FULL REVIEWS DIABETES MELLITUS, A COMPLEX AND HETEROGENEOUS

Nephrol Dial Transplant (2016) 31: 206–213 doi: 10.1093/ndt/gfu405 Advance Access publication 30 December 2014

Full Reviews Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a determinant of diabetic kidney disease Janaka Karalliedde and Luigi Gnudi Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, Cardiovascular Division, School of Life Science & Medicine, King’s College, London, UK

Correspondence and offprint requests to: Luigi Gnudi; E-mail: [email protected]

Historically patients with diabetes have been classified into two main categories: type-1 diabetes mellitus (T1DM), characterized by a near-absolute deficiency of insulin secretion and type-2 diabetes mellitus (T2DM) where the cause is a combination of insulin resistance and an insulin secretory defect. The multiple mechanisms implicated in the pathogenesis and treatment of T1DM and T2DM have been reviewed in detail [1–3]. In recent years, further classifications and categories of diabetes have been suggested that confirm the heterogeneous aetiology and range of clinical manifestations of diabetes [4]. As a clinician, it is important to be aware of these categories/ classifications as a better understanding of the pathogenesis of the patient’s hyperglycaemia often helps in deciding on the best clinical care/management and for risk stratification for microand macrovascular chronic complications. This review aims to summarize the main diagnostic classification categories for diabetes with a particular focus on the implications of the diagnosis for future risk of renal disease and the putative common pathways that underlie the clinical presentation of diabetes and diabetic renal disease.

A B S T R AC T Diabetes mellitus (DM) is increasingly recognized as a heterogeneous condition. The individualization of care and treatment necessitates an understanding of the individual patient’s pathophysiology of DM that underpins their DM classification and clinical presentation. Classical type-2 diabetes mellitus is due to a combination of insulin resistance and an insulin secretory defect. Type-1 diabetes is characterized by a nearabsolute deficiency of insulin secretion. More recently, advances in genetics and a better appreciation of the atypical features of DM has resulted in more categories of diabetes. In the context of kidney disease, patients with DM and microalbuminuria are more insulin resistant, and insulin resistance may be a pathway that results in accelerated progression of diabetic kidney disease. This review summarizes the updated classification of DM, including more rarer categories and their associated renal manifestations that need to be considered in patients who present with atypical features. The benefits and limitations of the tests utilized to make a diagnosis of DM are discussed. We also review the putative pathways and mechanisms by which insulin resistance drives the progression of diabetic kidney disease.

C L A S S I F I C AT I O N

Keywords: diabetes, insulin resistance, kidney disease

Type-1 diabetes mellitus T1DM is the cause of diabetes in ∼5–10% of all patients with diabetes (Table 1). T1DM is characterized by auto-immune process that leads to progressive pancreatic beta cell destruction that eventually results in absolute insulin deficiency. T1DM has been previously termed insulin-dependent diabetes or juvenileonset diabetes. In T1DM, the rate of beta cell loss can be

INTRODUCTION Diabetes is a heterogeneous condition characterized by hyperglycaemia as a consequence of defects in insulin secretion, insulin resistance/action or combination of both of these factors. © The Author 2014. Published by Oxford University Press Downloaded fromonhttps://academic.oup.com/ndt/article-abstract/31/2/206/2459940 behalf of ERA-EDTA. All rights reserved. by guest on 09 August 2018

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Table 1. Classification diabetes according to degree of insulin deficiency and insulin resistance and suitable treatments for hyperglycaemia Insulin deficiency

Insulin resistance

Diabetes treatment

Type 1 diabetes

+++++

CKD Fast progressor +++ CKD Slow progressor +/−

Insulin

Idiopathic diabetes and ketosis prone diabetes

++++

++

Insulin ± metformin if feature of insulin resistance

Type 2 diabetes

++

CKD Fast progressor +++++ CKD Slow progressor +++

Oral agents/insulin/GLP-1 receptor agonists

Monogenic diabetes

++

+

Oral agents (sulphonylurea) or insulin NB: Glucokinase mutation—often no oral agents needed, diet/lifestyle advice

