Current Diabetes Reviews - Volume 8, Issue 3, 2012

Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive. The ‘thrifty phenotype’ hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. Results of a series of studies demonstrate the powerful influence of the mother’s metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation non-genetically and can be reversed and prevented. Such hypothesis has been expanded on by the “Developmental Origins of Health and Disease” (DOHaD) hypothesis which describes the origin of adult disease in terms of fetal developmental ‘plasticity’ or the ability of the fetus to respond to poor in-utero conditions. A wealth of epidemiological evidence has provided a convincing link between a sub-optimal gestational environment and an increased propensity to develop adult onset metabolic disease. In this paper the factors that participate in the programming of the fetus and infants that lead to endocrine dysfunction in postnatal life are reviewed.

Type 2 DM is associated with high rates of morbidity and premature mortality. Various potential health effects of coffee have been extensively studied, but data on habitual coffee consumption and the risk of type 2 diabetes mellitus have only recently been published. We systematically reviewed cohort studies (identified after searching through MEDLINE) from the period of January 2001 to August 2011 to find out the relation of degree of coffee consumption with development of diabetes mellitus. Information on study design, participant characteristics, measurement of coffee consumption and outcomes, adjustment for potential confounders, and estimates of associations was reviewed independently by 3 reviewers. The review included 13 cohort studies including 12, 47,387 participants and 9473 incident cases of type 2 diabetes. We compared the risk of diabetes amongst people with different degrees of coffee consumption. We concluded that habitual coffee consumption is associated with a lower risk of type 2 diabetes. Participants who drank 4 to 6 cups and more than 6 to 7 cups of coffee per day had a lower risk of type 2 diabetes compared with those who drank less than 2 cups per day. Advantage of filtered coffee over pot boiled, decaffeinated coffee over caffeinated coffee and stronger inverse correlation in < 60 years age group was also noted. However, based on this review, increasing coffee consumption as a public health strategy can’t be recommended. More detailed studies of coffee consumption, including appropriate measures of postprandial hyperglycemia and insulin sensitivity, are required.

Dipeptidyl peptidase -4 inhibitors represent a novel way to augment the incretin system and one of the newest class of medications in the treatment of type 2 diabetes mellitus. Their mechanism of action is to decrease the inactivation of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, both of which are involved in maintaining euglycemia subsequent to carbohydrate intake. Currently investigated agents include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Each agent has been shown to provide significant improvements in glycemic control compared to placebo. They are effective when added to other oral diabetes agents and in the cases of sitagliptin, vildagliptin, and alogliptin in addition to insulin. These agents may not provide as significant improvement in glucose concentrations as some other medications including metformin, thiazolidinediones, or glucagon-like peptide 1 agonists. The lack of head to head clinical data comparing the various dipeptidyl peptidase 4 inhibitors does not allow for specific recommendations if one agent is more effective or safer than another within the class. Their side effect profile suggests they are very well tolerated and have few drug interactions. For patients with mildly elevated glucose concentrations, they are therapeutic options in both drug-naive patients as well as those not optimally controlled on other diabetes medications.

Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose-lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARγ) partial agonistic property. The additional PPARγ agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARγ-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy.

Charcot neuroarthropathy (CN) is a devastating condition affecting the feet in patients with diabetes. The pathophysiology of (CN) is still incompletely understood, although main etiological components have been identified. The cornerstone of treatment of acute CN is immediate effective offloading, typically with total contact casting, and reduction in weight-bearing. The main current targets of pharmacological intervention are the inhibition of excess osteoclast activation and suppression of an excess pro-inflammatory cytokine response. Anti-resorption therapy, especially with bisphosphonates, has been used in randomized trials. The trials so far have demonstrated improved symptom control, a more rapid decline in foot temperature and a significant decrease in bone turnover markers. An understanding of the molecular pathways of bone resorption will help in the development of novel adjunctive pharmacological therapies which might further improve the outcome in patients with CN.

Accurate identification of infection in diabetic foot lesions is essential as the alternative can result in complicated medical and/or surgical interventions. The aim should be the differentiation between colonization and infection to avoid premature initiation of antimicrobial therapy. Diabetic foot ulcers provide a suitable environment for a diversity of microorganisms to first contaminate then subsequently colonize the wound. Infection can occur when a pathogenic factor produced by one or more microorganisms exceeds the capacity of the host immune system causing tissue damageand triggering both local and systemic inflammatory responses. The progression from wound colonization to infection is influenced by various factors including type and depth of the wound, blood supply, immune status of the patient. The quantity of microbial flora and pathogenicity expressed by the microorganisms involved will also have an effect.

