Preserving insulin function in diabetes: a case report

Abstract

Background

This case report explores the long-term dynamics of insulin secretion and glycemic control in two patients with diabetes mellitus type 2 over 20 years. The observations underscore the impact of lifestyle interventions, including weight loss and calorie restriction, on insulin secretion patterns and glucose levels during 75 g oral glucose tolerance tests. Additionally, the role of hemoglobin A1c fluctuations, influenced by various factors such as body weight, exercise, and pharmacological interventions, is investigated.

Case presentation

Case 1 involves a Japanese woman now in her late 70s who successfully maintained her hemoglobin A1c below 7% for over two decades through sustained weight loss and lifestyle changes. Despite a gradual decline in the homeostasis model assessment of β cell function, the patient exhibited remarkable preservation of insulin secretion patterns over the 20-year follow-up. In case 2, a Japanese woman, now in her early 70s, experienced an improvement in hemoglobin A1c to 6.3% after a period of calorie limitation due to a wrist fracture in 2018. This incident seemed to trigger a temporary rescue of pancreatic β cell function, emphasizing the dynamic nature of insulin secretion. Both cases highlight the potential for pancreatic β cell rescue and underscore the persistence of insulin secretion over the 20-year follow-up. Additionally, we have briefly discussed three additional cases with follow-ups ranging from 10 to 17 years, demonstrating similar trends in glucose and insulin ratios.

Conclusions

Long-term lifestyle interventions, such as weight loss and calorie restriction, can preserve pancreatic β cell function and maintain glycemic control in type 2 diabetes patients over 20 years. Two patients showed stable or improved insulin secretion and favorable hemoglobin A1c levels, challenging the traditional view of irreversible β cell decline. The findings highlight the importance of personalized, nonpharmacological approaches, suggesting that sustained lifestyle changes can significantly impact diabetes management and potentially rescue β cell function.

Background

Type 2 diabetes mellitus (DM) presents a global health challenge characterized by insulin resistance and impaired insulin secretion [1]. Previous research, particularly using homeostatic model assessment (HOMA), has indicated that β cell function is already destroyed by approximately 50% by the time patients are diagnosed with DM. Subsequently, β cell function declines by around 4% each year. The traditional understanding suggests that β cell function experiences irreversible loss, necessitating insulin treatment once specific thresholds (15%) are reached [1,2,3]. This relationship is expressed by the following equation: HOMA-β = [immunoreactive Insulin (IRI) μU/mL × 360/fasting plasma glucose (FPG) mg/dL − 63]. However, emerging studies, such as the one conducted by Gregg et al. in 2012, propose that intensive lifestyle interventions (ILI) may contribute to partial remission of type 2 diabetes, challenging the prevailing belief in irreversible decline [4]. Furthermore, investigations have demonstrated the reversal of diabetes through a very low-calorie diet (VLCD). During VLCD therapy, volunteers adhered to the following regimen: (1) consuming 600–700 kilocalories a day for 8 weeks, (2) gradually returning to eating food over the next 2 weeks, and (3) undergoing follow-up once a month and supported with a maintenance program over the next 6 months. On average, volunteers lost 14 kg in body weight. A total of 40% (12/30) of patients diagnosed with diabetes less than 10 years prior reversed their condition, and 6 months later, they remained diabetes-free [5,6,7].

This backdrop establishes the foundation for our case series, spanning over 20 years, aiming to explore the long-term dynamics of insulin secretion and glycemic control in patients with DM. The objective is to investigate the role of lifestyle modifications, including weight loss and dietary changes, in influencing the disease course and challenging established paradigms regarding β cell function decline.

The existing literature emphasizes the significance of personalized approaches to diabetes management, considering factors beyond pharmacological interventions [1]. Our case series contributes to this evolving narrative by presenting two cases with sustained insulin secretion patterns over two decades, offering insights into the potential impact of lifestyle interventions on pancreatic β cell function.

