On the Pulse of Insulin

Insulin is not simply pumped out of the pancreas in a constant stream or, at least, it shouldn’t be. Like many other hormones, insulin is secreted in short bursts, or pulses, by the beta-cells in the islets of langerhans and act in unison to pump out insulin like a slow heart beat. These pulses of insulin were first observed in 1979 in the blood of fasted healthy volunteers measuring their insulin levels every minute for one to two hours (Lang 1979).

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Normal pulses of  insulin, C-peptide, and glucose measured in blood from a peripheral vein in a healthy fasted human (Lang 1979).

Rather than staying at a steady level in the blood, insulin pulses up and down every few minutes. C-peptide, which is secreted along with insulin, follows the same pattern. Changes in glucose can be seen but are too small to see clearly. After eating food requiring insulin secretion, the height of each peak increases as more insulin is released in each pulse while the pulses themselves remain roughly the same time apart.

These pulses of insulin are now thought to happen roughly every 5-6 minutes. This was longer in older studies, but newer studies with better detections methods suggest a shorter gap between the pulses. As well as these fast pulses, slower oscillations  of insulin every 80–180 minutes have also been measured (Polonsky 1988). These longer oscillations are called an ultradian rhythm, because they have a period of recurrence shorter than a day but longer than an hour.

How the cells in each islet, and all the separate islets in the pancreas, coordinate their pulses of insulin release is complex story that is still not fully understood and would be a blog post in itself. However, from an evolutionary perspective, it is likely that this controlled nature of pulsing insulin release is beneficial to us because maintaining the machinery for this pulsatile release is costly.

Pulses of insulin are more effective at activating insulin receptors than a constant exposure of insulin, at least in the liver where this has been most studied (Meier 2005). The pancreas releases insulin into the portal vein, which flows directly into the liver before spreading out through the rest of the body, so the liver feels the greatest effect of these insulin pulses. In contrast, a constant exposure to insulin results in increased insulin resistance. The physiologically normal pattern of insulin pulses is important for hepatic insulin signaling and glycemic control, and liver insulin resistance in diabetes is likely in part due to impaired pulsatile insulin secretion (Matveyenko 2012).

Larger separate pulses of insulin result in more insulin being cleared by the liver, so less reaches the rest of the body (Meier 2005). In contrast, smaller less-defined pulses would mean a greater exposure of the rest of the body to insulin, as less is cleared by the liver.

Where this gets more interesting is that individuals with type 2 diabetes have been found to have shorter and highly irregular pulses in their insulin (Hunter 1996). Weight loss only partially reversed the abnormalities in insulin pulses in patients with diabetes (Gumbiner 1996). The longer ultradian cycles of insulin secretion were also found to be disrupted in diabetic patients (Polonsky 1988).

Abnormal insulin pulses have also been found in the first-degree relatives of diabetic patients, compared to unrelated controls, suggesting that the abnormal oscillations in insulin secretion may be an early phenomenon in the development of type 2 diabetes. (O’Rahilly 1998).

insulin 2

Plasma insulin profile of a health person (top) and a first degree relative of a patient with diabetes (bottom) (O’Rahilly 1988).

Abdominal fat is associated with both insulin resistance and decreasing gaps between the pulses of insulin release. This suggests the increased frequency of insulin pulses may play a role in causing insulin resistance in individuals with more abdominal fat. The insulin interpulse interval was the primary determinant of insulin sensitivity in this study and the increased frequency of insulin pulses were suggested to play a role in inducing insulin resistance in individuals with greater abdominal fat (Peiris 1992).

As disordered insulin secretion may cause intracellular insulin resistance, it may be an initiating factor in the progression to type 2 diabetes (Schofield 2012). Constant exposure to insulin has an effect of inducing insulin resistance, the brief drop in insulin between each pulse in healthy individuals helps to prevent this.

