Involvement of insulin-like growth factor-I in the control of glucose homeostasis

Insulin-like growth factor-I (IGF-I) has significant structural homology with proinsulin. IGF-I binds to insulin receptors, stimulates insulin-like actions and enhances insulin sensitivity. However, because circulating IGF-I is bound to high-affinity binding proteins and has relatively low affinity for insulin receptors, most of its ability to alter insulin sensitivity is mediated indirectly (i.e. through suppression of growth hormone, a known insulin antagonist). Direct effects of IGF-I on insulin actions are tissue specific, occurring principally in skeletal muscle and kidney. Genetic manipulations in experimental mouse models have been used to analyze the role of endogenous IGF-I on insulin action. These studies have shown that suppression of growth hormone is important for enhancing insulin action in the liver and that deletion of the IGF-I receptor in skeletal muscle results in severe insulin resistance. IGF-I also suppresses renal gluconeogenesis, which might contribute to its glucose-lowering actions. In humans, IGF-I enhances insulin sensitivity and lowers blood glucose in patients with either extreme insulin resistance or type 2 diabetes. It also decreases insulin requirement in patients with insulin-deficient diabetes. Taken together, these findings suggest that IGF-I is functioning coordinately with insulin to regulate glucose homeostasis.     

Insulin and the insulin receptor in experimental models of learning and memory

Insulin is best known for its action on peripheral insulin target tissues such as the adipocyte, muscle and liver to regulate glucose homeostasis. In the central nervous system (CNS), insulin and the insulin receptor are found in specific brain regions where they show evidence of participation in a variety of region-specific functions through mechanisms that are different from its direct glucose regulation in the periphery. While the insulin/insulin receptor associated with the hypothalamus plays important roles in regulation of the body energy homeostasis, the hippocampus- and cerebral cortex-distributed insulin/insulin receptor has been shown to be involved in brain cognitive functions. Emerging evidence has suggested that insulin signaling plays a role in synaptic plasticity by modulating activities of excitatory and inhibitory receptors such as glutamate and GABA receptors, and by triggering signal transduction cascades leading to alteration of gene expression that is required for long-term memory consolidation. Furthermore, deterioration of insulin receptor signaling appears to be associated with aging-related brain degeneration such as the Alzheimer's dementia and cognitive impairment in aged subjects suffering type 2 diabetes mellitus.     

Insulin resistance in obesity as the underlying cause for the metabolic syndrome

The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic syndrome.     

Novel peptides under development for the treatment of type 1 and type 2 diabetes mellitus

Recent availability of expanded treatment options for both type 1 and type 2 diabetes has not translated into easier and significantly better glycemic and metabolic management. Patients with type 1 diabetes continue to experience increased risk of hypoglycemic episodes and progressive weight gain resulting from intensive insulin treatment, despite the recent availability of a variety of insulin analog. Given the progressive nature of the disease, most patients with type 2 diabetes inevitably proceed from oral agent monotherapy to combination therapy and, ultimately, require exogenous insulin replacement. Insulin therapy in type 2 diabetes is also accompanied by untoward weight gain. Both type 1 and type 2 diabetes continue to be characterized by marked postprandial hyperglycemia. Two hormones still in development are candidates for pharmacologic intervention, have novel modes of action (some centrally mediated), and show great promise in addressing some of the unmet needs of current diabetes management. Pramlintide acetate, an analog of the beta cell hormone amylin and the first non-insulin related therapeutic modality for type 1 and type 2 diabetic patients with severe beta cell failure, may be useful as adjunctive therapy to insulin. The principal anti-diabetic effects of pramlintide arise from interactions via its cognate receptors located in the central nervous system resulting in postprandial glucagon suppression, modulation of nutrient absorption rate, and reduction of food intake. Another polypeptide hormone, exendin-4, exerts at least some of its pharmacologic actions as an agonist at the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 and related compounds exhibit multiple modes of action, the most notable being a glucose-dependent insulinotropic effects and the potential to preserve or improve the beta-cell function. The latter effect could potentially halt or delay the progressive deterioration of the diabetic state associated with type 2 diabetes. Physiologically, both amylin and glucagon-like peptide (GLP)-1, along with insulin, are involved in a coordinated and concerted interplay between hormones acting both centrally and peripherally to provide meticulous control over the rate of appearance of exogenous and endogenous glucose and to match that rate to the rate of glucose disappearance. Both hormones are deficient in diabetes. Therapies directed at restoring this complex physiology have the potential to facilitate glucose control and thus minimize the attendant complications of diabetes.     

