Impaired hypoglycemia awareness in diabetes: epidemiology, mechanisms and therapeutic approaches

Impaired awareness of hypoglycemia (IAH) is a frequent complication of insulin therapy. Up to half insulin-treated individuals with type 1 and type 2 diabetes report the problems with hypoglycemia awareness, and 15–25% of patients have a permanent IAH. A recurrent hypoglycemia is a cornerstone in IAH formation. The repeated episodes of hypoglycemia impair neurohumoral response to hypoglycemia, reduce its symptoms and induce inadequate brain adaptation to low glucose levels. In this regard, the IAH phenomenon can be considered as an example of "metabolic memory" in diabetes. The IAH is associated with episodes of severe hypoglycemia, fear of hypoglycemia and cognitive dysfunction. These associates can be combined into IAH syndrome. Development of IAH becomes a serious barrier in diabetes management. A growing body of evidence indicates that IAH is a reversible condition. If the syndrome is present, the hypoglycemia avoidance should be primary goal of the treatment. Structured training under specialized programs with psychological support is the most reasonable therapeutic approach to IAH amending. Technological approaches, including continuous subcutaneous insulin infusion, real-time continuous glucose monitoring, closed-loop insulin delivery systems ("artificial pancreas"), and islet transplantation also showed efficacy in hypoglycemia awareness improvement in some clinical studies. The diabetes management in patients with IAH is time-consuming and expensive. Therefore, step-by-step approach, from insulin personalization and therapeutic training to advanced medical technologies, should be recommended for these patients

Risk factors for decreased bone mineral density in men with type 2 diabetes.

BACKGROUND: Type 2 diabetes and osteoporosis are widespread diseases in the middle-aged and elderly people. Most studies of osteoporosis in patients with type 2 diabetes have been performed in women; meantime risk factors for lowering bone mineral density (BMD) in men have been little studied.AIMS: to identify risk factors for decreased BMD at the lumbar spine, femoral neck and forearm in men with type 2 diabetes.METHODS: Eighty two men from 50 to 75 years old, with duration of diabetes for at least one year, were included in the study. Individuals with known risk factors for secondary osteoporosis were not included. Twenty-three men with normal BMD having no diabetes or obesity were acted as control. The T-score at the lumbar spine, femoral neck and forearm of a non-dominant arm, as well as body composition parameters, were evaluated by dual-energy X-ray absorptiometry. The levels of hormones that affect bone metabolism (parathyroid hormone, free testosterone, 25-OH vitamin D) were measured in blood serum by ELISA. Risk factors for reducing BMD were identified using multivariate regression analysis and receiver operating characteristic (ROC) curves.RESULTS: Among patients with diabetes, 49 individuals had normal BMD and 33 showed decreased T-score values (<-1 SD). Free testosterone <5.92 pg/ml was predictor for decreased BMD at the lumbar spine (OR=4.4, p=0.04). For femoral neck, the risk factors were body weight <95.5 kg (OR=2.8, p=0.04), total fat mass <27 kg (OR=3.3, p=0.03), truncal fat mass<17.5 kg(OR=4.5, p=0.006), android (central abdominal) fat mass <3.2 kg(OR=4.0, p=0.01), gynoid (hip) fat mass <3.5 kg(OR=3.3, p=0.02), and lean mass <59 kg(OR=3.0, p=0.04). Risk factors for reduced BMD at the forearm were diabetes duration>15.5 years (OR=3.7, p=0.03) and HbA1c <8.15% (OR=3.8, p=0.03). Parathyroid hormone and 25-OH-vitamin D did not predict BMD independently.CONCLUSIONS: In men with type 2 diabetes, low free testosterone is a risk factor for decreased BMD in the lumbar spine, and diabetes duration is a risk factor for decreased BMD in the forearm. The presence of obesity is associated with an increase in BMD in the femoral neck; a high HbA1c is associated with an increase in BMD in the forearm

Clinical and laboratory characteristics of the patterns of chronic kidney disease in patients with type 2 diabetes

