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In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment.

Multiple pathogenic pathways are able to deregulate glucose homoeostasis leading to diabetes. The 3243A>G mutation in the mtDNA (mitochondrial DNA)-encoded tRNALeu,UUR gene was found by us to be associated with a particular diabetic subtype, designated MIDD (maternally inherited diabetes and deafness). This mutation causes an imbalance in the mitochondrion between proteins encoded by the nuclear and mitochondrial genomes, resulting in a gradual deterioration of glucose homoeostasis during life. Remarkably, carriers of the 3243A>G mutation are generally not obese. The mutation also results in enhanced radical production by mitochondria. We propose that this mutation leads to the development of diabetes due to an inappropriate storage of triacylglycerols within adipocytes. The result is a fatty acid-induced deterioration of pancreatic β-cell function. In combination with an enhanced radical production in the β-cell due to the mutation, this leads to an age-dependent, accelerated decline in insulin production. In common Type 2 (non-insulin-dependent) diabetes, which is generally associated with obesity, a decline in mitochondrial function in adipose cells seems to result in an inappropriate scavenging of fatty acids by β-oxidation. As a consequence, a systemic overload with fatty acids occurs, leading to an enhanced decline in β-cell function due to lipotoxicity.

In 79 South Indian nuclear pedigrees ascertained via probands with NIDDM and both parents living, parental diabetic status was established through previously diagnosed NIDDM (n= 97) or oral glucose tolerance testing (n= 61). There was no significant difference between diabetes prevalence in mothers and fathers (60 vs 53 (76 % vs 67 %), respectively, p= 0.22). ‘Age at diabetes diagnosis’ survival curves did differ according to parental gender (p= 0.02) but this may reflect gender differences in health provision rather than pathophysiology. No maternal excess effects of the magnitude evident in previous studies were detected, suggesting either ethnic differences or overestimation of the maternal effect when reported histories of parental diabetes have been used. The tRNALeu(UUR)gene region was studied for diabetes‐associated variation given the role of mutations in this gene in some pedigrees displaying maternal transmission of NIDDM. None of 142 unrelated South Indian NIDDM subjects displayed the MELAS mutation at nt3243. However, sequencing identified two variants of potential importance: (a) at nt3290 in the tRNALeu(UUR)gene, seen in 7/142 diabetic and 1/85 control subjects (p= 0.11), (b) at nt3316 in the ND1 gene (4/142 vs 1/85 subjects, respectively (p= 0.51)). Further studies are needed to determine the relevance of these variants to the development of NIDDM.

Hypertriglyceridaemia and increased amounts of liver fat are acknowledged cardiovascular risk factors, especially among type 2 diabetes patients. The incretins glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known from their insulinotropic effects, but recent studies have shown effects on lipid metabolism and liver fat.