New solutions for type 2 diabetes mellitus: the role of pioglitazone

Type 2 diabetes mellitus remains a significant burden to the Canadian healthcare system. Over 2 million Canadians have diabetes, with 85 to 90% having type 2 diabetes. Insulin resistance is a major pathophysiological mechanism in the development of type 2 diabetes. Insulin resistance can be defined as an impaired biological response to the metabolic and/or mitogenic effects of either exogenous or endogenous insulin. As a consequence of insulin resistance, type 2 diabetes is characterised by decreased glucose transport and utilisation at the level of muscle and adipose tissue and increased glucose production by the liver. The traditional oral agents used to treat type 2 diabetes clearly do not address the underlying insulin resistance responsible for the development of diabetes. Thiazolidinediones (TZDs) represent a relatively new class of oral hypoglycaemic medications that have been shown to reverse some of the metabolic processes believed responsible for the development of insulin resistance and, ultimately, type 2 diabetes. Research has demonstrated that TZDs activate peroxisome proliferator activator receptors, in particular, the gamma-receptor isoform. Pioglitazone is a TZD that reduces plasma glucose levels by increasing peripheral glucose utilisation and decreasing hepatic glucose production. Clinical studies with pioglitazone have demonstrated the following: absolute reductions in glycosylated haemoglobin of 0.8 to 2.6%; reductions in fasting plasma glucose of 1.7 to 4.4 mmol/L; an increase in high density lipoprotein cholesterol of 8.7 to 12.6%; and a decrease in triglycerides of 18.2 to 26.0%, with no significant effects on low density lipoprotein or total cholesterol.     

Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus

Insulin resistance and the vascular complications of diabetes include activation of the inflammation cascade, endothelial dysfunction, and oxidative stress. The comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to correct them. Increased C-reactive protein, interleukin 6, tumor necrosis factor alpha and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with cardiovascular and non-cardiovascular complications of both type 1 and type 2 diabetes. We sought to review the clinical implications of the inflammation theory, including the relevance of inflammation markers as predictors of type 2 diabetes in clinical studies, and the potential treatments of diabetes, inferred from the pathophysiology.     

Myocardial insulin resistance and cardiac complications of diabetes

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.     

Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control

Destruction and dysfunction of pancreatic beta-cells, resulting in absolute and relative insulin deficiency, represent key abnormalities in the pathogenesis of type 1 and type 2 diabetes, respectively. Following the discovery of amylin, a second beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli, it was realized that diabetes represents a state of bihormonal beta cell deficiency and that lack of amylin action may contribute to abnormal glucose homeostasis. Experimental studies show that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects. These include a suppression of postprandial glucagon secretion and a vagus-mediated regulation of gastric emptying, thereby helping to control the influx of endogenous and exogenous glucose, respectively. In animal studies, amylin has also been shown to reduce food intake and body weight, consistent with an additional satiety effect. Pramlintide is a soluble, non-aggregating, injectable, synthetic analog of human amylin currently under development for the treatment of type 1 and insulin-using type 2 diabetes. Long-term clinical studies have consistently demonstrated that pre-prandial s.c. injections of pramlintide, in addition to the current insulin regimen, reduce HbA(1c) and body weight in type 1 and type 2 diabetic patients, without an increase in insulin use or in the event rate of severe hypoglycemia. The most commonly observed side effects were gastrointestinal-related, mainly mild nausea, which typically occurred upon initiation of treatment and resolved within days or weeks. Amylin replacement with pramlintide as an adjunct to insulin therapy is a novel physiological approach toward improved long-term glycemic and weight control in patients with type 1 and type 2 diabetes.     

