A critical review of biogas production and usage with legislations framework across the globe.

This review showcases a comprehensive analysis of studies that highlight the different conversion procedures attempted across the globe. The resources of biogas production along with treatment methods are presented. The effect of different governing parameters like feedstock types, pretreatment approaches, process development, and yield to enhance the biogas productivity is highlighted. Biogas applications, for example, in heating, electricity production, and transportation with their global share based on national and international statistics are emphasized. Reviewing the world research progress in the past 10 years shows an increase of ~ 90% in biogas industry (120 GW in 2019 compared to 65 GW in 2010). Europe (e.g., in 2017) contributed to over 70% of the world biogas generation representing 64 TWh. Finally, different regulations that manage the biogas market are presented. Management of biogas market includes the processes of exploration, production, treatment, and environmental impact assessment, till the marketing and safe disposal of wastes associated with biogas handling. A brief overview of some safety rules and proposed policy based on the world regulations is provided. The effect of these regulations and policies on marketing and promoting biogas is highlighted for different countries. The results from such studies show that Europe has the highest promotion rate, while nowadays in China and India the consumption rate is maximum as a result of applying up-to-date policies and procedures.

Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene, insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects.

BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families.

Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians.

Familial genetic studies of type 2 diabetes (T2DM) of different human populations, including the French Caucasians, suggested evidence for linkage of T2DM and human chromosome 20q13, a region where maps the melanocortin 3 receptor gene (MC3R). Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM. We therefore undertook a molecular study to assess the role of genetic variations of this gene in a large cohort of French families with T2DM. In these patients, we identified two missense mutations in the MC3R gene: Val(81)Ile and Lys(6)Thr. These two variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium tests results, we found that these MC3R gene-coding variants were not associated with diabetes or obesity. These variants were found, however, marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects. Overall, the present study provides no evidence for a major role of the MC3R coding mutations underlying the genetic linkages of T2DM and the MC3R gene region on chromosome 20q13 in T2DM families from France and other geographical origins.

No evidence for linkage or for diabetes-associated mutations in the activin type 2B receptor gene (ACVR2B) in French patients with mature-onset diabetes of the young or type 2 diabetes.

Activins are members of the transforming growth factor-beta superfamily. They have a wide range of biological effects on cell growth and differentiation. For transmembrane signaling, activins bind directly to activin receptor type 2A (ACVR2A) or 2B (ACVR2B). Transgenic and knock-out mice for the ACVR2B gene display various endocrine pancreas-related abnormalities, including islet hypoplasia and glucose intolerance, demonstrating the crucial role of ACVR2B in the regulation of pancreas development. We have thus examined the contribution of this factor to the development of mature-onset diabetes of the young (MODY) and type 2 diabetes. No evidence of linkage at the ACVR2B locus has been detected in MODY families with unknown etiology for diabetes or found in affected sib pairs from families with type 2 diabetes. Mutation screening of the coding sequence in MODY probands and in a family with severe type 2 diabetes, including a case of pancreatic agenesis, showed single nucleotide polymorphisms that did not cosegregate with MODY and were not associated with type 2 diabetes. Our results indicate that ACVR2B does not represent a common cause of either MODY or type 2 diabetes in the French Caucasian population.

Genetic variation in the hepatocyte nuclear factor-3beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians.

Mutations in genes encoding hepatocyte nuclear factor (HNF) are responsible for three of the five subtypes of maturity-onset diabetes of the young (MODY). This observation and molecular studies indicate that the HNF network is required for normal function of pancreatic beta-cells. This suggests that transcription factors involved in this complex network are candidates for genetic defects in MODY. Because the HNF-3beta gene is implicated in this network, we screened it for mutations in 21 probands of French ancestry with clinical diagnosis of MODY and early-onset type 2 diabetes. All of the five known MODY genes, HNF-4alpha, glucokinase, HNF-1alpha, HNF-1beta, and IPF1, were previously excluded as being the cause of diabetes in these families. By direct sequencing, we identified two transitions, an A-to-G at position -213 and a C-to-T at position -63 in the promoter and exon 1, respectively, of the HNF-3beta gene. A G-to-C transversion at position +32 in the intron 1 and three transitions, C-to-T at position 291, A-to-G at position 837, and G-to-A at position 1188 in the exon 3, resulting in noncoding mutations Ala97Ala, Gly279Gly, and Gln396Gln, respectively, were also identified. The allele frequencies were not significantly different between a control group and MODY probands. Familial segregation studies and linkage analysis showed that genetic variation in the HNF-3beta gene is unlikely to be the cause of early-onset type 2 diabetes in these Caucasian families.

The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.

Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.

Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes.

BETA 2/NEUROD1 is a key regulator of pancreatic islet morphogenesis and insulin gene transcription. The BETA 2/NEUROD1 gene-locus lies on human chromosome 2q32, in a region previously linked to Type 1 diabetes (IDDM7). Recently, a significant association has been reported between NEUROD1-A45T polymorphism and Type 1 diabetes in the Japanese population. In an attempt to replicate this observation, we performed a case/control study in the French population. We failed to find any association between the A45T polymorphism and the disease-trait. The study therefore suggests that NEUROD1 is unlikely to play a major role in susceptibility to Type 1 diabetes in the French population.

Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

The K+ inwardly rectifier channel (KIR) is one of the two sub-units of the pancreatic islet ATP-sensitive potassium channel complex (I(KATP)), which has a key role in glucose-stimulated insulin secretion and thus is a potential candidate for a genetic defect in Type II (non-insulin-dependent) diabetes mellitus. We did a molecular screening of the KIR6.2 gene by single strand conformational polymorphism (SSCP) and direct sequencing in 72 French Caucasian Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and 1337V), that have also been identified in other Caucasian Type II diabetic subjects. These variants were genotyped in French cohorts of 191 unrelated Type II diabetic probands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and 1337V variants were not very different between Type II diabetic subjects and control groups. In contrast, analysis of the E23K variant showed that the KK homozygocity was more frequent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015). Analyses in a recessive model (KK vs EK/EE) tended to show a stronger association of the K allele with diabetes (p = 0.0097, corrected p-value for multiple testing < 0.02). The data for the E23K variant obtained here and those obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to be significantly associated with Type II diabetes (0.001 < or = p < or = .00106, corrected p-values for multiple testing p < or = 0.01). This study shows that KIR6.2 polymorphisms are frequently associated with Type II diabetes in French Caucasians. Furthermore, a meta-analysis combining different Caucasian groups suggests an significant role of KIR6.2 in the polygenic context of Type II diabetes.

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4alpha/MODY1/TCF14) on chromosome 20q, glucokinase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1alpha/MODY3/TCF1) on chromosome 12q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13q and hepatocyte nuclear factor-1 beta (HNF-1beta/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4alpha, HNF-1alpha and HNF-1beta genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T-->A) and one deletion mutation (P379fsdelT) were found in the HNF-1alpha gene, but no MODY-associated mutations were found in the HNF-4alpha and HNF-1beta genes. Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1alpha gene, and 11 (16%) have no mutations in the HNF-4alpha, IPF1 and HNF-1beta genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additional locus that can cause MODY.

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene.

Several candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) map on chromosome 20, including the phosphoenolpyruvate carboxykinase gene (PCK1) and one of the maturity onset diabetes of the young genes (MODY1). Thus, we have investigated the entire long arm of chromosome 20. Linkage analyses were conducted in a total sample of 148 NIDDM families (301 NIDDM sib pairs) and in a subset of 42 early onset NIDDM families, where genetic components are likely to play a more important role (55 NIDDM sib pairs diagnosed at or before 45 years of age), using 10 highly polymorphic markers with an average map density of 7.5 cM. Using affected sib pair methods (two-point linkage and multipoint linkage analyses), significant results were obtained with the 20q13 region, in the vicinity of the PCK1 locus, only in the subset of 55 early onset NIDDM sib pairs (multipoint MLS = 2.74, P = 0.0004; MLS = 2.34, P = 0.0009 when using a conservative weighting procedure). Moreover, another region spanning the ribophorin II (RPNII, phospholipase C (PLC1) and adenosine deaminase (ADA) loci suggested linkage with NIDDM (multipoint MLS of 1.81 in all NIDDM sib pairs, P = 0.003; MLS = 1.31, P = 0.012 when using a conservative weighting procedure). Whereas our study suggests the location of a susceptibility locus for early onset NIDDM in the PCK1 gene region, further investigation in larger data sets is required to confirm these results and assess the role of other regions on chromosome 20q in human NIDDM.

Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs.

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.

Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians.

The sulfonylurea receptor (SUR) is a key component in glucose-stimulated insulin secretion. Obesity and NIDDM are frequently associated and share some metabolic abnormalities, suggesting that they might also share some susceptibility genes. Thus, the SUR encoding gene is a plausible candidate for a primary pancreatic beta-cell defect and thus for hyperglycemia and weight gain. Through association and linkage studies, we have investigated the potential role of the SUR gene in families with NIDDM and in two independent sets of morbidly obese families. The exon 22 T-allele at codon 761 was more common in patients with NIDDM (7.7%) and morbid obesity (7.8%) than in control subjects (1.8%, P = 0.030 and P = 0.023, respectively). This variant was associated with morbid obesity (odds ratio 3.71, P = 0.017) and NIDDM (odds ratio 2.20, P = 0.04; association dependent on BMI). Although the frequencies for intron 24 variant were similar in all groups, morbidly obese patients homozygous for the c-allele had a more deleterious form of obesity. Sib-pair linkage studies with NIDDM in French Caucasian families gave no evidence for linkage to the SUR locus. However, in one set of the obese families, we found an indication for linkage with a SUR-linked microsatellite marker (D11S419, P = 0.0032). We conclude that in Caucasians, the SUR locus may contribute to the genetic susceptibility to NIDDM and obesity.

Indication for genetic linkage of the phosphoenolpyruvate carboxykinase (PCK1) gene region on chromosome 20q to non-insulin-dependent diabetes mellitus.

There is strong evidence that non-insulin-dependent-diabetes mellitus (NIDDM) has a polygenic mode of inheritance. Nevertheless, major gene effects may be involved in its pathogenesis, especially in forms with an early age of onset. We performed linkage analyses between 4 candidate genes for insulin resistance and NIDDM in a set of 55 multigenerational French Caucasian families, using the affected sib-pair approach. No significant results were obtained with glycogen synthase (GSY), insulin receptor substrate-1 (IRS-1) and apolipoprotein C-II (APOC-II) genes. However, a significant trend towards linkage was found between NIDDM and the phosphoenolpyruvate carboxykinase gene (PCK1) located on chromosome 20q (p = 0.005 for the mean estimated proportion of alleles shared identically by descent, mean IBD = 0.55), particularly among sib-pairs with diabetes diagnosed before the age of 46 years (p = 0.0003, mean IBD = 0.66). These results suggest that the PCK1 gene or a nearby locus contributes to the development of NIDDM in the French population.