Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries

Abstract Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and therefore, our approach is especially applicable to low- or middle-income countries.

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A global perspective on the issue of access to insulin

Diabetologia ◽

10.1007/s00125-020-05375-2 ◽

2021 ◽

Author(s):

David Beran ◽

Maria Lazo-Porras ◽

Camille M. Mba ◽

Jean Claude Mbanya

Keyword(s):

Type 1 Diabetes ◽

Diabetes Management ◽

Multinational Companies ◽

Global Perspective ◽

Patient Access ◽

Middle Income ◽

Middle Income Countries ◽

Wide Range ◽

Pricing And Reimbursement

AbstractThe discovery of insulin in 1921 changed the prognosis for people with type 1 diabetes. A century later, availability and affordability of insulin remain a challenge in many parts of the globe. Using the WHO’s framework on understanding the life cycle of medicines, this review details the global and national challenges that affect patients’ abilities to access and afford insulin. Current research and development in diabetes has seen some innovations, but none of these have truly been game-changing. Currently, three multinational companies control over 95% of global insulin supply. The inclusion of insulin on the WHO’s Prequalification Programme is an opportunity to facilitate entry of new companies into the market. Many governments lack policies on the selection, procurement, supply, pricing and reimbursement of insulin. Moreover, mark-ups in the supply chain also affect the final price to the consumer. Whilst expenses related to diabetes are mostly covered by insurance in high-income countries, many patients from low- and middle-income countries have to pay out of their own pockets. The organisation of diabetes management within the healthcare system also affects patient access to insulin. The challenges affecting access to insulin are complex and require a wide range of solutions. Given that 2021 marks the centenary of the discovery of insulin, there is need for global advocacy to ensure that the benefits of insulin and innovations in diabetes care reach all individuals living with diabetes. Graphical abstract

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Insulin Resistance Markers in Type 1 Diabetes Mellitus

Romanian Journal of Diabetes Nutrition and Metabolic Diseases ◽

10.1515/rjdnmd-2015-0012 ◽

2015 ◽

Vol 22 (1) ◽

pp. 89-98 ◽

Cited By ~ 1

Author(s):

Mihaela Larisa Bîcu ◽

Daniel Bîcu ◽

Mihaela Ionela Vladu ◽

Diana Clenciu ◽

Ana Maria Cristina Chirila ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Large Scale ◽

Overweight And Obesity ◽

Macrovascular Complications ◽

Main Role ◽

Euglycemic Hyperinsulinemic Clamp ◽

Current Medical Practice ◽

Type 1 Dm

Abstract Insulin resistance (IR) is a fundamental disorder of type 2 Diabetes Mellitus (DM), but it is also involved in the etiopathogenesis of type 1 DM, with important implications in the onset and progression of micro- and macrovascular complications in type 1 DM. Overweight plays the main role in the increased incidence of both types of DM, exacerbating IR. The epidemic increase of overweight and obesity makes it difficult to diagnose the exact phenotype of DM, as IR and autoimmunity often coexist. Many studies showed an increase in incidence of micro- and macrovascular complications in patients with type 1 DM with IR, compared to patients with type 1 DM without IR. The gold standard of IR evaluation is represented by the method of euglycemic-hyperinsulinemic clamp, applied on a reduced scale in research. Thus, it is necessary to identify early IR markers (clinical or biological markers), less laboured ones, that could be used on a large scale in current medical practice, for the IR determination in type 1 DM. Clinicians and health experts should prevent/ reduce the epidemic of overweight and obesity in young people, thus decreasing IR, and implicitly the chronic complications of DM.

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Severe insulin resistance in a patient with type 1 diabetes and stiff-man syndrome treated with insulin lispro

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(98)00072-2 ◽

1998 ◽

Vol 41 (3) ◽

pp. 197-202 ◽

Cited By ~ 7

Author(s):

Irl B Hirsch ◽

David D'Alessio ◽

Lily Eng ◽

Connie Davis ◽

Åke Lernmark ◽

...

Keyword(s):

Insulin Resistance ◽

Type 1 Diabetes ◽

Insulin Lispro ◽

Severe Insulin Resistance ◽

Stiff Man Syndrome

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Antiretroviral Treatment Sequencing Strategies to Overcome HIV Type 1 Drug Resistance in Adolescents and Adults in Low-Middle-Income Countries

The Journal of Infectious Diseases ◽

10.1093/infdis/jit109 ◽

2013 ◽

Vol 207 (suppl 2) ◽

pp. S63-S69 ◽

Cited By ~ 14

Author(s):

A. De Luca ◽

R. L. Hamers ◽

J. M. Schapiro

Keyword(s):

Drug Resistance ◽

Antiretroviral Treatment ◽

Middle Income ◽

Middle Income Countries ◽

Low Middle Income Countries ◽

Adolescents And Adults ◽

Treatment Sequencing ◽

Hiv Type 1

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Type 1 diabetes developed in a type 2 diabetic patient with severe insulin resistance

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2005.04.007 ◽

2005 ◽

Vol 70 (3) ◽

pp. 298-302 ◽

Cited By ~ 3

Author(s):

Tadashi Suehiro ◽

Fumiaki Osaki ◽

Yukio Ikeda ◽

Kaoru Arii ◽

Fumi Nakayama ◽

...

Keyword(s):

Insulin Resistance ◽

Type 1 Diabetes ◽

Diabetic Patient ◽

Severe Insulin Resistance ◽

Type 2 Diabetic

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Serum Insulin Bioassay Reflects Insulin Sensitivity and Requirements in Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-00892 ◽

2017 ◽

Vol 102 (10) ◽

pp. 3814-3821 ◽

Cited By ~ 2

Author(s):

Joseph A M J L Janssen ◽

Gemma Llauradó ◽

Aimee J Varewijck ◽

Per-Henrik Groop ◽

Carol Forsblom ◽

...