Diabetic retinopathy is one of the leading causes of vision loss worldwide. Fluorescein angiogram still plays a primary role in its diagnosis but new non-invasive technologies as optical coherence tomography, fundus autofluorescence and microperimetry are gaining popularity in the last years. Anatomical changes found with these devices have been widely described but their correlation with visual function needs to be assessed and several features have been proposed as indicators of visual prognosis. The aim of this paper is to give a scope of the actual role of these techniques in the evaluation of retinal impairment secondary to diabetes.

The diabetic foot remains a major cause of morbidity worldwide. Even though considerable progress has been achieved over the past years, there is still an urgent need for improvement. While established therapeutic modalities (revascularization, casting and debridement) remain the mainstay of management, there is, therefore, continuous development of new treatment options. This review provides an outlook of advances in topical treatment, including bioengineered skin substitutes (such as Dermagraft, Apligraf, HYAFF, OASIS and Graftjacket), extracellular matrix proteins (such as Hyalofill and E-matrix), as well as miscellaneous further therapeutic adjuncts. Although promising, new therapies should not, for the time being, constitute the basis of management, since clinical experience has not yet confirmed their effectiveness in hard-to-heal diabetic foot ulcers. Furthermore, their cost-effectiveness merits further investigation. Instead, they should only be considered in combination with established treatments or be attempted when these have not been successful. Moreover, we should not be oblivious to the fact that established and emerging treatments need to be practised in the setting of multidisciplinary foot clinics to reduce the number of amputations.

The prevalence of type 2 diabetes mellitus has reached epidemic proportions and continues to grow in nations throughout the world. This disease is typically accompanied by other related conditions that each pose a hazard to the health of these patients and exacerbate the risk associated with diabetes for cardiovascular morbidity and mortality. Despite guideline recommendations for assessment and treatment of all of these related conditions, many patients do not achieve treatment goals. In this article, an archetypal case study is presented based on patient characteristics and conditions typically encountered in the clinic. After sustaining a myocardial infarction, the patient undergoes comprehensive evaluation and is noted to have multiple poorly controlled risk factors for cardiovascular disease and nephropathy. A multidisciplinary approach is advocated, not only to address blood glucose levels, but also to treat risk factors and comorbid conditions commonly associated with type 2 diabetes mellitus (adverse lifestyle behaviors, obesity, hypertension, albuminuria, and dyslipidemia) and complications resulting from this disease (secondary cardiovascular events, as well as nephropathy, retinopathy, and neuropathy). This comprehensive approach helps to maximize both the likelihood of reaching treatment targets for blood glucose, blood pressure, and serum lipids, and reducing the long-term risk of diabetes-related morbidity and mortality.

Diabetes can be associated with a number of peripheral nerve disorders. The commonest is slowly-progressive axonal distal symmetrical sensori-motor neuropathy. Sensory loss and positive sensory symptoms are its main manifestations. Lumbosacral radiculoplexus neuropathy (LSRPN) is a distinct entity, accompanied by severe lumbar, hip, leg pain and weight loss, with subsequent weakness. Although typically unilateral, bilaterality is described, with spontaneous recovery usual over several months. The upper limb counterpart, cervical radiculoplexus neuropathy is rare. Acute painful neuropathies, including “diabetic neuropathic cachexia”, are infrequent. Accompanying weight loss is usual and burning pains in the extremities are severe. Insulin-triggered acute painful neuropathy is well-described although infrequent and still poorly-understood. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represents an immunemediated treatable disorder, usually causing prominent diffuse motor weakness, which was described as more common in diabetics. More recent epidemiological data have however been conflicting and it is possible that CIDP is no more frequent in diabetics than in the general population. Diagnosis is made by electrophysiology and cerebrospinal fluid analysis. A painless diabetic motor neuropathy, thought to be caused by ischaemic injury and microvasculitis, has recently been postulated as separate from LSRPN and CIDP. Other focal and multifocal neuropathies that can occur in diabetics are cranial or truncal. Entrapment neuropathies are more often of median and ulnar nerves, and may in some cases benefit from decompression. Finally, autonomic neuropathies are well-described in diabetes and can be diverse in presentation with cardiovascular, gastrointestinal, urogenital and sudomotor manifestations. Their management can be difficult with debilitating symptoms despite treatment.