Mitochondrial diabetes

+++

+/−

Oral agents (caution with metformin) and insulin

Latent autoimmune diabetes of adults

+++

+

Insulin ± metformin if feature of insulin resistance

Diseases of the exocrine pancreas

+++

+/−

Insulin

Type-2 diabetes mellitus T2DM is the major cause of diabetes worldwide and accounts for nearly 90–95% of those with diabetes. T2DM is heterogeneous disease as patients can range from those with predominantly an insulin resistance phenotype but with sufficient beta cell reserve to remain insulin independent to those who may require early insulin treatment during the course of their disease [4]. It is important to note that nearly all patients

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at the time of diagnosis of T2DM have some degree of impaired insulin secretion [1]. Most patients with T2DM are overweight or obese (in particular centrally obese). Obesity, physical inactivity, hypertension, certain ethnicities (e.g. Middle Eastern, South Asian and Hispanic) and dyslipidaemia are risk factors for T2DM. There is often a family history of T2DM and several genetic risk markers have been proposed; however, none of these markers are currently used in routine clinical practice [4]. Historically T2DM has been a disease in older adults but there is an emerging epidemic of T2DM in paediatric subjects and young adults that reflects increasing rates of obesity. Data from the USA on new-onset diabetes in adolescents shows a dramatic rise in the incidence of T2DM over the last 20–30 years from 3 to 45% of all cases with a significant percentage of subjects from ethnic minority groups [6]. These patients are at enhanced risk of early onset of albuminuria and display accelerated progression of albuminuria when compared with T1DM subjects of similar age and adult T2DM patients with similar duration of diabetes [6]. Pima Indians with youngonset T2DM have high prevalence rates of hypertension (18%) and microalbuminuria (22%) at diagnosis with estimated prevalence rates of microalbuminuria of 60% and proteinuria of 17% before the age of 30 [6]. In Canadian patients with either T1D or T2D diagnosed in youth, T2DM patients had a 4-fold risk of renal failure with a lower mean age of onset of microalbuminuria MA (14.9 versus 15.3 years) despite a lower mean duration (1.6 versus 6.3 years) of diabetes [7]. Although the exact mechanisms for this enhanced renal risk are yet to be elucidated, increased insulin resistance may be one of the factors involved [6]. Idiopathic diabetes and ketosis prone diabetes In clinical practice, there are patients who present with hyperglycaemia who do not display either clear evidence of an autoimmune aetiology for their diabetes or characteristic features of T2DM. These patients, often of Asian or Afro-Caribbean ancestry, are characterized by relative insulin deficiency and are prone to developing diabetic ketoacidosis. Diabetes

t in diabetic kidney disease?

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variable with rapid loss being more often seen in children and young adults who often present for the first time with diabetic ketoacidosis. There is increasing evidence that suggests that rates of T1DM are increasing worldwide by between 2 and 5% per year [5]. Scandinavia has the highest prevalence of T1DM (∼20% of the total number of people with DM). The onset of T1DM usually occurs in children older than 4 years of age with a peak incidence in early adolescence and puberty in subjects who present below the age of 20 years. More than 50% of patients with new-onset T1DM are older than 20 years of age. Some adults may have a history of modest fasting hyperglycaemia for some time which progresses and develops into severe hyperglycaemia and/or ketoacidosis due to the presence of concurrent illnesses which indicates that residual beta cell function has become insufficient to prevent ketoacidosis and that exogenous insulin is now required [4]. At the time of diagnosis, 80–90% of patients with T1DM will have raised titres of one or more of the following auto-antibodies to insulin, glutamic acid decarboxylase (GAD65), tyrosine phosphatases IA-2 and IA-2β [4]. T1DM has strong HLA associations, and these patients are also prone to other autoimmune disorders such as thyroid disease (Graves disease, Hashimoto’s thyroiditis), Addison’s disease, vitiligo, coeliac disease, autoimmune hepatitis, myasthenia gravis and pernicious anaemia. Most patients with T1DM are of normal or low weight; however increasingly, patients can present with T1DM at raised body mass indices and, therefore, it is important to note that obesity per se does not exclude the diagnosis of T1DM.

