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This paper reviews the effects of renal insufficiency on the pharmacokinetics of oral antidiabetic drugs. Of the 3 groups of drugs currently available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), the sulphonylureas and metformin are, in general, well-tolerated and generally safe. In patients with chronic renal insufficiency, however, care must be exercised in the use of many of these drugs, as accumulation, either of the active drug or of active metabolites, can lead to serious adverse effects such as hypoglycaemia or, with metformin, lactic acidosis. The sulphonylurea drugs, to a greater or lesser degree, are metabolised in the liver to a variety of active or inactive compounds which, in general, are excreted by the kidneys. In addition, varying amounts of parent compound may depend on renal elimination. As a result, sulphonylurea drugs such as tolazamide, acetohexamide, chlorpropamide and glibenclamide (glyburide) are more likely to cause significant hypoglycaemia, as the metabolism of these drugs, compared with other commonly prescribed sulphonylureas, can lead to the accumulation of either the parent drug or the active metabolite in the presence of renal insufficiency. Tolbutamide, glipizide, gliclazide and gliquidone are much less likely to cause hypoglycaemia as their metabolites are either inactive or have minimal hypoglycaemic potency. Metformin is dependent on renal excretion and is not significantly metabolised. As a result, caution is required when treating patients with renal insufficiency where metformin accumulation can occur, with the danger of lactic acidosis. Although the correlation between creatinine clearance (CLCR) and total oral clearance of drug is weaker than the correlation between CLCR and renal clearance (CLR) of metformin, it is clear that renal insufficiency is associated with most cases of metformin-induced lactic acidosis. For this reason, clinicians in general would regard a raised plasma creatinine as a contraindication to metformin treatment. Acarbose, an alpha-glucosidase inhibitor, and a relatively new agent for treating NIDDM, is likely to be safe in patients with impaired renal function, as the drug is not significantly absorbed from the gut, but data on this subject are lacking.
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PMID:Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. 885 33

Prophylactic insulin treatment prevents the development of hyperglycemia in animal models of insulin-dependent diabetes mellitus. Acarbose is a new antidiabetic drug which improves hyperglycemia by inhibiting alpha-glucosidase. In the present study, we determined the preventive effect of acarbose against multiple low-dose streptozotocin (MLDSTZ)-induced diabetes mellitus. The male ICR mice were fed acarbose (40 mg/100 g) containing powdered chow before the start of STZ administration. The mice were sacrificed at 3 and 10 days after the final STZ injection. MLDSTZ decreased serum immunoreactive insulin (IRI) levels and increased plasma glucose levels. Acarbose administration tended to decrease plasma glucose and serum IRI levels were significantly reduced in vehicle-treated mice. Acarbose administration significantly attenuated the degree of inflammation and destruction in pancreatic islets after MLDSTZ administration. In conclusion, acarbose-induced attenuation of acute hyperglycemia following MLDSTZ partially prevents the severity of pancreatic islet damage.
Diabetes Res Clin Pract 1996 Jun
PMID:Acarbose partially prevents the development of diabetes mellitus by multiple low-dose streptozotocin administration. 887 71

Glucose homeostasis is maintained by a balance between the release and action of insulin, and the counterregulatory responses mediated principally by glucagon, catecholamines, growth hormone and cortisol. Hence, the effects of a drug on glucose metabolism may be mediated by any of these agents singly or in combination. Host factors, such as inherent glucoregulatory mechanisms, concurrent diseases, organ function and concomitant medications also increase the risk of drug-induced disturbances of glucose homeostasis in susceptible individuals. By far the most important agents causing hypoglycaemia are insulin and the sulphonylureas. Alcohol (ethanol), over-zealous glycaemic control, hypoglycaemic unawareness, detective counterregulation especially in insulin-dependent diabetes mellitus (IDDM), and renal and liver impairment are all important predisposing factors. Although antihyperglycaemic agents such as metformin and alpha-glucosidase inhibitors do not cause hypoglycaemia alone, they may enhance the hypoglycaemic effects of potent hypoglycaemic agents such as insulin and sulphonylureas. On the other hand, the potential hypoglycaemic effects of ACE inhibitors, alpha-blockers, lipid-lowering agents and recombinant human insulin-like growth factor demonstrated in experimental settings, are of potential therapeutic interest. Iatrogenic hypoglycaemia and intensive insulin treatment are associated with hypoglycaemic unawareness which may be obviated by meticulous avoidance of hypoglycaemia. Effective patient education remains an important preventive measure. Oral glucose is used to treat mild hypoglycaemic episodes while more severe episodes are treated by intravenous glucose or glucagon. Nasal glucagon and theophylline are other experimental measures to improve recovery from hypoglycaemia. In refractory hypoglycaemia due to hyperinsulinaemia such as during sulphonylurea overdosage or quinine treatment, the long-acting somatostatin, octreotide, may suppress insulin release and restore euglycaemia. Diuretics, beta-blockers, sympathomimetics, corticosteroids and sex hormones are commonly prescribed drugs which may have adverse effects on carbohydrate metabolism especially in patients with diabetes mellitus or those who are at risk of developing glucose intolerance. Pentamidine was frequently associated with dysglycaemia due to its pancreatic beta-cell cytotoxic effects but is now used less often to treat Pneumocystis carinii pneumonia in immunosuppressed patients. Despite the large number of anecdotal reports of drug-induced disturbances of glucose metabolism, many of the so-called adverse drug reactions were either idiosyncratic or coincidental. Nevertheless, they emphasise the complex nature of glucose homeostasis and its potential interactions with drugs, host factors and disease states. An understanding of these relationships may allow more critical interpretation of these clinical observations, better prediction of drug induced adverse effects on carbohydrate metabolism and the implementation of more rational therapy. Hence, the hypoglycaemic effects of a drug may be turned to a therapeutic advantage in patients with glucose intolerance. Similarly, the hyperglycaemic effect of a drug may help to treat refractory hypoglycaemia.
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PMID:Drug-induced disorders of glucose metabolism. Mechanisms and management. 888 64

