We now know that there is a sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell’s respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent – in fact, even in uncontrolled diabetic hyperglycaemia, whole body glucose uptake is inevitably increased (unless there is severe ketosis). Even under conditions of extreme ketoacidosis there is no significant membrane barrier to glucose uptake – the block occurs ‘lower down’ in the metabolic pathway where the excess of ketones competitively blocks the metabolites of glucose entering the Krebs cycle. Under these conditions, glucose is freely transported into the cell but the pathway of metabolism is effectively blocked at the entry point to the Krebs cycle by the excess of metabolites arising from fat and protein breakdown. As a result of this competitive block at the entry point to the Krebs cycle, intracellular glucose metabolites increase ‘damming back’ throughout the glycolytic pathway, leading to accumulation of free intracellular glucose and inhibiting initial glucose phosphorylation. As a result, much of the ‘free’ intracellular glucose transported into the cell is transported back out of the cell into the extracellular fluid. Thus under conditions of ketoacidosis, glucose metabolism (but not glucose uptake) is impaired as a direct consequence of the metabolism of fat – the ‘glucose–fatty acid’ cycle (Randle et al. 1965).
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The facts are that in diabetes the fasting blood glucose is a very good measure of the severity of insulin deficiency. There is a linear correlation between the fasting blood glucose and the rate of hepatic glucose production (Ra) and thus with the rate of glucose disappearance (Rd). Since, in diabetes, the fasting blood glucose exceeds the renal threshold, not all glucose leaving the circulation is actually being metabolised. By collecting the urine and quantifying the urinary glucose losses it is easy to measure the true rate of glucose utilisation and the rate of urinary glucose loss. Glycosuria can account for as much as 30% of glucose turnover but even under these conditions, after correcting whole body glucose turnover for urinary glucose losses, tissue glucose utilisation is increased compared with normal. Thus insulin is NOT needed for glucose uptake and utilisation in man – glucose uptake is NOT insulin dependent.

When insulin is administered to people with diabetes who are fasting, blood glucose concentration falls. It is generally assumed that this is because insulin increases glucose uptake into tissues, particularly muscle. In fact this is NOT the case and is another error arising from extrapolating from in vitro rat data. It has been shown quite unequivocally that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production (Ra) without stimulating peripheral glucose uptake (Brown et al.1978). As hepatic glucose output is ‘switched off’ by the chalonic action of insulin, glucose concentration falls and glucose uptake actually decreases. Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration! The explanation for this is that because, even in the face of insulin deficiency, there are plenty of glucose transporters in the cell membranes. The factor determining glucose uptake under these conditions is the concentration gradient across the cell membrane; this is highest in uncontrolled diabetes and falls as insulin lowers blood glucose concentration primarily (at physiological insulin concentrations) through reducing hepatic glucose production.

When insulin is given to patients with uncontrolled diabetes it switches off a number of metabolic processes (lipolysis, proteolysis, ketogenesis and gluconeogenesis) by a similar chalonic action. The result is that free fatty acid (FFA) concentrations fall effectively to zero within minutes and ketogenesis inevitably stops through lack of substrate. It takes a while for the ketones to clear from the circulation, as the ‘body load’ is massive as they are water and fat soluble and distribute within body water and body fat. Since both ketones and FFA compete with glucose as energy substrate at the point of entry of substrates into the Krebs cycle, glucose metabolism increases inevitably as FFA and ketone levels fall (despite the concomitant fall in plasma glucose concentration). Thus insulin increases glucose metabolism more through reducing FFA and ketone levels than it does through recruiting more glucose transporters into the muscle cell membrane.