Vascular effects of insulin

Insulin as a vascular hormone, apart from its effect on intermediary metabolism, has been considered to play an important role in cardiovascular regulation and pathophysiology of cardiovascular diseases such as essential hypertension, congestive cardiac failure and atherosclerosis. Insulin induces pressor effects by mechanisms of increased sympathetic activity, renal sodium retention and proliferation of vascular smooth muscle cells. On the other hand, accumulating evidence indicates that insulin decreases vascular resistance and increases organ blood flow especially in skeletal muscle tissue, indicating that insulin is a vasodilator. Several mechanisms underlying insulin-induced vasodilation have been proposed. Insulin enhances calcium efflux from vascular smooth muscle cells by activating the plasma membrane Ca(2+)-ATPase and causes hyperpolarization by stimulating Na+, K(+)-ATPase and sodium/potassium pump. Insulin also stimulates nitric oxide (NO) synthase and increases release of NO from vascular endothelium to cause vasodilation. An increase in cyclic AMP levels is induced by insulin, via activation of insulin receptors, beta-adrenoceptors and calcitonin gene-related peptide receptors. However, main cause of mechanisms mediating the vasodilation remain obscure. Hypertension is associated with insulin resistance and hyperinsulinemia. Insulin resistance may contribute to hypertension by sympathetic overactivity, endothelium dysfunction and decreased vasodilator action of insulin. Therefore, insulin must be considered a vasoactive peptide and more investigations are needed to better understand the full significance of the hemodynamic effect of insulin.     

Advanced approaches in insulin delivery

Diabetes is a syndrome of disordered metabolism and inappropriate hyperglycemia resulting from a deficiency of insulin secretion or insulin resistance. Insulin, a pancreatic hormone, helps to lower the blood sugar levels. The structural features of insulin and insulin receptors are summarized. Diabetic patients use insulin in the form of injections, which involves lots of pain, and a need for non-invasive, alternative mode of insulin administration is desired. These challenges have lead to attempts in insulin therapy using oral, nasal, pulmonary, rectal, transdermal, buccal, gene therapy, islet cell transplantation and diabetes vaccine. Among all the approaches pulmonary administration has achieved some clinical significance. Future approaches that can be exploited for insulin therapy in Insulin Dependent Diabetes Mellitus [IDDM] have been summarized. Insulin inhalers or tablets for IDDM are interesting alternatives.     

Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus

Insulin detemir (Levemir) is a soluble long-acting human insulin analogue acylated with a 14-carbon fatty acid. The fatty acid modification allows insulin detemir to reversibly bind to albumin, thereby providing slow absorption and a prolonged and consistent metabolic effect of up to 24 hours in patients with type 1 or type 2 diabetes mellitus. Insulin detemir has a more predictable, protracted and consistent effect on blood glucose than neutral protamine Hagedorn (NPH) insulin, with less intrapatient variability in glycaemic control, compared with NPH insulin or insulin glargine. Insulin detemir, administered once or twice daily, is at least as effective as NPH insulin in maintaining overall glycaemic control, with a similar or lower risk of hypoglycaemia, especially nocturnal hypoglycaemia, compared with NPH insulin in patients with type 1 or type 2 diabetes. Insulin detemir also provides the added clinical benefit of no appreciable bodyweight gain in patients with type 1 diabetes and less bodyweight gain than NPH insulin in patients with type 2 diabetes. Insulin detemir is, therefore, a promising new option for basal insulin therapy in patients with type 1 or 2 diabetes.     

PHARMAC and long-acting insulin analogues: a poor man's insulin pump--but to the poor man

Insulin glargine is a long-acting insulin analogue providing a more predictable and reproducible circulating insulin profile than other available basal insulin products. Hypoglycaemia is one of the main limiting factors to patients with diabetes requiring insulin, in achieving tight glycaemic control and reduced rates of complications. Evidence from randomised controlled clinical trials demonstrates reduced rates of hypoglycaemia in patients with type 1 and type 2 diabetes using insulin glargine compared with other basal insulin. Insulin glargine has been registered for use in New Zealand since June 2001, but currently remains unsubsidised by PHARMAC. Reducing the incidence and impact of diabetes is one of the stated aims in the New Zealand Health Strategy and the complete lack of funding for pharmaceutical agents such as insulin glargine severely limits its accessibility to patients with diabetes and would seem in contradiction to this aim.     