Studies were carried out to assess various ways of improving glycaemic control and lipid profiles of patients with noninsulin-dependent diabetes mellitus (NIDDM) in whom glucose metabolism was poor. Part or all of the dose of the sulphonylurea that had been used to treat patients in Group 1 (n = 8) was replaced by an alpha-glucosidase inhibitor. Symptoms related to hypoglycaemia disappeared and the postprandial blood glucose level was significantly increased (P < 0.043) but serum lipid levels were not significantly altered and the mean glycosylated haemoglobin level was unchanged. In Group 2 (n = 10) patients, a large part of the insulin dose was replaced by an alpha-glucosidase inhibitor. Hypoglycaemia-related symptoms disappeared but there were no significant changes in lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. The third group of patients (n = 9) had been treated with insulin alone and were given additional alpha-glucosidase inhibitor without changing their insulin dose. This did not significantly change their lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. In Group 4 (n = 9) the addition of an alpha-glucosidase inhibitor to the initial sulphonylurea did not produce any significant changes in mean postprandial blood glucose or glycosylated haemoglobin levels. The results for individual patients indicated that the glycosylated haemoglobin levels had improved after the change of treatment only in those patients whose connective peptide immunoreactivity was > or = 6.0 ng/ml.
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PMID:The effect of an alpha-glucosidase inhibitor and insulin on glucose metabolism and lipid profiles in non-insulin-dependent diabetes mellitus. 889 48

The effect of adding a very low dose of a sulphonylurea (tolbutamide) to the treatment of 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) was investigated. Patients took 0.1 mg tds of an alpha-glucosidase inhibitor orally for 8 weeks, and 50 mg tds of the sulphonylurea, tolbutamide, for the last 4 weeks of this period. The glycosylated haemoglobin level was significantly reduced during the combined treatment period compared with the level after treatment with alpha-glucosidase inhibitor alone (P = 0.035), although not compared with the pretreatment level. There were no significant changes in post-prandial blood glucose, serum lipid levels or connective peptide immunoreactivities. These preliminary results indicate that the addition of a very low dose of tolbutamide to a recommended diet and treatment with an alpha-glucosidase inhibitor, may improve glucose metabolism without raising insulin secretion or influencing lipid metabolism.
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PMID:The effect of a very low dose of tolbutamide combined with an alpha-glucosidase inhibitor in non-insulin-dependent diabetes mellitus. 889 47

Since impaired glucose tolerance (IGT) is a major risk factor for non-insulin-dependent diabetes mellitus (NIDDM), some kinds of intervention aiming to prevent or to delay the onset of NIDDM in subjects with IGT might be considered. Besides life style modification, drug therapy which could correct insulin deficiency and insulin resistance, might prevent progression to NIDDM. One agent is an alpha-glucosidase inhibitor, which delays the absorption of glucose from the intestine. The resulting decrease in postprandial hyperglycemia and hyperinsulinemia could theoretically decrease insulin resistance in IGT subjects and, it is hoped, prevent or delay progression to NIDDM. Metformin, an antihyperglycemic drug of the biguanide class, may be effective in subjects with IGT by reducing hepatic glucose output, enhancing insulin sensitivity, or through other mechanisms such as weight loss. New insulin sensitizers, such as troglitazone and pioglitazone, improve insulin-mediated glucose disposal by enhancing tissue sensitivity to the actions of insulin and reversing the insulin resistance, characteristic of NIDDM. Sulfonylureas might be another candidates of drug intervention to IGT whose insulin secretory abilities are markedly reduced. As far as the question, "Can NIDDM be prevented or delayed?" is concerned, a prospective study using life style modification or above-mentioned drugs, should be performed on long-term basis.
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PMID:[Drug therapy in subjects with impaired glucose tolerance]. 891 39

