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Review
. 2024 Jan 8:14:1151873.
doi: 10.3389/fendo.2023.1151873. eCollection 2023.

Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review

Patricio H Contreras  1   2 , Pilar Vigil  1   2
Affiliations
Review

Across-species benefits of adrenalectomy on congenital generalized lipoatrophic diabetes: a review

Patricio H Contreras et al. Front Endocrinol (Lausanne). .

Abstract

Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.

Keywords: Berardinelli-Seip syndrome; Ketoconazole; RU-486; adipose insulin resistance; adrenalectomy; anti-glucocorticoid therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The eruptive xanthomas of the hand disappeared after 12 weeks of anti-glucocorticoid therapy.
Figure 2
Figure 2
Serum triglycerides fell more slowly than insulin values during therapy with Mifepristone alone; when we added Ketoconazole, the levels achieved the minimal observed value. After Ketoconazole discontinuation, these values rose slightly.
Figure 3
Figure 3
After two weeks of Mifepristone alone, the serum insulin level dropped from levels above 400 to between 10 and 20 mU/L; after we added Ketoconazole (tenth week), serum insulin fell to a minimum of 7 mU/L. The serum insulin value of the fifth week is not available.
Figure 4
Figure 4
Serum glucose values oscillated during the anti-glucocorticoid trial. After a week with Ketoconazole, they achieved the lowest level (138 mg/dL), rising to 200 mg/dl two weeks after discontinuation.
Figure 5
Figure 5
This Graph shows the fall in Adipo-IR-TG values from a sky-high baseline level of 2,960,000 to 4,936 mU/L*mg/dL at the end of the ninth week.
Figure 6
Figure 6
This Graph shows the fall in Adipo-IR-TG values from the second to the ninth week with more detail. These values fell from 36,250 to 4,936 mU/L*mg/dL.
Figure 7
Figure 7
Here, we show the fall in Adipo-IR-TG values in week ten, from days 1 to 7 (Mifepristone plus Ketoconazole combined treatment). These values fell from 4,560 to 1,610 mU/L*mg/dL (probably acceptable values, up to 600 mU/L*mg/dL).
Figure 8
Figure 8
Proposed pathogenesis of CGL in 5 steps: 1. Constitutional adipose insulin resistance secondary to congenital defective adipocyte triglyceride storage. This defect leads to unrestrained lipolysis and reduced lipogenesis. 2. This situation leads to an empty-adipocyte syndrome with severe hypoleptinemia. 3. The reduced leptin action results in an adrenal axis overactivity, presumably with high plasma free-cortisol levels. 4. The latter effect produces cortisol-driven, unrestrained lipolysis and lean organ steatosis. 5. Three factors, liver steatosis, muscle steatosis, and islet b-cell apoptosis, lead to grotesque insulin-resistant lipoatrophic diabetes.
Figure 9
Figure 9
Hypothetical, possible pathogenic sequence (five steps) of obesity leading to Type 2 diabetes: 1. Obesity –with triglyceride-replete adipose cells– leads to hyperleptinemia and leptin resistance. 2. Leptin resistance leads to reduced leptin action. 3. The latter effect should result in adrenal cortex overactivity with elevated free cortisol levels in serum. 4. Enhanced corticosteroid exposure of adipose tissue should lead to excessive lipolysis (adipose insulin resistance) and peripheral lean organ steatosis (liver, muscle, and islet beta-cell).
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References

    1. Mantzoros CS. Lipodystrophic syndromes. Uptodate (2023).
    1. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. . Leptin replacement therapy for lipodystrophy. New Engl J Med (2002) 346(8):570–8. doi: 10.1056/NEJMoa012437 - DOI - PubMed
    1. Contreras PH. Berardinelli-Seip Syndrome: Report of an Old Case Successfully Treated with Anti-Glucocorticoid Therapy Followed by Bilateral Adrenalectomy. Chapter 7. In: Infante M, editor. Evolving Concepts in Insulin Resistance. (London, UK: Intechopen; ) (2022). p. 159–78.
    1. Haluzik M, Dietz KR, Kim JK, Marcus-Samuels B, Shulman GI, Gavrilova O, et al. . Adrenalectomy improves diabetes in A-ZIP/F-1 lipoatrophic mice by increasing both liver and muscle insulin sensitivity. Diabetes (2002) 51:2113–8. doi: 10.2337/diabetes.51.7.2113 - DOI - PubMed
    1. Nielsen TS, Jessen N, Jørgensen JEL, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol (2014) 52:R199–222. doi: 10.1530/JME-13-0277 - DOI - PubMed

Grants and funding

The Reproductive Health Research Institute, Santiago, Chile, covered the publication cost.