Case presentation

Case 1: housewife currently in her late 70s

A Japanese woman, currently in her late 70s, presented to the clinic for a medical check-up over 21 years ago. She had been treated for essential hypertension for 20 years at another clinic without a DM diagnosis. The patient had not previously experienced symptoms of thirst, polyuria, or polydipsia but had a sibling with diabetes. Upon physical examination, her blood pressure was 170/100 mmHg. Her height was 151.5 cm and her weight was 94 kg, yielding a body mass index (BMI) of 40.9 kg/m². Urinalysis was negative for glucose, protein, ketones, and urobilinogen normal positive, with a pH of 6. The patient’s FPG was 128 mg/dL, and her hemoglobin A1c (HbA1c) was 6.6%. After 1 week, 75 g OGTT was performed to explore treatment options.

The patient received metformin (250 mg) three tablets/day for diabetes and manidipine hydrochloride (10 mg) two tablets/day for hypertension. In 2003, amlodipine (5 mg) one tablet and LOSARRHYD.LD (losartan potassium, hydrochlorothiazide) one tablet were both prescribed. In 2006, her BP was 120–130/70–80 mmHg. In early 2002, total cholesterol (TC) was 346 mg/dL, high-density lipoproteins—cholesterol (HDL-C) was 49 mg, triglyceride (TG) was 205 mg, and low-density lipoproteins—cholesterol (LDL-C) was 256 mg/dL. Atorvastatin (10 mg, one tablet) was started. In early 2003, TC was 228 mg/dL, HDL-C was 57 mg/dL, TG was 148 mg/dL, and LDL-C was 141 mg/dL.

Table 1 presents the 75 g OGTT results. These data indicated a diabetic glucose profile in 2002. However, the glucose curve showed an almost normal pattern in 2017 as compared with 2002. The ratio of glucose area under the curve (AUC) in 2017/2002 was 0.89 (155.5 mg.h/dL and 173.2 mg.h/dL). The ratio of insulin AUC in 2017/2002 was 9.53 (34.3 μU.h/mL and 3.6 μU/mL). These ratios show that insulin secretion increased, resulting in a normal glucose curve.

Table 1 The comparison of 75 g OGTT in case 1

After 5 years, 75 g OGTT was performed again (Table 1). The ratio of glucose AUC 2022/2002 was 0.95 (165.5 mg.h/dL and 173.2 mg.h/dL). The ratio of insulin AUC 2022/2002 was 10.2 (36.7 μU.h/mL and 3.6 μU.h/mL). The AUC of both glucose and insulin were almost the same in 2017 and 2022. In particular, insulin secretion remained stable for more than 20 years. In terms of HOMA-β, β cell function gradually declined (50.0% in 2002, 31.3% in 2017, and 22.9% in 2022). Figure 1 illustrates the correlation between weight and HbA1c over 20 years. To avoid any potential bias or intention, these data points were systematically extracted from the same month every year, spanning almost every month’s laboratory data of patients diagnosed with diabetes.

Fig. 1

Weight versus hemoglobin A1c over 20 years in case 1. The patient lost approximately 30 kg in body weight over 10 years. BMI was 27.7 kg/m² and was maintained

Case 2: housewife now in her early 70s

A Japanese woman, now in her early 70s, presented to the clinic for further examination almost 21 years ago, as her blood glucose level was found to be high at a group medical checkup. She had a history of thirst since 2000, and polyuria, polydipsia, and easy fatigue were recognized since mid 2002. A family history of DM was found in her two brothers. On physical examination, her height was 155 cm and her weight was 56 kg, yielding a BMI of 23.3 kg/m². Urinalysis revealed glucose positive 3 (around 300 mg/dL) without protein or ketones and a pH of 5. The 2 hour postprandial plasma glucose level (PG) was 419 mg/dL, and HbA1c was 10.4%.

Nutrition counseling was directed to a dietary and behavioral program. Metformin (250 mg, three tablets/day) was prescribed. When first diagnosed with DM, the patient had high motivation to improve her condition. Her HbA1c has improved to below 8% within 3 months. She lost 4 kg in body weight over 8 years and maintained good control for around 10 years (Fig. 2, similar to case 1, the data points presented in case 2 were collected systematically following a time-controlled approach). However, her HbA1c rose to around 8% even when her weight was maintained between 52 and 53 kg. Therefore, a DPP-4 inhibitor (one tablet) and glimepiride (1 mg, two tablets) were prescribed in 2013.

