Current Research and the clinical and metabolic consequences of diabetes type 1 and 2

Diabetes Mellitus [DM] is a condition where reduced quantities or lack of response to insulin results in the accumulation of glucose in blood leading to acute or chronic complications. Insulin is a hormone produced in the pancreas which enables cells to absorb glucose to be converted to energy. DM is classified as type 1 [T1] and type 2[T2] diabetes. T1 or juvenile diabetes is an autoimmune disease and is a result of the lack of production of insulin in the body due to T-cell mediated destruction of beta [β] cells within the pancreas (Wen, Ley 2008) with elevated levels of blood sugar [fasting blood sugar levels above 120mg/dL] (Fig.2). The incidence of T1 has increased over the past decade in developed countries prompting environmental changes that may influence the pathogenesis of the disease. Current research indicates T1DM is associated within 18 loci of which 2 genes stimulate T cell activation. Human leukocyte antigen [HLA] on chromosome 6 contributes to half of all familial T1DM. The HLA combination DR4-DQ8 and DR3-DQ2 is present in paediatric T1 subjects while 1% of all paediatric patients with T1 contain a 3^rd gene DR15-DQ6. A diagrammatic representation of the process of T cell activation in T1 patients is shown in figure 1.

 T2 or non insulin dependent diabetes is a result of insulin resistance and insulin deficiency due to a malfunction of glucose homeostasis prompting elevated levels of blood glucose (Fig. 3). Although T2 may be managed via dietary modifications and exercise in the initial stages, the latter stages of the complex disorder is difficult to treat more effectively due to the interruptions in 1 or more mechanisms involving the homeostasis of normal levels of glucose such as insulin secretion, insulin sensitivity, glucose production and uptake (Buchwald et al 2009) (Fig. 3). According to the WHO [World Health Organisation] an estimated 180 million of the world population have diabetes and may double by 2030 while in 2005 a record of 1.1 million deaths occurred globally due to the disease. An estimated 80% of these deaths occurred in developing and under-developed countries and around 40% was amongst the elderly of 70 years of age with 55% being females. WHO has projected that deaths due to this chronic condition will increase by 50%within the next 10 years (WHO).

T1 and T2 have similar clinical and metabolic consequences and Fig. 4 illustrates these characteristics amongst paediatric patients although some are common to paediatric and adult patients, such as polyuria, polydipsia, ketonuria, hypertension [HT], hyperlipidemia [HL], polycystic ovary syndrome and metabolic syndrome. Other metabolic consequences in DM patients include hypercholesterolemia [HC], diabetic ketoacidosis [DKA], hyperproteinuria [HP], hyperglycaemia [HG] and glycosuira (Abu-Lebdeh et al 1996). DKA along with hyperglycaemic hyperosmalr state is the most dangerous complication in DM (Neville et al 2009). The cause of DKA is the over production of β-hydroxybutyric acid and acetoacetic acid which dissociate at physiological pH resulting in excess hydrogen binding to bicarbonates causing reduced bicarbonate levels thus ketones circulate in their anion form resulting in an anion gap that is characteristic of DKA. Elevated levels of counter-regulatory hormones result in insulin deficiency causing hepatic production of glucose and decrease uptake of glucose resulting in HG, thus stimulating lipolysis and ketogenesis causing DKA. HG and DKA results in osmotic dieresis leading to dehydration. Diagnosis of DKA is based upon dehydration, HG in the presence or absence of ketones in urine or plasma, blood pH, serum osmolarity and bicarbonate levels. DKA may result in further complications amongst some DM patients such as cerebral oedema, adult respiratory distress syndrome, hyperchloremic metabolic acidosis, hypokalemia and vascular thrombosis. Treatment for the condition is via fluid, potassium, insulin, bicarbonate and phosphate therapy (Chiasson et al, 2005).

HC or high levels of cholesterol contributes to cardiovascular disease[CVD] in diabetics and is related to HL. Cholesterol is classified as low density lipoprotein [LDL] and high density lipoprotien[ HDL]. HDL reduces cholesterol and transports to the liver while LDL contributes to CVD (Herbert et al 2009). Clinical diagnosis of HC is via blood tests determining the levels of serum LDL, HDL, triglycerides[TG] and total plasma cholesterol (Renard et al 2004). The combination of DM and excess cholesterol in diet cause microvascular lesions and embolisim of lipid. HC promotes CVD risk by 10 fold in T1 patients via atherosclerosis lesions (Johansson et al, 2008).

HL is another metabolic condition associated with DM. Both HL and HT are co-contributers to CVD amongst T2 patients in addtion to HG (Wolfs et al 2009). Current clinical trails indicate the reduction of cholesterol and tight HG regulation amongst such patients reduces the risk of CVD thus  intensive therpay programmes have been introduced to DM patients to reduce HL as apart of a primary preventative strategy (Cruz et al 2009). Combinational therpay is another form of treatment using lipid and TG lowering drugs such as Ezetimibe, Colesevelam, Torcetrapib, Avasimbe, Implitapide and Niacin. Research studies indicate, these drugs may be of therapeutic use for cancer and neurodegenration due to their characteristics of suppressing oxidising species and modulating activity of T cells (Pahan, 2006).

