Mutations have been reported for the pore-forming Kcnj11 and the regulatory Abcc8 subunits of the ATP-sensitive potassium channel (KATP), whose function underlies the first phase of insulin secretion. In T2D patients, the first phase is almost completely lost while the second is severely diminished. Alterations in insulin signaling and the pathways downstream of it have been associated with insulin resistance, a hallmark of T2D. Mutations in the insulin gene alter the binding efficiency of the hormone to its receptor while mutations in the insulin receptor gene fall into two categories - those that diminish the affinity of the receptor for insulin and those that reduce its tyrosine kinase activity. The activity of the receptor is heavily regulated: kinases, phosphatases, and various adapters acting primarily as inhibitors control its autophosphorylation and substrate kinase activities. Activated protein kinase C - one of the inhibitors of the insulin receptor - is thought to play a role in insulin resistance and is a target for drug development. PI3K-Akt signaling, one of the two pathways triggered by insulin, in an Akt2 dependent and independent manner, contributes to the insulin-responsive translocation of the Glut4 glucose transporter to the plasma membrane. Mutations in the Akt2 gene have been identified in a diabetic human family with severe insulin resistance. Knock-down and gene silencing experiments confirm that loss of Akt2 diminishes insulin-mediated transporter activity and thus the ability of insulin to lower blood glucose levels. Polymorphisms in Tcf7l2 and Znt8 are also known risk factors, as are a few other mutations identified as contributing to T2D and associated complications. The Tcf7l2 transcription factor is a major effector of Wnt canonical signaling; directly and indirectly, it impacts on a transcriptional network important for beta cell function and insulin production. The Znt8 zinc transporter, almost exclusively expressed in the pancreatic islets, is associated with insulin secretory granules. Insulin is complexed with zinc as zinc-insulin hexamers.

It is possible that accumulated effects, stemming from alterations within several pathways, their regulators, upstream and downstream events including those underlying beta-cell functioning and gene expression, contribute to the onset and development of the disease, and each could be heightened by environmental factors. In addition to the handful of mutations in pathways altered in T2D, linkage analyses and GWAS studies have identified a number of candidate genes as potential susceptibility loci. Interestingly, some if not many of the SNPs are found in non-coding regions. miRNAs have also been identified with a potential role in the regulation of insulin secretion, beta-cell development, insulin gene expression and action, as well as in diabetic complications such as cardiac and myocardial dysfunction and diabetic nephropathy. Long-non-coding RNA (lncRNA), epigenetics and microbiota, are increasingly being shown to play important, though still not well understood roles, in the development of T2D. Several drugs are being used for the treatment of the condition. Potassium channel inhibitors such as repaglinide and nateglinide are used to stimulate insulin secretion. Metformin - an antihyperglycemic drug, reduces the levels of glucose both in the basal and the post-prandial state by stimulating adenosine monophosphate-activated protein kinase (AMPK) signaling. AMPK is unlikely to be the primary target; rather, inhibition of respiratory complex I and subsequent changes in the AMP:ATP ratio are likely to activate the AMPK energy sensor and fuel regulator.