NonSU Secretagogues

In order to improve postprandial glycaemic control, but to avoid hypoglycaemic episodes, the non-sulphonylurea moiety of glibenclamide, subsequently called meglitinide, was studied in the late 1970s and showed insulinotropic effects 18 . This finding led to the development of a relatively new class of medications repaglinide, a benzoic acid derivative and nateglinide, a phenyl-alanine derivative of meglitinide. Due to their short metabolic half-life and subsequent short stimulation of insulin...

Choice of Antidiabetic Agents to be Used in Combination

A number of potential combinations are depicted in Fig. 6b. Based on available clinical studies, a combining exenatide with metformin has the most obvious advantages A substantial reduction in HbA1c is associated with the numerically largest weight loss 119 (compared with combinations including sulfonylureas) 120,121 and no increased risk of hypoglycemia (despite better glycemic control) 119 . Addition to thiazolidinediones is similarly possible 122 . If exenatide is to be combined with...

Kjeld Hermansen

Keywords Insulin, insulin analogues, basal bolus insulin treatment, continuous subcutaneous insulin infusion, insulin pump, inhaled insulin, type 1 diabetes mellitus. The microvascular complications of type 1 diabetes mellitus (T1DM) were rarely noted before the discovery of insulin. The introduction of insulin therapy allowed patients to live long enough to develop diabetic retinopathy and diabetic nephropathy 1 . It was discussed extensively whether these complications were caused by...

Pharmacoepidemiology of Diabetes Safety Considerations

While phase 1 and 2 trials are necessary for the demonstration of early safety in humans, phase 3 trials (randomized controlled trials) are unsurpassed in design for the demonstration of the effects of a drug on the disease course (efficacy). Post-marketing phase 4 trials vary in design however, they are often not suited to evaluate therapeutic effects (effectiveness) in the population as a whole and long-term safety in non-selected groups of patients. Pharmacoepidemiology offers methods,...

The Need for Physiological Insulin Delivery

Physiologically, insulin secretion is characterized by rapid increases at meal times together with a lower and constant basal output during interprandial intervals, including during the night. Secretion falls acutely during exercise and prolonged fasting. These dynamic responses maintain euglycaemia (4.0-5.0 mM) at all times, except for 1-1.5 h after eating, consequently avoiding the damaging effects of hypergly-caemia. Insulin therapy in T1DM should aim to mimic nature, that is, limiting...

References

Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R et al. Management of hyperglycaemia in type 2 diabetes a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006 49(8) 1711-1721. 2. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, met-formin, or insulin in patients with type 2 diabetes mellitus...

Trends in the Use of Antidiabetic Drugs

A recent survey 11 of antihyperglycaemic drugs in ten European countries showed that their use increased in all countries but with very different treatment patterns. The use of insulin doubled from 1994 to 2003 in some countries (England and Germany) but remained stable in others (Belgium, Portugal, Italy). The use of biguanides increased substantially, whereas the use of sulphonylureas increased more moderately in most countries. Insulin accounted for more than 50 of the daily antidiabetic...

Secretion and Action of Incretin Hormones in Physiology

Physiological Roles of Gastrointestinal Peptide Hormones The ingestion of nutrients elicits the secretion of gastrointestinal hormones intimately involved in the regulation of gut and gallbladder motility, digestive juice secretion, and postprandial carbohydrate metabolism. In particular, incretin hormones stimulate insulin secretion from the endocrine pancreas. Through the action of incretin hormones, enteral nutrition provides a more potent insulinotropic stimulus relative to an isoglycemic...

Mechanisms of Action of Metformin

The mechanism by which metformin exerts its antihyperglycaemic effects is still not entirely clear, but may be mediated by activation of hepatic and muscle adenosine monophosphate-activated protein kinase 2 , which is a major regulator of lipid and glucose metabolism. Metformin improves fasting and postprandial glucose levels during an oral glucose tolerance test, whereas the plasma insulin response to glucose is unchanged or may be decreased in patients with hyperinsulinemia 3 . Metformin...

Establishing a Third Category IFG Why and What is IFG

The new category - Impaired Fasting Glycaemia - was introduced by the ADA expert committee in 1997. This was in many ways the logical consequence of their recommendation to stop using the OGTT, as this would make the diagnosis of IGT impossible. The hope was that through establishing the new category IFG it would be possible to identify a group comparable to the IGT with respect to risk of progression to diabetes and risk of developing CVD. As already discussed, the DECODE-study showed that...

Insulin Resistance Hyperinsulinemia and the IRS

Insulin resistance is not a disease, but a physiological abnormality that increases the likelihood that one or more of the abnormalities listed in Table 2 will be present. Furthermore, because the abnormalities seen in Table 2 occur more commonly in insulin-resistant individuals, they are at increased risk to develop one or more of the clinical syndromes listed in Table 3. However, the relationship between insulin resistance and the changes seen in Tables 2 and 3 is complicated, and the...