Insulin glargine: a new long-acting insulin product.

The pharmacodynamics, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of insulin glargine are reviewed. Current treatment regimens for patients with type 1 diabetes mellitus and some with type 2 are designed to provide a basal insulin level with intermittent preprandial insulin coverage. Insulin glargine precipitates after subcutaneous injection, slowing absorption. Insulin glargine is used as a basal insulin and exhibits a flat pharmacokinetic profile, with a duration of action of at least 24 hours. Hypoglycemia is the most commonly reported adverse effect, especially within the first four weeks after a switch to insulin glargine. Insulin glargine should not be mixed with any other insulin product and should be administered with a syringe that has not been used for other insulin products or other medications. Insulin glargine is administered once daily at bedtime. Patients previously receiving twice-daily isophane insulin (NPH) should receive an insulin glargine dosage 20% less than the total daily dose of NPH insulin. Clinical trials did not consistently show improvements in hemoglobin A1c levels when patients with type 1 diabetes mellitus were switched from NPH insulin once or twice daily to insulin glargine. Insulin glargine should be considered for patients who continue to have elevated morning blood glucose levels and problems with nocturnal hypoglycemia despite receiving NPH insulin at bedtime. In patients with type 2 diabetes mellitus, insulin glargine significantly improved glycemic control compared with once-daily NPH insulin, but not when it was compared with combined treatment with once- or twice-daily NPH insulin. Clinical trials assessing progression of retinopathy and nephropathy and comparing insulin glargine therapy with continuous subcutaneous insulin infusion therapy are needed to more clearly determine insulin glargine's role. Insulin glargine is a new long-acting formulation that can provide prolonged basal glucose control in patients with diabetes mellitus.     

Regulation of insulin release: analysis of the insulin secretory cascade and possible contribution to novel anti-diabetic drug development

Insulin is the only 'hypoglycemic' hormone synthesized in and secreted from the pancreatic beta cell. Type 2 diabetes results from both secretory failure in the beta cell and insulin resistance in the target tissues for insulin. Attempts to develop anti-diabetic drugs that induce insulin secretion from residual beta cells in type 2 diabetic patients originate from the serendipitous discovery of sulphonylureas as hypoglycemic agents 60 years ago. Generally, secretion is carried out by sequential processes such as granule formation, intracellular traffic, granule docking/priming and the final step, exocytosis (secretory cascade). In the beta cell, recent progress in cell biology enables us to analyze each step in the secretory cascade and to reveal controlling mechanisms. This review describes regulatory mechanisms of insulin release by distinct nutrients, hormones and neurotransmitters, and roles of second messengers and protein phosphorylation in the insulin secretory cascade. Possible development of insulinotropic drugs for the treatment of type 2 diabetes has been also discussed.     

Role of SNARE's in the GLUT4 translocation response to insulin in adipose cells and muscle

Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface. This is achieved by differentially modulating GLUT4 exocytosis and endocytosis, between a specialized intracellular compartment and the plasma membrane. Ligands which activate the heterotrimeric GTP-binding proteins Gs and Gi appear to modulate insulin-stimulated glucose transport through effects on the fusion of docked GLUT4-containing vesicles with the plasma membrane. In insulin resistance states, reduced cellular GLUT4 levels in adipose cells fully account for the decreased glucose transport response to insulin in these cells. In contrast, although insulin-stimulated GLUT4 translocation is also impaired in muscle, total cellular levels of GLUT4 are not altered. The defect in muscle has been attributed to a GLUT4 trafficking problem and thus studies of this mechanism could provide clues as to the nature of the impairment. The movement of GLUT4-containing vesicles from an intracellular storage site to the plasma membrane and the fusion of docked GLUT4-containing vesicles with the plasma membrane are conceptually similar to some secretory processes. A general hypothesis called the SNARE hypothesis (soluble NSF attachment protein receptors where NSF stands for N-ethylmaleimide-sensitive fusion protein) postulates that the specificity of secretory vesicle targeting is generated by complexes that form between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's). Several v- and t-SNARE's have been identified in adipose cells and muscle. VAMP2 and VAMP3/cellubrevin (v-SNARE's) have been shown to interact with the t-SNARE's syntaxin 4 and SNAP-23. The cytosolic protein NSF has the characteristic of binding to the v-/t-SNARE complex through its interaction with alpha-SNAP, another soluble factor. Furthermore, recent studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and thus are likely to be involved in the Gs- and Gi-mediated modulation of the glucose transport response to insulin as well. This review summarizes recent advances on the normal mechanism of GLUT4 translocation and discusses how this process could be affected in insulin resistant states such as type II diabetes.     