Keyword(s):

Insulin Resistance ◽

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Serum Insulin ◽

Glycosylated Hemoglobin ◽

Insulin Dose ◽

Biologically Active ◽

Insulin Analogs ◽

Insulin Requirements

Abstract Context Insulin resistance could increase insulin requirements in type 1 diabetes (T1D). Current insulin immunoassays do not detect insulin analogs. Kinase insulin receptor (IR) activation (KIRA) bioassays specific for human IR isoforms A (IR-A) and B (IR-B) permit assessment of all circulating insulin bioactivity. We studied whether IR-A and IR-B KIRA assays are related to direct measures of insulin sensitivity or insulin doses in T1D. Design We evaluated 31 adult patients with T1D (age 45.7 ± 1.6 years, body mass index 28.8 ± 0.7 kg/m2). Serum IR-A and IR-B bioactivities were measured by KIRA bioassays. Insulin sensitivity of glucose production (Ra) was measured by the euglycemic hyperinsulinemic clamp technique in which a low insulin dose (0.4 mU/kg/min for 240 minutes) was combined with D-[3-3H] glucose infusion to measure rates of Ra and utilization and insulin action on antilipolysis from suppression of serum free fatty acids. Results Baseline circulating IR-A bioactivity was 53 ± 7 pmol/L, and IR-B bioactivity was 81 ± 11 pmol/L. Compared with baseline, insulin infusion significantly increased IR-A (P < 0.001) and IR-B (P < 0.001) bioactivities. Fasting IR-A and IR-B bioactivities were positively related to endogenous Ra (r = 0.44, P = 0.01 and r = 0.38, P < 0.05). Fasting IR-A (r = 0.43, P = 0.02) and IR-B (r = 0.47, P = 0.01) bioactivities were significantly correlated with insulin requirements and glycosylated hemoglobin (IR-A: r = 0.52, P = 0.002; IR-B: r = 0.48, P = 0.006). Conclusions Circulating IR-A and IR-B bioactivities are associated with insulin resistance, high insulin requirements, and poor glycemic control in T1D. Measurement of IR bioactivity by KIRA assays provides a tool to assess the amount of biologically active insulin in groups of T1D patients treated with insulin analogs.

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SAT-631 Increased Incidence of Diabetic Nephropathy in Veterans with Severe Insulin Resistance

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1593 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jonathan Trejo ◽

Lyan Gondin Hernandez ◽

Lucy M A Esteve ◽

Libia Vasquez ◽

Sheila Pinkson ◽

...

Keyword(s):

Insulin Resistance ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Microvascular Complications ◽

South Texas ◽

Diabetes Clinic ◽

Severe Insulin Resistance ◽

Insulin Resistant ◽

Resistant Group

Abstract Recently, cluster analysis has been used to classify adult onset diabetes based on pathophysiologic profile. Using autoimmunity status, BMI, insulin resistance, and beta cell function, this classification system can predict diabetes associated complications. Individuals with primarily insulin resistant phenotype have been associated with increased incidence of nephropathy while those with insulin deficient phenotype are associated with retinopathy. Clinically, patients with severe insulin resistance can be defined as those who require high doses of insulin to achieve glycemic control, such as patients on U-500 insulin requiring more than 200 units of insulin a day. To characterize the clinical and metabolic phenotype of insulin-resistant patients from a South Texas VA diabetes clinic, we evaluated presence of macro or microvascular complications and beta-cell autoimmunity and function in this population. A retrospective cohort study was completed at the South Texas VA Diabetes Clinic. Charts were reviewed for anthropometric measurements, presence of macro and microvascular complications, anti-diabetic medication, lipid profile and HbA1c over 3 visits, autoimmunity (anti-GADab), and beta-cell function (fasting C-peptide). Patients with insulin doses >200 U/day or on U-500 insulin were categorized as “severe insulin-resistant”. Those with insulin doses < 0.5 U/kg/day were categorized as “mild insulin resistance” as a control group. Out of 120 patients, 30 met criteria for severe insulin resistance (n=30, M/F=29/1 age 61±1.6 years (yr), BMI 41±0.9 kg/m2, duration of diabetes 18.3±0.3 yr, HbA1c -8.4±0.2%, total daily insulin dose (TDD) 301±31U). 30 patients with insulin use <0.5 U/kg/day met criteria for mild insulin resistance (N=30, M/F: 28/2, age 62±2 yr, BMI 30±1 kg/m2, duration of diabetes 12±1.2 yr, HbA1c 7.2±0.2%, TDD 17±2U). Prevalence of nephropathy was higher in the insulin resistant group vs the mild insulin resistant group (76% vs 43%, p<0.05). There was no difference in prevalence of retinopathy (p=0.095) or CAD (p=0.6) between the groups. There was no difference in use of ACE-i or SGLT-2i between the groups. Insulin resistant subjects had a higher plasma triglyceride (325±0.3 vs 202±0.3 mg/dl, p=0.04). Prevalence of GAD ab was not different between the groups (3% vs 0%). Fasting C-peptide concentrations were similar in both groups (5.6±0.3 vs 5.2±0.25 ng/ml, p=0.3). HbA1c in the insulin resistant group improved between visits 1 and 3 (p<0.01). Weight increased over three visits in the severe insulin resistant group as opposed to mild weight loss in the mild insulin resistant group. Our results support the high prevalence of diabetic nephropathy in patients with severe insulin resistance, although it is unclear that insulin resistance is the etiology. Long-term follow up of these patients may provide insight into the underlying mechanisms of these complications.

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