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auto-antibody levels are not raised, and levels of C-peptide as index of beta cell reserve can be variable. Patients who present with atypical features and ketosis-prone diabetes may be further classified depending on diabetes auto-antibody titres (GAD and IA-2) and poor residual beta cell function [fasting C-peptide <1.0 ng/mL (0.33 nmol/L) or a peak C-peptide response <1.5 ng/mL (0.5 nmol/L) after glucagon stimulation test (1 mg i.v.)]. In a cohort patients with ketosis-prone diabetes from the USA (45% African American, 40% Hispanic), patients with absent beta cell function with or without raised auto-antibody titres demonstrated clinical and biochemical characteristics of T1DM, with >1% of the subjects initially classified with absent beta cell function showing improvement in beta cell function during follow-up (all remaining on insulin treatment) [8]. In nearly half of the patients with adequate beta cell function with the presence of autoimmune markers, the clinical course is similar to T1DM with progressive deterioration of beta cell function and need for exogenous insulin therapy within 12–60 months [8]. In patients without autoimmunity and preserved beta cell function, who represent the majority (∼75%) of cases who presented in this study, most patients showed clinical and biochemical characteristics of T2DM with improved beta cell function after 6–12 months, and in concordance with other studies nearly 70% are normoglycaemic within 2–3 months of follow-up and 40% remained free of insulin 10 years after their first presentation [8, 9]. Increasing evidence indicates that such patients with ketosisprone diabetes (with adequate beta cell function and absent diabetic auto-antibodies) accounts for more than half of newly diagnosed black and Hispanic patients with diabetic ketoacidosis [10]. The renal outcomes in this specific population of patients remain unknown at present due to lack of long-term follow-up data. Monogenic diabetes Patients with monogenic diabetes or maturity-onset diabetes of the young (MODY) are characterized by onset of hyperglycaemia at a young age, often below 25 years. These patients have impaired insulin secretion and the conditions are inherited in an autosomal dominant pattern. Some authors suggest that MODY may be the underlying cause of diabetes in 1–2% of patients diagnosed with diabetes, but this estimate needs to be confirmed from larger population-based screening studies as higher rates are likely from selective sampling from high-risk cohorts. In a patient with MODY, optimal treatments are different from that in T1DM or T2DM and as first-degree relatives have a 50% probability of inheriting the same mutation, being aware of the clinical features and presentation is important [11]. Mutations in the genes encoding the enzyme glucokinase (GCK) and the nuclear transcription factors such as hepatocyte nuclear factor-1α (HNF1A) and hepatocyte nuclear factor-4α (HNF4A) are the common causes of MODY. Patients with HNF1A have a low renal threshold for urinary glucose excretion and are characterized by marked sensitivity to sulphonylureas. In contrast, HNF4A have a normal renal urinary glucose excretion threshold but similar marked sensitivity to sulphonylureas [11]. A history of neonatal

