Type 2 diabetes and cardiovascular disease represent a serious threat to the health of the population worldwide. Although overall adiposity and particularly visceral adiposity are established risk factors for these diseases, in the recent years fatty liver emerged as an additional and independent factor. However, the pathophysiology of fat accumulation in the liver and the cross-talk of fatty liver with other tissues involved in metabolism in humans are not fully understood. Here we discuss the mechanisms involved in the pathogenesis of hepatic fat accumulation, particularly the roles of body fat distribution, nutrition, exercise, genetics, and gene-environment interaction. Furthermore, the effects of fatty liver on glucose and lipid metabolism, specifically via induction of subclinical inflammation and secretion of humoral factors, are highlighted. Finally, new aspects regarding the dissociation of fatty liver and insulin resistance are addressed.

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Causes and Metabolic Consequences of Fatty Liver

The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or other co-morbidity, including hypertension and ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin-angiotensin-aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past 30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg.

/pdf/diabetic-kidney-disease-33198zm7m0.pdf

Diabetic kidney disease

Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM) and both conditions are increasing in prevalence. CKD is estimated to affect ∼50% patients with T2DM globally, and its presence and severity markedly influences disease prognosis. CKD is more common in certain patient populations, including the elderly, those with youth-onset diabetes mellitus, those who are obese, certain ethnic groups, and disadvantaged populations. These same settings have also seen the greatest increase in the prevalence of T2DM, as exemplified by the increasing prevalence of T2DM in low-to- middle income countries. Patients from low-to-middle income countries are often the least able to deal with the burden of T2DM and CKD and the health-care facilities of these countries least able to deal with the demand for equitable access to renal replacement therapies. The increasing prevalence of younger individuals with T2DM, in whom an accelerated course of complications can be observed, further adds to the global burden of CKD. Paradoxically, improvements in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment. This Review explores how the changing epidemiology of T2DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.

Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease

OBJECTIVE —To give an up-to-date profile of nephropathy and the involvement of risk factors in a large, prospective cohort of patients with type 1 diabetes and largely pediatric and adolescent onset of disease. RESEARCH DESIGN AND METHODS —A total of 27,805 patients from the nationwide, prospective German Diabetes Documentation System survey were included in the present analysis. Inclusion criteria were at least two documented urine analyses with identical classification. Urine analyses, treatment regimens, diabetes complications, and risk factors were recorded prospectively. Baseline characteristics were age at diagnosis 9.94 years (median [interquartile range 5.8–14.3]), age at last visit 16.34 years (12.5–22.2), and follow-up time 2.5 years (0.43–5.3). Cumulative incidence of nephropathy was tested by Kaplan-Meier analysis and association with risk factors by logistic regression. RESULTS —Nephropathy was classified as normal in 26,605, microalbuminuric in 919, macroalbuminuric in 78, and end-stage renal disease (ESRD) in 203 patients. After calculated diabetes duration of 40 years, 25.4% (95% CI 22.3–28.3) had microalbuminuria and 9.4% (8.3–11.4) had macroalbuminuria or ESRD. Risk factors for microalbuminuria were diabetes duration (odds ratio 1.033, P P P P P CONCLUSIONS —Diabetes duration, A1C, dyslipidemia, blood pressure, and male sex were identified as risk factors for nephropathy. Therefore, besides the best possible metabolic control, early diagnosis and prompt treatment of dyslipidemia and hypertension is mandatory in patients with type 1 diabetes.

https://care.diabetesjournals.org/content/diacare/30/10/2523.full.pdf

Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex.

Background
Chronic kidney disease (CKD) is a long-term condition and has been described as the gradual loss of kidney function over time. Early in the disease process, people with CKD often experience no symptoms. For a long time, CKD has been an underdiagnosed condition. Even in the absence of symptoms, CKD appears to add significantly to the burden of cardiovascular disease and death and, for an important minority, can progress to kidney failure.

Objective
To systematically review the evidence of the clinical effectiveness and cost-effectiveness of early referral strategies for management of people with markers of renal disease.

Data sources
Electronic searches of 12 major databases (such as MEDLINE, EMBASE, CINAHL, etc.) were conducted for the time period of 1990 to April 2008 to identify studies comparing early referral to other care options for people with CKD. Additional searching was performed in the NHS Economic Evaluation Database to support the cost-effectiveness literature review.

Review methods
Two authors reviewed all titles, abstracts and full papers to select relevant literature. A Markov model was constructed to represent the natural history of CKD. The model allowed cohorts to be tracked according to estimated glomerular filtration rate (eGFR) status and the presence of other complications known to influence CKD progression and the incidence of cardiovascular events.