BACKGROUND: A growing body of evidence demonstrates increasing prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in subjects with type 2 diabetes (T2D), while proportion of albuminuric pattern is decreasing. AIMS: To determine the clinical and laboratory parameters associated with different patterns of CKD in patients with T2D. METHODS: This observational, single-center, cross-sectional study included 360 patients with T2D duration ≥10 years. Patients with urinary albumin/creatinine ratio (UACR) <3 mg/mmol and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 were classified as no-CKD group (n=89). Patients with UACR <3 mg/mmol and eGFR <60 ml/min/1.73 m2 formed NA-CKD group (n=111). Individuals with eGFR ≥60 ml/min/1.73 m2 and UACR mg/mmol ≥3 were recorded as albuminuric with preserved renal function (A-CKD–, n=87). Patients with eGFR <60 ml/min/1.73 m2 and UACR mg/mmol ≥3 mg/mmol were considered as albuminuric CKD group (A-CKD+, n=73). Urinary nephrin and podocin, the podocyte injury markers, and whey acidic protein four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial involvement, was assessed by ELISA and compared to control (20 non-diabetic subjects). RESULTS: Age ≥65 years (p=0.0001), duration of T2D ≥15 years (p=0.0009), female sex (p=0.04), and therapy with diuretics (p=0.0005) were found as risk factors for NA-CKD. The risk factors for A-CKD were male sex (p=0.01), smoking (p=0.01), waist-to-hip ratio >1 (p=0.01) and HbA1c levels >8% (p=0.005). The duration of T2D ≥15 years (p=0.01) and the use of dihydropyridine calcium channel blockers (p=0.01) were associated with A-CKD+. In T2D groups, the urinary excretion of nephrin and podocin was increased (all p<0.001), more markedly in albuminuric individuals (p<0.01 vs. NA-CKD). WFDC-2 excretion was increased in men from all diabetic groups (p<0.05) and in women with decreased eGFR only (p<0.05 vs. the control and NA-CKD). CONCLUSIONS: The CKD patterns in T2D are heterogeneous according to their clinical and laboratory characteristics. The changes in the excretion of nephrin and podocin indicate the association of albuminuric patterns with podocyte injury. A decrease in eGFR in women with T2D is associated with an increase in urinary excretion of WFDC-2, tubulointerstitial fibrosis marker

Lipodystrophy at the insulin injection sites: current trends in epidemiology, diagnostics and prevention

Lipodystrophy at the injection sites is most common local complication of insulin therapy. The history of its study started in 1926, when first cases of lipoatrophy at the sites of insulin injections were described. As we moved to human insulin and insulin analogues, immune mediated atrophic form of lipodystrophy has been replaced by hypertrophic one, which reflects anabolic and mitogenic effect of insulin. Lipohypertrophy at the injection sites is detected by physical examination in 40-70% of insulin-treated subjects. The detection efficiency depends on health care provider`s skills. Therefore, training of medical doctors and nurses in physical examination of injection sites seems to be reasonable. In recent years, ultrasound was introduced for diagnostics of insulin-induced lipohypertrophy. The method is more sensitive compared to palpation; ultrasound-verified lipohypertropthy was detected in more than 80% of cases. In patients with wide-spread lipohypertrophy ultrasound can be used to find suitable sites for injections (“ultrasound injection map”). Strain sonoelastography and 3D-power Doppler ultrasound can be used for quantitative estimation of rigidity and vascularization of lipohypertrophy. Both MRI and infrared images are considered as promising diagnostic tools. In a number of studies, it has been shown that the presence of lipohypertrophy is associated with high HbA1c levels, enhanced glycemic variability, «unexplained» hypoglycemia, and increased insulin doses. Thereby, lipohypertrophy aggravates the diabetes-related costs. The main risk factor for lipohypertrophy is inappropriate injection technique, including the lack of the site rotation, injections into lipodystrophic lesions, small injection area, reuse or excessive length of the needles. Accordingly, training patients in the injection technique is the basis for prevention of complication. The cessation of injections in lipohypertrophy areas and regular site rotation is essential for adequate titration of insulin dose and achievement of glycemic targets