Fig. 2

Weight versus hemoglobin A1c over 20 years in case 2. The patient lost 4 kg over 8 years. Despite this, her hemoglobin A1c increased to 8%. However, a significant short-term calorie reduction after a right wrist fracture in early 2018 may have contributed to the improvement of her hemoglobin A1c level to nearly normal

On 20 January 2018, a 75 g OGTT was performed to assess the glucose and insulin profiles. C-peptide index (CPI), calculated using the formula CPI = blood C-peptide (fasting)/FPG (fasting plasma glucose) × 100 (1.4/147 × 100) was 0.93.

Eventually, the patient was persuaded to use insulin and was taught how to prepare and inject. However, in early 2018, she accidentally sustained a fracture of the right wrist before initiating insulin treatment. The patient was unable to cook and did not consume sufficient calories for 3 months. Our dietitian estimated she was taking more than 1800 kcal before the surgery, which has reduced to less than 1200 kcal for the first month postsurgery. On 16 May her blood glucose was 90 mg/dL, and her HbA1c was 6.3%. Only INISYNC (alogliptin: DPP-4 inhibition and metformin) was prescribed.

In contrast to the accident in 2018, she broke her left wrist in early 2009. At that time, she could cook and eat sufficiently using her right hand. As she could not work outside and had to stay home, her HbA1c increased to 7.9%.

In mid 2018, a 75 g OGTT was performed again to assess any profile changes in glucose and insulin (Table 2). The ratio of glucose AUC in May/January was 0.46 (37.3 mg.h/dL and 193 mg.h/dL). The ratio of insulin AUC in May/January was 3.74 (24.55 μU.h/mL and 6.55 μU.h/mL). This experience indicates that the shock of sudden calorie limitation may reactivate β cell function.

Table 2 The comparison of 75 g OGTT in case 2

The 75 g OGTT results from late 2022 were compared with that in early 2018. The ratio of glucose AUC in 2022/2018 was 0.36 (70.2 mg.h/dL and 193 mg.h/dL), and the ratio of insulin AUC in 2022/2018 was 3.3 (21.6 μU.h/mL and 6.55 μU.h/mL). These data indicate a similar tendency to the above data. Insulin secretion was maintained in 2022, after she was diagnosed with type 2 diabetes more than 20 years ago. HOMA-β cell function was 11.65% in the beginning of 2018, 14.41% in mid 2018, and 11.56% in 2022. Neither hypertension nor hyperlipidemia were found over 20 years during the follow-up.

Overall, the patient’s HOMA-β cell function declined below 15%, except in mid 2018. The AUC of insulin and glucose in the 75 g OGTT indicated that insulin therapy was not yet required.

Outcome and follow-up

Similar to the aforementioned cases, we have also monitored three additional individuals (A.T., J.T., and M.K.) albeit for 17 years, 15 years, and 10 years, respectively. They also showed a decrease in the ratio of glucose and an increase in the ratio of insulin AUC. Case A.T. was a Japanese woman in her early 80s who had a ratio of glucose AUC 2022/2005 of 0.46, a ratio of insulin AUC of 4, and HOMA-β of 9.4% in 2005 and 27.4% in 2022. Case J.T. was a man in his late 70s who had a ratio of glucose AUC in 2022/2008 of 0.99, a ratio of insulin AUC of 4, and HOMA-β of 9.4% in 2008 and 8.8% in 2023. Case M.K. was a Japanese woman in her early 70s who had a glucose AUC 2019/2012 of 0.9, a ratio of insulin AUC of 3.7, and HOMA-β of 15.2% in 2012 and 41.3% in 2019.

