Type 2 diabetes and remission: practical management guided by pathophysiology

Abstract

The twin cycle hypothesis postulated that type 2 diabetes was a result of excess liver fat causing excess supply of fat to the pancreas with resulting dysfunction of both organs. If this was so, the condition should be able to be returned to normal by calorie restriction. The Counterpoint study tested this prediction in short-duration type 2 diabetes and showed that liver glucose handling returned to normal within 7 days and that beta-cell function returned close to normal over 8 weeks. Subsequent studies have demonstrated the durability of remission from type 2 diabetes. Remarkably, during the first 12 months of remission, the maximum functional beta-cell mass returns completely to normal and remains so for at least 24 months, consistent with regain of insulin secretory function of beta cells which had dedifferentiated in the face of chronic nutrient oversupply. The likelihood of achieving remission after 15% weight loss has been shown to be mainly determined by the duration of diabetes, with responders having better beta-cell function at baseline. Remission is independent of BMI, underscoring the personal fat threshold concept that type 2 diabetes develops when an individual acquires more fat than can be individually tolerated even at a BMI which in the nonobese range. Observations on people of South Asian or Afro-American ethnicity confirm that substantial weight loss achieves remission in the same way as in the largely White Europeans studied in detail. Diagnosis of type 2 diabetes can now be regarded as an urgent signal that weight loss must be achieved to avoid a progressive decline of health.

Keywords: aetiology; liver fat; pancreas fat; personal fat threshold; remission; type 2 diabetes; weight loss.

Fig. 1

The twin cycle hypothesis of the aetiology of type 2 diabetes: Any excess carbohydrate must undergo de novo lipogenesis, and this promotes fat accumulation in the liver. As insulin stimulates de novo lipogenesis, individuals with relative insulin resistance in muscle (determined by genetic or lifestyle factors) will accumulate liver fat more readily because of higher plasma insulin levels. Resistance to insulin suppression of hepatic glucose production will result from the increased liver fat. Over many years, the slight increase in fasting plasma glucose level will stimulate increased basal insulin secretion rates. The resulting hyperinsulinaemia will speed the conversion of excess calories into liver fat. A vicious cycle of hyperinsulinemia and blunted suppression of hepatic glucose production becomes established. At the same time, export of very‐low‐density lipoprotein triglyceride will increase fat delivery to all tissues including the islets. The increased fatty acid availability in and around pancreatic islets impairs the acute insulin secretion in response to ingested food, and at a certain point, postprandial hyperglycaemia will develop. Day‐long hyperglycaemia will further increase insulin secretion rates, resulting in increased hepatic lipogenesis, spinning the liver cycle faster and driving on the pancreas cycle. Eventually, the fatty acid and glucose inhibitory effects on the islets reach a trigger level leading to a relatively sudden onset of clinical diabetes. Figure adapted from [4].

Fig. 2

The Counterpoint study. Metabolic changes after initiation of a very‐low‐energy diet (~700 kcal per day) and withdrawal of metformin therapy in people with type 2 diabetes (red) and matched nondiabetic controls (studied at a single time‐point) (blue). Figure shows changes in (a) fasting plasma glucose, (b) hepatic triglyceride content, (c) hepatic insulin sensitivity index, (d) pancreatic triglyceride content and (e) immediate insulin response (known as ‘first‐phase’) to a 3 mmol/L increase in plasma glucose concentration. Figure adapted from Lim et al [13].

Fig. 3

Colour‐coded MRI scans showing the change in regional fat content before and after 8 weeks of an 800kcal/day diet. In this individual, no liver pathology has been identified, but liver fat content was very high (left panel). The extent of hepatic steatosis in most people with type 2 diabetes has not widely been appreciated. In the whole DiRECT cohort at baseline, liver fat content averaged 16% [78], hugely raised above the accepted normal upper level of 5.5%. Dietary weight loss restores normality (right panel).

Fig. 4

The Counterbalance study. Thirty people with type 2 diabetes of up to 23 years of duration lost approximately 15 kg in weight and then maintained steady weight for 6 months. Those achieving nondiabetic fasting plasma glucose levels were classified as responders and those remaining in the diabetic range as nonresponders. Panel (a): change in HbA1c in responders (closed symbols) and nonresponders (open symbols). Panel (b): decrease in liver fat content in both groups despite ongoing overweight or obesity. Bars show data at baseline, postweight loss and after 6 months of weight stability within the responder and nonresponder groups. Panel (c): decrease in intra‐pancreatic fat. Panel (d): At baseline, the first‐phase insulin response was higher in responders and increased to normal levels, whereas the grossly deficient baseline level in nonresponders hardly changed. Figure adapted with permission from the American Diabetes Association [45]. ^*** P < 0.0001 vs. baseline (responders); ^††† P < 0.0001, ^†† P < 0.01 vs. baseline (non‐responders); ^‡‡‡ P < 0.0001, ^‡‡ P < 0.001, ^‡ P < 0.05 vs. baseline (relapsers); ^### P < 0.0001, ^# P < 0.01 vs. 5 months (relapsers).

Fig. 5

Change in weight and glucose control in DiRECT. Changes are shown for weight (panel a), fasting plasma glucose (panel b) and HbA1c (panel c) responders (solid circles) and nonresponders (open circles). Data on matched nondiabetic controls (NDC) studied at one time‐point are shown as a dotted line. Figure reproduced with permission from Taylor et al 2018 [38] with 24 month data from Al‐Mrabeh et al 2020 [36]. ^*** P < 0.001 responders vs. baseline; ^††† P < 0.0001, ^†† P < 0.01 nonresponders vs. baseline; ^‡‡ P < 0.0001, ^‡‡ P < 0.001, ^‡ P < 0.05 vs. baseline (relapsers); ^### P < 0.0001, ^# P < 0.05, ^### P < 0.001 relapsers vs. 5 months.

Fig. 6

Changes over 2 years in DiRECT. Change in liver fat (a), hepatic VLDL1‐TG production (b), fasting plasma VLDL1‐TG (c), VLDL1 palmitic acid (d), intra‐pancreatic fat (e) and beta‐cell function (f) between baseline and 24 months in responders (white), nonresponders(black) and relapsers (grey). Relapsers show significant increase in liver fat, VLDL1‐TG production rate, VLDL‐TG plasma concentration and VLDL1‐TG palmitic acid with return to baseline levels of pancreas fat and first‐phase insulin secretion. Data are presented as mean ± SEM except for first‐phase insulin (median with IQ range). Figure reproduced with permission from Al‐Mrabeh A et al 2020 [36]. *P ≤ 0.05 vs. responders, **P ≤ 0.01 vs. responders, ***P ≤ 0.001 vs. responders.

Fig. 7

The personal fat threshold. (a) Frequency distribution of BMI for a typical group of individuals (red dotes) with type 2 diabetes (T2DM). (b) Frequency distribution of BMIs in blue for the individuals depicted in panel A before they gained weight. The red frequency distribution, when diabetes had developed, is right‐shifted (red arrow). This is commonly interpreted as a higher prevalence of obesity. (c) Three individuals from panel B are shown, one obese, one overweight and one ‘normal’ weight. Weight loss of 15 kg in each case results in return to normal glucose metabolism – although classification by the population measure of BMI remains the same. Each individual has a personal fat threshold (vertical dotted lines) above which excess fat is stored within liver and pancreas, and diabetes will develop if the individual also has beta cells susceptible to fat‐induced metabolic stress. For each such individual, moving to the right of their personal fat threshold triggers T2DM (red arrows), and moving to the left of the line restores normal glucose tolerance (blue arrows).