excretion rate. No significant difference emerged between the groups with respect to age of the patients, known duration of diabetes, metabolic control, BMI, or residual beta-cell pancreatic function. Endogenous creatinine clearance was significantly reduced under conditions of overt diabetic nephropathy, compared with normo and microalbuminuric patients (p < 0.01). Urinary excretion of GLP-1 was significantly higher in normoalbuminuric patients compared to controls (490.4 +/- 211.5 vs. 275.5 +/- 132.1 pg/min; p < 0.05), with further increase under incipient diabetic nephropathy conditions (648.6 +/- 305 pg/min; p < 0.01). No significant difference resulted, in contrast, between macroproteinuric patients and non-diabetic subjects. Taking all patients examined into account, a significant positive relationship emerged between urinary GLP-1 and creatinine clearance (p = 0.004). In conclusion, an early tubular impairment in type 2 diabetes would occur before the onset of glomerular permeability alterations. The tubular dysfunction seems to evolve with the development of persistent microalbuminuria. Finally, the advanced tubular involvement, in terms of urinary GLP1 excretion, under overt diabetic nephropathy conditions would be masked by severe concomitant glomerular damage with the coexistence of both alterations resulting in a peptide excretion similar to control subjects.
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PMID:Urinary excretion of glucagon-like peptide 1 (GLP-1) 7-36 amide in human type 2 (non-insulin-dependent) diabetes mellitus. 1156 Dec 19

Ageing is associated with an increased incidence of hypertension, macrovascular disease and type 2 diabetes (non-insulin-dependent diabetes). It has been suggested that a common mechanism may be responsible for all of these pathological states since all of these conditions often cluster in the same individual. Epidemiological and clinical data have consistently demonstrated an association between insulin resistance and/or hyperinsulinaemia and glucose intolerance, dyslipidaemia and elevated systolic blood pressures. Therefore, insulin resistance and hyperinsulinaemia have been proposed as the causal link among the elements of the clusters. The elderly are more glucose intolerant and insulin resistant, but it remains controversial whether this decrease in function is due to an inevitable consequence of 'biological ageing' or due to environmental or lifestyle variables, noticeably increased adiposity/altered fat distribution and physical inactivity. An increase of these modifiable factors has been shown to result in increases in insulin resistance and hyperinsulinaemia and vice versa. However, insulin secretion appears to decrease with age even after adjustments for differences in adiposity, fat distribution and physical activity. The glucose intolerance of ageing may be due, in part, to decreased insulin sensitivity of pancreatic / cells to insulinotropic gut hormones (GLP1/GIP) and in part to alterations of hepatic glucose production.
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PMID:Glucose tolerance, glucose utilization and insulin secretion in ageing. 1185 90

The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic beta-cells, develop diabetes secondary to beta-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.
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PMID:cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. 1284 10

Over the last decade, remarkable strides in incretin hormone biology have laid the foundation for our more recent appreciation that GLP-1 not only regulates mature beta-cell function but also critically regulates beta-cell differentiation, beta-cell proliferation and beta-cell survival. Dysregulated beta-cell growth and function are central to the pathophysiology of both type 1 and type 2 diabetes. Thus, GLP-1 receptor agonists are being intensively developed for the treatment of human diabetes and are likely to become available to clinical use in the near future. A general overview of beta-cell development will be provided, with particular emphasis on recent contributions to our understanding of pancreas and islet development during the embryonic, fetal and neonatal periods. The transcriptional hierarchy and extracellular signals governing events during these periods will be highlighted. Evidence suggesting a role for endogenous GLP-1 and GLP-1 receptor during beta-cell development will be reviewed. Finally, the therapeutic potential for intervention with GLP1 receptor agonists during the neonatal period will be discussed.
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PMID:The development of beta-cell mass: recent progress and potential role of GLP-1. 1565 13

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid hormone produced by intestinal L cells. It has been proposed that GLP-1 can be used as a new treatment for type 2 diabetes mellitus because it acts to augment insulin secretion and its effectiveness is maintained in type 2 diabetic patients. Despite its many remarkable advantages as a therapeutic agent for diabetes, GLP-1 is not immediately clinically applicable because of its extremely short half-life. One way to overcome this drawback is GLP1 gene delivery, which enables GLP-1 production in the body. In this study, the effect of GLP1 gene delivery was evaluated both in vitro and in vivo using a new plasmid constructed with a GLP1 (7-37) cDNA. The expression of the GLP1 gene was driven by a SV40 promoter/enhancer. To increase the expression level of GLP-1, nuclear factor kappaB binding sites were introduced. The in vitro results showed expression of GLP-1 and in vitro activity of GLP-1, which is a glucose-dependent insulinotropic action. A single systemic administration of polyethyleneimine/pSIGLP1NFkappaB complex into DIO mice resulted in increasing insulin secretion and decreasing blood glucose levels for a duration longer than 2 weeks.
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PMID:Glucagon-like peptide-1 plasmid construction and delivery for the treatment of type 2 diabetes. 1603 8

Over the past years, there has been an explosive increase in the prevalence of type 2 diabetes (T2DM) and this is expected to continue, entailing associated morbidity and mortality. An increasing number of studies explore the different ways T2DM could be prevented. On-going lifestyle modifications need to be addressed. High-risk patients should be given counselling on weight loss, possibly using a low glycaemic index diet, with a target of around 7-10% over 6-12 months, as well as instruction for increasing physical activity to around 150 min of physical exercise weekly (NNT = 4-8). Moderate alcohol consumption and coffee consumption may also be of benefit (NNT = 89 and 66, respectively). Metformin (NNT = 14), acarbose (NNT = 11) and troglitazone (NNT = 6) have been shown to prevent/delay T2DM and angiotensin-converting enzyme (ACE) inhibitors and statins appear to have an adjunctive role (NNT = 42 and 112, respectively). Trials with orlistat and bariatric surgery have also prevented T2DM (NNT = 36 and 6, respectively), and forthcoming treatment with GLP1 mimetics appears promising. Diabetes prevention studies should help create well-defined strategies for screening and treating high-risk populations in the real world, as prevention is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.
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PMID:Diabetes prevention: is there more to it than lifestyle changes? 1670 Aug 60


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