Diabetes mellitus associated with the mutation of the ABCC8 gene (MODY 12): features of clinical course and therapy

Maturity-Onset Diabetes of the Young (MODY) is a heterogeneous group of diseases associated with genes mutations leading to dysfunction of pancreatic β-cells. Among the 14 identified MODY variants, MODY 1–5 are the most studied. The article reports a MODY 12 clinical case, with mutation in ABCC8, encoding the sulphonylurea receptor. Diabetes mellitus manifested in a 27-year-old man with hyperglycaemia up to 24 mmol/L, without ketosis. Non-proliferative diabetic retinopathy, microalbuminuria, dyslipidaemia and carotid atherosclerosis were revealed upon initial examination. The levels of pancreatic islet cell antibodies and glutamate decarboxylase antibodies were negative, while the level of C-peptide was within the normal range. Insulin therapy in the basal-bolus regimen was provided with a gradual dose reduction due to frequent hypoglycaemia. The preproliferative retinopathy with macular oedema was revealed after 4 months of therapy, and panretinal photocoagulation of both eyes was performed. A molecular genetics study revealed a mutation in the gene ABCC8, the same mutation was found in patient’s mother and uncle. Insulin therapy was cancelled, and the treatment of gliclazide MR 60 mg/day was initiated, which resulted in extreme glycaemic excursions. Thereby, sodium–glucose cotranporter-2 (SGLT2) inhibitor dapagliflozin 10 mg/day was added. A reduction in glucose variability parameters were observed on combination therapy. After 6 months till 1.5 years of treatment, glycaemic control was optimal, no hypoglycaemic episodes were observed. This case study demonstrates clinical features of MODY 12, and the potential of combination of sulfonylurea and SGLT2 inhibitor in the treatment of this disease

Insulin-induced lipohypertrophy: clinical and ultrasound characteristics

Background: Lipohypertrophy is primary dermal complication of insulin therapy. The data on the prevalence of lipohypertrophy in diabetic subjects are inconsistent, that may be due to the lack of sensitivity and subjectivity of palpation as diagnostic technique. Meanwhile, the reliability of lipohypertrophy detection can be increased by ultrasound. Aims: to compare clinical and ultrasound characteristics and to determine the risk factors of insulin-induced lipohypertrophy in diabetic subjects. Materials and methods: We observed 82 patients, including 26 individuals with type 1 diabetes and 56 subjects with type 2 diabetes. Duration of insulin therapy varied from 3 months to 37 years (median 14 years). The sites of insulin injections were assessed by palpation and ultrasound. Visualization protocol included gray-scale densitometry, strain elastography, and 3D Doppler power ultrasound. Scaled evaluation of ultrasound sings was applied. Insulin injection technique was assessed by questionnaire. Serum levels of insulin antibodies were determined by ELISA. Results: Lipohypertrophy was revealed by palpation and ultrasound in 57 and 80 patients (70% and 98%) respectively. Total lipohypertrophy area, acoustic density and total ultrasound score showed weak positive correlations with daily insulin dose (r=0.3, r=0.3 and r=0.35, respectively, all p0.006). Patients receiving insulin analogues had smaller area of abdominal lipohypertrophy than those on human insulin (p=0.03). A positive correlation was found between abdominal lipohypertrophy area and mean postprandial glucose (r=0.35, p=0.001). A rare needle change and injections in lipohypertrophy sites were the most common deviations in insulin injection technique (70 and 47 subjects, 85% and 53% respectively). The levels of insulin antibodies showed no association with lipohypertrophy parameters. Conclusions: Patients with type 1 and type 2 diabetes demonstrate high prevalence of lipohypertrophy in insulin injection sites. Ultrasonography is more sensitive method of diagnostics of lipohypertrophy compared with palpation. Insulin-induced lipohypertrophy is associated with errors in injection technique and higher insulin doses