Side Effects of DPP4 Inhibitors Sitagliptin and Vildagliptin

A number of theoretical concerns have been expressed regarding potential adverse effects of DPP-4 inhibitors. In particular, the large number of physiological substrates of DPP-4 39,140 gave rise to speculations that inhibiting the action of this protease might interfere with numerous other hormonal axes, thereby potentially causing adverse reactions. Furthermore, since DPP-4 is also expressed on T-lymphocytes as CD26, it was speculated that chronic DPP-4 inhibition might alter immune functions...

Contributors

Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, 4, 5000 Odense C, Denmark, Department of Ophthalmology, rhus University Hospital, DK-8000 rhus C, Denmark, toke.bek mail.tele.dk Department of Medicine, University College London Medical School, 5 University Street, WC1 6JJ London, UK, rmhajbe ucl.ac.uk Universities of Manchester, UK, Miami, FL, USA Consultant Physician, Manchester Royal Infirmary, Manchester, UK, ABoulton med.miami.edu Director Steno Diabetes Center,...

Weight Gain

Pioglitazone and rosiglitazone are both associated with dose-dependent and time-dependent weight gain. The average weight gain ranged from 0.5 to 3.5 kg in patients treated with either drug as monotherapy. When either drug was combined with insulin or a sulfonylurea, the weight gain was more dramatic. Mechanisms for weight gain with thiazolidinediones may include increased adipogenesis resulting from PPAR-y activation, fluid retention, and increased appetite 65 . In general, improvement in...

Conventional Intensified Insulin Therapy or Multiple Daily Insulin Injections MDI

In conventional intensified insulin therapy (MDI) using the basal-bolus approach with MDI, continuous basal insulin supply is obtained by once- or twice-daily subcutaneous injections of longer-acting preparations, supplemented by mealtime injections of more rapid-acting formulations. These include structurally unchanged regular insulin preparations and short-acting insulin analogues (SIAs), which dissociate more rapidly than regular insulins and are absorbed faster. The glucose-lowering effect...

Clinical Efficacy of Metformin HbAlc Lowering But No Weight Gain

In placebo-controlled trials, metformin lowered HbAlc concentrations by about 1.0-2.0 8,9 . The efficacy of metformin monotherapy was equivalent to the monotherapy of sulfonylurea or thiazoliden-diones 10,11 . The greatest advantage of metformin compared with other anti-diabetic agents (insulin, sulfonylureas or thiazolidendiones) has been the fact that it is associated with weight loss but not with weight gain 1,9-14 . This has been shown for drug-nai've patients as well as for patients...

Side Effects Contraindications and Safety of Metformin

Gastrointestinal side effects, including abdominal discomfort and diarrhoea, are the most common adverse events, occurring 10-15 of patients, depending on the dose 1,8,11 . These side effects usually improve with continued use and are minimal if started at a low dose (e.g. 250-500 mg d) and slowly titrated upward. Discontinuation of therapy because of side effects occurs in less than 4 of patients. Because metformin does not increase insulin secretion 3 , biochemically documented hypogly-caemia...

Inhaled Insulin

Subcutaneous injection has been the only route of insulin administration for daily use by patients with T1DM for the past 80 years. A barrier to insulin therapy relates among other things to patient fears and anxiety about insulin injections. Although needles have become smaller and sharper, thereby causing less painful injections some people consider needles and injections a perceived stigma for diabetic subjects. It is only recently that alternative routes of insulin administration are...

Comparison of Biphasic Premix Insulin Analogues with Biphasic Premix Human Insulins

Several new biphasic premix insulin analogues have been introduced during the last years. Novomix 30, contains 30 rapid-acting aspart and 70 protamin - crystallised aspart. HumaLog Mix 25 , contains 25 rapid-acting lipro and 75 protamine-crystallised lispro. Biphasic premix analogues are available in other differently proportioned premix preparations, but these are used less frequently. The new premix insulin analogues can be injected immediately before a meal and the peak insulin concentration...

Potassium Bicarbonate and Phosphate

Even though the body is potassium depleted, with a typical deficit of around 5 mmol kg, initial potassium values are usually normal or elevated. Insulin therapy, rehydration and correction of acidosis all cause a decrease in serum potassium and 20-30 mmol potassium h may be administered once potassium levels are below 5.0 mmol L, provided renal function is intact. Subsequent potassium administration is guided by frequent concentration measurements adjuvant oral administration may be used in...

Pharmacological Interventions

There are three pharmacological agents often referred to as insulin sensitizers two thiazoli-denedione TZD compounds rosiglitazone and pioglitazone and metformin. Despite the frequency with which this term is applied to metformin, in the absence of weight loss, insulin-stimulated glucose disposal does not increase in metformin-treated individuals 59-61 . It is outside the province of this chapter to discuss the mechanism of action of met-formin, nor its use as an effective treatment of type 2...