Results
From 36 relevant natural history studies, CKD was found to be, despite marked heterogeneity between studies, a marker of increased risk of mortality, renal progression and end-stage renal disease. Mortality was generally high and increased with stage of CKD. After adjustment for comorbidities, the relative risk of mortality among those with CKD identified from the general population increased with stage. For clinical populations, the relative risk was higher. All three outcomes increased as eGFR fell. Only seven studies, and no randomised controlled trials, were identified as relevant to assessing the clinical effectiveness of early referral strategies for CKD. In the five retrospective studies constructed from cohorts starting on renal replacement therapy (RRT), mortality was reduced in the early referral group (more than 12 months prior to RRT) even as late as 5 years after initiation of RRT. Only two studies included predialysis participants. One study, in people screened for diabetic nephropathy, reported a reduction in the decline in renal function associated with early referral to nephrology specialists (eGFR decline 3.4 ml/min/1.73 m(2)) when compared with a similar group that had no access to nephrology services until dialysis was required (eGFR decline 12.0 ml/min/1.73 m(2)). The second study, among a group of veterans with two creatinine levels of at least 140 mg/dl, reported that a composite end point of death or progression was lower in the group receiving nephrology follow-up than in those receiving only primary care follow-up. The greatest effect was observed in those with stage 3 or worse disease after adjustment for comorbidities, age, race, smoking and proteinuria {stage 3: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.61 to 0.9)]; stage 4: HR 0.75 (95% CI 0.45 to 0.89)}. In the base-case analysis, all early referral strategies produced more quality-adjusted life-years (QALYs) than referral upon transit to stage 5 CKD (eGFR 15 ml/min/1.73 m(2)). Referral for everyone with an eGFR below 60 ml/min/1.73 m(2) (stage 3a CKD) generated the most QALYs and, compared with referral for stage 4 CKD (eGFR < 30 ml/min/1.73 m(2)), had an incremental cost-effectiveness ratio of approximately 3806 pounds per QALY.

Limitations
Because of a lack of data on the natural history of CKD in individuals without diabetes, and a lack of evidence on the costs and effects of early referral, the Markov model relied on many assumptions. The findings were particularly sensitive to changes in eGFR decline rates and the relative effect of early referral on CKD progression and cardiovascular events; the latter parameter being derived from a single non-randomised study.

Conclusions
Despite substantial focus on the early identification and proactive management of CKD in the last few years, we have identified significant evidence gaps about how best to manage people with CKD. There was some evidence to suggest that the care of people with CKD could be improved and, because these people are at risk from both renal and cardiovascular outcomes, strategies to improve the management of people with CKD have the potential to offer an efficient use of health service resources. Given the number of people now being recognised as having markers of kidney impairment, there is an urgent need for further research to support service change.

Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.

OBJECTIVE —Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS —A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8–9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS —In patients with normoalbuminuria ( n = 66), progression was associated with male sex ( P P = 0.02), and LDL-free cholesterol ( P = 0.02). In patients with microalbuminuria ( n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P n = 36), a significant decline in the renal function (>3 ml · min −1 · year −1 ) was independently associated with poor glycemic control, hypertension, and LDL size ( P P CONCLUSIONS —Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.

https://care.diabetesjournals.org/content/diacare/29/2/317.full.pdf

Serum lipids and the progression of nephropathy in type 1 diabetes.

Dyslipidemia is independently associated with cardiovascular disease (CVD) in type 1 diabetes (1,2). In this article, we report the specific lipid abnormalities associated with new-onset CVD in an enriched cohort of patients with type 1 diabetes.

The study design and selection criteria have been previously described (3,4). Briefly, 153 patients with type 1 diabetes were recruited in the U.K. from the Diabetes outpatient clinics at Guy's and King's College Hospitals ( n = 75) and in Finland from the Helsinki University Central Hospital ( n = 78). Patients were recruited to represent differing degrees of urinary albumin excretion and matched for duration of diabetes and glycemic control. Participants were then followed for a median of 8.8 years, during which time they received standard medical care, including lipid-lowering agents where indicated.

Full methods of baseline examination have been published elsewhere (3–6). Briefly, clinical data were obtained from patient records including age, sex, diabetes onset, duration of diabetes, medication history, and the presence of microvascular complications. Lipids and lipid fractions were estimated in fasting samples and processed as previously described (3–6). The study outcome was defined post hoc by the occurrence of a fatal or nonfatal cardiovascular event, including coronary heart disease (myocardial infarction, coronary revascularization, or angioplasty), cerebrovascular disease (stroke), or peripheral vascular disease (amputation associated with large vessel disease) based on clinical records.

A total of 148 …

http://care.diabetesjournals.org/content/diacare/30/10/2706.full.pdf

Vashti Mills

Papers

Serum lipids and the progression of nephropathy in type 1 diabetes.

HDL composition predicts new-onset cardiovascular disease in patients with type 1 diabetes.