Serum adipokine concentrations in patients with type 2 diabetes: the relationships with distribution, hypertrophy and vascularization of subcutaneous adipose tissue

Academy of Sciences, Novosibirsk, Russia 2Novosibirsk State Medical University, Novosibirsk, Russia BACKGROUND: Adipose tissue (AT) dysfunction plays an important role in metabolic disorders in obesity and type 2 diabetes. The role of distribution, hypertrophy and vascularization of AT in adipokine secretion disturbances remain to be clarified. AIMS: To determine the relationships between serum concentrations of adipokines and the mass and distribution of AT, diameter of adipocytes and vascularization of subcutaneous AT in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 125 patients were examined, including 82 subjects with obesity. Thirty persons without diabetes and obesity, matched by sex and age, were acted as control. Concentrations of leptin, resistin, visfatin, adipsin and adiponectin in fasting serum were determined using multiplex analysis. Mass and distribution of AT was assessed by dual-energy X-ray absorptiometry. Samples of SAT were obtained from umbilical region using a knife biopsy in 25 patients and in 15 individuals who died in accidents. Blood and lymphatic vessels in SAT were revealed with immunohistochemistry, using antibody to CD-34 and podoplanin respectively. The volume and numerical density, ultrastructure of blood and lymphatic vessels, and mean diameter of subcutaneous adipocytes were evaluated. RESULTS: Patients with diabetes, as compared to control, had significantly higher levels of leptin, resistin, adipsin and visfatin (all p<0.001). Adiponectin showed no differences. Concentrations of leptin, resistin, visfatin, adipsin and adiponectin correlated positively with gynoid fat mass. Additionally, leptin and adipsinshowed positive correlations with truncal and central abdominal fat mass. Concentration of leptin, but not other adipokines, was associated with hypertrophy of subcutaneous adipocytes. A decrease in volumetric density of microvessels(р=0.01) and increase in volume and numerical density of lymphatic vessels (both р=0.02) was observed in subcutaneous AT from diabetic subjects. The swelling of cytoplasm, mitochondria, cisterns of granular endoplasmic reticulum and reduced content of micropinocytotic vesicles was revealed in lymphatic capillaries. Resistin and visfatin showed inverse associations with density of microvessels. CONCLUSION: Endocrine dysfunction of AT in patients with type 2 diabetes, manifested by elevation of serum concentrations of leptin, resistin, visfatin and adipsin, is associated with mass and distribution of AT, hypertrophy of subcutaneous adipocytes and vascularization abnormalities of subcutaneous AT

Diabetes mellitus type 1 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidlines

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks

Hypoglycemia has been recognized as a risk factor for diabetic vascular complications and cognitive decline, but the molecular mechanisms of the effect of hypoglycemia on target organs are not fully understood. In this work, gene networks of hypoglycemia and cardiovascular disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, cognitive decline, and Alzheimer’s disease were reconstructed using ANDSystem, a text-mining-based tool. The gene network of hypoglycemia included 141 genes and 2467 interactions. Enrichment analysis of Gene Ontology (GO) biological processes showed that the regulation of insulin secretion, glucose homeostasis, apoptosis, nitric oxide biosynthesis, and cell signaling are significantly enriched for hypoglycemia. Among the network hubs, INS, IL6, LEP, TNF, IL1B, EGFR, and FOS had the highest betweenness centrality, while GPR142, MBOAT4, SLC5A4, IGFBP6, PPY, G6PC1, SLC2A2, GYS2, GCGR, and AQP7 demonstrated the highest cross-talk specificity. Hypoglycemia-related genes were overrepresented in the gene networks of diabetic complications and comorbidity; moreover, 14 genes were mutual for all studied disorders. Eleven GO biological processes (glucose homeostasis, nitric oxide biosynthesis, smooth muscle cell proliferation, ERK1 and ERK2 cascade, etc.) were overrepresented in all reconstructed networks. The obtained results expand our understanding of the molecular mechanisms underlying the deteriorating effects of hypoglycemia in diabetes-associated vascular disease and cognitive dysfunction