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hyperinsulinaemia and hypoglycaemia with associated macrosomia is often described [11]. Patients with GCK mutations have a mild fasting hyperglycaemia throughout life, are often detected during screening and characteristically demonstrate a small incremental glucose rise after carbohydrate load [11]. In a recent study, despite a median duration of 48.6 years of hyperglycaemia, GCK patients had a significantly lower prevalence of vascular complications when compared with subjects with young-onset T2DM (4 versus 30%). Moreover, clinically significant vascular complications were not significantly different from age-matched controls, and neither patients with GCK patients nor controls had proteinuria. In GCK patients and controls, microalbuminuria was rare (GCK, 1%, controls, 2%), in contrast to young-onset T2DM where 10% had proteinuria and 21% microalbuminuria [12]. HNF1B which accounts for 5–10% of MODY cases is characterized by malformations of the genitourinary tract (especially renal cysts and other renal developmental abnormalities) as well as pancreatic atrophy and exocrine insufficiency. HNF1B is the second most prevalent dominantly inherited kidney disease with heterogeneous renal involvement. However, a large series of 377 patients demonstrated that the severity of the renal disease associated with HNF1B mutations can be highly variable from early onset renal failure in children/ neonates to normal renal function in adulthood [13]. In children, hyperechogenic kidneys or bilateral renal cystic hypodysplasia is often observed. Renal manifestations of the disease include renal cysts (mostly cortical cysts), a solitary kidney, pelvicalyceal abnormalities, hypokalaemia and hypomagnesaemia. Extra renal features include infertility, abnormal liver function tests, genital tract abnormalities, Fanconi syndrome and chromophobe renal carcinoma [14]. Patients with HNF1B diabetes who develop end-stage renal disease are eligible for combined pancreas and kidney transplantation [14]. Adult patients with HNF1A and 4A present between the ages of 1–45 years most often because GCK can present at any age. In patients where MODY features of obesity and insulin resistance are absent, the presence of beta cell antibodies is rare and normal C-peptide levels are observed. In contrast to T1DM and idiopathic diabetes, diabetic ketoacidosis is rare. Similar to T2DM, a family history of diabetes is present in MODY and a parental history of diabetes frequent. Neonatal diabetes is rare and reported to have an incidence of one in 400 000–500 000 live births, is often diagnosed in the first 6 months of life and can either be transient or permanent [15]. The most common genetic defect causing transient disease is a defect on ZAC/HYAMI genes imprinting, whereas permanent neonatal diabetes is most commonly a defect mutation in KCNJ11, encoding the Kir6.2 subunit of the ATPsensitive potassium (K(ATP)) channel. This defect causes 30–60% of cases of diabetes diagnosed in patients <6 months of age. Patients present with ketoacidosis or severe hyperglycaemia and are treated with insulin. Diagnosing heterozygousactivating mutations in KCNJ11 has important clinical implications, since such children can be well managed with sulphonylureas [16].

J. Karalliedde and L. Gnudi

Mitochondrial diabetes maternally inherited diabetes and deafness Maternally inherited diabetes and deafness (MIDD) is caused by a mitochondrial DNA defect. Most cases (nearly 85%) are associated with m.3243A>G mutation. Associated findings include deafness due to bilateral sensorineural hearing loss in 85–98% of cases and the presence of a pattern macular dystrophy in around 80% of cases. A very strong family history of diabetes, a low or normal BMI, deafness and presence of retinal dystrophy should prompt an investigation for MIDD. Approximately 8% of MIDD cases present as T1DM with acidosis and ketonuria but the majority present with an insidious onset similar to T2DM. Microvascular complications out of keeping with duration of diabetes are often observed. Nearly 46% of MIDD cases progress to require insulin within 10 years of treatment [17]. MIDD can be distinguished from MODY by the presence of maternal transmission in conjunction with hearing impairment or macular dystrophy. Mitochondrial genetic studies confirm the diagnosis of MIDD. In MIDD, treatment with metformin is less effective and may actually be harmful because of the increased risk of lactic acidosis in these individuals. Patients with MIDD should be advised to maintain their carbohydrate intake carefully when ill, as some can experience strokelike episodes when there is lack of carbohydrates on sick days [18].