Mitochondrial dysfunction in diabetes mellitus

This review discusses the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of the most common form of diabetes, type II diabetes mellitus. Mitochondrial mutations have been linked to the development of diabetes mellitus as part of several rare syndromes, accounting for approximately 1.5% of all cases of the disease (“classic” mitochondrial diabetes). The characteristics of classic mitochondrial diabetes are intermediate between those of type I and type II diabetes, more closely resembling the latter. By studying the biochemical, cellular, and physiologic consequences of mitochondrial DNA mutations that cause classic mitochondrial diabetes, we may also gain important insights into the pathogenesis of type II diabetes mellitus. Individuals with classic mitochondrial diabetes exhibit a variety of defects in mitochondrial electron transfer enzyme activities. Complex I and Complex IV activities in skeletal muscle are almost universally decreased in mitochondrial diabetics compared with control individuals. The major physiologic abnormality in classic mitochondrial diabetes is delayed and insufficient insulin secretion in response to a glucose load. Insulin resistance is less commonly observed in these patients. The link between mitochondrial function and insulin secretion is supported by cellular studies in which introduction of inhibitors of oxidative phosphorylation or depletion of mitochondrial DNA markedly impairs glucose mediated insulin secretion from pancreatic β‐cells. Evidence for mitochondrial dysfunction in the common form of type II diabetes includes excessive free radical levels in the plasma of diabetics, increased reactive oxygen species, and decreased ATP synthase activity in cybrids constructed from mitochondria of diabetic patients, and maternal inheritance of the disease. By using the occurrence of diabetes in rare mitochondrial syndromes as an example, evidence supporting a relationship between mitochondrial dysfunction and the common form of type II diabetes is discussed. Mitochondrial function may represent a novel area for the development of therapeutic and diagnostic strategies for type II diabetes mellitus. Drug Dev. Res. 46:67–79, 1999. © 1999 Wiley‐Liss, Inc.     

Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders

The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.     

Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimer��s Disease

There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the course of the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactions between diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and are frequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This is currently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinical and biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucose metabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidence from a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported by a number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions were induced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brains demonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition, diabetes induces its own distinct features of neuropathology different from AD. There are common pathological features to be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence that vascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II) diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors and affect insulin signaling and cell survival. It has even been suggested that AD could be considered as “type 3 diabetes” since insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycation endproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproducts plays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβ peptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have been conducted, further understanding the common pathological processes of diabetes and AD are needed to determine whether these diseases share common therapeutic targets.     

Insulin glulisine

Insulin glulisine is a rapid-acting human insulin analogue that has a faster onset of action and shorter duration of action than regular human insulin (RHI) in patients with type 1 or 2 diabetes mellitus and is efficacious in controlling prandial blood glucose levels in these patients. In large, well designed trials in patients with type 1 diabetes, insulin glulisine demonstrated a similar degree of glycaemic control, as measured by glycosylated haemoglobin (HbA(1c)) levels, to RHI after 12 weeks and insulin lispro after 26 weeks. Pre-meal insulin glulisine was also more effective than RHI at controlling 2-hour post-prandial glucose excursions in patients with type 1 or 2 diabetes over a period of 12 weeks. In patients with type 2 diabetes, insulin glulisine induced significantly greater reductions in HbA(1c) levels and 2-hour post-breakfast and post-dinner blood glucose levels than RHI over a period of 26 weeks. Insulin glulisine was generally well tolerated by patients with type 1 or 2 diabetes and had a similar safety profile to insulin lispro or RHI. Severe hypoglycaemia was experienced by similar proportions of insulin glulisine or comparator insulin (insulin lispro or RHI) recipients with type 1 or type 2 diabetes.