Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2003 Jun 1;549(Pt 2):333-46.
doi: 10.1113/jphysiol.2002.037895. Epub 2003 Apr 25.

A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex

Johan H Koeslag  1 , Peter T Saunders, Elmarie Terblanche
Affiliations
Review

A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex

Johan H Koeslag et al. J Physiol. .

Abstract

Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic alpha- and beta-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The result of an archetypical hyperglycaemic clamp experiment (Grodsky, 1972; Gerich et al. 1974; Bolaffi et al. 1986; Tsuchiyama et al. 1992)
When the endocrine pancreas is exposed to an abrupt hyperglycaemic clamp (e.g. 15 mmol l−1), there is an initial spike of insulin release lasting less than 10 min. This is followed by a prolonged ‘second phase’ of progressively increasing rates of insulin secretion for more than 2 h. This ‘second phase’ is characteristic of an integral response, in which the rate of insulin release is not determined by the static error in the blood sugar concentration (in this case, 15–5 = 10 mmol l−1), but by the error multiplied by the time that the error persists (i.e. the ‘time integral of the error’). Since the error in a hyperglycaemic clamp experiment remains constant, the time integral of the error increases with time. The rate of insulin secretion therefore increases as a function of time, as shown. An abrupt hypoglycaemic clamp (1 mmol l−1) also produces a spike in glucagon secretion, similarly followed by a gradual rise in glucagon secretion (Weir et al. 1974). Reproduced by kind permission of the Society for Endocrinology from Koeslag et al. (1997).
Figure 2
Figure 2. The proposed model of pancreatic islet function
The functional units of the endocrine pancreas are suggested to be sub-islet heterologous syncytial aggregates of electrically coupled α-and β-cells which operate as flip-flop mechanisms. They are either in the Ab (glucagon-secreting) or aB (insulin-secreting) mode. Ab → aB and aB→Ab transitions occur spontaneously, but are influenced by paracrine secretions from neighbouring units. The relative effectivenesses of the two types of paracrine secretion are determined by the blood sugar concentration. A rise in the blood sugar level above 5 mmol l−1 promotes the effectiveness of GABA relative to that of pancreastatin, whereas a blood sugar level below 5 mmol l−1 promotes pancreastatin's effectiveness. A fall in the blood sugar level below 5 mmol l−1 will therefore produce a progressive increase in the number of Ab units (at the expense of aB units), which comes to a halt (i.e. no further increase in the number of Ab units) only when the blood sugar concentration normalises. Reproduced by kind permission of the Society for Endocrinology from Koeslag et al. (1997).
Figure 3
Figure 3. A diagrammatic representation of the effect of the plasma glucose and somatostatin-28 concentrations on the mechanism described in Fig. 2
Ab → aB and aB→Ab transitions occur at all blood glucose concentrations. Since the system operates as a flip-flop mechanism, the point at which the number of Ab → aB transitions equals the number of aB→Ab transitions is also the point at which the rate of increase of both is zero. Since this is the only equilibrium point, it defines the homeostat's set point (5 mmol glucose l−1). At blood glucose levels below 5 mmol l−1Ab units increase in number at the expense of aB units; at blood glucose levels above 5 mmol l−1 the opposite happens. Somatostatin-28 inhibits both insulin and glucagon secretion. It probably does so by inactivating a proportion of the α-β-cell syncytial units, thereby reducing the overall functional size of the endocrine pancreas. At high plasma somatostatin-28 concentrations there are, therefore, fewer flip-flopping units, resulting in the graph on the right. The point at which the number of Ab → aB transitions equals the number of aB→Ab transitions is, however, not affected by the plasma somatostatin-28 concentration. (Although we assume that somatostatin inhibits insulin and glucagon secretion by reducing the number of active syncytial units, all forms of inhibition produce the graph on the right.)
Figure 4
Figure 4. A schematic representation of the effect of the plasma somatostatin-28 concentration on the rate at which growth hormone (hGH) secretion increases or decreases at different blood glucose concentrations
The response of the endocrine pancreas to different blood glucose concentrations (Fig. 3) is depicted in the background. Somatostatin-28 inhibits hGH secretion. It therefore depresses the hGH response curve in the manner indicated by the arrows: a given hGH response requires a much lower blood glucose level when the somatostatin-28 concentration is high than when it is low. From the graph it is clear that there is a unique intermediate somatostatin-28 concentration that causes the hGH response curve to cross the zero rate of change line at exactly the same point as the pancreatic Ab-aB cross-over point. At this unique somatostatin-28 concentration the entire insulin-glucagon-hGH homeostat is in equilibrium. It determines the blood glucose set point, which, in the diagram, is indicated to be 5 mmol glucose l−1. Any stressor that causes a deviation of the blood sugar level away from set point elicits a disequilibrium that has as its effect the return of the blood sugar concentration to set point. If the stress persists (e.g. prolonged exercise) the blood sugar and plasma somatostatin levels will always return to their equilibrium values, but the plasma levels at which insulin, glucagon and hGH stabilise will be different from those at rest.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adeghate E, Ponery AS. GABA in the endocrine pancreas: cellular localisation and function in normal and diabetic rats. Tissue Cell. 2002;34:1–6. - PubMed
    1. Adeghate E, Ponery AS, Pallot DJ, Singh J. Distribution of neurotransmitters and their effects on glucagon secretion from in vitro normal and diabetic pancreatic tissues. Tissue Cell. 2000;32:266–274. - PubMed
    1. Aguilar-Bryan L, Bryan J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocrinol Rev. 1999;20:101–135. - PubMed
    1. Ahlborg B. Blood glucose during prolonged physical exercise in man. Förvarsmed. 1969;3(suppl 1):85–99.
    1. Ämmälä C, Ashcroft FM, Rorsman P. Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells. Nature. 1993;363:356–358. - PubMed

LinkOut - more resources