HT or elevated levels of arterial blood pressure [BP] is a modified risk for CVD and co-exists with DM due to obesity, insulin resistance and hyperinsulinemia. HG may also cause vasculature changes leading to HT although long term effects are unknown (Grevin et al 2007). T1 patients with HG due to insulin deficiency and insulin therapy may control the condition by reducing glucose concentrations to prevent HT. Large quantities of insulin used to control HG may cause weight gain thus effecting BP thus HT. This combination may have clinical consequences as HT is a co-conspirer to both micro and macro vascular complications of DM (De Bore et al, 2008). Arterial HT is associated with nephropathy in T1 patients while insulin resistance in T2 play a major role in the pathogenesis of HT. Patients subjected to severe forms of DM are coherent to aggressive HT therapy while others respond to combinational therapy. T2 subjects respond to angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, diuretics, β-adrenoreceptor blockers and calcium channel blockers (Sampanis et al 2008).

DM is a leading cause of blindness, renal and neurological diseases and amputations amongst adults and the elderly. In 2000’ alone an estimated 2.9 million deaths globally were attributed to diabetes thus DM is the fifth leading cause of death. Elevated levels of T2 amongst adults and paediatric subjects are due to lack of physical exercise, obesity and lack of nutritious food in diets. Paediatric patients with elevated BMI’s [body mass index]  are generally diagnosed with T2 via their elevated levels of C-reactive proteins, reduced amounts of adiponectin which also increases the risk of CVD during their adolescence and adult years (WHO, 2009).

DM is associated with different types of neuropathic syndromes which may cause either mild or traumatic neuro-degenerative problems. A variety of neuropathies exist under the classification of diabetic neuropathies [DN]. Some of these conditions are associated with HG, metabolic syndrome and inflammatory or immune system related processes. Many types of nerves are affected ranging from large fibre sensorys to small fibre sensories to symmetric and asymmetric autonomic and motor nerves. The process may also damage distal and cranial nerves, nerve trunks and nerve roots. Neuropathies associated with DM are classified into DN based on their pathophysiology (Fig.6) and DN based on anatomical patterns (Fig.7) i.e. symmetrical and asymmetrical. Diabetic sensorymotor polyneuropathy [DPN] is caused by changes in nerves and blood vessels as a result of exposure to chronic HG and may occur amongst T1 and T2 diabetics. The syndrome represents a slow progressive sensory deficit with symptoms initiating in the lower part and spreading to the upper part of the body along with autonomic symptoms. DPN may involve both large and small fibres and the aetiology of the disease is microvascular damage. The Rochester Diabetic Neuropathy Study conducted amongst 380 patients resulted in 66% of T1 and 59% of T2 patients had various forms of neuropathy. However, the common type of neuropathy amongst T1 and T2 patients was DPN (Dyck et, al 2008). The association of the disease with HG suggest that DPN may be managed by improved control of sugars in blood. Another disorder in DN is diabetic autonomic neuropathy [DAN] which may occur in DM subjects in the presence or absence of large fibre neuropathy. In a study conducted with DM [T1 and T2] patients and a control group resulted 54% of T1 and 73% T2 patients had mild to moderate autonomic impairment (Low et,al 2004). Autonomic failure results in hypotension, nausea, erectile dysfunction and constipation of the GI tract while instability in such subjects results in morbidity and high surgical risk. Acute painful diabetic neuropathy with weight loss and cachexia is also associated with DM. The disease initiates with sudden weight loss with severe pain followed by excessive sensitivity of the legs and feet. Insulin neuritis is a rare form of neuropathy associated with DM patients shortly after insulin therapy and is therefore more common amongst T1 subjects. Hypoglycaemic neuropathies are a result of HG and may damage the peripheral nervous system [PNS] amongst DM patients with regular hypoglycaemic episodes although the mechanism is not fully understood (Sinnreich et al 2005). DKA results in central nervous system abnormalities and may result in polyneuropathies after an episode of DKA. DM patients may be subjected to ischemic tissue damage in the brain and organs, however, limited information is available. Chronic inflammatory demyelinating polyradiculoneuropathy [CIDP] in DM is an immune system mediated disease of the PNS resulting in myelin sheath damage followed by loss of axons. The disease is characterised by hyporeflexia, symmetric and proximal weakness with some patients coherent of recurrent episodes accompanied with elevated levels of CSF proteins. Immunomodulatory therapies such as intravenous immunoglobulin, azathioprine and steroids are used to treat the condition. Diabetic lumbosacral radiculoplexus neuropathy [DLRPN] or diabetic amyotrophy occur amongst 1% of the DM population and is common to T2 subjects and has the highest morbidity in DN. Diabetic cervical radiculoplexus neuropathy [DCRN] is more consistent  with elderly T2 patients. 

