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Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today's society and is likely responsible in part for the considerable rise in type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease prevention and therapeutics. In this regard, the goal of this article is to highlight the role of the circadian system, and islet circadian clocks in particular, as potential regulators of β-cell function and survival. To date, studies have shown that islet clocks respond to changes in feeding patterns, and regulate a multitude of critical cellular processes in insulin secreting β-cells (e.g. insulin exocytosis, mitochondrial function and response to oxidative stress). Subsequently, either genetic or environmental disruption of normal islet clock performance compromises β-cell function and leads to loss of glycaemic control. Future work is warranted to further unravel the role of circadian clocks in human islet function in health and contributions to pathogenesis of T2DM., (© 2015 John Wiley & Sons Ltd.)

Regulation of blood glucose concentrations requires an adequate number of beta-cells that respond appropriately to blood glucose levels. beta-Cell mass cannot yet be measured in humans in vivo, necessitating autopsy studies, although both pre- and postmorbid changes may confound this approach. Autopsy studies report deficits in beta-cell mass ranging from 0 to 65% in type 2 diabetes (T2DM), and approximately 70-100% in type 1 diabetes (T1DM), and, when evaluated, increased beta-cell apoptosis in both T1DM and T2DM. A deficit of beta-cell mass of approximately 50% in animal studies leads to impaired insulin secretion (when evaluated directly in the portal vein) and induction of insulin resistance. We postulate three phases for diabetes progression. Phase 1: selective beta-cell cytotoxicity (autoimmune in T1DM, unknown in T2DM) leading to impaired beta-cell function and gradual loss of beta-cell mass through apoptosis. Phase 2: decompensation of glucose control when the pattern of portal vein insulin secretion is sufficiently impaired to cause hepatic insulin resistance. Phase 3: adverse consequences of glucose toxicity accelerate beta-cell dysfunction and insulin resistance. The relative contribution of beta-cell loss versus beta-cell dysfunction to diabetes onset remains an area of controversy. However, because cytotoxicity sufficient to induce beta-cell apoptosis predictably disturbs beta-cell function, it is naive to attempt to distinguish the relative contributions of these linked processes to diabetes onset.

Background: The impact of chronic alcohol consumption on hepatic gluconeogenesis (HGN) between males and females is unknown. To determine the effects of chronic alcohol consumption (8 weeks) on HGN, the isolated liver perfusion technique was used on 24-hr-fasted male and female Wistar rats., Methods: After surgical isolation, livers were perfused (single pass) for 30 min with Krebs-Henseleit bicarbonate buffer and fresh bovine erythrocytes with no added substrate (washout period). After the washout period, livers were perfused with lactate (10 mM) and [U-14C]lactate (15,000 dpm/ml) using the recirculation method., Results: There was no significant difference in HGN between males and females fed the control diet. In contrast, the females chronically fed the ethanol diet (FE) had significantly lower HGN rates (2.73 +/- 0.37 micromol/min x g liver protein(-1)), whereas males fed the ethanol diet (ME) had significantly higher HGN rates (4.99 +/- 0.45 micromol/min x g liver protein(-1)) than controls (3.83 +/- 0.34 micromol/min x g liver protein(-1)). Concomitant decreases were also observed for both 14C-lactate incorporation into 14C-glucose and rates of lactate uptake for FE, while corresponding increases were observed for 14C-lactate incorporation into 14C-glucose for ME. The livers from ME were able to convert a greater percentage of the lactate into glucose, resulting in the elevation in gluconeogenic capacity., Conclusion: Chronic alcohol consumption lowers the hepatic gluconeogenic capacity from lactate in females and elevates HGN in males.