Alpha-glucosidase inhibitor can suppress postprandial hyperglycemia by delaying the absorption of carbohydrates in the intestine, and may be useful in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) and preserved insulin secretion. We encountered an obese elderly patient with NIDDM in whom gait disturbance had developed after cerebral hemorrhage and who suffered from ileus after treatment with voglibose. The patient had received voglibose which is reported to cause fewer abdominal symptoms than acarbose, for 15 days. The patient, a 63-year-old woman, was given a diagnosis of NIDDM in February 1995, and was treated with a sulfonylurea agent. However, her glycemic control remained poor and she was admitted to our hospital in April 1995. Her body mass index was 30.5 kg/m2 and laboratory investigation revealed a fasting plasma glucose level of 211 mg/dl, a postprandial (2 h) plasma glucose level of 288 mg/dl, HbAlc of 9.9%, a fasting insulin level of 9 microU/ml, urinary C-peptide excretion of 95.7 micrograms/ day, and an coefficient of variation of R-R value of 2.1%. Fifteen days after glibenclamide was replaced by to voglibose, abdominal pain, nausea, constipation, and ausculatory sounds of gurgling developed, and niveau were noted on an abdominal roentgenogram which indicated that simple ileus had developed. Voglibose was discontinued and the patient was treated with an enema and hot air. She recovered from simple ileus on the next day. This patient had had two abdominal surgeries and a cerebral hemorrhage, and her daily physical activities were limited, which might have contributed to ileus. In elderly patients with NIDDM, a history of abdominal surgery and the amount of daily exercise must be considered when deciding whether or not to give alpha-glucosidase inhibitors.
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PMID:[Occurrence of ileus after voglibose treatment in an elderly diabetic patient with gait disturbance caused by cerebral hemorrhage]. 892

In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.
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PMID:New treatments for patients with type 2 diabetes mellitus. 894 6

A survey of food components with alpha-glucosidase (AGH) inhibitory activity was conducted to identify a prophylactic effect for diabetes in food. Sardine muscle hydrolyzed by alkaline protease showed potent activity (IC50 = 48.7 mg/ml) as well as green and oolong teas (IC50 = 11.1 and 11.3 mg/ml, respectively). Furthermore, hydrolyzates prepared by various proteases gave differing AGH inhibitory activity. DEAE-Sephadex chromatography of the alkaline protease hydrolyzate eluted potent AGH inhibitors (IC50 = 15.6 mg/ml) with a 50 mM phosphate buffer (pH 7.0) containing 0.3 M NaCl, and their subsequent separation by HPLC in an ODS column showed that there were some inhibitors possessing primary amino groups. This indicates that they would have been high anionic and peptidic compounds.
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PMID:In vitro survey of alpha-glucosidase inhibitory food components. 898 34

In patients suffering from insulin-dependent diabetes mellitus (IDDM) with or without preclinical and clinical signs of diabetic nephropathy, the degree of epithelial cell lesions in the renal tubules was assessed from the urinary activities of enzymes at various sites, such as lysosomal (N-acetyl-beta-D-glucosaminidase (NAG) and beta-galactosidase (beta-GA)), brush edge membranous (alanine aminopeptidase (AAP), and cytosolic (alpha-glucosidase (alpha-GL)). Patients from Groups 1 and 2 had no preclinical and clinical signs of nephropathy. In Group 1 patients, the magnitude of enzymuria was not different from that in normalcy. However, Group 2 patients exhibited significant increases in urinary NAG and beta-GA activities as compared to Group 1 patients and healthy individuals. In Group 3 patients with microproteinuria from 0.05 to 0.5 mg protein per ml urine, displayed a further enhancement of NAG and beta-GA activities as compared to Group 2 patients and significantly higher activity than did Groups 1 and 2 patients and healthy individuals. In Group 4 patients with macroproteinuria of > 0.5 mg/ml), greater increases in the activities of NAG, beta-GA, and AAP were not found, however, there was a significant increase in alpha-G1 activity. The findings suggest the varying degrees of epithelial cell damage in the renal tubules in patients of different groups and the possibility of early detection of lesion in the proximal portion of nephronic tubules in IDDM patients as assessed from urinary enzyme levels.
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PMID:[Urinary enzymes in insulin-dependent diabetes mellitus]. 899 62


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