Discussion and conclusions

The traditional view of β cell function decline posits that this decline involves a progressive and irreversible loss in patients with type 2 diabetes [1,2,3]. In 2012, Greg et al. suggested that ILI is associated with a greater likelihood of partial remission of T2DM, compared with diabetes support and education [4]. Besides, multiple authors have shown that diabetes could be reversed by a VLCD [5,6,7].

In our case 1, the pancreatic function was retained following weight loss, improving the insulin secretion pattern in the 75 g OGTT compared with 20 years prior. In case 2, HbA1c was maintained at around 8% from 2013 to 2017, even though the patient maintained her weight at around 52 kg and was prescribed additional medication. We intended to initiate insulin therapy at the beginning of 2018. However, in early 2018, before starting insulin treatment, the patient broke her right wrist. She was forced to maintain a low-calorie diet in the month following this accident. Insulin secretion on 28 May was improved compared with that in early 2018. This substantial calorie limitation over a short period may be responsible for rescuing pancreatic cells.

In 2017, Perry suggested three major mechanisms to explain the blood glucose concentration lowering effect of VLCD in diabetic rodents in the liver: (1) decreasing the concentration of lactate and amino acids into glucose, (2) decreasing the rate of liver glycogen conversion to glucose, and (3) decreasing fat content, which improves the response of the liver to insulin [8].

In 2018, using cross-sectional magnetic resonance imaging (MRI), Taylor et al. showed that high-fat liver at baseline (30.4%) decreased to 1.3% after weight loss intervention, with similar findings in terms of pancreas fat (8.9 to 7.5%). The twin cycle hypothesis suggests that type 2 diabetes develops due to an accumulation of excess liver fat, leading to an increased supply of fat to the pancreas. Consequently, dysfunction occurs in both organs [9].

The UKPDS cohort of patients with T2DM (enrolled between 1977 and 1991) had a median BMI of only 28 kg/m². One in three of those studied had a BMI of less than 25 kg/m². Each individual could have a personal fat threshold (PFT), and surpassing this threshold would likely lead to the development of T2DM. Maintenance of a BMI below their level of susceptibility resulted in the return of normal glucose control. The authors hypothesized that PFT is independent of BMI [10]. According to the PFT theory, our two cases seemed to remain within their respective PFTs.

In case 1, the patient’s height was 152 cm, and her weight was 94 kg (BMI 40.7) in 2002, but she lost weight, falling to 64 kg (BMI 27.7) in 2017 (Fig. 1), which she has been able to maintain. During this time, her HOMA-IR improved from 3.3 to 0.85. Table 1 presents that the ratio of insulin AUC was 9.53 (2017/2002), and the ratio of glucose AUC was 0.89 (2017/2002). With regards to the intake of metformin, based on the findings from the TODAY study [11], it is evident that metformin, when used in combination with other treatments, can significantly improve insulin sensitivity and β-cell function initially; however, the long-term effectiveness in maintaining glycemic control does not differ significantly among various treatment groups. The patients’ weight loss may have also played a role in effectively lowering blood pressure, reducing cholesterol and triglyceride levels, and facilitating the remission of T2DM [12].

In case 2, the patient’s height was 155 cm, weight was 57 kg (BMI 23.7) at the beginning of 2018, and by 2 May, her weight had reduced to 46 kg (BMI 19.1) (Fig. 2). During this time, her HOMA-IR improved from 0.85 to 0.56. Table 2 presents that the ratio of insulin AUC was 3.74 (mid 2018/beginning of 2018), while the ratio of glucose AUC was 0.46 (mid 2018/beginning of 2018). As presented in Table 2, the AUC of glucose and insulin was almost the same in mid 2018 and 2022, meaning pancreas function remained stable for 4 years. Neither hypertension nor dyslipidemia were found over the 20 years.

This case report emphasizes the importance of maintaining insulin secretion patterns using the 75 g OGTT over long periods, as well as maintaining a healthy lifestyle including body weight by calorie intake exercise and pharmacological intervention. All these factors are important to keep a better HbA1c. Both HOMA-β and the AUC of insulin are considered indicators of pancreatic β cell function, but neither indicator was consistent in our data [13, 14].