 Another clinical complication of DM is diabetic retinopathy [DR] resulting in complete or partial blindness. Management strategies for DR include early detection via ophthalmoscope, digital imaging and telemedical screening, pars plana vitreous surgery; pharmacotherapy’s and laser photocoagulation methods (Huo et al 2007). Glycaemic control is important in the prevention and progression of DR. DR is common amongst T2 patients while only 10-15% of T1 patients are subjected to the condition. The mechanisms by which DR occur is unknown although it is suggested imbalance in electrolytes due to elevations in aldose reductase causes cell death  resulting in the formation of microaneurism and  components of the extracellular matrix depositing around the pericytes (Singh et al 2009). Retinal leukostasis results in capillary occlusions, damage of endothelial cells, leakage of vasculature and non-perfusion. Vaso-proliferative factors induce neovascularisation which is stimulated by retinal ischemia and is mediated by vascular endothelial growth factors [VEGF] which are angiogenic factors resulting in proliferative diabetic retinopathy [PDR].  The duration of diabetes plays a major role in the determination of the incidence of DR and its severity along with glycaemia control, age, sex, hypertension, neuropathy, genetics, anaemia, serum lipid content and pregnancy. Classification of DR includes non-proliferative diabetic retinopathy (Figure 9) [NPDR], PDR and diabetic macular oedema [DMO] (Kotoula et al 2005). Modern diagnostics include optical coherent tomography [OCT] and non-mydriatic fundus photography.

Diabetic nephropathy [DNEPH], proteinuria, elevated BP, reduced glomerular filtrate [GFR] is similar in both T1 and T2. However, the causes of renal dysfunction may differ. T1 patients subjected to DNEPH consist of hypertrophy of the kidneys, tubular atrophy and arteriole lesions with the progression of the disease followed by structural changes in the glomerulus with thickening of the basement membrane and mesangial expansion while T2 subjects consist of a normal glomerular structure and lack tubular or arteriolar abnormalities despite being positive for proteinuria (Figure 10). DMEPH risk factors include age, race, dyslipidemia, hyperfiltration and increased levels of BP. Clinical manifestation of the disease is related to the changes in the structures of the renal system (King et al 2009). Renal insufficiency in T1 subjects occur with the increase in mesengial expansion and width of glomerular basement membrane. Manifestations of abnormalities of glomerular tubular junction [GTJ] in T2 patients result in the obstruction of the proximal tubule while amongst T1 patients GTJ lesions contribute to loss of renal function. These lesions and the rate of progress of the disease are varied amongst T1 and T2 patients (Fioretto et al 2007). Management and the treatment strategies of dysfunction include control of hyperlipedemia via dietary restrictions, glycaemia control and renal transplantation therapy (Olubenga E et al 2004).

T1 and T2 patients are subjected to high risks involving cardiomyopathy and heart failure related deaths occur in the presence or absence of vascular diseases.  Cardiovascular risk increases in T1 patients with increased HT, LDL and renal dysfunction (Wang et al 2006). Cardiomyopathy amongst DM patients involves a cluster of features such as low diastolic compliance, intestital fibrosis and hypertrophy of myocytes although the mechanisms causing the condition are unclear but oxidative stress is considered to be a major cause. Current research involves rodent models of T1 and T2 followed by genetic engineering methods in the understanding of the molecular mechanism involving diabetic cardiomyopathy [DC] (Bugger et al 2009). Preventative therapies include antioxidants such as Metallothionein [MT]. MT is a protein, rich with cystein containing properties such as metal binding. MT plays a major role in the regulation of calcium, insulin sensitivity, zinc homeostasis and antioxidant action resulting in the use of MT in animal models and patients to explore possibilities of prevention of diabetes related complications such as DC. DM subjects with dyslipidemia, obesity, thrombosis, hypertension, autonomic neuropathy, dysfunction of the endothelium and coronary artery disease are prone to cardiac failure. The following diagram in figure 11 shows the features of DM patients that contribute to heart failure (De bore et al 2008). Reduced diastolic compliance is frequently observed amongst T2 patients along with left ventricular hypertrophy. Clinical features of DC are shown in figure 12.

Research in the development of new therapies for both T1 and T2 include various therapeutic forms of insulin such as insulin analogues [either rapid or long acting or premixed], insulin regimens, islet transplant and oral hypoglycaemic drugs such as sulphonyureas, biguanide, DPP-4 inhibitors, α-glucosidase inhibitor and thiazolidinediones (Krentz et al 2005). T1 patients use therapeutic insulin which enters systemic circulation via the use of pumps, patches, sprays, inhalers and injections while hypoglycaemic drugs are the key in maintaining latter stages of T2DM (Liberatore et al 2006). Although problems persist in understanding the full implications and mechanisms of DM continued clinical trials may provide a reliable insight into the disease in the near future.