To speculate a little, the implications of this are quite interesting to me. Firstly, take as an example someone with a healthy pattern of  insulin release and nice, large, separate pulses of insulin. If they eat foods requiring insulin, the pulses of insulin they produce will effectively activate their insulin receptors to clear away that glucose without inducing insulin resistance. These pulses of insulin can even encourage insulin sensitivity.

However, if we take as a second example an individual who has already lost this careful coordination of pulsing insulin release, the effects could be quite different. If they eat foods requiring insulin, the uncoordinated cells in their pancreas will release a more constant stream of insulin into their blood. The lack of clear pulses of insulin will not work as effectively at shutting down glucose production in the liver, less insulin will be cleared by the liver, and the rest of the body will be exposed to more insulin. This constant exposure of insulin receptors to insulin will generate greater insulin resistance, requiring more insulin to have the same effect.

It seems to me that carbohydrate intake could have very different consequences in these two individuals. Unfortunately, this pulsatility of insulin is not easy to measure and, currently, it does not seem clear what causes the coordinated release of insulin to break down, or how, or even whether it can be restored.

References:
Lang DA, Matthews DR, Peto J, Turner RC. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979 Nov 8;301(19):1023-7.
In a study of whether oscillations in plasma glucose and insulin occur in human beings, plasma samples were taken at one-minute intervals from 10 normal subjects for periods lasting between one and two hours. In five subjects the basal plasma insulin concentrations cycled regularly, with a mean period of 13 minutes and mean amplitude of 1.6 mU per liter (11.5 pmol per liter). A concurrent plasma glucose cycle was demonstrated, with a mean amplitude (after averaging to minimize random error) of 0.05 mmol per liter (1 mg per decliter). The average plasma glucose cycle was two minutes in advance of the plasma insulin. In the subjects with less regular plasma insulin cycles, a similar plasma glucose rise was demonstrated two minutes before the insulin rise. These phase relations are compatible with the presence of a negative-feedback loop between the liver and pancreatic beta cells that regulates both basal plasma insulin and glucose concentrations, although the cyclic beta-cell secretion could be independent of plasma glucose.
Peiris AN, Stagner JI, Vogel RL, Nakagawa A, Samols E. Body fat distribution and peripheral insulin sensitivity in healthy men: role of insulin pulsatilityJ Clin Endocrinol Metab. 1992 Jul;75(1):290-4.
Abdominal fat distribution is associated with insulin resistance in healthy young men. Factors modulating this phenomenon remain unclear. Pulsatile insulin release has been implicated as a potential regulator of insulin action. The relationship of pulsatility of peripheral insulin levels to fat distribution and peripheral insulin sensitivity was examined in 10 healthy men. Fat distribution was determined by the waist to hip ratio. Peripheral insulin sensitivity was assessed by the euglycemic clamp at an insulin infusion rate of 287 pmol/min.m2. Pulsatility of insulin was assessed by sampling every 2 min for 90 min in the basal state. The characteristics of insulin pulses were assessed by the computer program Pulsar. The waist to hip ratio was negatively associated with insulin sensitivity (r = -0.70, P less than 0.05) and insulin pulse interval (r = -0.66, P less than 0.05). The insulin pulse interval was positively correlated with peripheral insulin sensitivity (r = 0.73, P less than 0.05). The insulin interpulse interval was the primary determinant of insulin sensitivity. The increased frequency of insulin pulses may play a role in inducing insulin resistance in individuals with abdominal fat distribution.
Gumbiner B, Van Cauter E, Beltz WF, Ditzler TM, Griver K, Polonsky KS, Henry RR. Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction. J Clin Endocrinol Metab. 1996 Jun;81(6):2061-8.
Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.
Hunter SJ, Atkinson AB, Ennis CN, Sheridan B, Bell PM. Association between insulin secretory pulse frequency and peripheral insulin action in NIDDM and normal subjects. Diabetes. 1996 May;45(5):683-6.
