Microbiota signatures in type-2 diabetic patients with chronic kidney disease - A Pilot Study

The human microbiota is paramount for normal host physiology. Altered host-microbiome interactions are part of the pathogenesis of numerous common ailments. Currently, much emphasis is placed on the involvement of the microbiome in the pathogenesis of type-2 diabetes mellitus (T2DM), impaired glucose tolerance, and other metabolic disorders (i.e. obesity). Several studies found highly significant correlations of specific intestinal bacteria with T2DM. A better understanding of the role of the microbiome in diabetes and its complications might provide new insights in the development of new therapeutic principles. Our pilot study investigates the microbiota patterns in Romanian type-2 diabetic patients with diabetic kidney disease. Fecal samples were collected from type 2-diabetic patients and healthy controls and further used for bacterial DNA isolation. Using 16 rDNA qRT-PCR, we analyzed phyla abundance (Bacteroidetes, Firmicutes) as well as the relative abundance of specific bacterial groups (Lactobacillus sp., Enterobacteriaceae, Ruminococus sp., Prevotella sp., Faecalibacterium sp., Clostridium coccoides, Clostridium leptum). Our study also investigates the diabetic fungal microbiome for the first time. Furthermore, we report significant correlations between the treatment regimen and microbiota composition in diabetic nephropathy

Pancreatogenic type 3C diabetes

Background. The relationship between chronic pancreatitis and diabetes is well established. This form of diabetes is secondary to exocrine pancreatic disorder and is known as diabetes mellitus type 3c (T3cDM). Materials and Methods. In this retrospective study we included 261 patients, 59 patients being diagnosed with chronic pancreatitis and secondary diabetes mellitus, and admitted in the Fundeni Clinical Institute, 2nd Department of Gastroenterology or N.C. Paulescu Institute/ Carol Davila University of Medicine and Pharmacy. Results and Discussions. Patients were 22.2% women and 77.8% men, with an average age of 56.8 years and 53.4 years respectively. 63% came from urban areas. The mean duration of chronic pancreatitis was six years. Non-diabetic patients were compared with patients who were previously diagnosed with T3cDM and who had been analyzed for body mass index (BMI). Imaging investigations were also performed to confirm pseudotumors or pancreatic tumours. Patients already considered non-diabetic had basal blood glucose values and were mostly overweight and obese. In this context, insulin resistance cannot be excluded for this group of patients. Conclusions. T3cDM is a new pathological entity that needs to be explored more deeply, and that should benefit from both a diagnostic stratification and treatment

Metformin Indications, Dosage, Adverse Reactions, and Contraindications

Metformin or dimethyl biguanide is the oral antidiabetic drug with the most extensive experience of prescribing in the clinical practice of type 2 diabetes mellitus. In this chapter, we reviewed the indications, contraindications, and adverse drug reactions (ADR) of metformin. The most significant adverse drug reactions of metformin are lactic acidosis, allergies, hypoglycemia, vitamin B12 deficiency, altered taste, and gastrointestinal intolerance. Metformin is contraindicated in severe chronic diseases (hepatic, renal, and cardiac failure) or acute complications of diabetes (ketoacidosis and hyperosmolar state). Metformin is considered by all international guidelines the first-line treatment in type 2 diabetes mellitus (T2DM) together with medical, nutritional therapy. It is one of the most prescribed molecules worldwide. Furthermore, metformin can also be prescribed for other diseases like polycystic ovary syndrome or prediabetes (impaired glucose tolerance/fasting hyperglycemia). Recent studies have shown positive results concerning the use of metformin for cardiovascular or neuroprotective effects; also, several scientific papers are suggesting an antitumor or antiaging effect of metformin. Having such an excellent efficiency in practice, thus predicting its sustainability on the pharmaceutical market, research is directed toward characterizing metformin action on bacteria genera in the gut. Modifying the microbiota composition by pre- and probiotics could improve metformin action

The insulin polymorphism -23Hph increases the risk for type 1 diabetes mellitus in the Romanian population