Diseases of the exocrine pancreas Pancreatitis, surgical pancreatectomy, pancreatic infections and malignancy can all cause diabetes. Often extensive damage of the pancreas is required for diabetes to develop with the notable exception of adenocarcinomas that can result in diabetes despite only a small portion of the pancreas being affected. Cystic fibrosis and haemochromatosis also damages beta cells and results in diabetes. The prevalence of diabetes among European children and adults with cystic fibrosis ∼12%, rising to 30% in adults screened for diabetes [20]. Patients with cystic fibrosis-


Other rare categories of diabetes Excessive abnormal production of hormones such as growth hormone, cortisol, glucagon and epinephrine that antagonize insulin action can cause diabetes. Patients with acromegaly, Cushing’s syndrome, glucagonoma and pheochromocytoma demonstrate glucose intolerance and often can present with overt clinical and biochemical features of DM. Of interest, diabetes often occurs in individuals with pre-existing defects in insulin secretion, and hyperglycaemia may resolve when the hormone excess is treated/resolved [4]. Hypokalaemia inhibits insulin secretion and when severe as in somatostatinomas and aldosteronoma can cause diabetes which resolves following successful treatment of the lesion. Several drugs can impair insulin secretion or insulin action and may precipitate diabetes in individuals with a pre-disposition towards diabetes. Examples include nicotinic acid, glucocorticoids. More recently, patients receiving α-interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency. Other drugs known to cause diabetes include diazoxide, thyroid hormones, β-blockers, thiazide diuretics and possibly statins. The stiff-man syndrome is an autoimmune disorder of the central nervous system. A third of these patients will develop diabetes and are often characterized by raised levels of GAD. Anti-insulin receptor antibodies can be found in patients with systemic lupus erythematosus and other autoimmune diseases. These patients often also have features of insulin resistance such as acanthosis nigricans. Several diseases due to chromosomal abnormalities are associated with increased risk of developing diabetes. These conditions include Down’s syndrome, Klinefelter’s syndrome and


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Latent autoimmune diabetes of adults As described earlier, there is a subgroup of patients who are diagnosed with features of T2DM but have pancreatic autoantibodies. It is unclear whether latent autoimmune diabetes of adults (LADA; also known as, type 1½ diabetes, ‘autoimmune diabetes in adults’, hybrid diabetes or slowonset diabetes in adults) represents a category of diabetes on its own. This has been discussed in detail in a comprehensive review of the genetics of diabetes and its impact on clinical features and presentation [19]. In brief, there are no unified diagnostic criteria for LADA but many use the following three criteria: positivity for GAD antibody, age at diagnosis of diabetes >35 years and the lack of need for insulin therapy in the first 6–12 months after diagnosis. Auto-antibody positivity is associated with younger age at onset, reduced beta cell function and faster progression to insulin dependency. Patients with high GAD antibody titres had clinical features of insulin deficiency resulting in higher HbA1C, lower BMI, a lower prevalence of metabolic syndrome features such as central obesity and dyslipidaemia [19].

related diabetes rarely develop ketoacidosis. However, similar T2DM patients have features of both decreased insulin secretion and sensitivity. Recent data suggest that that individuals with cystic fibrosis have a 3-fold greater mortality if they develop hyperglycaemia (defined as HbA1c ≥6.5%) independent of other known risk factors [21]. The association between hereditary haemochromatosis (HH) and diabetes is well documented with the term bronze diabetes often used to describe this cause of diabetes. Epidemiologic studies that have evaluated the prevalence of frequency of hereditary haemochromatosis (HFE) genotypes in HH have however reported discordant results [22]. Several studies have reported no difference in the frequency of HFE genotypes at known mutation sites in individuals with and without self-reported diabetes while other reports have reported increased frequencies of diabetes. As the development of diabetes is agerelated, inclusion of younger adults without diabetes in some of the studies and the selection criteria used may explain these discrepancies. Moreover, as younger subjects being included result in a lower prevalence, they may be at risk for developing diabetes as they get older. Loss of insulin secretory capacity is likely the primary defect contributing to development of diabetes with insulin resistance playing a secondary role. In recent cross-sectional studies, the prevalence of diabetes in HH was found to be 13–23% and impaired glucose tolerance 15–30% [22].

Turner’s syndrome. Wolfram syndrome, also named ‘DIDMOAD’ (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), is an autosomal recessive disorder where renal tract abnormalities and a neurodegenerative disorder are observed is characterized by insulin-deficient diabetes.