Abnormalities of both insulin secretion and insulin action occur in NIDDM. It is not clear, however, which is the primary defect. Recently, it has been suggested that the frequency of insulin pulses is an important factor regulating insulin action in normal humans. We examined the relationship between pulsatile insulin secretion and insulin action in eight NIDDM subjects and eight health matched control subjects. Insulin action was assessed prevailing fasting glucose levels before and after hyperinsulinemia (2-h insulin infusion at 2.0 mU / kg / min). Pulsatility of insulin was assessed by sampling every 2 min for 90 min after an overnight fast and identifying insulin pulses using the computer program Pulsar. Fasting plasma glucose and postabsorptive endogenous glucose production were both greater in diabetic subjects compared with control subjects (10.1 +/- 1.2 vs. 5.4 +/- 0.1 mmol/l, P < 0.01; 11.8 +/- 0.8 vs. 9.9 +/- 0.4 micromol / kg / min, P < 0.05). During the 2.0 mU insulin infusion, glucose clearance was lower in the diabetic subjects (3.6 +/- 0.7 vs. 6.9 +/- 0.5 ml / kg / min), P < 0.05), whereas endogenous glucose production was suppressed to a similar degree in both groups (4.5 +/- 0.8 vs. 3.6 +/- 0.7 micromol x kg(-1) x min(-1), NS). The frequency of insulin pulses and glucose clearance were negatively correlated in both diabetic subjects (r = -0.75, P < 0.05) and normal control subjects (r = -0.82, P < 0.01). This negative correlation was also present in both groups taken together (r = -0.72, P < 0.001). There was no correlation between insulin pulse frequency and endogenous glucose production either in the fasting state or during hyperinsulinemia. We concluded that the frequency of insulin pulses and peripheral insulin sensitivity are closely linked in NIDDM and normal subjects.
Meier JJ, Veldhuis JD, Butler PC. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes. 2005 Jun;54(6):1649-56.
In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is approximately 100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25-39], BMI 24.9 kg/m(2) [21.2-27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg . kg(-1) . min(-1) by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 +/- 0.1 to 6.4 +/- 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 +/- 0.18 vs. 2.55 +/- 0.38 pmol . kg(-1) . min(-1); P < 0.01), but fractional hepatic insulin clearance was stable (78.2 +/- 4.4 vs. 84 0. +/- 3.9%, respectively; P = 0.18). Insulin secretory-burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 +/- 0.2 vs. 4.5 +/- 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (<1 min) time lag. Insulin secretory-burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, approximately 80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic insulin delivery.
Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter EAbnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988 May 12;318(19):1231-9.
To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.
Satin LS, Butler PC, Ha J, Sherman AS. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol Aspects Med. 2015 Apr;42:61-77.
Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern, has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM.
Schofield CJ, Sutherland C. Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes. Diabet Med. 2012 Aug;29(8):972-9.
For many years, the development of insulin resistance has been seen as the core defect responsible for the development of Type 2 diabetes. However, despite extensive research, the initial factors responsible for insulin resistance development have not been elucidated. If insulin resistance can be overcome by enhanced insulin secretion, then hyperglycaemia will never develop. Therefore, a β-cell defect is clearly required for the development of diabetes. There is a wealth of evidence to suggest that disorders in insulin secretion can lead to the development of decreased insulin sensitivity. In this review, we describe the potential initiating defects in Type 2 diabetes, normal pulsatile insulin secretion and the effects that disordered secretion may have on both β-cell function and hepatic insulin sensitivity. We go on to examine evidence from physiological and epidemiological studies describing β-cell dysfunction in the development of insulin resistance. Finally, we describe how disordered insulin secretion may cause intracellular insulin resistance and the implications this concept has for diabetes therapy. In summary, disordered insulin secretion may contribute to development of insulin resistance and hence represent an initiating factor in the progression to Type 2 diabetes.

 

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