The insulin -23Hph and IGF2 Apa polymorphisms were genotyped in Romanian patients with T1DM (n = 204), T2DM (n = 215) or obesity (n = 200) and normoponderal healthy subjects (n = 750). The genotypes of both polymorphisms were distributed in concordance with Hardy-Weinberg equilibrium in all groups. The -23Hph AA genotype increased the risk for T1DM (OR: 3.22, 95%CI: 2.09-4.98, p < 0,0001), especially in patients without macroalbuminuria (OR: 4.32, 95%CI: 2.54-7.45, p < 0,0001). No other significant association between the alleles or genotypes of insulin -23Hph and IGF2 Apa and diabetes or obesity was identified

A Critical View over the Newest Antidiabetic Molecules in Light of Efficacy-A Systematic Review and Meta-Analysis

The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with diabetes mellitus (DM). We aimed to establish the efficacy (A1c hemoglobin reduction) and safety of the newest antidiabetic drugs (considered so due to their novelty in medical practice use), specifically DPP-4i, SGLT-2i, GLP-1 Ra, and tirzepatide. The present meta-analysis followed the protocol registered at Prospero with the CRD42022330442 registration number. The reduction in HbA1c in the DPP4-i class for tenegliptin was 95% CI -0.54 [-1.1, 0.01], p = 0.06; in the SGLT2-iclass for ipragliflozin 95% CI -0.2 [-0.87, 0.47], p = 0.55; and for tofogliflozin 95% CI 3.13 [-12.02, 18.28], p = 0.69, while for tirzepatide it was 0.15, 95% CI [-0.50, 0.80] (p = 0.65). The guidelines for treatment in type 2 DM are provided from cardiovascular outcome trials that report mainly major adverse cardiovascular events and data about efficacy. The newest antidiabetic non-insulinic drugs are reported to be efficient in lowering HbA1c, but this effect depends between classes, molecules, or patients' age. The newest antidiabetic drugs are proven to be efficient molecules in terms of HbA1c decrease, weight reduction, and safety, but more studies are needed in order to characterize exactly their efficacy and safety profiles

Pancreatogenic type 3C diabetes

Background. The relationship between chronic pancreatitis and diabetes is well established. This form of diabetes is secondary to exocrine pancreatic disorder and is known as diabetes mellitus type 3c (T3cDM). Materials and Methods. In this retrospective study we included 261 patients, 59 patients being diagnosed with chronic pancreatitis and secondary diabetes mellitus, and admitted in the Fundeni Clinical Institute, 2nd Department of Gastroenterology or N.C. Paulescu Institute/ Carol Davila University of Medicine and Pharmacy. Results and Discussions. Patients were 22.2% women and 77.8% men, with an average age of 56.8 years and 53.4 years respectively. 63% came from urban areas. The mean duration of chronic pancreatitis was six years. Non-diabetic patients were compared with patients who were previously diagnosed with T3cDM and who had been analyzed for body mass index (BMI). Imaging investigations were also performed to confirm pseudotumors or pancreatic tumours. Patients already considered non-diabetic had basal blood glucose values and were mostly overweight and obese. In this context, insulin resistance cannot be excluded for this group of patients. Conclusions. T3cDM is a new pathological entity that needs to be explored more deeply, and that should benefit from both a diagnostic stratification and treatment

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Pancreatogenic type 3C diabetes

Background. The relationship between chronic pancreatitis and diabetes is well established. This form of diabetes is secondary to exocrine pancreatic disorder and is known as diabetes mellitus type 3c (T3cDM). Materials and Methods. In this retrospective study we included 261 patients, 59 patients being diagnosed with chronic pancreatitis and secondary diabetes mellitus, and admitted in the Fundeni Clinical Institute, 2nd Department of Gastroenterology or N.C. Paulescu Institute/ Carol Davila University of Medicine and Pharmacy. Results and Discussions. Patients were 22.2% women and 77.8% men, with an average age of 56.8 years and 53.4 years respectively. 63% came from urban areas. The mean duration of chronic pancreatitis was six years. Non-diabetic patients were compared with patients who were previously diagnosed with T3cDM and who had been analyzed for body mass index (BMI). Imaging investigations were also performed to confirm pseudotumors or pancreatic tumours. Patients already considered non-diabetic had basal blood glucose values and were mostly overweight and obese. In this context, insulin resistance cannot be excluded for this group of patients. Conclusions. T3cDM is a new pathological entity that needs to be explored more deeply, and that should benefit from both a diagnostic stratification and treatment

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

New susceptibility loci associated with kidney disease in type 1 diabetes

WOS:000309817900008Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.Peer reviewe