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DIAGNOSIS OF DIABETES MELLITUS Until recently, the laboratory diagnosis of diabetes has been based on the presence of elevated fasting plasma glucose or 2-h post-oral glucose tolerance test glucose. The relationship between glucose levels and presence of diabetic retinopathy has been one of the major drivers behind the threshold glucose level for diagnosis (Figure 1). In epidemiological studies, subjects with glucose values below the established diagnostic cut-offs of fasting (no caloric intake for at least 8 h) plasma glucose level 126 mg/dL (7.0 mmol/L) and 2-h plasma glucose post-standard 75 mg glucose tolerance tests of 200 mg/dL (11.1 mmol/L) had a very low prevalence of diabetic retinopathy and, above these thresholds, the prevalence of diabetic retinopathy increased linearly. HbA1c is used frequently in clinical practice as a bio-marker of glucose control/glycaemic management over the preceding 8–12 weeks and also correlates well with microvascular complications of diabetes. More recently in many countries, including the UK, an HbA1c ≥6.5% (the cut-off level above where prevalence of retinopathy increases) is now used to diagnose diabetes [4]. Using HbA1c is often more convenient as fasting is not required and there is less variability, but the measurement can be misleading in some groups of patients (renal impairment, haemoglobinopathies, any condition affecting red cell turnover, etc.) [23]. In these settings where HbA1c is inaccurate and potentially misleading, glucose cut-off levels used along with clinical features and symptoms should be used to make the diagnosis of diabetes. It is recommended that a test result diagnostic of diabetes should be repeated (ideally with the same diagnostic test) to exclude laboratory error, unless the diagnosis is clearly apparent from the clinical symptoms. In the situation where the results of two different tests are present if both are above the diagnostic thresholds, the diagnosis of diabetes is confirmed. If however the results of the two different tests are discordant, it is recommended that the test whose result is above the diagnostic cut-off point should be repeated, and the

F I G U R E 1 : Diagnosis of DM. HbA1C ≥6.5%.


diagnosis made on the basis of the confirmed test. In the scenario where the repeat test is below the diagnostic cut-off point, it is advised that patients is followed up closely and repeat testing performed within 3–6 months.

I N S U L I N R E S I S TA N C E : M A J O R DETERMINANT OF DIABETIC KIDNEY DISEASE Clinical trials in both T1DM [Diabetes Control and Complication Trial] and in T2DM [United Kingdom Prospective Diabetes Study] have established that the rate of development and progression of diabetic kidney disease is closely associated to glycaemic control [24–27]. However, in many patients with diabetes, despite poor glycaemic control, diabetic kidney disease, as assessed by development of albuminuria or fall in glomerular filtration rate does not develop. Therefore, hyperglycaemia appears necessary but not sufficient to cause renal damage and other factors are required for the clinical manifestation of diabetic kidney disease. Importantly patients with T1DM and microalbuminuria are characterized by increased insulin resistance [28, 29]. The severity of insulin resistance also strongly relates with the development of microalbuminuria in patients with T2DM and normal renal function [30] (Figure 2). It is also worth remembering that a large proportion of diabetic patients (T1DM and T2DM) can present with significant renal impairment and normoalbuminuria [31–33]; in this scenario, it is difficult to postulate a role of insulin resistance as renal deterioration per se can be a cause of insulin resistance [34]. Longitudinal studies will have to dissect the potential cause effect relationship between insulin resistance and kidney disease. Insulin resistance has been implicated in the development of glomerular hypertension and hyperfiltration [35], seen in the initial phase of diabetic kidney disease [36, 37], when the interaction between metabolic and haemodynamic perturbations plays a critical role on the pathophysiological mechanism leading to kidney disease progression [36, 38–41]. The mechanisms at the basis of metabolic-mediated disruption of capillary vasoregulation are complex and include an increase in vascular nitric oxide (NO) [42] and transforming growth factor β1 (TGF-β1) [43, 44] which have been implicated in vasodilation of both afferent and efferent glomerular arteriolae. This is paralleled by activation of the local tissue renin–angiotensin aldosterone system [45] with local excess production of angiotensin II. The documented higher sensitivity of the efferent (versus the afferent) glomerular arteriole to the vasoconstrictive action of angiotensin II, contributes to the imbalance in arteriolar tone which then results in higher glomerular capillary pressure [46, 47]. These results in a disproportionate systemic pressure are transmitted to the glomerular circulation resulting in glomerular cells mechanical elongation and activation of the cellular mechanisms that lead to glomerular damage [48]. In both T1DM and T2DM, insulin resistance per se contributes to higher salt sensitivity [49, 50], which closely associates


F I G U R E 2 : Major mediators of insulin resistance-driven renal function decline. TGF-β1, transforming growth factor β1; BP, blood pressure; TNFα, tumour necrosis factor α; IL-6, interleukin 6.


associated with increases circulating levels of cytokines and chemokines. Of these, interleukin-6 and tumour necrosis factor-α have been involved in diabetic kidney disease progression [65]. Oxidative stress is a mediator of insulin resistance and a major determinant of diabetic kidney disease [66]. The clinical evidence and knowledge of insulin resistance being an important player in the pathophysiology of diabetic glomerulopathy has recently being explored in experimental animal model where the insulin receptor (IR) was deleted in a podocyte-specific manner [67]. Podocyte IR-null mice are characterized by glomerular lesions similar to those seen in experimental animal model of diabetes [67]. Importantly, podocytes, but not glomerular endothelial cells, have been found to be insulin responsive and able to increase glucose uptake after insulin stimulation. Nephrin, an important component of the slit diaphragm, appears to be necessary for podocyte response to insulin, and down-regulation of nephrin expression, as seen in diabetes, is paralleled by a reduction in insulin-mediated podocytes glucose transport and significant changes in podocytes cytoskeleton which would contribute to the disruption of the glomerular filtration barrier and albuminuria [67–70].

CONCLUSIONS The classification of DM reflects heterogeneous nature of the condition and diverse clinical presentations. Patients with diabetic kidney disease are characterized by insulin resistance with growing clinical and experimental evidence indicating that insulin resistance is an important and crucial player in the


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with increase in blood pressure, albuminuria and renal function decline. In the early phase of diabetic kidney disease, insulin resistance and the associated poor glycaemic control also associate with up-regulation of the Na+/glucose transporter sGLT2 [51, 52] that, in turn, leads to an increase in proximal tubular salt (Na+) reabsorption and secondary worsening of hyperfiltration through the physiologic action of the tubule-glomerular feedback system [53]. Change in adipokine levels in insulin-resistant states have been implicated in the pathophysiology of kidney disease: low circulating levels of adiponectin, a known insulin sensitizer secreted by adipocytes, as observed in insulin-resistant/obese patients have been implicated in endothelial dysfunction [54, 55] and albuminuria in experimental models of diabetes [56]. The existing association between insulin resistance (low adiponectin) and albuminuria [57] makes adiponectin a promising potential future target for the treatment of chronic vascular complications in diabetes, but further studies are needed to definitively link adiponectin, endothelial dysfunction and albuminuria [58]. Leptin circulating levels, on the contrary, is increased in patients with diabetes and insulin resistance [59]. Leptin has been implicated in increased sympathetic nervous activity and development of hypertension [60]. Further high leptin levels have been implicated in activation of the TGF-β1/TGF-β receptor system and in a direct profibrotic and pro-oxidative role in glomerular cells [61]. Leptin has been considered as a proinflammatory cytokine that increases in inflammation [62] that, in turn, is closely linked with insulin resistance [63, 64], and is

pathophysiology of diabetic kidney disease. Clinicians managing patients with diabetes need to have an understanding of the individual patient’s pathophysiology that underpins their classification as this will significantly help in the clinical management and risk stratification for diabetes chronic vascular complications.

C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.

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